CA2183577C - Methods and compositions for pulmonary delivery of insulin - Google Patents
Methods and compositions for pulmonary delivery of insulin Download PDFInfo
- Publication number
- CA2183577C CA2183577C CA002183577A CA2183577A CA2183577C CA 2183577 C CA2183577 C CA 2183577C CA 002183577 A CA002183577 A CA 002183577A CA 2183577 A CA2183577 A CA 2183577A CA 2183577 C CA2183577 C CA 2183577C
- Authority
- CA
- Canada
- Prior art keywords
- insulin
- composition
- dry powder
- pharmaceutical carrier
- powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Biophysics (AREA)
- Emergency Medicine (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Dispersion Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
Systemic delivery of insulin to a mammalian host is accomplished by inhalati on of a dry powder of insulin. It has been found that dry insulin powders are rapidly absorbed through the alveolar regions of the lungs.
Description
METHODS AND COMPOSITIONS FOR PULMONARY DELIVERY OF INSULIN
BACRGROUND OF THE INVENTION
1. Field of the Invention The present invention relates generally to methods and compositions for the respiratory delivery of insulin to diabetic patients. More particularly, the present invention relates to the pulmonary delivery of dry powder insulin preparations for rapid systemic absorption through the lungs.
Insulin is a 50 amino acid polypeptide hormone having a molecular weight of about 6,000 which is produced in the pancreatic ~-cells of normal (non-diabetic) individuals.
Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels, and a systemic deficiency causes diabetes. Survival of diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels.
Insulin is most commonly administered by subcutaneous injection, typically into the abdomen or upper thighs. In order to maintain acceptable blood glucose levels, it is often necessary to inject insulin at least once or twice per day, with supplemental injections of rapid-acting insulin being administered when necessary. Aggressive treatment of diabetes can require even more frequent injections, where the patient closely monitors blood glucose levels using home diagnostic kits. The present invention is particularly concerned with the administration of rapid acting insulins which are able to provide serum insulin peaks within one hour and glucose troughs within 90 minutes.
The administration of insulin by injection is undesirable in a number of respects. First, many patients find it difficult and burdensome to inject themselves as ~ t~ W O 95/24183 2 1 8 3 5 7 7 PCT/US95/01563 frequently as necessary to maintain acceptable blood glucose levels. Such reluctance can lead to non-compliance, which in the most serious cases can be life-threatening. Moreover, systemic absorption of insulin from subcutaneous injection is relatively slow, frequently requiring from 45 to 90 minutes, even when fast-acting insulin formulations are employed.
Thus, it has long been a goal to provide alternative insulin formulations and routes of administration which avoid the need for self-injection and which can provide rapid systemic availability of the insulin.
A variety of such alternative insulin administration roots have been proposed, including intranasal, intrarectal, and intravaginal.
While these techniques avoid the discomfort and poor compliance associated with subcutaneous injection, they each suffer from their own limitations. Intrarectal and intravaginal are inconvenient, uncomfortable, and the latter is not available to the entire population of diabetics.
Intranasal delivery would be convenient and probably less objectionable than injection, but requires the use of potentially toxic "penetration enhancers" to effect passage of insulin across the nasal mucosa, which is characterized by a thick epithelial layer which is resistant to the passage of macromolecules. Of particular interest to the present invention is pulmonary insulin delivery where a patient inhales an insulin formulation and systemic absorption occurs through the thin layer of epithelial cells in the alveolar regions of the lung. Such pulmonary insulin delivery appears to provide more rapid systemic availability than does subcutaneous injection and avoids the use of a needle.
Pulmonary insulin delivery, however, has yet to achieve widespread acceptance. Heretofore, pulmonary delivery has been most often accomplished through nebulization of liquid insulin formulations, requiring the use of cumbersome liquid nebulizers. Moreover, the aerosols formed by such nebulizers have a very low insulin concentration, necessitating a large number of inhalations to provide an adequate dosage. insulin concentration is limited due to the low solubility of insulin A~4 ~ WO 95/24183 2183577 PCT/US95/01563 in suitable aqueous solutions. in some cases, as many as 80 or more breaths may be required to achieve an adequate dosage, resulting in an administration time from 10 to 20 minutes, or -more.
It would be desirable to provide improved methods and compositions for the pulmonary delivery of insulin. It would be particularly desirable if such methods and compositions were sufficiently convenient to permit self-administration even away from home and were able to deliver a desired total dosage with a relatively low number of breaths, preferably fewer than ten. Such methods and compositions should also provide for rapid systemic absorption of the insulin, preferably reaching a serum peak within 45 minutes or less and a resulting glucose trough within about one hour or less. Such rapid acting formulations will preferably be suitable for use in aggressive treatment protocols where injection of intermediate and long-acting insulin can be reduced or eliminated. The compositions of the present invention should also be stable, preferably consisting of a concentrated dry powder formulation.
2. Description of the Backaround Art The respiratory delivery of aerosolized aqueous insulin solutions is described in a number of references, beginning with Gansslen (1925) R1in. Wochenschr. 4:71 and including Laube et al. (1993) JAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J. U:293-297; Wigley et al. (1971) Diabetes ZQ:552-556. Corthorpe et al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol. Pharmacol. 3:161-167;
Hastings et al. (1992) J. App1. Physiol. " :1310-1316; Liu et al. (1993) JAMA 2-U:2106-2109; Nagano et al. (1985) Jikeikai Med. J. U:503-506; Sakr (1992) Int. J. Phar. 3_6:1-7; and Yoshida et al. (1987) C1in. Res. _U:160-166. Pulmonary delivery of dry powder medicaments, such as insulin, in a large particle carrier vehicle is described in U.S. Patent No.
5,254,330. A metered dose inhaler (MDI) for delivering crystalline insulin suspended in a propellant is described in Lee and Sciara (1976) J. Pharm. Sci. 6.5:567-572. A MDI for 21 8 3 5 7 7 PCTIUS95/01563 =
BACRGROUND OF THE INVENTION
1. Field of the Invention The present invention relates generally to methods and compositions for the respiratory delivery of insulin to diabetic patients. More particularly, the present invention relates to the pulmonary delivery of dry powder insulin preparations for rapid systemic absorption through the lungs.
Insulin is a 50 amino acid polypeptide hormone having a molecular weight of about 6,000 which is produced in the pancreatic ~-cells of normal (non-diabetic) individuals.
Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels, and a systemic deficiency causes diabetes. Survival of diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels.
Insulin is most commonly administered by subcutaneous injection, typically into the abdomen or upper thighs. In order to maintain acceptable blood glucose levels, it is often necessary to inject insulin at least once or twice per day, with supplemental injections of rapid-acting insulin being administered when necessary. Aggressive treatment of diabetes can require even more frequent injections, where the patient closely monitors blood glucose levels using home diagnostic kits. The present invention is particularly concerned with the administration of rapid acting insulins which are able to provide serum insulin peaks within one hour and glucose troughs within 90 minutes.
The administration of insulin by injection is undesirable in a number of respects. First, many patients find it difficult and burdensome to inject themselves as ~ t~ W O 95/24183 2 1 8 3 5 7 7 PCT/US95/01563 frequently as necessary to maintain acceptable blood glucose levels. Such reluctance can lead to non-compliance, which in the most serious cases can be life-threatening. Moreover, systemic absorption of insulin from subcutaneous injection is relatively slow, frequently requiring from 45 to 90 minutes, even when fast-acting insulin formulations are employed.
Thus, it has long been a goal to provide alternative insulin formulations and routes of administration which avoid the need for self-injection and which can provide rapid systemic availability of the insulin.
A variety of such alternative insulin administration roots have been proposed, including intranasal, intrarectal, and intravaginal.
While these techniques avoid the discomfort and poor compliance associated with subcutaneous injection, they each suffer from their own limitations. Intrarectal and intravaginal are inconvenient, uncomfortable, and the latter is not available to the entire population of diabetics.
Intranasal delivery would be convenient and probably less objectionable than injection, but requires the use of potentially toxic "penetration enhancers" to effect passage of insulin across the nasal mucosa, which is characterized by a thick epithelial layer which is resistant to the passage of macromolecules. Of particular interest to the present invention is pulmonary insulin delivery where a patient inhales an insulin formulation and systemic absorption occurs through the thin layer of epithelial cells in the alveolar regions of the lung. Such pulmonary insulin delivery appears to provide more rapid systemic availability than does subcutaneous injection and avoids the use of a needle.
Pulmonary insulin delivery, however, has yet to achieve widespread acceptance. Heretofore, pulmonary delivery has been most often accomplished through nebulization of liquid insulin formulations, requiring the use of cumbersome liquid nebulizers. Moreover, the aerosols formed by such nebulizers have a very low insulin concentration, necessitating a large number of inhalations to provide an adequate dosage. insulin concentration is limited due to the low solubility of insulin A~4 ~ WO 95/24183 2183577 PCT/US95/01563 in suitable aqueous solutions. in some cases, as many as 80 or more breaths may be required to achieve an adequate dosage, resulting in an administration time from 10 to 20 minutes, or -more.
It would be desirable to provide improved methods and compositions for the pulmonary delivery of insulin. It would be particularly desirable if such methods and compositions were sufficiently convenient to permit self-administration even away from home and were able to deliver a desired total dosage with a relatively low number of breaths, preferably fewer than ten. Such methods and compositions should also provide for rapid systemic absorption of the insulin, preferably reaching a serum peak within 45 minutes or less and a resulting glucose trough within about one hour or less. Such rapid acting formulations will preferably be suitable for use in aggressive treatment protocols where injection of intermediate and long-acting insulin can be reduced or eliminated. The compositions of the present invention should also be stable, preferably consisting of a concentrated dry powder formulation.
2. Description of the Backaround Art The respiratory delivery of aerosolized aqueous insulin solutions is described in a number of references, beginning with Gansslen (1925) R1in. Wochenschr. 4:71 and including Laube et al. (1993) JAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J. U:293-297; Wigley et al. (1971) Diabetes ZQ:552-556. Corthorpe et al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol. Pharmacol. 3:161-167;
Hastings et al. (1992) J. App1. Physiol. " :1310-1316; Liu et al. (1993) JAMA 2-U:2106-2109; Nagano et al. (1985) Jikeikai Med. J. U:503-506; Sakr (1992) Int. J. Phar. 3_6:1-7; and Yoshida et al. (1987) C1in. Res. _U:160-166. Pulmonary delivery of dry powder medicaments, such as insulin, in a large particle carrier vehicle is described in U.S. Patent No.
5,254,330. A metered dose inhaler (MDI) for delivering crystalline insulin suspended in a propellant is described in Lee and Sciara (1976) J. Pharm. Sci. 6.5:567-572. A MDI for 21 8 3 5 7 7 PCTIUS95/01563 =
delivering insulin into a spacer for regulating inhalation flow rate is described in U.S. Patent No. 5,320,094. The intrabronchial administration of recombinant insulin is briefly described in Schltiter et al. (Abstract) (1984) Diabetes 33:75A and ICohler et al. (1987) Atemw. Lungenkrkh.
12:230-232. Intranasal and respiratory delivery of a variety of polypeptides, including insulin, in the presence of an enhancer, are described in U.S. Patent No. 5,011,678 and Nagai et al. (1984) J. Contr. ReI.1:15-22. Intranasal delivery of insulin in the presence of enhancers and/or contained in controlled release formulations are described in U.S. Patent Nos. 5,204,108; 4,294,829; and 4,153,689; PCT Applications WO
93/02712, WO 91/02545, WO 90/09780, and WO 88/04556; British Patent 1,527,605; Ryd"en and Edman (1992) Int. J. Pharm. 8l:1-10; and BjSrk and Edman (1988) Int. J. Pharm. =41:233-238. The preparation and stability of amorphous insulin were described by Rigsbee and Pikal at the American Association of Pharmaceutical Sciences (AAPS), November 14-18, 1993, Lake Buena Vista, Florida. Methods for spray drying polypeptide, polynucleotide and other labile drugs in a carrier which forms an amorphous structure which stabilize the drug are described in European patent application 520 748.
SUMMARY OF TSE INVENTION
According to the present invention, methods and compositions for the aerosolization and systemic delivery of insulin to a mammalian host, particularly a human patient suffering from diabetes, provide for rapid absorption into blood circulation while avoiding subcutaneous injection. In particular, the methods of the present invention rely on pulmonary delivery of insulin in the form of a dry powder.
Surprisingly, it has been found that inhaled dry insulin powders are deposited in the alveolar regions of the lung and rapidly absorbed through the epithelial cells of the alveolar region into blood circulation. Thus, pulmonary delivery of insulin powders can be an effective alternative to administration by subcutaneous injection.
WO 95/24183 21" 35/ / PCT/US95/01563 = 5 In a first aspect of the present invention, insulin is provided as a dry powder, usually but not necessarily in a substantially amorphous state, and dispersed in an air or other physiologically acceptable gas stream to form an aerosol. The aerosol is captured in a chamber having a mouthpiece, where it is available for a subsequent inhalation by a patient. Optionally, the dry powder insulin is combined with a pharmaceutically acceptable dry powder carrier, as described in more detail below. The insulin powder preferably comprises particles having a diameter less then 10 m, more preferably less than 7.5 gm, and most preferably below 5 m, usually being in the range from 0.1 m to 5 m. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are absorbed in the lung without the use of penetration enhancers such as those required for absorption through the nasal mucosa and upper respiratory tract.
In a second aspect, the present invention provides insulin compositions consisting essentially of dry powder insulin having an average particle size below 10 gm which may be combined with dry powder pharmaceutical carriers. The insulin composition is preferably free from penetration enhancers and comprises particles having a diameter less than 10 m, preferably less than 7.5 m, and most preferably below 5 m, usually being in the range from 0.1 m to 5 m.
Usually, the insulin dry powder will have from 5g to 99% by weight insulin in the composition, more usually from 15% to 80k, in a suitable pharmaceutical carrier, usually a carbohydrate, an organic salt, an amino acid, peptide, or protein, as described in more detail hereinafter.
in a third aspect of the present invention, insulin dry powders are prepared by dissolving insulin in an aqueous buffer to form a solution and spray drying the solution to produce substantially amorphous particles having a particle size less than 10 m, preferably less than 7.5 m, and most preferably below 5 m, usually being in the range from 0.1 m to 5Am. Optionally, the pharmaceutical carrier is also dissolved in the buffer, to form a homogeneous solution, wherein spray drying of the solution produces individual particles comprising insulin, carrier buffer, and any other components which were present in the solution. Preferably the carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a substantially amorphous structure upon spray drying. The amorphous carrier may be either glassy or rubbery and enhances stability of the insulin during storage. Advantageously, such stabilized formulations are also able to effectively deliver insulin to the blood stream upon inhalation to the alveolar regions of the lungs.
A further understanding of the nature and advantages of the invention will become apparent by reference to the remaining portions of the specification and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic illustration of a system for aerosolizing a dose of insulin according to the method of the present invention.
Fig. 2 is a schematic illustration of a patient inhaling an aerosolized dose of insulin from the system of Fig. 1.
Figs. 3A and 3B are graphs illustrating the absorption of recombinant human insulin in rats and resulting glucose response following aerosolization of three different dry powder formulations. Each point represents the mean value from three different rats. At zero time, the dry powder aerosol generator was turned on. Aerosolization was complete at 5 min, 14 min and 20 min for the 87% insulin/citrate, 20%
insulin-mannitol/citrate and 20% insulin-raffinose/citrate powders, respectively. Animals were fasted overnight.
Figs. 4A and 4B are graphs illustrating mean serum time-concentration insulin and glucose profiles, respectively comparing aerosol and subcutaneous administrations in cynomolgus monkeys. The mean value for three monkeys is reported for the aerosol group, and the mean value for four monkeys is reported for the subcutaneous group.
Fig. 5A is a graph illustrating the mean insulin concentration over time for subcutaneous injection (O) and for inhalation of three puffs (i) in humans.
WO 95/24183 2183577 PCTlUS95/01563 Fig. 5B shows the mean glucose concentration corresponding to the insulin concentrations of Fig. 5A.
Fig. 6A is a graph illustrating serum insulin concentration over time as a result of subcutaneous injection (o) and three puffs of aerosol administration (0) in humans.
Fig. 6B is a graph illustrating the serum glucose levels corresponding to the insulin levels in Fig. 6A.
Figs. 7A and 7B provide a comparison of the intersubject variability of serum insulin (7A) and glucose levels (7B) for subcutaneous administration (o) and aerosol administration (0).
Figs. 8A, SB, and 8C show rpHPLC chromatograms of a human insulin. Fig. 8A is a chromatograph of an insulin standard stressed in 10 mM HC1 at 25 C, showing human insulin eluting at 23.87 minutes desamido insulin eluting at 30.47 minutes. Fig. 8B shows a similar chromatogram of a human insulin standard. Fig. 8C shows a similar chromatogram of reconstituted, spray-dried insulin formulation prepared according to the present invention.
Fig. 9 shows an ultraviolet spectra of an insulin formulation before and after spray drying. No light scattering was observed in the visible spectrum, indicating that insulin did not aggregate during the spray drying process.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
According to the present invention, insulin is provided as a dry power. By "dry powder" it is meant that the moisture content of the powder is below about 10% by weight, usually below about 5% by weight, and preferably being below about 3% by weight. By "powder," it is meant that the insulin comprises free flowing particulates having a size selected to permit penetration into the alveoli of the lungs, preferably being less than 10 m in diameter, preferably less than 7.5 m, and most preferably less than 5 m, and usually being in the range from 0.1 pcm to 5 m in diameter.
The present invention is based at least in part.on the unexpected observation that dry powder insulins are - - ------- - - _ . - -2 18J ~ PCT/US95/01563 ~
12:230-232. Intranasal and respiratory delivery of a variety of polypeptides, including insulin, in the presence of an enhancer, are described in U.S. Patent No. 5,011,678 and Nagai et al. (1984) J. Contr. ReI.1:15-22. Intranasal delivery of insulin in the presence of enhancers and/or contained in controlled release formulations are described in U.S. Patent Nos. 5,204,108; 4,294,829; and 4,153,689; PCT Applications WO
93/02712, WO 91/02545, WO 90/09780, and WO 88/04556; British Patent 1,527,605; Ryd"en and Edman (1992) Int. J. Pharm. 8l:1-10; and BjSrk and Edman (1988) Int. J. Pharm. =41:233-238. The preparation and stability of amorphous insulin were described by Rigsbee and Pikal at the American Association of Pharmaceutical Sciences (AAPS), November 14-18, 1993, Lake Buena Vista, Florida. Methods for spray drying polypeptide, polynucleotide and other labile drugs in a carrier which forms an amorphous structure which stabilize the drug are described in European patent application 520 748.
SUMMARY OF TSE INVENTION
According to the present invention, methods and compositions for the aerosolization and systemic delivery of insulin to a mammalian host, particularly a human patient suffering from diabetes, provide for rapid absorption into blood circulation while avoiding subcutaneous injection. In particular, the methods of the present invention rely on pulmonary delivery of insulin in the form of a dry powder.
Surprisingly, it has been found that inhaled dry insulin powders are deposited in the alveolar regions of the lung and rapidly absorbed through the epithelial cells of the alveolar region into blood circulation. Thus, pulmonary delivery of insulin powders can be an effective alternative to administration by subcutaneous injection.
WO 95/24183 21" 35/ / PCT/US95/01563 = 5 In a first aspect of the present invention, insulin is provided as a dry powder, usually but not necessarily in a substantially amorphous state, and dispersed in an air or other physiologically acceptable gas stream to form an aerosol. The aerosol is captured in a chamber having a mouthpiece, where it is available for a subsequent inhalation by a patient. Optionally, the dry powder insulin is combined with a pharmaceutically acceptable dry powder carrier, as described in more detail below. The insulin powder preferably comprises particles having a diameter less then 10 m, more preferably less than 7.5 gm, and most preferably below 5 m, usually being in the range from 0.1 m to 5 m. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are absorbed in the lung without the use of penetration enhancers such as those required for absorption through the nasal mucosa and upper respiratory tract.
In a second aspect, the present invention provides insulin compositions consisting essentially of dry powder insulin having an average particle size below 10 gm which may be combined with dry powder pharmaceutical carriers. The insulin composition is preferably free from penetration enhancers and comprises particles having a diameter less than 10 m, preferably less than 7.5 m, and most preferably below 5 m, usually being in the range from 0.1 m to 5 m.
Usually, the insulin dry powder will have from 5g to 99% by weight insulin in the composition, more usually from 15% to 80k, in a suitable pharmaceutical carrier, usually a carbohydrate, an organic salt, an amino acid, peptide, or protein, as described in more detail hereinafter.
in a third aspect of the present invention, insulin dry powders are prepared by dissolving insulin in an aqueous buffer to form a solution and spray drying the solution to produce substantially amorphous particles having a particle size less than 10 m, preferably less than 7.5 m, and most preferably below 5 m, usually being in the range from 0.1 m to 5Am. Optionally, the pharmaceutical carrier is also dissolved in the buffer, to form a homogeneous solution, wherein spray drying of the solution produces individual particles comprising insulin, carrier buffer, and any other components which were present in the solution. Preferably the carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a substantially amorphous structure upon spray drying. The amorphous carrier may be either glassy or rubbery and enhances stability of the insulin during storage. Advantageously, such stabilized formulations are also able to effectively deliver insulin to the blood stream upon inhalation to the alveolar regions of the lungs.
A further understanding of the nature and advantages of the invention will become apparent by reference to the remaining portions of the specification and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic illustration of a system for aerosolizing a dose of insulin according to the method of the present invention.
Fig. 2 is a schematic illustration of a patient inhaling an aerosolized dose of insulin from the system of Fig. 1.
Figs. 3A and 3B are graphs illustrating the absorption of recombinant human insulin in rats and resulting glucose response following aerosolization of three different dry powder formulations. Each point represents the mean value from three different rats. At zero time, the dry powder aerosol generator was turned on. Aerosolization was complete at 5 min, 14 min and 20 min for the 87% insulin/citrate, 20%
insulin-mannitol/citrate and 20% insulin-raffinose/citrate powders, respectively. Animals were fasted overnight.
Figs. 4A and 4B are graphs illustrating mean serum time-concentration insulin and glucose profiles, respectively comparing aerosol and subcutaneous administrations in cynomolgus monkeys. The mean value for three monkeys is reported for the aerosol group, and the mean value for four monkeys is reported for the subcutaneous group.
Fig. 5A is a graph illustrating the mean insulin concentration over time for subcutaneous injection (O) and for inhalation of three puffs (i) in humans.
WO 95/24183 2183577 PCTlUS95/01563 Fig. 5B shows the mean glucose concentration corresponding to the insulin concentrations of Fig. 5A.
Fig. 6A is a graph illustrating serum insulin concentration over time as a result of subcutaneous injection (o) and three puffs of aerosol administration (0) in humans.
Fig. 6B is a graph illustrating the serum glucose levels corresponding to the insulin levels in Fig. 6A.
Figs. 7A and 7B provide a comparison of the intersubject variability of serum insulin (7A) and glucose levels (7B) for subcutaneous administration (o) and aerosol administration (0).
Figs. 8A, SB, and 8C show rpHPLC chromatograms of a human insulin. Fig. 8A is a chromatograph of an insulin standard stressed in 10 mM HC1 at 25 C, showing human insulin eluting at 23.87 minutes desamido insulin eluting at 30.47 minutes. Fig. 8B shows a similar chromatogram of a human insulin standard. Fig. 8C shows a similar chromatogram of reconstituted, spray-dried insulin formulation prepared according to the present invention.
Fig. 9 shows an ultraviolet spectra of an insulin formulation before and after spray drying. No light scattering was observed in the visible spectrum, indicating that insulin did not aggregate during the spray drying process.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
According to the present invention, insulin is provided as a dry power. By "dry powder" it is meant that the moisture content of the powder is below about 10% by weight, usually below about 5% by weight, and preferably being below about 3% by weight. By "powder," it is meant that the insulin comprises free flowing particulates having a size selected to permit penetration into the alveoli of the lungs, preferably being less than 10 m in diameter, preferably less than 7.5 m, and most preferably less than 5 m, and usually being in the range from 0.1 pcm to 5 m in diameter.
The present invention is based at least in part.on the unexpected observation that dry powder insulins are - - ------- - - _ . - -2 18J ~ PCT/US95/01563 ~
readily and rapidly absorbed through the lungs of a host. it was surprising that dry powder insulins could reach the alveolar region of the lungs, as water-soluble drugs such as insulin particles are known to be hygroscopic. See, e.g.
Byron, ed., Respiratory Drug Delivery, CRC Press, Boca Raton (1990), p. 150. Thus, it would have been expected that as the particles passed through the airways of the lung (which has a relative humidity in excess of 99% at 37 C), the individual particles would have a tendency to absorb water and grow to an effective particle size larger than the 10 m upper limit of the present invention. If a substantial fraction of the insulin particles were larger than the target size range, it would be expected that the particles would deposit within the central airways of the lungs rather than the alveolar region, thus limiting delivery and subsequent systemic absorption.
Moreover, the fluid layer over the epithelial cells of the lungs is very thin, usually a fraction of the diameter of the insulin powders being delivered. Thus, it was unpredictable prior to the present invention whether the dry insulin particles would dissolve upon deposition within the alveolar regions of the lungs. Surprisingly, the dry insulin powders are apparently able to both penetrate into the alveolar regions of the lungs and dissolve once they have deposited within the alveolar region of the lung. The dissolved insulin is then able to cross the epithelial cells into circulation.
It is presently believed that the effective absorption of insulin results from a rapid dissolution in the ultrathin (< 0.1 m) fluid layer of the alveolar lining. The particles of the present invention thus have a mean size which is from 10 to 50 times larger than the lung fluid layer, making it unexpected that the particles are dissolved and the insulin systemically absorbed in a rapid manner. indeed, as shown in the Experimental section hereinafter, the dry insulin formulations of the present invention can provide even more rapid serum insulin peaks and glucose troughs than afforded by subcutaneous injection, which is presently the most common form of administration. An understanding of the precise ~ WO 95/24183 218J 5 77 / PCT/U595/01563 mechanism, however, is not necessary for practicing the present invention as described herein.
Preferred compositions according to the present invention will be substantially free from penetration enhancers. "Penetration enhancers" are surface active compounds which promote penetration of insulin (or other drugs) through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations. Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate;
fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like. The use of penetration enhancers in formulations for the lungs, however, is generally undesirable because the epithelial blood barrier in the lung can be adversely affected by such surface active compounds. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
Insulin dry powders suitable for use in the present invention include amorphous insulins, crystalline insulins, and mixtures of both amorphous and crystalline insulins. Dry powder insulins are preferably prepared by spray drying under conditions which result in a substantially amorphous powder having a particle size within the above-stated range.
Alternatively, amorphous insulins could be prepared by lyophilization (freeze-drying), vacuum drying, or evaporative drying of a suitable insulin solution under conditions to produce the amorphous structure. The amorphous insulin so produced can then be ground or milled to produce particles within the desired size range. Crystalline dry powder insulins may be formed by grinding or jet milling of bulk crystalline insulin. The preferred method for forming insulin powders comprising particulates in the desired size range is spray drying, where pure, bulk insulin (usually in a crystalline form) is first dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH in the range from about 2 to 9. The insulin is dissolved WO 95/24183 ~ f ! C PCT/US95/01563 at a concentration from 0.01% by weight to 1% by weight, usually from 0.1% to 0.2%. The solutions may then be spray dried in conventional spray drying equipment from commercial suppliers, such as Buchi, Niro, and the like, resulting in a 5 substantially amorphous particulate product.
The dry insulin powders may consist essentially of insulin particles within the requisite size range and be substantially free from any other biologically active components, pharmaceutical carriers, and the like. Such 10 "neat" formulations may include minor components, such as preservatives, present in low amounts, typically below 10% by weight and usually below 5% by weight. Using such neat formulations, the number of inhalations required for even high dosages can be substantially reduced, often to only a single breath.
The insulin powders of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the insulin concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the insulin compositions and to improve the dispersability of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the insulin and to improve handling characteristics of the insulin such as flowability and consistency to facilitate manufacturing and powder filling.
Suitable carrier materials may be in the form of an amorphous powder, a crystalline powder, or a combination of amorphous and crystalline powders. Suitable materials include carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like;
disaccharides, such as lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-0-cyclodextrin;
and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; (b) amino acids, such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, and the like; (c) organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins, such as aspartame, human serum albumin, gelatin, and the like; (e) alditols, such as mannitol, xylitol, and the like. A preferred group of carriers includes lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, tromethamine hydrochloride, human serum albumin, and mannitol.
Such carrier materials may be combined with the insulin prior to spray drying, i.e., by adding the carrier material to the buffer solution which is prepared for spray drying. In that way, the carrier material will be formed simultaneously with and as part of the insulin particles.
Typically, when the carrier is formed by spray drying together with the insulin, the insulin will be present in each individual particle at a weight percent in the range from 5%
to 95%, preferably from 20% to 80%. The remainder of the particle will primarily be carrier material (typically being from 5% to 95%, usually being from 20% to 80% by weight), but will also include buffer(s) and may include other components as described above. The presence of carrier material in the particles which are delivered to the alveolar region of the lung (i.e., those in the requisite size range below 10 m) has been found not to significantly interfere with systemic absorption of insulin.
Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder insulin by blending. The separately prepared powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the insulin powder, typically being in the range from 25 m to 100 gm. Carrier particles in this size range will generally not penetrate into the alveolar region of the lung and will often separate from the insulin in the delivery device prior to inhalation. Thus, the particles which penetrate into the alveolar region of the lung will consist essentially of insulin and buffer. A
preferred carrier material is crystalline mannitol having a size in the above-stated range.
The dry insulin powders of the present inventions may also be combined with other active components. For example, it may be desirable to combine small amounts of amylin or active amylin analogues in the insulin powders to improve the treatment of diabetes. Amylin is a hormone which is secreted with insulin from the pancreatic 0-cells in normal (non-diabetic) individuals. It is believed that amylin modulates insulin activity in vivo, and it has been proposed that simultaneous administration of amylin with insulin could improve blood glucose control. Combining dry powder amylin with insulin in the compositions of the present invention will provide a particularly convenient product for achieving such simultaneous administration. Amylin may be combined with insulin at from 0.1% by weight to 10% by weight (based on the total weight of insulin in a dose), preferably from 0.5% by weight to 2.5% by weight. Amylin is available from commercial suppliers, such as Amylin Corporation, San Diego, California, and can be readily formulated in the compositions of the present invention. For example, amylin may be dissolved in aqueous or other suitable solutions together with the insulin, and optionally carriers, and the solution spray dried to produce the powder product.
The dry powder insulin compositions of the present invention are preferably aerosolized by dispersion in a flowing air or other physiologically acceptable gas stream in a conventional manner. One system suitable for such dispersion is described in WO 93/00951, the full disclosures of which are incorporated herein by reference.
Referring to Fig. 1 herein, dry, free-flowing insulin powder is introduced into a high velocity air or gas stream, and the resulting dispersion introduced into a holding chamber 10.
The holding chamber 10 includes a mouthpiece 12 at an end opposite to the entry point of the air powder dispersion. The volume of the chamber 10 is sufficiently large to capture a desired dose and may optionally have baffles and/or one-way valves for promoting containment. After a dose of the insulin powder has been captured in chamber 10, a patient P (Fig. 2) inhales on the mouthpiece 12 to draw the aerosolized dispersion into his lungs. As the patient P inhales, make-up air is introduced through a tangentially oriented air inlet port 14, whereby the air flows in a generally vortical pattern to sweep the aerosolized insulin from the chamber into the patient's lungs. The volume of the chamber and the aerosolized dose are such that a patient is able to completely inhale the entire aerosolized insulin dose followed by sufficient air to ensure that the insulin reaches the lower alveolar regions of the lung.
such aerosolized insulin powders are particularly useful in place of subcutaneous injections of rapid acting insulin in the treatment of diabetes and related insulin-deficiencies. Surprisingly, it has been found that the aerosol administration of dry powder insulin results in significantly more rapid insulin absorption and glucose response than is achieved by subcutaneous injection. Thus, the methods and compositions of the present invention will be particularly valuable in treatment protocols where a patient monitors blood glucose levels frequently and administers insulin as needed to maintain a target serum concentration, but will also be useful whenever systemic insulin administration is required. The patient can achieve a desired dosage by inhaling an appropriate amount of insulin, as just described. The efficiency of systemic insulin delivery via the method as just described will typically be in the range from about 15% to 30%, with individual dosages (on a per inhalation basis), typically being in the range from about 0.5 mg to 10 mg. Usually, the total dosage of insulin desired during a single respiratory administration will be in the range from about 0.5 mg to 15 mg. Thus, the desired dosage may be effective by the patient taking from 1 breath to 4 breaths.
The following examples are offered by way of illustration, not by way of limitation.
Byron, ed., Respiratory Drug Delivery, CRC Press, Boca Raton (1990), p. 150. Thus, it would have been expected that as the particles passed through the airways of the lung (which has a relative humidity in excess of 99% at 37 C), the individual particles would have a tendency to absorb water and grow to an effective particle size larger than the 10 m upper limit of the present invention. If a substantial fraction of the insulin particles were larger than the target size range, it would be expected that the particles would deposit within the central airways of the lungs rather than the alveolar region, thus limiting delivery and subsequent systemic absorption.
Moreover, the fluid layer over the epithelial cells of the lungs is very thin, usually a fraction of the diameter of the insulin powders being delivered. Thus, it was unpredictable prior to the present invention whether the dry insulin particles would dissolve upon deposition within the alveolar regions of the lungs. Surprisingly, the dry insulin powders are apparently able to both penetrate into the alveolar regions of the lungs and dissolve once they have deposited within the alveolar region of the lung. The dissolved insulin is then able to cross the epithelial cells into circulation.
It is presently believed that the effective absorption of insulin results from a rapid dissolution in the ultrathin (< 0.1 m) fluid layer of the alveolar lining. The particles of the present invention thus have a mean size which is from 10 to 50 times larger than the lung fluid layer, making it unexpected that the particles are dissolved and the insulin systemically absorbed in a rapid manner. indeed, as shown in the Experimental section hereinafter, the dry insulin formulations of the present invention can provide even more rapid serum insulin peaks and glucose troughs than afforded by subcutaneous injection, which is presently the most common form of administration. An understanding of the precise ~ WO 95/24183 218J 5 77 / PCT/U595/01563 mechanism, however, is not necessary for practicing the present invention as described herein.
Preferred compositions according to the present invention will be substantially free from penetration enhancers. "Penetration enhancers" are surface active compounds which promote penetration of insulin (or other drugs) through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations. Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate;
fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like. The use of penetration enhancers in formulations for the lungs, however, is generally undesirable because the epithelial blood barrier in the lung can be adversely affected by such surface active compounds. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
Insulin dry powders suitable for use in the present invention include amorphous insulins, crystalline insulins, and mixtures of both amorphous and crystalline insulins. Dry powder insulins are preferably prepared by spray drying under conditions which result in a substantially amorphous powder having a particle size within the above-stated range.
Alternatively, amorphous insulins could be prepared by lyophilization (freeze-drying), vacuum drying, or evaporative drying of a suitable insulin solution under conditions to produce the amorphous structure. The amorphous insulin so produced can then be ground or milled to produce particles within the desired size range. Crystalline dry powder insulins may be formed by grinding or jet milling of bulk crystalline insulin. The preferred method for forming insulin powders comprising particulates in the desired size range is spray drying, where pure, bulk insulin (usually in a crystalline form) is first dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH in the range from about 2 to 9. The insulin is dissolved WO 95/24183 ~ f ! C PCT/US95/01563 at a concentration from 0.01% by weight to 1% by weight, usually from 0.1% to 0.2%. The solutions may then be spray dried in conventional spray drying equipment from commercial suppliers, such as Buchi, Niro, and the like, resulting in a 5 substantially amorphous particulate product.
The dry insulin powders may consist essentially of insulin particles within the requisite size range and be substantially free from any other biologically active components, pharmaceutical carriers, and the like. Such 10 "neat" formulations may include minor components, such as preservatives, present in low amounts, typically below 10% by weight and usually below 5% by weight. Using such neat formulations, the number of inhalations required for even high dosages can be substantially reduced, often to only a single breath.
The insulin powders of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the insulin concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the insulin compositions and to improve the dispersability of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the insulin and to improve handling characteristics of the insulin such as flowability and consistency to facilitate manufacturing and powder filling.
Suitable carrier materials may be in the form of an amorphous powder, a crystalline powder, or a combination of amorphous and crystalline powders. Suitable materials include carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like;
disaccharides, such as lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-0-cyclodextrin;
and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; (b) amino acids, such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, and the like; (c) organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins, such as aspartame, human serum albumin, gelatin, and the like; (e) alditols, such as mannitol, xylitol, and the like. A preferred group of carriers includes lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, tromethamine hydrochloride, human serum albumin, and mannitol.
Such carrier materials may be combined with the insulin prior to spray drying, i.e., by adding the carrier material to the buffer solution which is prepared for spray drying. In that way, the carrier material will be formed simultaneously with and as part of the insulin particles.
Typically, when the carrier is formed by spray drying together with the insulin, the insulin will be present in each individual particle at a weight percent in the range from 5%
to 95%, preferably from 20% to 80%. The remainder of the particle will primarily be carrier material (typically being from 5% to 95%, usually being from 20% to 80% by weight), but will also include buffer(s) and may include other components as described above. The presence of carrier material in the particles which are delivered to the alveolar region of the lung (i.e., those in the requisite size range below 10 m) has been found not to significantly interfere with systemic absorption of insulin.
Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder insulin by blending. The separately prepared powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the insulin powder, typically being in the range from 25 m to 100 gm. Carrier particles in this size range will generally not penetrate into the alveolar region of the lung and will often separate from the insulin in the delivery device prior to inhalation. Thus, the particles which penetrate into the alveolar region of the lung will consist essentially of insulin and buffer. A
preferred carrier material is crystalline mannitol having a size in the above-stated range.
The dry insulin powders of the present inventions may also be combined with other active components. For example, it may be desirable to combine small amounts of amylin or active amylin analogues in the insulin powders to improve the treatment of diabetes. Amylin is a hormone which is secreted with insulin from the pancreatic 0-cells in normal (non-diabetic) individuals. It is believed that amylin modulates insulin activity in vivo, and it has been proposed that simultaneous administration of amylin with insulin could improve blood glucose control. Combining dry powder amylin with insulin in the compositions of the present invention will provide a particularly convenient product for achieving such simultaneous administration. Amylin may be combined with insulin at from 0.1% by weight to 10% by weight (based on the total weight of insulin in a dose), preferably from 0.5% by weight to 2.5% by weight. Amylin is available from commercial suppliers, such as Amylin Corporation, San Diego, California, and can be readily formulated in the compositions of the present invention. For example, amylin may be dissolved in aqueous or other suitable solutions together with the insulin, and optionally carriers, and the solution spray dried to produce the powder product.
The dry powder insulin compositions of the present invention are preferably aerosolized by dispersion in a flowing air or other physiologically acceptable gas stream in a conventional manner. One system suitable for such dispersion is described in WO 93/00951, the full disclosures of which are incorporated herein by reference.
Referring to Fig. 1 herein, dry, free-flowing insulin powder is introduced into a high velocity air or gas stream, and the resulting dispersion introduced into a holding chamber 10.
The holding chamber 10 includes a mouthpiece 12 at an end opposite to the entry point of the air powder dispersion. The volume of the chamber 10 is sufficiently large to capture a desired dose and may optionally have baffles and/or one-way valves for promoting containment. After a dose of the insulin powder has been captured in chamber 10, a patient P (Fig. 2) inhales on the mouthpiece 12 to draw the aerosolized dispersion into his lungs. As the patient P inhales, make-up air is introduced through a tangentially oriented air inlet port 14, whereby the air flows in a generally vortical pattern to sweep the aerosolized insulin from the chamber into the patient's lungs. The volume of the chamber and the aerosolized dose are such that a patient is able to completely inhale the entire aerosolized insulin dose followed by sufficient air to ensure that the insulin reaches the lower alveolar regions of the lung.
such aerosolized insulin powders are particularly useful in place of subcutaneous injections of rapid acting insulin in the treatment of diabetes and related insulin-deficiencies. Surprisingly, it has been found that the aerosol administration of dry powder insulin results in significantly more rapid insulin absorption and glucose response than is achieved by subcutaneous injection. Thus, the methods and compositions of the present invention will be particularly valuable in treatment protocols where a patient monitors blood glucose levels frequently and administers insulin as needed to maintain a target serum concentration, but will also be useful whenever systemic insulin administration is required. The patient can achieve a desired dosage by inhaling an appropriate amount of insulin, as just described. The efficiency of systemic insulin delivery via the method as just described will typically be in the range from about 15% to 30%, with individual dosages (on a per inhalation basis), typically being in the range from about 0.5 mg to 10 mg. Usually, the total dosage of insulin desired during a single respiratory administration will be in the range from about 0.5 mg to 15 mg. Thus, the desired dosage may be effective by the patient taking from 1 breath to 4 breaths.
The following examples are offered by way of illustration, not by way of limitation.
E%PERIMENTAL
Materials and Methods Materials Crystalline human zinc insulin, 26.3 Units/mg, (Lilly Lot #784KK2) was obtained from Eli Lilly and Company, Indianapolis, IN and found to be >99% pure as measured by rpHPLC. USP mannitol was obtained from Roquette Corporation (Gurnee, IL). Raffinose was purchased from Pfanstiehl Laboratories (Waukegan, IL). Sodium citrate dihydrate, USP, ACS and citric acid monohydrate USP were obtained from J.T.
Baker (Phillipsburg, NJ).
Powder Production Insulin powders were made by dissolving bulk crystalline insulin in sodium citrate buffer containing excipient (mannitol, or raffinose, or none) to give final solids concentration of 7.5 mg/ml and a pH of 6.7t0.3. The spray dryer was operated with an inlet temperature between 110 C to 120 C and a liquid feed rate of 5 ml/min, resulting in an outlet temperature between 70 C and 80"C. The solutions were then filtered through a 0.22 m filter and spray dried in a Buchi Spray Dryer to form a fine white amorphous powder.
The resulting powders were stored in tightly capped containers in a dry environment (<10% RH).
Powder Analyses The particle size distribution of the powders was measured by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle Size Analyzer following dispersion of the powders in Sedisperse A-li (Micromeritics, Norcross, GA). The moisture content of the powders was measured by the Karl Fischer technique using a Mitsubishi CA-06 Moisture Meter.
The integrity of insulin before and after powder processing was measured against a reference standard of human insulin by redissolving weighed portions of powder in distilled water and comparing the redissolved solution with the original solution put into the spray dryer. Retention time and peak area by rpHPLC were used to determine whether the insulin molecule had been chemically modified or degraded in process. W absorbance was used to determine insulin concentration (at 278 nm) and presence or absence of insoluble aggregates (at 400 nm). In addition, the pHs of the starting 5 and reconstituted solutions were measured. The amorphous nature of the insulin powder was confirmed by polarizing light microscopy.
Rat Aerosol Exposures 10 Rat experiments were conducted in an aerosol exposure room. Female rats (280-300 gm) were fasted overnight. Animals (21-24/experiment) were placed in Plexiglas tubes and mounted into a 48 port, nose-only aerosol exposure chamber (In-Tox Products, Albuquerque, NM). Airflow 15 to the bzone was breathing maintained at 7.2-9.8 liters/minute and removed by vacuum so that there was a slight negative pressure (-1.5 cm H20) in the chamber as measured by a magnahelic gauge. Aerosol exposure times were between 5-20 minutes depending on how much powder was fed into the chamber.
Powders were fed by hand into a small Venturi nozzle which dispersed the powder particles to form a fine aerosol cloud.
The Venturi nozzle was operated at a pressure in excess of 15 psig, and the air flow was set at 7.2 E/min to 9.8 P/min.
The Venturi nozzle was fitted into the bottom of a clear Plexiglas dispersion chamber (750 ml) which passed the aerosol directly into a nose-only exposure chamber.
Rat Aerosol Chamber Calibration The concentration of the powder at the breathing zone was measured by taking multiple, timed filter samples at the breathing zone with In-Tox filter holders at a vacuum flow of 2 liters/min. The chamber was calibrated both with and without animals. Powder mass was determined gravimetrically.
The particle size of the powders at the breathing zone was measured with cascade impactor (In Tox Products) placed at a breathing hole and operated at a flow of 2 liters/min. Powder mass on each stage was determined gravimetrically.
r c f; [ C 2183577 WO 95/24183 pCT/US95l01563 Each powder test utilized 21-24 rats and the aerosol exposures lasted 5-20 minutes. Three rats were killed at 0 time and then at -7, 15, 30, 60, 90, 120, 180, and 240 minutes after the termination of the aerosol exposure. Animals were anesthetized, their abdomens opened, and a large blood sample was drawn from the ventral aorta. The animals were then killed by cervical dislocation.
Blood was allowed to clot at room temperature for 30 minutes and then centrifuged for 20 minutes at 3500 rpm in serum separator tubes. Serum was either analyzed immediately or frozen at -80 C until analysis. As soon as possible (0-7 min) after the termination of the aerosol dosing, 3 rats were killed, their blood drawn and their lungs lavaged with six 5 ml rinses of phosphate buffered saline (PBS). The amount of insulin in the final pooled lavage sample was used as the aerosol dose for the rat in calculations of bioavailability.
Primate Exposure system Young, wild-captured, male cynomolgus monkeys strain Macaca fascicularis (2-5 kg) (Charles River Primates, Inc.) were used for the primate aerosol studies (3-4 animals/group).
The animals were either subcutaneously injected with Humulin (Eli Lilly, Indianapolis, Indiana) or exposed to a powder aerosol of insulin. Each animal was placed in a head-only exposure unit to provide a fresh supply of the test atmosphere at an adequate flow rate (7 L/min) to provide minimum oxygen requirements of the animal. The animals were restrained in a chair-like apparatus which placed them in an upright sitting position. The hoods were clear allowing the animals complete visualization of their environment. An indwelling catheter was placed in the leg so that blood samples could be taken at any time. The monkeys were fully awake during the whole procedure and appeared to be calm. Primate blood was treated the same as rat (see above).
35. The primate aerosol exposure system included a breath monitor that allowed quantification of the amount of air inhaled by each monkey. This value, coupled with measurements of the concentration of insulin in the inspired air allowed the calculation of exactly how much insulin was inhaled by each animal.
Human Trials Insulin was administered to 24 normal human subjects subcutaneously as well as by inhalation of aerosolized dry insulin powders. Each subcutaneous injection consisted of 10.4U of Humulin R, 100 U/ml (Eli Lilly, Indianapolis, Indiana). The dry insulin powders were amorphous and prepared by spray drying as described above with 20% by weight mannitol excipient. Doses (5 mg) of the insulin dry powder were dispersed in a high-velocity air stream to produce a fine aerosol that was captured in a chamber. Each subject inhaled the aerosol powder by taking a slow, deep breath of each aerosol bolus or "puff." Powder was administered in three puffs (for a dosage of 31.9U). Serum insulin and glucose levels were determined over time, as described below.
Serum Assays Serum insulin levels in rats, primates, and humans were determined using Coat-A-Count radio immunoassay kits for human insulin (Diagnostic Products Corporation, Los Angeles, CA). Standard curves were run with every batch of samples.
The sensitivity of the assay was approximately 43 pg/ml. The within assay variability (%CV) is <5%. Glucose assays were performed by California Veterinary Diagnostics, Inc. in West Sacramento, CA using the Glucose/HK Reagent System Pack for the Boehringer Mannheim/Hitachi 747 Analyzer. The within assay variability (%CV) is <3%.
In the rate experiments, relative bioavailabilities of the aerosol were calculated by comparing the dose adjusted, immunoreactive insulin (IRI) area under the curve (AUC) of the concentration-time profile with that obtained from subcutaneous injection. In rats the total lavaged insulin mass was used as the aerosol dose. Some insulin is absorbed before the lungs can be lavaged so the dose estimated by this technique is probably a slight underestimate of the total * Trade-mark ..._...._._ ~...~...._........,M . .__... _ _........ _~_. __ .
.._~_..____..._-_ .,,., WO 95124183 PCT/'t7S95/01563 deposited dose. No corrections for this presumed loss were made.
In the monkey experiments, relative bioavailabilities were calculated similar to the rats above except that instead of using lavaged lung insulin as the aerosol dose, the total amount of insulin inhaled was used.
In the rats, only material deposited in the lungs, not insulin deposited in the nasal passages and throat, was included in the dose estimate. In the monkeys, all insulin that entered the animals was included in the dose estimate.
Results of Insulin Absorption in Rats All of the insulin powders used in the animal studies had particle sizes (mass median diameters) ranging between 1-3 )im and moisture contents <3%. The insulin purity of the powders as measured by rpHPLC was >97%. Representative chromatographs of the 20% insulin formulation are shown in Fig. SC. The powders yielded a clear solution upon reconstitution with pure water with an ultraviolet absorbance value <0.01 at 400 nm and a pH of 6.7 0.3. Representative ultraviolet (W) spectra for the 20% insulin formulation are shown in Fig. 9.
The following three insulin powder formulations were tested in rats as aerosols in the In-Tox 48 port, exposure chamber.
1. 87.9% insulin; 11.5% sodium citrate; 0.6%
citric acid. - --2. 20% insulin; 66% mannitol: 12.4% sodium citrate: 0.6% citric acid.
3. 20% insulin; 66t raffinose; 12.4% sodium citrate: 0.6% citric acid.
Table 1 lists the key measurements in the three different rat exposure studies including characterizations of the aerosol at the breathing zone and chamber operating conditions. A fraction of the powder fed into the venturi nozzle reached the breathing zones of the rats (30-67$) because of losses in the walls due to impaction and incomplete dispersion of the powder during powder feed. The particle size of the aerosol at the breathing zone, however, was ideal for pulmonary deposition (1.3-1.9 m) and was somewhat smaller than the original formulation particle size (2.0-2.8 m) due to selective loss of the larger particles in the animal exposure chamber.
Table 1. Rat Aerosol Exposure Measurements 88% 20% 20% insulin Insulin Insulin Raffinose Marnni tol Chamber Flow Rate 7.2 L/min 9.6 L/min 9.8 L/min Powder Mass Median 2.2 m 2.8 m 2.0 m Diameter (MMD) Powder Fed into Chamber 70 mgs 255 mgs 260 mgs Powder Feed Time 5 min 14 min 20 min Powder at Breathing 40 mgs 171 mgs 88 mgs Zone Insulin at Breathing 35 mgs 34 mgs 18 mgs Zone ~ Total Powder at 57% 67% 34%
Breathing Zone Mass Median Aerodynamic 1.1 mg/L 1.3 mg/L 0.45 mg/L
Diameter (MAD) Particle Size at 1.4 m 1.9 m 1.3 m Breathing Zone Insulin Recovered in 30.7f5.2 12.7 6.9 31.6 12.9 Lavage g g g Serum Insulin AUC 104 201 150 (ng min/ml) Table 2 shows the rat serum insulin and glucose results from the three aerosol and one SC study. Fig. 3A and 3B show the serum immunoreactive insulin (IRI) concentration-time profiles and the serum glucose concentration-time profiles for the three formulations administered by aerosol.
Table 3 presents the insulin tmax, and the glucose tmin from the different studies as well as the relative-bioavailability of the aerosol compared to SC injection.
Table 2. Serum Insulin and Glucose Results in Rats Formulation Route Time Serum Serum (min) Insulin Glucose (pg/ml l (mg/dl#1 S.D.) S.D.)n=3rats n=3rats/ /
timept timept 88% Insulin Aerosol 0 230 184 106 12 (Aerosol Aerosol 12 1020 312 114 10 exposure completed at Aerosol 21 165 768 81 10 minute 5) Av. Dose=31 Aerosol 36 876 764 66 7 pg/rat Aerosol 66 684 416 62 15 Aerosol 96 568 128 65 10 Aerosol 126 564 260 73 11 Aerosol 186 712 140 93 5 20% Insulin- Aerosol 0 476 56 165 18 Mannitol (Aerosol Aerosol 22 1476 428 117 15 exposure completed at Aerosol 35 2480 892 101 19 minute 14) Av. Dose=13 Aerosol 57 1204 64 64 13 g/rat Aerosol 87 1084 396 63 17 Aerosol 117 664 180 105 38 Aerosol 147 1228 416 108 22 Aerosol 207 676 100 119 33 20% Insulin- Aerosol 0 426 97 157 37 Raffinose (Aerosol Aerosol 27 2948 2816 139 46 exposure completed at Aerosol 42 1504 592 181 11 minute 20) 20a Formulation Route Time Serum Serum (min) Insulin Glucose (pg/ml l (mg/dl l S.D.) S.D.)n=3rats n=3rats/ /
timept timept Av. Dose=32 Aerosol 57 1272 496 124 45 pg/rat Aerosol 87 852 164 128 17 Aerosol 117 604 156 124 9 Aerosol 147 532 172 172 12 Aerosol 207 556 100 218 34 20% Insulin- Subcutan 0 360 140 107 5 Mannitol Dose=30 g Subcutan 15 14200 3160 53 2 Insulin/rat Subcutan 30 10160 720 24 5 Subcutan 60 11000 1080 28 6 Subcutan 90 2440 1160 25 7 Subcutan 120 3520 840 49 3 Subcutan 180 1280 800 40 17 Subcutan 240 400 260 77 34 Table 3 A Comparison of Aerosol and Subcutaneous (SC) Insulin in Animals Rat Rat Rat Aerosol Rat Monkey Monkey SC Aerosol 20% Insulin Aerosol SC Aerosol 88% Mannitol 20% 20% Insulin Insulin Insulin Mannitol Raff-inose Insulin Max* 15 16min 21 min 17 min 15 min 30 min min Glucose 30 31 min 43 min 37 min 45 min 45 min Min. * mm Glucose Drop 77% 42% 62% 21% 45% 73%
Rel Bioavail. 100% 10%** 44%** 14%** 100% 12%***
* T's measured from end of aerosol exposure period.
2 0 Glucose min = time to > 85% of maximal reduction observed in study ** Based on insulin recovered by lavage from lung at end of aerosol exposure *** Based on insulin inhaled, includes losses in nasal passages and throat All three formulations provided rapid absorbing insulin to the rats systemic circulation (Figs. 3A and 3B).
The bioavailability and glucose response were higher for the 20% insulin/mannitol powder (Table 3), although without performing many replicate experiments, it is uncertain if the difference was significant.
21a Primate Results A dose identical to what was used in the human trial (0.2 U/kg, -27 g/monkey) was injected into four monkeys to provide the SC data with which to compare the aerosol results (Figs. 4A and 4B). Table 4 shows the monkey aerosol exposure data. Table 5 shows the,mean serum insulins and glucoses for the aerosol exposure and the subcutaneous study. The aerosol dose yielded a robust insulin and glucose response (high dose). Fig. 4 shows a comparison of the mean serum insulin profiles from the two aerosol and one SC study. From the AUCs of these profiles the relative bioavailability of the aerosol insulin was calculated to be 12%.
Materials and Methods Materials Crystalline human zinc insulin, 26.3 Units/mg, (Lilly Lot #784KK2) was obtained from Eli Lilly and Company, Indianapolis, IN and found to be >99% pure as measured by rpHPLC. USP mannitol was obtained from Roquette Corporation (Gurnee, IL). Raffinose was purchased from Pfanstiehl Laboratories (Waukegan, IL). Sodium citrate dihydrate, USP, ACS and citric acid monohydrate USP were obtained from J.T.
Baker (Phillipsburg, NJ).
Powder Production Insulin powders were made by dissolving bulk crystalline insulin in sodium citrate buffer containing excipient (mannitol, or raffinose, or none) to give final solids concentration of 7.5 mg/ml and a pH of 6.7t0.3. The spray dryer was operated with an inlet temperature between 110 C to 120 C and a liquid feed rate of 5 ml/min, resulting in an outlet temperature between 70 C and 80"C. The solutions were then filtered through a 0.22 m filter and spray dried in a Buchi Spray Dryer to form a fine white amorphous powder.
The resulting powders were stored in tightly capped containers in a dry environment (<10% RH).
Powder Analyses The particle size distribution of the powders was measured by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle Size Analyzer following dispersion of the powders in Sedisperse A-li (Micromeritics, Norcross, GA). The moisture content of the powders was measured by the Karl Fischer technique using a Mitsubishi CA-06 Moisture Meter.
The integrity of insulin before and after powder processing was measured against a reference standard of human insulin by redissolving weighed portions of powder in distilled water and comparing the redissolved solution with the original solution put into the spray dryer. Retention time and peak area by rpHPLC were used to determine whether the insulin molecule had been chemically modified or degraded in process. W absorbance was used to determine insulin concentration (at 278 nm) and presence or absence of insoluble aggregates (at 400 nm). In addition, the pHs of the starting 5 and reconstituted solutions were measured. The amorphous nature of the insulin powder was confirmed by polarizing light microscopy.
Rat Aerosol Exposures 10 Rat experiments were conducted in an aerosol exposure room. Female rats (280-300 gm) were fasted overnight. Animals (21-24/experiment) were placed in Plexiglas tubes and mounted into a 48 port, nose-only aerosol exposure chamber (In-Tox Products, Albuquerque, NM). Airflow 15 to the bzone was breathing maintained at 7.2-9.8 liters/minute and removed by vacuum so that there was a slight negative pressure (-1.5 cm H20) in the chamber as measured by a magnahelic gauge. Aerosol exposure times were between 5-20 minutes depending on how much powder was fed into the chamber.
Powders were fed by hand into a small Venturi nozzle which dispersed the powder particles to form a fine aerosol cloud.
The Venturi nozzle was operated at a pressure in excess of 15 psig, and the air flow was set at 7.2 E/min to 9.8 P/min.
The Venturi nozzle was fitted into the bottom of a clear Plexiglas dispersion chamber (750 ml) which passed the aerosol directly into a nose-only exposure chamber.
Rat Aerosol Chamber Calibration The concentration of the powder at the breathing zone was measured by taking multiple, timed filter samples at the breathing zone with In-Tox filter holders at a vacuum flow of 2 liters/min. The chamber was calibrated both with and without animals. Powder mass was determined gravimetrically.
The particle size of the powders at the breathing zone was measured with cascade impactor (In Tox Products) placed at a breathing hole and operated at a flow of 2 liters/min. Powder mass on each stage was determined gravimetrically.
r c f; [ C 2183577 WO 95/24183 pCT/US95l01563 Each powder test utilized 21-24 rats and the aerosol exposures lasted 5-20 minutes. Three rats were killed at 0 time and then at -7, 15, 30, 60, 90, 120, 180, and 240 minutes after the termination of the aerosol exposure. Animals were anesthetized, their abdomens opened, and a large blood sample was drawn from the ventral aorta. The animals were then killed by cervical dislocation.
Blood was allowed to clot at room temperature for 30 minutes and then centrifuged for 20 minutes at 3500 rpm in serum separator tubes. Serum was either analyzed immediately or frozen at -80 C until analysis. As soon as possible (0-7 min) after the termination of the aerosol dosing, 3 rats were killed, their blood drawn and their lungs lavaged with six 5 ml rinses of phosphate buffered saline (PBS). The amount of insulin in the final pooled lavage sample was used as the aerosol dose for the rat in calculations of bioavailability.
Primate Exposure system Young, wild-captured, male cynomolgus monkeys strain Macaca fascicularis (2-5 kg) (Charles River Primates, Inc.) were used for the primate aerosol studies (3-4 animals/group).
The animals were either subcutaneously injected with Humulin (Eli Lilly, Indianapolis, Indiana) or exposed to a powder aerosol of insulin. Each animal was placed in a head-only exposure unit to provide a fresh supply of the test atmosphere at an adequate flow rate (7 L/min) to provide minimum oxygen requirements of the animal. The animals were restrained in a chair-like apparatus which placed them in an upright sitting position. The hoods were clear allowing the animals complete visualization of their environment. An indwelling catheter was placed in the leg so that blood samples could be taken at any time. The monkeys were fully awake during the whole procedure and appeared to be calm. Primate blood was treated the same as rat (see above).
35. The primate aerosol exposure system included a breath monitor that allowed quantification of the amount of air inhaled by each monkey. This value, coupled with measurements of the concentration of insulin in the inspired air allowed the calculation of exactly how much insulin was inhaled by each animal.
Human Trials Insulin was administered to 24 normal human subjects subcutaneously as well as by inhalation of aerosolized dry insulin powders. Each subcutaneous injection consisted of 10.4U of Humulin R, 100 U/ml (Eli Lilly, Indianapolis, Indiana). The dry insulin powders were amorphous and prepared by spray drying as described above with 20% by weight mannitol excipient. Doses (5 mg) of the insulin dry powder were dispersed in a high-velocity air stream to produce a fine aerosol that was captured in a chamber. Each subject inhaled the aerosol powder by taking a slow, deep breath of each aerosol bolus or "puff." Powder was administered in three puffs (for a dosage of 31.9U). Serum insulin and glucose levels were determined over time, as described below.
Serum Assays Serum insulin levels in rats, primates, and humans were determined using Coat-A-Count radio immunoassay kits for human insulin (Diagnostic Products Corporation, Los Angeles, CA). Standard curves were run with every batch of samples.
The sensitivity of the assay was approximately 43 pg/ml. The within assay variability (%CV) is <5%. Glucose assays were performed by California Veterinary Diagnostics, Inc. in West Sacramento, CA using the Glucose/HK Reagent System Pack for the Boehringer Mannheim/Hitachi 747 Analyzer. The within assay variability (%CV) is <3%.
In the rate experiments, relative bioavailabilities of the aerosol were calculated by comparing the dose adjusted, immunoreactive insulin (IRI) area under the curve (AUC) of the concentration-time profile with that obtained from subcutaneous injection. In rats the total lavaged insulin mass was used as the aerosol dose. Some insulin is absorbed before the lungs can be lavaged so the dose estimated by this technique is probably a slight underestimate of the total * Trade-mark ..._...._._ ~...~...._........,M . .__... _ _........ _~_. __ .
.._~_..____..._-_ .,,., WO 95124183 PCT/'t7S95/01563 deposited dose. No corrections for this presumed loss were made.
In the monkey experiments, relative bioavailabilities were calculated similar to the rats above except that instead of using lavaged lung insulin as the aerosol dose, the total amount of insulin inhaled was used.
In the rats, only material deposited in the lungs, not insulin deposited in the nasal passages and throat, was included in the dose estimate. In the monkeys, all insulin that entered the animals was included in the dose estimate.
Results of Insulin Absorption in Rats All of the insulin powders used in the animal studies had particle sizes (mass median diameters) ranging between 1-3 )im and moisture contents <3%. The insulin purity of the powders as measured by rpHPLC was >97%. Representative chromatographs of the 20% insulin formulation are shown in Fig. SC. The powders yielded a clear solution upon reconstitution with pure water with an ultraviolet absorbance value <0.01 at 400 nm and a pH of 6.7 0.3. Representative ultraviolet (W) spectra for the 20% insulin formulation are shown in Fig. 9.
The following three insulin powder formulations were tested in rats as aerosols in the In-Tox 48 port, exposure chamber.
1. 87.9% insulin; 11.5% sodium citrate; 0.6%
citric acid. - --2. 20% insulin; 66% mannitol: 12.4% sodium citrate: 0.6% citric acid.
3. 20% insulin; 66t raffinose; 12.4% sodium citrate: 0.6% citric acid.
Table 1 lists the key measurements in the three different rat exposure studies including characterizations of the aerosol at the breathing zone and chamber operating conditions. A fraction of the powder fed into the venturi nozzle reached the breathing zones of the rats (30-67$) because of losses in the walls due to impaction and incomplete dispersion of the powder during powder feed. The particle size of the aerosol at the breathing zone, however, was ideal for pulmonary deposition (1.3-1.9 m) and was somewhat smaller than the original formulation particle size (2.0-2.8 m) due to selective loss of the larger particles in the animal exposure chamber.
Table 1. Rat Aerosol Exposure Measurements 88% 20% 20% insulin Insulin Insulin Raffinose Marnni tol Chamber Flow Rate 7.2 L/min 9.6 L/min 9.8 L/min Powder Mass Median 2.2 m 2.8 m 2.0 m Diameter (MMD) Powder Fed into Chamber 70 mgs 255 mgs 260 mgs Powder Feed Time 5 min 14 min 20 min Powder at Breathing 40 mgs 171 mgs 88 mgs Zone Insulin at Breathing 35 mgs 34 mgs 18 mgs Zone ~ Total Powder at 57% 67% 34%
Breathing Zone Mass Median Aerodynamic 1.1 mg/L 1.3 mg/L 0.45 mg/L
Diameter (MAD) Particle Size at 1.4 m 1.9 m 1.3 m Breathing Zone Insulin Recovered in 30.7f5.2 12.7 6.9 31.6 12.9 Lavage g g g Serum Insulin AUC 104 201 150 (ng min/ml) Table 2 shows the rat serum insulin and glucose results from the three aerosol and one SC study. Fig. 3A and 3B show the serum immunoreactive insulin (IRI) concentration-time profiles and the serum glucose concentration-time profiles for the three formulations administered by aerosol.
Table 3 presents the insulin tmax, and the glucose tmin from the different studies as well as the relative-bioavailability of the aerosol compared to SC injection.
Table 2. Serum Insulin and Glucose Results in Rats Formulation Route Time Serum Serum (min) Insulin Glucose (pg/ml l (mg/dl#1 S.D.) S.D.)n=3rats n=3rats/ /
timept timept 88% Insulin Aerosol 0 230 184 106 12 (Aerosol Aerosol 12 1020 312 114 10 exposure completed at Aerosol 21 165 768 81 10 minute 5) Av. Dose=31 Aerosol 36 876 764 66 7 pg/rat Aerosol 66 684 416 62 15 Aerosol 96 568 128 65 10 Aerosol 126 564 260 73 11 Aerosol 186 712 140 93 5 20% Insulin- Aerosol 0 476 56 165 18 Mannitol (Aerosol Aerosol 22 1476 428 117 15 exposure completed at Aerosol 35 2480 892 101 19 minute 14) Av. Dose=13 Aerosol 57 1204 64 64 13 g/rat Aerosol 87 1084 396 63 17 Aerosol 117 664 180 105 38 Aerosol 147 1228 416 108 22 Aerosol 207 676 100 119 33 20% Insulin- Aerosol 0 426 97 157 37 Raffinose (Aerosol Aerosol 27 2948 2816 139 46 exposure completed at Aerosol 42 1504 592 181 11 minute 20) 20a Formulation Route Time Serum Serum (min) Insulin Glucose (pg/ml l (mg/dl l S.D.) S.D.)n=3rats n=3rats/ /
timept timept Av. Dose=32 Aerosol 57 1272 496 124 45 pg/rat Aerosol 87 852 164 128 17 Aerosol 117 604 156 124 9 Aerosol 147 532 172 172 12 Aerosol 207 556 100 218 34 20% Insulin- Subcutan 0 360 140 107 5 Mannitol Dose=30 g Subcutan 15 14200 3160 53 2 Insulin/rat Subcutan 30 10160 720 24 5 Subcutan 60 11000 1080 28 6 Subcutan 90 2440 1160 25 7 Subcutan 120 3520 840 49 3 Subcutan 180 1280 800 40 17 Subcutan 240 400 260 77 34 Table 3 A Comparison of Aerosol and Subcutaneous (SC) Insulin in Animals Rat Rat Rat Aerosol Rat Monkey Monkey SC Aerosol 20% Insulin Aerosol SC Aerosol 88% Mannitol 20% 20% Insulin Insulin Insulin Mannitol Raff-inose Insulin Max* 15 16min 21 min 17 min 15 min 30 min min Glucose 30 31 min 43 min 37 min 45 min 45 min Min. * mm Glucose Drop 77% 42% 62% 21% 45% 73%
Rel Bioavail. 100% 10%** 44%** 14%** 100% 12%***
* T's measured from end of aerosol exposure period.
2 0 Glucose min = time to > 85% of maximal reduction observed in study ** Based on insulin recovered by lavage from lung at end of aerosol exposure *** Based on insulin inhaled, includes losses in nasal passages and throat All three formulations provided rapid absorbing insulin to the rats systemic circulation (Figs. 3A and 3B).
The bioavailability and glucose response were higher for the 20% insulin/mannitol powder (Table 3), although without performing many replicate experiments, it is uncertain if the difference was significant.
21a Primate Results A dose identical to what was used in the human trial (0.2 U/kg, -27 g/monkey) was injected into four monkeys to provide the SC data with which to compare the aerosol results (Figs. 4A and 4B). Table 4 shows the monkey aerosol exposure data. Table 5 shows the,mean serum insulins and glucoses for the aerosol exposure and the subcutaneous study. The aerosol dose yielded a robust insulin and glucose response (high dose). Fig. 4 shows a comparison of the mean serum insulin profiles from the two aerosol and one SC study. From the AUCs of these profiles the relative bioavailability of the aerosol insulin was calculated to be 12%.
Table 4. Monkey Aerosol Exposure Data Animal Grav. Avg Inhaled Est. Est. Body Est. AUC
ID filter Aerosol Volume Inhaled Inhaled Wt. Insulin (ng Mass Conc. (L) Aerosol Insulin (Kg) Dose min/
(mg) ( g/L) Mass Mass ( g/kg) ml) (pg) ( g) #1, 23- 1.07 178 8.96 1597 320 3.92 81.5 347 #2, 23- 1.01 168 19.98 3363 673 3.81 176.6 1196 #3, 122- 0.97 162 14.68 2373 475 4.1 115.7 739 20 Hnman Results The comparative results between respiratory delivery and subcutaneous injection are set forth in Table 5 below.
Respiratory aerosol delivery resulted in more rapid absorption (peak at 20 minutes) than injection (peak at 60 minutes) with 25 a more rapid glucose response (trough at 60 minutes) than with injection (trough at 90. minutes). Reproducibility was as good if not better with aerosol than with injection in both insulin and glucose response. Injection doses were carefully adjusted.
for weight, aerosol doses were not. Biological activity of aerosol insulin, based on glucose response, relative to injection was 28-36%. Bioavailability of aerosol insulin, based on area-under-the-insulin curve, relative to injection was 22.8% for the 3 puff group.
ID filter Aerosol Volume Inhaled Inhaled Wt. Insulin (ng Mass Conc. (L) Aerosol Insulin (Kg) Dose min/
(mg) ( g/L) Mass Mass ( g/kg) ml) (pg) ( g) #1, 23- 1.07 178 8.96 1597 320 3.92 81.5 347 #2, 23- 1.01 168 19.98 3363 673 3.81 176.6 1196 #3, 122- 0.97 162 14.68 2373 475 4.1 115.7 739 20 Hnman Results The comparative results between respiratory delivery and subcutaneous injection are set forth in Table 5 below.
Respiratory aerosol delivery resulted in more rapid absorption (peak at 20 minutes) than injection (peak at 60 minutes) with 25 a more rapid glucose response (trough at 60 minutes) than with injection (trough at 90. minutes). Reproducibility was as good if not better with aerosol than with injection in both insulin and glucose response. Injection doses were carefully adjusted.
for weight, aerosol doses were not. Biological activity of aerosol insulin, based on glucose response, relative to injection was 28-36%. Bioavailability of aerosol insulin, based on area-under-the-insulin curve, relative to injection was 22.8% for the 3 puff group.
Table 5 Serum Insulin and Glucose Results in Humans INSULIN
Subject #s Dose/ Dose in Increase Time of Relative Injection or Subject* in Serum Maximum Bioavailability Blister Insulin Based on U/m1 Insulin AUC
1-24 10.4U 10.4U 5.8-20.9 60 min 100.0%
(SC
Injection) 7-24(3 76.OU 31.9U 6.1-28.5 20 min 22.8%
puffs) GLUCOSE
Subject #s Drop in Mean mg/dl drop Time of %SC Relative Serum Minimum Bioactivity Glucose mg/dl Based on Glucose Drop 1-24 93.6-64.9 28.7 90 min 100% 100%
(SC
Injection) 7-24 (3 91.8-67.6 24.2 60 min 84.3% 27.4%
puffs) *Device Eff--42%
23a The results of the human trials are further presented in Figs. 5A-5B. Fig. 5A show-s mean serum insulin over time for subcutaneous injection (0), inhalation (3 puffs, =). Mean serum glucose levels are similarly presented in Fig.
5B. Insulin peaks and glucose troughs are shown in Figs. 6A
and 6B, respectively, while intersubject variability in serum insulin and glucose are presented in Figs. 7A and 7B, respectively.
In addition, the shallow inspirations (tidal breathing) of the monkeys during the aerosol exposures do not represent the optimal breathing maneuver for deep lung deposition. A higher bioavailability was observed in humans (Table 5), as expected, when the optimum breathing maneuver was used and the aerosol bolus was taken by oral inhalation rather than by nasal inhalation.
Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
Subject #s Dose/ Dose in Increase Time of Relative Injection or Subject* in Serum Maximum Bioavailability Blister Insulin Based on U/m1 Insulin AUC
1-24 10.4U 10.4U 5.8-20.9 60 min 100.0%
(SC
Injection) 7-24(3 76.OU 31.9U 6.1-28.5 20 min 22.8%
puffs) GLUCOSE
Subject #s Drop in Mean mg/dl drop Time of %SC Relative Serum Minimum Bioactivity Glucose mg/dl Based on Glucose Drop 1-24 93.6-64.9 28.7 90 min 100% 100%
(SC
Injection) 7-24 (3 91.8-67.6 24.2 60 min 84.3% 27.4%
puffs) *Device Eff--42%
23a The results of the human trials are further presented in Figs. 5A-5B. Fig. 5A show-s mean serum insulin over time for subcutaneous injection (0), inhalation (3 puffs, =). Mean serum glucose levels are similarly presented in Fig.
5B. Insulin peaks and glucose troughs are shown in Figs. 6A
and 6B, respectively, while intersubject variability in serum insulin and glucose are presented in Figs. 7A and 7B, respectively.
In addition, the shallow inspirations (tidal breathing) of the monkeys during the aerosol exposures do not represent the optimal breathing maneuver for deep lung deposition. A higher bioavailability was observed in humans (Table 5), as expected, when the optimum breathing maneuver was used and the aerosol bolus was taken by oral inhalation rather than by nasal inhalation.
Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
Claims (52)
1. A method for aerosolizing a dose of insulin, said method comprising:
providing insulin as a dry powder;
dispersing an amount of the dry powder in a gas stream to form an aerosol;
and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient.
providing insulin as a dry powder;
dispersing an amount of the dry powder in a gas stream to form an aerosol;
and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient.
2. A method as in claim 1, wherein the insulin is substantially free from penetration enhancers.
3. A method as in claim 1, wherein the insulin is present in a dry powder carrier at a weight concentration in the range from about 5% to 99%.
4. A method as in claim 3, wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide, or protein.
5. A method as in claim 1, wherein the insulin dry powder comprises particles having an average size below 10 µm.
6. A method as in claim 1, wherein the dry powder comprises individual particles including both insulin and a carrier material.
7. A method as in claim 6, wherein the insulin is present in the individual particles at from 5% to 99% by weight.
8. A method for preparing a stable, dry powder insulin composition, said method comprising:
dissolving insulin in an aqueous buffer to form a solution; and spray drying the solution to produce a composition comprising amorphous particles having an average size below 10 µm.
dissolving insulin in an aqueous buffer to form a solution; and spray drying the solution to produce a composition comprising amorphous particles having an average size below 10 µm.
9. A method as in claim 8, wherein the insulin is dissolved in a aqueous buffer together with a pharmaceutical carrier, wherein a dry powder having insulin present in individual particles at from 5% to 99% by weight is produced upon spray drying.
10. A method as in claim 9, wherein the pharmaceutical carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a powder upon spray drying.
11. A method as in claim 10, wherein the carbohydrate is selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose.
12. A method as in claim 10, wherein the organic salt is selected from the group consisting of sodium citrate, sodium acetate, and sodium ascorbate.
13. An insulin composition for pulmonary delivery, said composition comprising individual particles which include spray-dried amorphous powder insulin present at from 5% to 99% by weight in a pharmaceutical carrier material and have a size below µm.
14. An insulin composition as in claim 13, wherein the composition is substantially free from penetration enhancers.
15. An insulin composition as in claim 13, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin, and trehalose.
16. An insulin composition as in claim 13, wherein the pharmaceutical carrier material comprises an organic salt selected from the group consisting of sodium citrate, sodium gluconate, and sodium ascorbate.
17. An insulin composition produced by the method of any one of claims 8-12.
18. A method of aerosolizing a dose of insulin for pulmonary delivery, said method comprising:
providing insulin as a dry powder;
dispersing an amount of the dry powder in a gas stream to form an aerosol;
and capturing the aerosol in a chamber having a mouthpiece, wherein the moisture content of said dry powder is below about 5% by weight and wherein the insulin dry powder comprises particles having an average size below 10 µm.
providing insulin as a dry powder;
dispersing an amount of the dry powder in a gas stream to form an aerosol;
and capturing the aerosol in a chamber having a mouthpiece, wherein the moisture content of said dry powder is below about 5% by weight and wherein the insulin dry powder comprises particles having an average size below 10 µm.
19. The method as in claim 18, wherein the insulin is substantially free from penetration enhancers.
20. The method as in claim 18, wherein the insulin is present in a dry powder carrier at a weight concentration in the range from about 5% to 99% wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide or protein.
21. The method as in claim 18, wherein the dry powder comprises individual particles including both insulin and a carrier material wherein the insulin is present in the individual particles at from 5% to 99% by weight.
22. A method for preparing a stable, dry powder insulin composition for pulmonary delivery, said method comprising:
dissolving insulin in an aqueous buffer to form a solution; and spray drying the solution to produce substantially amorphous particles having an average size below 10 µm, wherein the moisture content of said dry powder insulin is below about 5% by weight.
dissolving insulin in an aqueous buffer to form a solution; and spray drying the solution to produce substantially amorphous particles having an average size below 10 µm, wherein the moisture content of said dry powder insulin is below about 5% by weight.
23. The method as in claim 22, wherein the insulin is dissolved in an aqueous buffer together with a pharmaceutical carrier, wherein a dry powder having insulin present in individual particles at from 5% to 99% by weight is produced upon spray drying and wherein the pharmaceutical carrier is a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose, organic salt selected from the group consisting of sodium citrate, sodium gluconate and sodium ascorbate, amino acid, peptide, or protein which produces a powder upon spray drying.
24. An insulin composition for pulmonary delivery, said composition comprising individual particles which include spray-dried amorphous powder insulin present at from 5% to 99% by weight in a pharmaceutical carrier material, said spray-dried amorphous powder insulin having an average particle size below 10 µm and wherein the moisture content of said spray-dried amorphous powder insulin is below about 5%
by weight.
by weight.
25. The insulin composition as in claim 24, wherein the composition is substantially free from penetration enhancers.
26. The insulin composition as in claim 24, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose, or an organic salt selected from the group consisting of sodium citrate, sodium gluconate and sodium ascorbate.
27. A use of the insulin composition defined in any one of claims 24-26 for pulmonary delivery.
28. A method of aerosolizing a dose of insulin for pulmonary delivery, said method comprising:
providing insulin as a dry powder;
dispersing an amount of the dry powder in a gas stream to form an aerosol;
and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient, wherein the moisture content of said dry powder is below about 5% by weight and wherein the insulin dry powder comprises particles having an average size below 10 µm.
providing insulin as a dry powder;
dispersing an amount of the dry powder in a gas stream to form an aerosol;
and capturing the aerosol in a chamber having a mouthpiece for subsequent inhalation by a patient, wherein the moisture content of said dry powder is below about 5% by weight and wherein the insulin dry powder comprises particles having an average size below 10 µm.
29. The method as in claim 28, wherein the insulin is substantially free from penetration enhancers.
30. The method as in claim 28, wherein the insulin is present in a dry powder carrier at a weight concentration in the range from about 5% to 99% wherein the powder carrier comprises a carbohydrate, organic salt, amino acid, peptide or protein.
31. The method as in claim 28, wherein the dry powder comprises individual particles including both insulin and a carrier material wherein the insulin is present in the individual particles at from 5% to 99% by weight.
32. A method for preparing a stable, dry powder insulin composition, said method comprising:
dissolving insulin in an aqueous buffer at a concentration in the range from 0.01% to 1% to form a solution; and spray drying the solution to produce substantially amorphous particles having an average size in the range from 0.1 µm to 5 µm.
dissolving insulin in an aqueous buffer at a concentration in the range from 0.01% to 1% to form a solution; and spray drying the solution to produce substantially amorphous particles having an average size in the range from 0.1 µm to 5 µm.
33. A method as in claim 32, wherein the insulin is dissolved in a aqueous buffer together with a pharmaceutical carrier, wherein a dry powder having insulin present in individual particles at from 5% to 99% by weight is produced upon spray drying.
34. A method as in claim 33, wherein the pharmaceutical carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a powder upon spray drying.
35. A method as in claim 34, wherein the pharmaceutical carrier is a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose.
36. A method as in claim 34, wherein the pharmaceutical carrier is an organic salt selected from the group consisting of sodium citrate, sodium acetate, and sodium ascorbate.
37. An insulin composition for pulmonary delivery, said composition comprising a dry powder of individual particles which include insulin present at from 20%
to 80% by weight in a pharmaceutical carrier material, wherein the particles have an average size in the range from 0.1 µm to 5 µm.
to 80% by weight in a pharmaceutical carrier material, wherein the particles have an average size in the range from 0.1 µm to 5 µm.
38. An insulin composition as in claim 37, wherein the composition is substantially free from penetration enhancers.
39. An insulin composition as in claim 37, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin, and trehalose.
40. An insulin composition as in claim 37, wherein the pharmaceutical carrier material comprises an organic salt selected from the group consisting of sodium citrate, sodium gluconate, and sodium ascorbate.
41. A method for preparing a stable, dry powder insulin composition, said method comprising: providing an aqueous solution of insulin and a pharmaceutical carrier dissolved in an aqueous buffer, wherein the insulin is present at 0.01 % to 1%
by weight and comprises from 20% to 80% of the total weight of insulin and pharmaceutical carrier in the solution; and spray drying the solution to produce amorphous particles comprising both the insulin and the pharmaceutical carrier having an average size in the range from 0.1 µm to 5 µm and a moisture content below 10%.
by weight and comprises from 20% to 80% of the total weight of insulin and pharmaceutical carrier in the solution; and spray drying the solution to produce amorphous particles comprising both the insulin and the pharmaceutical carrier having an average size in the range from 0.1 µm to 5 µm and a moisture content below 10%.
42. A method as in claim 41, wherein the pharmaceutical carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a powder upon spray drying.
43. A method as in claim 42, wherein the carbohydrate carrier is selected from the group consisting of mannitol, raffinose, lactose, malto dextrin and trehalose.
44. A method as in claim 42, wherein the carrier is an organic salt selected from the group consisting of sodium citrate, sodium acetate, and sodium ascorbate.
45. An insulin composition for pulmonary delivery, said composition comprising:
a dry powder of individual amorphous particles including both insulin and a pharmaceutical carrier, wherein the particles comprise from 20% to 80% insulin by weight, have an average particle size in the range from 0.1 µm to 5 µm, and have a moisture content below 10%.
a dry powder of individual amorphous particles including both insulin and a pharmaceutical carrier, wherein the particles comprise from 20% to 80% insulin by weight, have an average particle size in the range from 0.1 µm to 5 µm, and have a moisture content below 10%.
46. An insulin composition as in claim 45, wherein the particles consist essentially of the insulin and the pharmaceutical carrier.
47. An insulin composition as in claim 45, wherein the composition is substantially free from penetration enhancers.
48. An insulin composition as in claim 45, wherein the pharmaceutical carrier material comprises a carbohydrate selected from the group consisting of mannitol, raffinose, lactose, malto dextrin, and trehalose.
49. An insulin composition as in claim 45, wherein the pharmaceutical carrier material comprises an organic salt selected from the group consisting of sodium citrate, sodium gluconate, and sodium ascorbate.
50. An insulin composition prepared according to the method defined in claim or 23.
51. An insulin composition prepared according to the method defined in any one of claims 32-36.
52. An insulin composition prepared according to the method defined in any one of claims 41-44.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20747294A | 1994-03-07 | 1994-03-07 | |
US08/207,472 | 1994-03-07 | ||
US38347595A | 1995-02-01 | 1995-02-01 | |
US08/383,475 | 1995-02-01 | ||
PCT/US1995/001563 WO1995024183A1 (en) | 1994-03-07 | 1995-02-07 | Methods and compositions for pulmonary delivery of insulin |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2183577A1 CA2183577A1 (en) | 1995-09-14 |
CA2183577C true CA2183577C (en) | 2007-10-30 |
Family
ID=26902263
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002183577A Expired - Fee Related CA2183577C (en) | 1994-03-07 | 1995-02-07 | Methods and compositions for pulmonary delivery of insulin |
Country Status (23)
Country | Link |
---|---|
US (6) | US6685967B1 (en) |
EP (3) | EP0748213B1 (en) |
JP (2) | JPH10501519A (en) |
KR (1) | KR100419037B1 (en) |
CN (1) | CN1098679C (en) |
AT (2) | ATE264096T1 (en) |
AU (1) | AU689217B2 (en) |
BR (1) | BR9507023A (en) |
CA (1) | CA2183577C (en) |
CZ (1) | CZ295827B6 (en) |
DE (2) | DE69532884T2 (en) |
DK (1) | DK0748213T3 (en) |
ES (2) | ES2218543T3 (en) |
FI (1) | FI116195B (en) |
HU (1) | HUT75676A (en) |
IL (1) | IL112618A (en) |
MX (1) | MX9603936A (en) |
MY (1) | MY124282A (en) |
NO (1) | NO316661B1 (en) |
NZ (1) | NZ281112A (en) |
PL (1) | PL179443B1 (en) |
PT (1) | PT748213E (en) |
WO (1) | WO1995024183A1 (en) |
Families Citing this family (301)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US6673335B1 (en) * | 1992-07-08 | 2004-01-06 | Nektar Therapeutics | Compositions and methods for the pulmonary delivery of aerosolized medicaments |
DE69332105T2 (en) * | 1992-09-29 | 2003-03-06 | Inhale Therapeutic Systems San | PULMONAL DELIVERY OF ACTIVE FRAGMENT OF PARATHORMON |
US7448375B2 (en) * | 1993-01-29 | 2008-11-11 | Aradigm Corporation | Method of treating diabetes mellitus in a patient |
US6024090A (en) * | 1993-01-29 | 2000-02-15 | Aradigm Corporation | Method of treating a diabetic patient by aerosolized administration of insulin lispro |
US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US20010003739A1 (en) * | 1993-06-24 | 2001-06-14 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
US20030113273A1 (en) * | 1996-06-17 | 2003-06-19 | Patton John S. | Methods and compositions for pulmonary delivery of insulin |
US6051256A (en) * | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
MX9603936A (en) | 1994-03-07 | 1997-05-31 | Inhale Therapeutic Syst | Methods and compositions for pulmonary delivery of insulin. |
AU696387B2 (en) * | 1994-05-18 | 1998-09-10 | Inhale Therapeutic Systems, Inc. | Methods and compositions for the dry powder formulation of interferons |
US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
US6290991B1 (en) * | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US6586006B2 (en) | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
US5863563A (en) * | 1994-10-20 | 1999-01-26 | Alphagene Inc. | Treatment of pulmonary conditions associated with insufficient secretion of surfactant |
EP0806945B1 (en) * | 1994-12-22 | 2003-04-23 | AstraZeneca AB | Therapeutic preparation for inhalation containing parathyro d hormone, pth |
CN1088580C (en) | 1994-12-22 | 2002-08-07 | 阿斯特拉公司 | Aerosol drug formulations |
US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US6309671B1 (en) * | 1995-04-14 | 2001-10-30 | Inhale Therapeutic Systems | Stable glassy state powder formulations |
US6258341B1 (en) * | 1995-04-14 | 2001-07-10 | Inhale Therapeutic Systems, Inc. | Stable glassy state powder formulations |
US6428771B1 (en) | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
GB9515182D0 (en) † | 1995-07-24 | 1995-09-20 | Co Ordinated Drug Dev | Improvements in and relating to powders for use in dry powder inhalers |
DE19539574A1 (en) | 1995-10-25 | 1997-04-30 | Boehringer Mannheim Gmbh | Preparations and processes for stabilizing biological materials by means of drying processes without freezing |
WO1997026863A1 (en) | 1996-01-24 | 1997-07-31 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Process for the production of powdered pulmonary surfactant preparations |
CA2245708C (en) † | 1996-02-09 | 2008-01-22 | Bruce Joseph Roser | Solid formulations containing trehalose |
US6503480B1 (en) | 1997-05-23 | 2003-01-07 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US6254854B1 (en) | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
USRE37053E1 (en) | 1996-05-24 | 2001-02-13 | Massachusetts Institute Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US20020052310A1 (en) | 1997-09-15 | 2002-05-02 | Massachusetts Institute Of Technology The Penn State Research Foundation | Particles for inhalation having sustained release properties |
US5874064A (en) * | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5855913A (en) * | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
AUPO269996A0 (en) * | 1996-10-01 | 1996-10-24 | Walter And Eliza Hall Institute Of Medical Research, The | A method of prophylaxis and treatment |
JP2001507702A (en) * | 1996-12-31 | 2001-06-12 | インヘイル・セラピューティックス・システムズ・インコーポレテッド | Method for spray drying an aqueous suspension of a hydrophobic drug having a hydrophilic excipient and a composition made by the method |
US20030203036A1 (en) | 2000-03-17 | 2003-10-30 | Gordon Marc S. | Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients |
US6310038B1 (en) | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
JP3764174B2 (en) * | 1997-03-20 | 2006-04-05 | ノボ ノルディスク アクティーゼルスカブ | Zinc-free insulin crystals for use in pulmonary compositions |
US5898028A (en) * | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
US20030035778A1 (en) * | 1997-07-14 | 2003-02-20 | Robert Platz | Methods and compositions for the dry powder formulation of interferon |
DK0901786T3 (en) | 1997-08-11 | 2007-10-08 | Pfizer Prod Inc | Solid pharmaceutical dispersions with increased bioavailability |
US7052678B2 (en) | 1997-09-15 | 2006-05-30 | Massachusetts Institute Of Technology | Particles for inhalation having sustained release properties |
US6309623B1 (en) * | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
US20060165606A1 (en) * | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
ZA989744B (en) * | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
EP2311436A1 (en) | 1998-04-27 | 2011-04-20 | Altus Pharmaceuticals Inc. | Stabilized protein crystals, formulations containing them and methods of making them |
GB9814172D0 (en) * | 1998-06-30 | 1998-08-26 | Andaris Ltd | Formulation for inhalation |
US6451349B1 (en) | 1998-08-19 | 2002-09-17 | Quadrant Healthcare (Uk) Limited | Spray-drying process for the preparation of microparticles |
UA73924C2 (en) | 1998-10-09 | 2005-10-17 | Nektar Therapeutics | Device for delivering active agent formulation to lungs of human patient |
US20060171899A1 (en) * | 1998-12-10 | 2006-08-03 | Akwete Adjei | Water-stabilized aerosol formulation system and method of making |
US7087215B2 (en) * | 1998-12-21 | 2006-08-08 | Generex Pharmaceuticals Incorporated | Methods of administering and enhancing absorption of pharmaceutical agents |
WO2000047203A1 (en) * | 1999-02-12 | 2000-08-17 | Mqs, Inc. | Formulation and system for intra-oral delivery of pharmaceutical agents |
US6440463B1 (en) * | 1999-04-05 | 2002-08-27 | Pharmaceutical Discovery Corporation | Methods for fine powder formation |
US7001892B1 (en) | 1999-06-11 | 2006-02-21 | Purdue Research Foundation | Pharmaceutical materials and methods for their preparation and use |
US6858199B1 (en) | 2000-06-09 | 2005-02-22 | Advanced Inhalation Research, Inc. | High efficient delivery of a large therapeutic mass aerosol |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
AU779986B2 (en) | 1999-06-29 | 2005-02-24 | Mannkind Corporation | Purification and stabilization of peptide and protein pharmaceutical agents |
GB9916316D0 (en) * | 1999-07-12 | 1999-09-15 | Quadrant Holdings Cambridge | Dry powder compositions |
CA2374745A1 (en) * | 1999-08-09 | 2001-02-15 | Incyte Genomics, Inc. | Proteases and protease inhibitors |
US6586008B1 (en) * | 1999-08-25 | 2003-07-01 | Advanced Inhalation Research, Inc. | Use of simple amino acids to form porous particles during spray drying |
US7678364B2 (en) | 1999-08-25 | 2010-03-16 | Alkermes, Inc. | Particles for inhalation having sustained release properties |
US6749835B1 (en) * | 1999-08-25 | 2004-06-15 | Advanced Inhalation Research, Inc. | Formulation for spray-drying large porous particles |
US7252840B1 (en) | 1999-08-25 | 2007-08-07 | Advanced Inhalation Research, Inc. | Use of simple amino acids to form porous particles |
EP1210429A2 (en) * | 1999-09-10 | 2002-06-05 | Incyte Genomics, Inc. | Apoptosis proteins |
WO2001045731A1 (en) * | 1999-12-21 | 2001-06-28 | Rxkinetix, Inc. | Particulate drug-containing products and method of manufacture |
US6761909B1 (en) * | 1999-12-21 | 2004-07-13 | Rxkinetix, Inc. | Particulate insulin-containing products and method of manufacture |
FI20002217A (en) * | 1999-12-30 | 2001-07-01 | Orion Yhtymae Oyj | inhalation particles |
CN100333790C (en) * | 1999-12-30 | 2007-08-29 | 希龙公司 | Methods for pulmonary delivery of interleukin-2 |
ES2327606T3 (en) | 2000-01-10 | 2009-11-02 | Maxygen Holdings Ltd | CONJUGATES OF G-CSF. |
US6596261B1 (en) * | 2000-01-25 | 2003-07-22 | Aeropharm Technology Incorporated | Method of administering a medicinal aerosol formulation |
US6585957B1 (en) | 2000-01-25 | 2003-07-01 | Aeropharm Technology Incorporated | Medicinal aerosol formulation |
JP2003524646A (en) * | 2000-01-25 | 2003-08-19 | エアロファーム テクノロジー インコーポレイテッド | Pharmaceutical aerosol formulation |
US6540983B1 (en) * | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
US6540982B1 (en) * | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
EP1259611A2 (en) * | 2000-03-03 | 2002-11-27 | Incyte Genomics, Inc. | G-protein coupled receptors |
JP4711520B2 (en) * | 2000-03-21 | 2011-06-29 | 日本ケミカルリサーチ株式会社 | Bioactive peptide-containing powder |
US6447750B1 (en) * | 2000-05-01 | 2002-09-10 | Aeropharm Technology Incorporated | Medicinal aerosol formulation |
GB0010709D0 (en) * | 2000-05-03 | 2000-06-28 | Vectura Ltd | Powders for use a in dry powder inhaler |
AU6124601A (en) | 2000-05-10 | 2001-11-20 | Alliance Pharmaceutical Corporation | Phospholipid-based powders for drug delivery |
US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
US8404217B2 (en) * | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
GB0011807D0 (en) * | 2000-05-16 | 2000-07-05 | Quadrant Holdings Cambridge | Formulation for inhalation |
WO2001098323A2 (en) | 2000-06-16 | 2001-12-27 | Incyte Genomics, Inc. | G-protein coupled receptors |
US7575761B2 (en) * | 2000-06-30 | 2009-08-18 | Novartis Pharma Ag | Spray drying process control of drying kinetics |
US20020106368A1 (en) * | 2000-07-28 | 2002-08-08 | Adrian Bot | Novel methods and compositions to upregulate, redirect or limit immune responses to peptides, proteins and other bioactive compounds and vectors expressing the same |
AU2001277230A1 (en) * | 2000-08-01 | 2002-02-13 | Inhale Therapeutic Systems, Inc. | Apparatus and process to produce particles having a narrow size distribution andparticles made thereby |
US6613308B2 (en) | 2000-09-19 | 2003-09-02 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
US7608704B2 (en) | 2000-11-08 | 2009-10-27 | Incyte Corporation | Secreted proteins |
CN100400031C (en) * | 2000-11-29 | 2008-07-09 | 伊藤火腿株式会社 | Powdery preparations and proecss for producing the same |
EP1920763B2 (en) | 2000-11-30 | 2022-06-15 | Vectura Limited | Pharmaceutical compositions for inhalation |
EP2168571B1 (en) * | 2000-11-30 | 2018-08-22 | Vectura Limited | Particles for use in a Pharmaceutical Composition |
US20020106331A1 (en) * | 2000-12-08 | 2002-08-08 | Joan Rosell | Use of electrolytes (ions in solution) to suppress charging of inhalation aerosols |
US20020141946A1 (en) * | 2000-12-29 | 2002-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having rapid release properties |
EP1345629A2 (en) | 2000-12-29 | 2003-09-24 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
EP1797902A3 (en) * | 2000-12-29 | 2007-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
YU48703A (en) | 2001-02-27 | 2006-05-25 | Maxygen Aps | New interferon beta-like molecules |
US7905230B2 (en) | 2001-05-09 | 2011-03-15 | Novartis Ag | Metered dose inhaler with lockout |
US9994853B2 (en) | 2001-05-18 | 2018-06-12 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US6828297B2 (en) * | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US7540284B2 (en) | 2001-06-20 | 2009-06-02 | Novartis Pharma Ag | Powder aerosolization apparatus and method |
EP1270012A1 (en) * | 2001-06-21 | 2003-01-02 | Pfizer Products Inc. | Use of pulmonary administration of insulin for treatment of diabetes |
GB0208742D0 (en) | 2002-04-17 | 2002-05-29 | Bradford Particle Design Ltd | Particulate materials |
DE60217367T2 (en) * | 2001-09-19 | 2007-10-18 | Elan Pharma International Ltd. | NANOPARTICLE COMPOSITIONS CONTAINING INSULIN |
JP4795637B2 (en) | 2001-09-28 | 2011-10-19 | カーブ テクノロジー,インコーポレイティド | Nose nebulizer |
EP1446104B2 (en) * | 2001-11-01 | 2011-08-03 | Novartis AG | Spray drying methods |
AU2002366267B2 (en) | 2001-11-19 | 2007-05-10 | Becton, Dickinson And Company | Pharmaceutical compositions in particulate form |
PT1455755E (en) | 2001-11-20 | 2013-06-18 | Civitas Therapeutics Inc | Improved particulate compositions for pulmonary delivery |
CA2466525C (en) * | 2001-12-07 | 2011-05-17 | Eiffel Technologies Limited | Synthesis of small particles |
JP2005514393A (en) | 2001-12-19 | 2005-05-19 | ネクター セラピューティクス | Supplying aminoglycosides to the lung |
US8777011B2 (en) | 2001-12-21 | 2014-07-15 | Novartis Ag | Capsule package with moisture barrier |
US9657294B2 (en) | 2002-02-20 | 2017-05-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
AU2003222225A1 (en) * | 2002-02-20 | 2003-09-09 | Incyte Corporation | Receptors and membrane-associated proteins |
US9181551B2 (en) | 2002-02-20 | 2015-11-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
WO2003079992A2 (en) | 2002-03-20 | 2003-10-02 | Advanced Inhalation Research, Inc. | Pulmonary delivery for levodopa |
ES2300568T3 (en) | 2002-03-20 | 2008-06-16 | Mannkind Corporation | INHALATION APPARATUS |
US7754242B2 (en) * | 2002-03-20 | 2010-07-13 | Alkermes, Inc. | Inhalable sustained therapeutic formulations |
US7008644B2 (en) * | 2002-03-20 | 2006-03-07 | Advanced Inhalation Research, Inc. | Method and apparatus for producing dry particles |
US20050163725A1 (en) * | 2002-03-20 | 2005-07-28 | Blizzard Charles D. | Method for administration of growth hormone via pulmonary delivery |
ES2718455T3 (en) | 2002-03-20 | 2019-07-02 | Civitas Therapeutics Inc | Inhaled sustained therapeutic formulations |
JP2005521695A (en) * | 2002-03-20 | 2005-07-21 | アドバンスト インハレーション リサーチ,インコーポレイテッド | Method of administering growth hormone by pulmonary delivery |
JP2005533013A (en) | 2002-04-19 | 2005-11-04 | イスム リサーチ ディベロップメント カンパニー オブ ザ ヘブライ ユニバーシティ オブ エルサレム | Beta agonist compounds containing a nitric oxide donor group and a reactive oxygen species scavenging group, and use of the compounds in the treatment of respiratory disorders |
US8501232B2 (en) * | 2002-04-23 | 2013-08-06 | Nanotherapeutics, Inc. | Process of forming and modifying particles and compositions produced thereby |
GB0216562D0 (en) | 2002-04-25 | 2002-08-28 | Bradford Particle Design Ltd | Particulate materials |
US9339459B2 (en) | 2003-04-24 | 2016-05-17 | Nektar Therapeutics | Particulate materials |
US8122881B2 (en) * | 2002-05-09 | 2012-02-28 | Kurve Technology, Inc. | Particle dispersion device for nasal delivery |
US6941980B2 (en) | 2002-06-27 | 2005-09-13 | Nektar Therapeutics | Apparatus and method for filling a receptacle with powder |
SI1531794T1 (en) | 2002-06-28 | 2017-12-29 | Civitas Therapeteutics, Inc. | Inhalable epinephrine |
AU2003265431A1 (en) * | 2002-08-13 | 2004-02-25 | Incyte Corporation | Cell adhesion and extracellular matrix proteins |
US20070219353A1 (en) * | 2002-09-03 | 2007-09-20 | Incyte Corporation | Immune Response Associated Proteins |
AU2003279829A1 (en) * | 2002-10-04 | 2004-05-04 | Incyte Corp | Protein modification and maintenance molecules |
US20050164275A1 (en) * | 2002-10-18 | 2005-07-28 | Incyte Corporation | Phosphodiesterases |
US20070009886A1 (en) * | 2002-11-12 | 2007-01-11 | Incyte Corporation | Carbohydrate-associated proteins |
WO2004044165A2 (en) * | 2002-11-13 | 2004-05-27 | Incyte Corporation | Lipid-associated proteins |
WO2004048550A2 (en) * | 2002-11-26 | 2004-06-10 | Incyte Corporation | Immune response associated proteins |
US20040105818A1 (en) | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
US7516741B2 (en) | 2002-12-06 | 2009-04-14 | Novartis Ag | Aerosolization apparatus with feedback mechanism |
WO2004054606A1 (en) * | 2002-12-13 | 2004-07-01 | Pfizer Products Inc. | Method of decreasing hepatic glucose output in diabetic patients |
US20050236296A1 (en) * | 2002-12-30 | 2005-10-27 | Nektar Therapeutics (Formerly Inhale Therapeutic Systems, Inc.) | Carry case for aerosolization apparatus |
MXPA05007154A (en) | 2002-12-30 | 2005-09-21 | Nektar Therapeutics | Prefilming atomizer. |
US7669596B2 (en) | 2002-12-31 | 2010-03-02 | Novartis Pharma Ag | Aerosolization apparatus with rotating capsule |
CA2520265C (en) | 2003-04-09 | 2015-02-17 | Nektar Therapeutics | Aerosolization apparatus with capsule puncture alignment guide |
US8869794B1 (en) | 2003-04-09 | 2014-10-28 | Novartis Pharma Ag | Aerosolization apparatus with capsule puncturing member |
PL1610850T3 (en) | 2003-04-09 | 2012-11-30 | Novartis Ag | Aerosolization apparatus with air inlet shield |
WO2004098539A2 (en) | 2003-04-30 | 2004-11-18 | Incyte Corporation | Kinases and phosphatases |
US7683029B2 (en) * | 2003-05-07 | 2010-03-23 | Philip Morris Usa Inc. | Liquid aerosol formulations containing insulin and aerosol generating devices and methods for generating aerosolized insulin |
AU2004240629B2 (en) * | 2003-05-16 | 2010-02-25 | Arriva Pharmaceuticals, Inc. | Treatment of respiratory disease by inhalation of synthetic matrix metalloprotease inhibitors |
US7338171B2 (en) * | 2003-10-27 | 2008-03-04 | Jen-Chuen Hsieh | Method and apparatus for visual drive control |
JP2007517892A (en) * | 2004-01-12 | 2007-07-05 | マンカインド コーポレイション | Methods for reducing serum proinsulin levels in type 2 diabetes |
WO2005077338A1 (en) * | 2004-02-10 | 2005-08-25 | Advanced Inhalation Research, Inc. | Particles for inhalation rapid release properties |
US7279457B2 (en) * | 2004-03-12 | 2007-10-09 | Biodel, Inc. | Rapid acting drug delivery compositions |
US20080090753A1 (en) * | 2004-03-12 | 2008-04-17 | Biodel, Inc. | Rapid Acting Injectable Insulin Compositions |
WO2005092301A1 (en) | 2004-03-26 | 2005-10-06 | Universita' Degli Studi Di Parma | Insulin highly respirable microparticles |
US20060039985A1 (en) * | 2004-04-27 | 2006-02-23 | Bennett David B | Methotrexate compositions |
WO2005110379A2 (en) * | 2004-05-07 | 2005-11-24 | President And Fellows Of Harvard College | Pulmonary malarial vaccine |
US10508277B2 (en) | 2004-05-24 | 2019-12-17 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US7481219B2 (en) * | 2004-06-18 | 2009-01-27 | Mergenet Medical, Inc. | Medicine delivery interface system |
WO2006002140A2 (en) | 2004-06-21 | 2006-01-05 | Nektar Therapeutics | Compositions comprising amphotericin b |
US8513204B2 (en) | 2004-06-21 | 2013-08-20 | Novartis Ag | Compositions comprising amphotericin B, mehods and systems |
CA2910494C (en) | 2004-07-19 | 2018-10-23 | Biocon Limited | Insulin-oligomer conjugates, formulations and uses thereof |
MX2007001903A (en) | 2004-08-20 | 2007-08-02 | Mannkind Corp | Catalysis of diketopiperazine synthesis. |
KR101306384B1 (en) | 2004-08-23 | 2013-09-09 | 맨카인드 코포레이션 | Diketopiperazine salts, diketomorpholine salts or diketodioxane salts for drug delivery |
US7115561B2 (en) * | 2004-09-22 | 2006-10-03 | Patterson James A | Medicament composition and method of administration |
SE0402345L (en) * | 2004-09-24 | 2006-03-25 | Mederio Ag | Measured drug dose |
BRPI0517374A (en) * | 2004-10-29 | 2008-10-07 | Harvard College | formulation for treatment or prevention of respiratory infection, method for treatment |
US20060115468A1 (en) * | 2004-11-26 | 2006-06-01 | Kara Morrison | Dietary supplement for treating and preventing gastrointestinal disorders |
KR100770362B1 (en) * | 2004-12-30 | 2007-10-26 | (주)두비엘 | Spray-dried Multimeric Collectin Family Protein and Process for Preparing the Same |
WO2006076277A1 (en) * | 2005-01-10 | 2006-07-20 | Nektar Therapeutics | Compositions and methods for increasing the bioavailability of pulmonarily administered insulin |
CN100431634C (en) * | 2005-04-04 | 2008-11-12 | 陈庆堂 | Dry powder aerosolizing inhalator |
UA95446C2 (en) | 2005-05-04 | 2011-08-10 | Іллюміджен Байосайєнсіз, Інк. | Mutations in oas1 genes |
EP1893273B1 (en) | 2005-05-18 | 2014-06-25 | Nektar Therapeutics | Adapter for use with aerosolization device for endobronchial therapy |
US20070031342A1 (en) * | 2005-06-22 | 2007-02-08 | Nektar Therapeutics | Sustained release microparticles for pulmonary delivery |
US8074906B2 (en) * | 2005-07-07 | 2011-12-13 | Nanotherapeutics, Inc. | Process for milling and preparing powders and compositions produced thereby |
JP5465878B2 (en) | 2005-09-14 | 2014-04-09 | マンカインド コーポレイション | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US20070086952A1 (en) * | 2005-09-29 | 2007-04-19 | Biodel, Inc. | Rapid Acting and Prolonged Acting Inhalable Insulin Preparations |
US7713929B2 (en) | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US8084420B2 (en) | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US20070123449A1 (en) * | 2005-11-01 | 2007-05-31 | Advanced Inhalation Research, Inc. | High load particles for inhalation having rapid release properties |
GB0524194D0 (en) * | 2005-11-28 | 2006-01-04 | Univ Aston | Respirable powders |
TWI299993B (en) * | 2005-12-15 | 2008-08-21 | Dev Center Biotechnology | Aqueous inhalation pharmaceutical composition |
US9012605B2 (en) | 2006-01-23 | 2015-04-21 | Amgen Inc. | Crystalline polypeptides |
CN104383546B (en) | 2006-02-22 | 2021-03-02 | 曼金德公司 | Method for improving the pharmaceutical properties of microparticles comprising diketopiperazines and an active agent |
CA2642229C (en) | 2006-02-24 | 2015-05-12 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
WO2007121256A2 (en) | 2006-04-12 | 2007-10-25 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
US20080170996A1 (en) * | 2006-07-28 | 2008-07-17 | The Board Of Regents Of The University Of Texas System | Compositions and Methods for Stimulation of Lung Innate Immunity |
CN101573133B (en) | 2006-07-31 | 2014-08-27 | 诺沃-诺迪斯克有限公司 | PEGylated, extended insulins |
GB0616299D0 (en) * | 2006-08-16 | 2006-09-27 | Cambridge Consultants | Drug Capsules for dry power inhalers |
US20080063722A1 (en) * | 2006-09-08 | 2008-03-13 | Advanced Inhalation Research, Inc. | Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI) |
EP2074141B1 (en) | 2006-09-22 | 2016-08-10 | Novo Nordisk A/S | Protease resistant insulin analogues |
KR20090129998A (en) | 2007-02-11 | 2009-12-17 | 맵 파마슈티컬스, 인코포레이티드 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
WO2008124522A2 (en) * | 2007-04-04 | 2008-10-16 | Biodel, Inc. | Amylin formulations |
EP2152245B1 (en) | 2007-04-30 | 2015-12-02 | Novo Nordisk A/S | Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein |
WO2008137747A1 (en) | 2007-05-02 | 2008-11-13 | The Regents Of The University Of Michigan | Nanoemulsion therapeutic compositions and methods of using the same |
MX2010003979A (en) * | 2007-10-16 | 2010-06-02 | Biocon Ltd | An orally administerable solid pharmaceutical composition and a process thereof. |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
JP5350388B2 (en) * | 2007-10-25 | 2013-11-27 | ノバルティス アーゲー | Powder preparation of unit dose drug package |
EP2060268A1 (en) * | 2007-11-15 | 2009-05-20 | Novo Nordisk A/S | Pharmaceutical compositions for pulmonary or nasal delivery of peptides |
AU2009204309B2 (en) * | 2008-01-04 | 2012-11-22 | Biodel, Inc. | Insulin formulations for insulin release as a function of tissue glucose levels |
US9260502B2 (en) | 2008-03-14 | 2016-02-16 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
EP2910571B1 (en) | 2008-03-18 | 2016-10-05 | Novo Nordisk A/S | Protease stabilized, acylated insulin analogues |
CN104689432B (en) | 2008-06-13 | 2018-07-06 | 曼金德公司 | Diskus and the system for drug conveying |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
JP5479465B2 (en) | 2008-06-20 | 2014-04-23 | マンカインド コーポレイション | Interactive device and method for profiling inhalation efforts in real time |
TWI494123B (en) | 2008-08-11 | 2015-08-01 | Mannkind Corp | Use of ultrarapid acting insulin |
US20110105383A1 (en) * | 2008-09-10 | 2011-05-05 | Magnus Hook | Methods and compositions for stimulation of mammalian innate immune resistance to pathogens |
EP2350118B1 (en) | 2008-09-19 | 2016-03-30 | Nektar Therapeutics | Carbohydrate-based drug delivery polymers and conjugates thereof |
WO2010036945A2 (en) * | 2008-09-26 | 2010-04-01 | The Regents Of The University Of Michigan | Nanoemulsion therapeutic compositions and methods of using the same |
ES2650621T3 (en) | 2008-10-17 | 2018-01-19 | Sanofi-Aventis Deutschland Gmbh | Combination of an insulin and a GLP-1 agonist |
EP2894165B1 (en) | 2008-11-10 | 2023-01-04 | Alexion Pharmaceuticals, Inc. | Methods and compositions for treating complement-associated disorders |
WO2010057197A1 (en) | 2008-11-17 | 2010-05-20 | The Regents Of The University Of Michigan | Cancer vaccine compositions and methods of using the same |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
EP2388040A4 (en) | 2009-01-19 | 2013-12-25 | Mitsubishi Gas Chemical Co | Method for injecting drug into living body by electrospraying and device therefor |
JP5341532B2 (en) | 2009-01-19 | 2013-11-13 | 第一電子工業株式会社 | A pair of erroneous mating prevention keys and an electrical connector using the keys |
JP5802136B2 (en) | 2009-01-23 | 2015-10-28 | ライジェル ファーマシューティカルズ, インコーポレイテッド | Compositions and methods for inhibition of the JAK pathway |
CA2750711C (en) | 2009-01-26 | 2015-07-07 | Teva Pharmaceutical Industries Ltd. | Processes for coating a carrier with microparticles |
US9060927B2 (en) | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
CA2791847C (en) | 2009-03-04 | 2017-05-02 | Mannkind Corporation | An improved dry powder drug delivery system |
WO2010102065A1 (en) | 2009-03-05 | 2010-09-10 | Bend Research, Inc. | Pharmaceutical compositions of dextran polymer derivatives |
PL2405963T3 (en) | 2009-03-11 | 2014-04-30 | Mannkind Corp | Apparatus, system and method for measuring resistance of an inhaler |
DK2413902T3 (en) | 2009-03-18 | 2019-10-07 | Incarda Therapeutics Inc | Unit doses, aerosols, kits and methods for treating cardiac conditions by pulmonary administration |
CA3033133C (en) | 2009-03-25 | 2021-11-09 | The Board Of Regents Of The University Of Texas System | Compositions for stimulation of mammalian innate immune resistance to pathogens |
WO2010111132A2 (en) | 2009-03-27 | 2010-09-30 | Bend Research, Inc. | Spray-drying process |
US20120269882A1 (en) * | 2009-05-19 | 2012-10-25 | MOUNT SINAI SCHOOL OF MEDICINE Office of Technology & Business Development | Brain Delivery of Insulin to Treat Systemic Inflammation |
JP5908397B2 (en) | 2009-06-09 | 2016-04-26 | デフィルス、インコーポレイテッドDefyrus, Inc. | Interferon administration to prevent or treat pathogen infection |
EP2440184B1 (en) | 2009-06-12 | 2023-04-05 | MannKind Corporation | Diketopiperazine microparticles with defined specific surface areas |
CN102597005A (en) | 2009-06-23 | 2012-07-18 | 阿雷克森制药公司 | Bispecific antibodies that bind to complement proteins |
GB0918450D0 (en) | 2009-10-21 | 2009-12-09 | Innovata Ltd | Composition |
WO2011056889A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
PE20121362A1 (en) | 2009-11-13 | 2012-10-17 | Sanofi Aventis Deutschland | PHARMACEUTICAL COMPOSITION INCLUDING DESPRO36EXENDIN-4 (1-39) -LYS6-NH2, INSULIN GLY (A21) -ARG (B31) -ARG (B32) AND METHIONINE |
TWI468171B (en) | 2009-11-13 | 2015-01-11 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a glp-1 agonist and methionine |
US10842951B2 (en) | 2010-01-12 | 2020-11-24 | Aerami Therapeutics, Inc. | Liquid insulin formulations and methods relating thereto |
US8950394B2 (en) | 2010-01-12 | 2015-02-10 | Dance Biopharm Inc. | Preservative-free single dose inhaler systems |
CA2788078A1 (en) | 2010-01-26 | 2011-08-04 | Yissum Research Development Company Of The Hebrew University Of Jerusale M Ltd. | Compositions and methods for prevention and treatment of pulmonary hypertension |
NZ629829A (en) | 2010-04-30 | 2015-11-27 | Alexion Pharma Inc | Anti-c5a antibodies and methods for using the antibodies |
AU2011202239C1 (en) | 2010-05-19 | 2017-03-16 | Sanofi | Long-acting formulations of insulins |
US20130059916A1 (en) | 2010-05-26 | 2013-03-07 | Stephane Rocchi | Biguanide compounds and its use for treating cancer |
RU2571331C1 (en) | 2010-06-21 | 2015-12-20 | Маннкайнд Корпорейшн | Systems and methods for dry powder drug delivery |
RU2546520C2 (en) | 2010-08-30 | 2015-04-10 | Санофи-Авентис Дойчланд Гмбх | Application of ave0010 for production of medication for treatment of type 2 diabetes mellitus |
US8815294B2 (en) | 2010-09-03 | 2014-08-26 | Bend Research, Inc. | Pharmaceutical compositions of dextran polymer derivatives and a carrier material |
US9084944B2 (en) | 2010-09-03 | 2015-07-21 | Bend Research, Inc. | Spray-drying apparatus and methods of using the same |
PT2611529T (en) | 2010-09-03 | 2019-05-09 | Bend Res Inc | Spray-drying method |
WO2012040502A1 (en) | 2010-09-24 | 2012-03-29 | Bend Research, Inc. | High-temperature spray drying process and apparatus |
WO2012058210A1 (en) | 2010-10-29 | 2012-05-03 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA) |
DK2694402T3 (en) | 2011-04-01 | 2017-07-03 | Mannkind Corp | BLISTER PACKAGE FOR PHARMACEUTICAL CYLINDER AMPULS |
US9084727B2 (en) | 2011-05-10 | 2015-07-21 | Bend Research, Inc. | Methods and compositions for maintaining active agents in intra-articular spaces |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
CA2754237A1 (en) | 2011-05-27 | 2012-11-27 | The Regents Of The University Of California | Cyanoquinoline compounds having activity in correcting mutant-cftr processing and increasing ion transport and uses thereof |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
CN103917241A (en) | 2011-08-29 | 2014-07-09 | 赛诺菲-安万特德国有限公司 | Pharmaceutical combination for use in glycemic control in diabetes type 2 patients |
TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
AU2012328885B2 (en) | 2011-10-24 | 2017-08-31 | Mannkind Corporation | Methods and compositions for treating pain |
AU2012351947B2 (en) | 2011-12-16 | 2017-08-17 | Novartis Ag | Aerosolization apparatus for inhalation profile-independent drug delivery |
AU2012337241B2 (en) | 2011-12-30 | 2016-10-13 | Grifols, S.A. | Alpha1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations |
US9770192B2 (en) | 2012-03-19 | 2017-09-26 | Richard C. Fuisz | Method and system to amplify and measure breath analytes |
WO2013142038A2 (en) | 2012-03-23 | 2013-09-26 | Oxigene, Inc. | Compositions and methods for inhibition of cathepsins |
CN104364260B (en) | 2012-04-11 | 2017-02-22 | 诺和诺德股份有限公司 | insulin formulations |
AU2013289957B2 (en) * | 2012-07-12 | 2017-02-23 | Mannkind Corporation | Dry powder drug delivery systems and methods |
WO2014066856A1 (en) | 2012-10-26 | 2014-05-01 | Mannkind Corporation | Inhalable influenza vaccine compositions and methods |
US20140179597A1 (en) * | 2012-11-16 | 2014-06-26 | Steven Lehrer | Method for the treatment and prevention of Alzheimer's disease and central nervous system dysfunction |
EP3587404B1 (en) | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
HUE042381T2 (en) | 2013-04-03 | 2019-06-28 | Sanofi Sa | Treatment of diabetes mellitus by long acting formulations of insulins |
BR112016000937A8 (en) | 2013-07-18 | 2021-06-22 | Mannkind Corp | dry powder pharmaceutical formulations, method for making a dry powder formulation and use of a dry powder pharmaceutical formulation |
US10850289B2 (en) * | 2013-07-22 | 2020-12-01 | Inhalation Sciences Sweden Ab | Apparatus and method for generating an aerosol |
JP2016530930A (en) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | Ventilation device and method |
JP6499184B2 (en) | 2013-10-07 | 2019-04-10 | ノヴォ ノルディスク アー/エス | Novel derivatives of insulin analogues |
NZ711451A (en) | 2014-03-07 | 2016-05-27 | Alexion Pharma Inc | Anti-c5 antibodies having improved pharmacokinetics |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
CA2954287C (en) | 2014-07-08 | 2020-12-22 | Amphastar Pharmaceuticals, Inc. | Methods of preparing inhalable micronized insulin for pulmonary delivery |
US10286065B2 (en) | 2014-09-19 | 2019-05-14 | Board Of Regents, The University Of Texas System | Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
EP3204039B1 (en) | 2014-10-10 | 2022-06-08 | The Regents Of The University Of Michigan | Nanoemulsion compositions for preventing, suppressing or eliminating allergic and inflammatory disease |
CA2962719A1 (en) | 2014-10-31 | 2016-05-06 | Bend Research Inc. | Process for forming active domains dispersed in a matrix |
RS64300B1 (en) | 2014-12-12 | 2023-07-31 | Sanofi Aventis Deutschland | Insulin glargine/lixisenatide fixed ratio formulation |
CA3011902C (en) | 2015-02-25 | 2023-08-15 | Dance Biopharm, Inc. | Liquid insulin formulations and methods relating thereto |
TWI748945B (en) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | Treatment type 2 diabetes mellitus patients |
TW201705975A (en) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | Treatment of type 2 diabetes mellitus patients |
US10322168B2 (en) | 2016-01-07 | 2019-06-18 | Amphastar Pharmaceuticals, Inc. | High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same |
MX2018009248A (en) | 2016-02-01 | 2019-01-21 | Incarda Therapeutics Inc | Combining electronic monitoring with inhaled pharmacological therapy to manage cardiac arrhythmias including atrial fibrillation. |
CA3043480A1 (en) | 2016-11-09 | 2018-05-17 | The Board Of Regents Of The University Of Texas System | Methods and compositions for adaptive immune modulation |
CN110267660A (en) | 2016-12-16 | 2019-09-20 | 德克萨斯大学系统董事会 | The inhibitor of domain protein containing Bu Luomo 4 (BRD4) |
TWI700092B (en) | 2016-12-16 | 2020-08-01 | 丹麥商諾佛.儂迪克股份有限公司 | Insulin containing pharmaceutical compositions |
CN110869018A (en) | 2017-05-10 | 2020-03-06 | 英凯达治疗公司 | Unit dose, aerosol, kit and method for treating a cardiac condition by pulmonary administration |
EP3638312B1 (en) * | 2017-06-12 | 2024-02-21 | Elgan Pharma Ltd. | Multiparticulate granulate comprising insulin |
US11365241B2 (en) | 2017-07-27 | 2022-06-21 | Alexion Pharmaceuticals, Inc. | High concentration anti-C5 antibody formulations |
US11802154B2 (en) | 2017-12-20 | 2023-10-31 | Alexion Pharmaceuticals, Inc. | Humanized anti-CD200 antibodies and uses thereof |
US10744087B2 (en) | 2018-03-22 | 2020-08-18 | Incarda Therapeutics, Inc. | Method to slow ventricular rate |
US11389433B2 (en) | 2018-06-18 | 2022-07-19 | Board Of Regents, The University Of Texas System | BRD4 inhibitor treatment of IgE-mediated diseases |
WO2020092845A1 (en) | 2018-11-01 | 2020-05-07 | Rigel Pharmaceuticals, Inc. | Method and composition embodiments for treating acute myeloid leukemia |
WO2020123336A1 (en) | 2018-12-13 | 2020-06-18 | Qrumpharma Inc. | Compositions of bedaquiline, combinations comprising them, processes for their preparation, uses and methods of treatment comprising them |
EP3976050A1 (en) | 2019-05-24 | 2022-04-06 | Stichting Radboud universitair medisch centrum | Improved administration of glycylcyclines by inhalation |
WO2020243612A1 (en) | 2019-05-29 | 2020-12-03 | Rigel Pharmaceuticals, Inc. | Method of preventing and treating thrombosis |
US11020384B2 (en) | 2019-08-01 | 2021-06-01 | Incarda Therapeutics, Inc. | Antiarrhythmic formulation |
CN114698370A (en) | 2019-08-08 | 2022-07-01 | 里格尔药品股份有限公司 | Compounds and methods for treating cytokine release syndrome |
CA3147444A1 (en) | 2019-08-14 | 2021-02-18 | Rigel Pharmaceuticals, Inc. | Method of blocking or ameliorating cytokine release syndrome |
TW202228792A (en) | 2020-10-09 | 2022-08-01 | 殷漢生技股份有限公司 | Nanocarrier formulations for inhalation |
CN114712336B (en) * | 2020-12-22 | 2023-11-07 | 黄嘉若 | Aqueous aerosol for pulmonary administration, preparation method and application |
EP4304582A1 (en) | 2021-03-12 | 2024-01-17 | Alvarius Pharmaceuticals Ltd. | Compositions and methods for treating addictions comprising 5-meo-dmt |
AU2022257375A1 (en) * | 2021-04-11 | 2023-11-23 | Elgan Pharma Ltd | Insulin formulations and methods of using same in preterm infants |
WO2023183377A1 (en) | 2022-03-23 | 2023-09-28 | Rigel Pharmaceuticals, Inc. | Pyrimid-2-yl-pyrazole compounds as irak inhibitors |
Family Cites Families (252)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US558085A (en) * | 1896-04-14 | And william c | ||
US979993A (en) | 1910-03-24 | 1910-12-27 | Joseph Francis O'byrne | Projectile. |
US1855591A (en) | 1926-02-03 | 1932-04-26 | Wallerstein Co Inc | Invertase preparation and method of making the same |
US2598525A (en) | 1950-04-08 | 1952-05-27 | E & J Mfg Co | Automatic positive pressure breathing machine |
DE1812574U (en) | 1960-04-05 | 1960-06-02 | Felix Duerst | CONCRETE MIXER. |
NL250281A (en) | 1960-04-07 | |||
US3300474A (en) | 1964-02-12 | 1967-01-24 | Pharmacia Ab | Sucrose ether copolymerizates |
US3362405A (en) | 1964-04-06 | 1968-01-09 | Hamilton O. Hazel | Method and apparatus for admixing gas with solid particles |
BR6570825D0 (en) | 1964-07-04 | 1973-08-16 | Shiryo Kogyo Co Inc Nippon | PROCESS TO PRODUCE CRYSTALLIZED GRANULES FROM SUGAR AND OTHER CRYSTALLOID SOLUTIONS |
US3314803A (en) | 1966-01-26 | 1967-04-18 | Gen Foods Corp | Mannitol fixed flavor and method of making same |
US3674901A (en) | 1966-07-26 | 1972-07-04 | Nat Patent Dev Corp | Surgical sutures |
US3425600A (en) | 1966-08-11 | 1969-02-04 | Abplanalp Robert H | Pressurized powder dispensing device |
US3554768A (en) | 1967-08-01 | 1971-01-12 | Gen Foods Corp | Carbohydrate fixed acetaldehyde |
US3620776A (en) | 1968-06-28 | 1971-11-16 | Nestle Sa | Spray drying process |
US3619294A (en) | 1968-07-15 | 1971-11-09 | Penick & Ford Ltd | Method of combining crystalline sugar with impregnating agents and products produced thereby |
US3555717A (en) | 1968-10-24 | 1971-01-19 | Victor Comptometer Corp | Artificial fishing lure |
DE1812574A1 (en) | 1968-12-04 | 1970-06-11 | Riedel De Haen Ag | Process for the production of biocidal granules |
US3632357A (en) | 1969-07-29 | 1972-01-04 | Standard Brands Inc | Method of producing hard candy |
US3655442A (en) | 1969-08-27 | 1972-04-11 | California & Hawaiian Sugar | Method of making sugar and sugar products |
US3666496A (en) | 1969-09-03 | 1972-05-30 | Firmenich Inc | Water soluble,powdered,terpene-containing flavors |
US3937668A (en) * | 1970-07-15 | 1976-02-10 | Ilse Zolle | Method for incorporating substances into protein microspheres |
US3764716A (en) | 1970-11-16 | 1973-10-09 | American Potato Co | Preparation of dehydrated mashed potatoes |
US3745682A (en) | 1971-09-28 | 1973-07-17 | Pneu Dart Inc | Gun for propelling a drug or medicine projectile |
US4069819A (en) | 1973-04-13 | 1978-01-24 | Societa Farmaceutici S.P.A. | Inhalation device |
US3971852A (en) | 1973-06-12 | 1976-07-27 | Polak's Frutal Works, Inc. | Process of encapsulating an oil and product produced thereby |
GB1479283A (en) | 1973-07-23 | 1977-07-13 | Bespak Industries Ltd | Inhaler for powdered medicament |
FR2257351A1 (en) | 1974-01-11 | 1975-08-08 | Obert Jean Claude | Aerosol device for solid vaccines - feed and breaker screws deliver material sideways into blower chamber |
IT1016489B (en) | 1974-03-18 | 1977-05-30 | Isf Spa | INHALER |
DE2415159A1 (en) | 1974-03-29 | 1975-10-09 | Hoechst Ag | SPRAY PRODUCTS CONTAINING ALKALINE CANSULFONATE AND METHOD FOR THEIR MANUFACTURING |
US3948263A (en) | 1974-08-14 | 1976-04-06 | Minnesota Mining And Manufacturing Company | Ballistic animal implant |
JPS5134879A (en) | 1974-09-19 | 1976-03-24 | Eisai Co Ltd | Bishochukuryushinoseizoho |
US4005711A (en) | 1975-01-13 | 1977-02-01 | Syntex Puerto Rico, Inc. | Inhalation device |
US3964483A (en) | 1975-01-13 | 1976-06-22 | Syntex Puerto Rico, Inc. | Inhalation device |
FR2299011A1 (en) | 1975-01-29 | 1976-08-27 | Obert Jean Claude | PART AEROSOL GENERATOR |
US4102999A (en) | 1975-02-10 | 1978-07-25 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Process for producing stable macromomycin powder |
US3991304A (en) | 1975-05-19 | 1976-11-09 | Hillsman Dean | Respiratory biofeedback and performance evaluation system |
US4153689A (en) | 1975-06-13 | 1979-05-08 | Takeda Chemical Industries, Ltd. | Stable insulin preparation for nasal administration |
GB1527605A (en) | 1975-08-20 | 1978-10-04 | Takeda Chemical Industries Ltd | Insulin preparation for intranasal administration |
US3994421A (en) | 1975-09-29 | 1976-11-30 | American Cyanamid Company | Unitary therapeutic aerosol dispenser |
US4109019A (en) | 1975-11-18 | 1978-08-22 | William Percy Moore | Process for improved ruminant feed supplements |
NL7704348A (en) | 1977-04-21 | 1978-10-24 | Philips Nv | PROCEDURE FOR PREPARING A ATTENUATED TRANSMISSIBLE GASTROENTERITIS (TGE) VIRUS FOR USE IN LIVE VACCINES. |
US4180593A (en) | 1977-04-29 | 1979-12-25 | Cohan Allan N | Process for producing round spherical free flowing blown bead food products of controlled bulk density |
US4127502A (en) | 1977-06-10 | 1978-11-28 | Eastman Kodak Company | Stabilizers for reconstituted, lyophilized samples |
US4211769A (en) * | 1977-08-24 | 1980-07-08 | Takeda Chemical Industries, Ltd. | Preparations for vaginal administration |
DE2748132A1 (en) | 1977-10-27 | 1979-05-03 | Behringwerke Ag | STABILIZER FOR POLYSACCHARIDE |
NL7712041A (en) | 1977-11-01 | 1979-05-03 | Handelmaatschappij Voorheen Be | Suction equipment for powdery material - incorporates ejector type suction pump and cyclone type separator |
US4244949A (en) | 1978-04-06 | 1981-01-13 | The Population Council, Inc. | Manufacture of long term contraceptive implant |
EP0005585B1 (en) | 1978-05-03 | 1981-08-12 | FISONS plc | Inhalation device |
US4158544A (en) | 1978-07-17 | 1979-06-19 | Beckman Instruments, Inc. | Process for preparing a biological composition for use as a reference control in diagnostic analysis |
US4253468A (en) | 1978-08-14 | 1981-03-03 | Steven Lehmbeck | Nebulizer attachment |
US4588744A (en) | 1978-09-19 | 1986-05-13 | Mchugh John E | Method of forming an aqueous solution of 3-3-Bis(p-hydroxyphenyl)-phthalide |
US4503035B1 (en) | 1978-11-24 | 1996-03-19 | Hoffmann La Roche | Protein purification process and product |
GB2037735B (en) | 1978-12-21 | 1983-11-09 | Standard Telephones Cables Ltd | Glass composition |
SU1003926A1 (en) | 1979-01-24 | 1983-03-15 | Всесоюзный Научно-Исследовательский И Конструкторский Институт Автогенного Машиностроения | Powder feeder |
EP0036699B2 (en) | 1979-02-21 | 1987-09-02 | Imperial Chemical Industries Plc | Extraction of poly-beta-hydroxybutyric acid |
IT1116047B (en) | 1979-04-27 | 1986-02-10 | Sigma Tau Ind Farmaceuti | DEVICE FOR THE QUICK INHALATION OF POWDER DRUGS BY PERSONS SUFFERING FROM ASTHMA |
JPS6034925B2 (en) | 1979-07-31 | 1985-08-12 | 帝人株式会社 | Long-acting nasal preparation and its manufacturing method |
NL8020393A (en) | 1979-10-30 | 1981-09-01 | Riker Laboratories, Inc. Te Loughborough, Groot-Brittannie. | |
US4294624A (en) | 1980-03-14 | 1981-10-13 | Veltman Preston Leonard | Drying co-mingled carbohydrate solution and recycled product by dielectric heating |
US4452239A (en) | 1980-03-25 | 1984-06-05 | Hilal Malem | Medical nebulizing apparatus |
JPS56138110A (en) * | 1980-03-28 | 1981-10-28 | Teijin Ltd | Suppository containing citric acid or salt thereof |
EP0111216A3 (en) | 1980-03-31 | 1985-01-16 | Takeda Chemical Industries, Ltd. | Method for enzyme immunoassay and peptide-enzyme conjugate, its lyophilizate, antibody and kit therefor |
US4423079A (en) | 1980-07-14 | 1983-12-27 | Leo Kline | Growth promoting compositions for Lactobacillus sanfrancisco and method of preparation |
US4326524A (en) | 1980-09-30 | 1982-04-27 | Minnesota Mining And Manufacturing Company | Solid dose ballistic projectile |
US4327076A (en) | 1980-11-17 | 1982-04-27 | Life Savers, Inc. | Compressed chewable antacid tablet and method for forming same |
US4371557A (en) | 1981-01-21 | 1983-02-01 | General Foods Corporation | Maintenance of protein quality in foods containing reducing sugars |
US4327077A (en) | 1981-05-29 | 1982-04-27 | Life Savers, Inc. | Compressed chewable antacid tablet and method for forming same |
US4484577A (en) | 1981-07-23 | 1984-11-27 | Key Pharmaceuticals, Inc. | Drug delivery method and inhalation device therefor |
EP0072046B1 (en) | 1981-07-24 | 1986-01-15 | FISONS plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
GB2105189B (en) | 1981-07-24 | 1985-03-20 | Fisons Plc | Inhalation drugs |
US5260306A (en) | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
DE3141498A1 (en) | 1981-10-20 | 1983-04-28 | Bayer Ag, 5090 Leverkusen | Pharmaceutical containing kallikrein and process for its preparation |
NL193099C (en) | 1981-10-30 | 1998-11-03 | Novo Industri As | Stabilized insulin solution. |
US4713249A (en) | 1981-11-12 | 1987-12-15 | Schroeder Ulf | Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof |
SE8204244L (en) * | 1982-07-09 | 1984-01-10 | Ulf Schroder | Crystallized Carbohydrate Matrix for BIOLOGICALLY ACTIVE SUBSTANCES |
JPS58154548A (en) | 1982-03-09 | 1983-09-14 | Nippon Shinyaku Co Ltd | Stabilization of azulene derivative |
US4823784A (en) | 1982-04-30 | 1989-04-25 | Cadema Medical Products, Inc. | Aerosol inhalation apparatus |
US4659696A (en) * | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
US4599311A (en) | 1982-08-13 | 1986-07-08 | Kawasaki Glenn H | Glycolytic promotersfor regulated protein expression: protease inhibitor |
US4457916A (en) | 1982-08-31 | 1984-07-03 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for stabilizing Tumor Necrosis Factor and a stable aqueous solution or powder containing the same |
US4591552A (en) | 1982-09-29 | 1986-05-27 | New York Blood Center, Inc. | Detection of hepatitis B surface antigen (or antibody to same) with labeled synthetic peptide |
FI79651C (en) | 1982-10-08 | 1990-02-12 | Glaxo Group Ltd | Dosing device for medicine |
US4778054A (en) | 1982-10-08 | 1988-10-18 | Glaxo Group Limited | Pack for administering medicaments to patients |
US4559298A (en) | 1982-11-23 | 1985-12-17 | American National Red Cross | Cryopreservation of biological materials in a non-frozen or vitreous state |
ES8403520A1 (en) | 1983-02-08 | 1984-03-16 | Gandariasbeitia Aguirreche Man | Continuous prepn. of proteolytic and amylolytic enzymes |
JPS59163313A (en) | 1983-03-09 | 1984-09-14 | Teijin Ltd | Peptide hormone composition for nasal administration |
JPS6035263A (en) | 1983-08-05 | 1985-02-23 | Wako Pure Chem Ind Ltd | Stabilization of immunologically active substance immobilized on non-soluble carrier and physiologically active substance measuring reagent containing the same as composition unit |
US4649911A (en) | 1983-09-08 | 1987-03-17 | Baylor College Of Medicine | Small particle aerosol generator for treatment of respiratory disease including the lungs |
DE3345722A1 (en) | 1983-12-17 | 1985-06-27 | Boehringer Ingelheim KG, 6507 Ingelheim | INHALATOR |
US4534343A (en) | 1984-01-27 | 1985-08-13 | Trutek Research, Inc. | Metered dose inhaler |
WO1987000196A1 (en) | 1985-07-09 | 1987-01-15 | Quadrant Bioresources Limited | Protection of proteins and the like |
US4758583A (en) | 1984-03-19 | 1988-07-19 | The Rockefeller University | Method and agents for inhibiting protein aging |
US4820534A (en) | 1984-03-19 | 1989-04-11 | General Foods Corporation | Fixation of volatiles in extruded glass substrates |
US4927763A (en) | 1984-03-21 | 1990-05-22 | Chr. Hansen's Laboratory, Inc. | Stabilization of dried bacteria extended in particulate carriers |
DD238305A3 (en) | 1984-04-23 | 1986-08-20 | Maisan Werke Barby Veb | PROCESS FOR THE PREPARATION OF D-GLUCOSE AND STAERKEHYDROLYSATES |
US4617272A (en) | 1984-04-25 | 1986-10-14 | Economics Laboratory, Inc. | Enzyme drying process |
US4956295A (en) | 1984-05-21 | 1990-09-11 | Chr. Hansen's Laboratory, Inc. | Stabilization of dried bacteria extended in particulate carriers |
US4620847A (en) | 1984-06-01 | 1986-11-04 | Vsesojuzny Nauchno-Issledovatelsky Institut Meditsinskikh Polimerov | Device for administering powdered substances |
JPS60258195A (en) | 1984-06-05 | 1985-12-20 | Ss Pharmaceut Co Ltd | Alpha,alpha-trehalose fatty acid diester derivative and its preparation |
JPS60258125A (en) | 1984-06-06 | 1985-12-20 | Hayashibara Biochem Lab Inc | Water-soluble dried material containing proteinic physiologically active substance |
US4721709A (en) | 1984-07-26 | 1988-01-26 | Pyare Seth | Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions |
US4624251A (en) | 1984-09-13 | 1986-11-25 | Riker Laboratories, Inc. | Apparatus for administering a nebulized substance |
NZ209900A (en) | 1984-10-16 | 1989-08-29 | Univ Auckland | Automatic inhaler |
IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
DE3445010A1 (en) | 1984-12-10 | 1986-06-19 | Boehringer Mannheim Gmbh | CONTROL OR OAK SERUM FOR LIPID DIAGNOSTICS |
FR2575678B1 (en) | 1985-01-04 | 1988-06-03 | Saint Gobain Vitrage | PNEUMATIC POWDER EJECTOR |
US4857319A (en) | 1985-01-11 | 1989-08-15 | The Regents Of The University Of California | Method for preserving liposomes |
FR2575923B1 (en) | 1985-01-15 | 1988-02-05 | Jouveinal Sa | LACTULOSE-BASED LAXATIVE COMPOSITION, AND METHOD FOR THE PRODUCTION THEREOF |
US4830858A (en) | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
US4942544A (en) | 1985-02-19 | 1990-07-17 | Kenneth B. McIntosh | Medication clock |
JPS61194034A (en) | 1985-02-25 | 1986-08-28 | Teijin Ltd | Powdery composition for transnasal administration |
US4946828A (en) * | 1985-03-12 | 1990-08-07 | Novo Nordisk A/S | Novel insulin peptides |
GB8508173D0 (en) | 1985-03-28 | 1985-05-01 | Standard Telephones Cables Ltd | Controlled delivery device |
IL78342A (en) | 1985-04-04 | 1991-06-10 | Gen Hospital Corp | Pharmaceutical composition for treatment of osteoporosis in humans comprising a parathyroid hormone or a fragment thereof |
JPS63500175A (en) | 1985-05-22 | 1988-01-21 | リポソ−ム テクノロジ−,インコ−ポレイテツド | Liposome inhalation method and inhalation system |
US4847079A (en) | 1985-07-29 | 1989-07-11 | Schering Corporation | Biologically stable interferon compositions comprising thimerosal |
US4811731A (en) | 1985-07-30 | 1989-03-14 | Glaxo Group Limited | Devices for administering medicaments to patients |
US4719762A (en) | 1985-11-21 | 1988-01-19 | Toshiba Heating Appliances Co., Ltd. | Stored ice detecting device in ice making apparatus |
US4680027A (en) | 1985-12-12 | 1987-07-14 | Injet Medical Products, Inc. | Needleless hypodermic injection device |
JPS62174094A (en) | 1985-12-16 | 1987-07-30 | Ss Pharmaceut Co Ltd | Alpha, alpha-trehalose derivative and production thereof |
JPH0710344B2 (en) | 1985-12-26 | 1995-02-08 | 株式会社林原生物化学研究所 | Method for dehydrating hydrated substance by anhydrous glycosyl fructose |
SE453566B (en) | 1986-03-07 | 1988-02-15 | Draco Ab | POWDER INHALATOR DEVICE |
US4806343A (en) * | 1986-03-13 | 1989-02-21 | University Of Southwestern Louisiana | Cryogenic protectant for proteins |
US4897353A (en) | 1986-03-13 | 1990-01-30 | University Of Southwestern Louisiana | Cryogenic protection of phosphofructokinase using amino acids and zinc ions |
US5017372A (en) * | 1986-04-14 | 1991-05-21 | Medicis Corporation | Method of producing antibody-fortified dry whey |
US4739754A (en) | 1986-05-06 | 1988-04-26 | Shaner William T | Suction resistant inhalator |
US4762857A (en) | 1986-05-30 | 1988-08-09 | E. I. Du Pont De Nemours And Company | Trehalose as stabilizer and tableting excipient |
US4790305A (en) | 1986-06-23 | 1988-12-13 | The Johns Hopkins University | Medication delivery system |
US4926852B1 (en) | 1986-06-23 | 1995-05-23 | Univ Johns Hopkins | Medication delivery system phase one |
US5042975A (en) * | 1986-07-25 | 1991-08-27 | Rutgers, The State University Of New Jersey | Iontotherapeutic device and process and iontotherapeutic unit dose |
ES2053549T3 (en) | 1986-08-11 | 1994-08-01 | Innovata Biomed Ltd | A PROCESS FOR THE PREPARATION OF AN APPROPRIATE PHARMACEUTICAL FORMULATION FOR INHALATION. |
ATE76311T1 (en) * | 1986-08-19 | 1992-06-15 | Genentech Inc | DEVICE AND DISPERSION FOR INTRAPULMONARY DELIVERY OF POLYPEPTIDE GROWTH SUBSTANCES AND CYTOKINES. |
US4729754A (en) * | 1986-10-15 | 1988-03-08 | Rexnord Inc. | Sealed bushing joint for chain |
DE3636669C2 (en) | 1986-10-28 | 2001-08-16 | Siemens Ag | Arrangement for delivering aerosol to a patient's airways and / or lungs |
US5049388A (en) | 1986-11-06 | 1991-09-17 | Research Development Foundation | Small particle aerosol liposome and liposome-drug combinations for medical use |
US4833125A (en) | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
NZ222907A (en) | 1986-12-16 | 1990-08-28 | Novo Industri As | Preparation for intranasal administration containing a phospholipid absorption enhancing system |
US4906463A (en) * | 1986-12-22 | 1990-03-06 | Cygnus Research Corporation | Transdermal drug-delivery composition |
US5093316A (en) | 1986-12-24 | 1992-03-03 | John Lezdey | Treatment of inflammation |
JPS63186799A (en) | 1987-01-29 | 1988-08-02 | 不二製油株式会社 | Production of powdery oils and fats |
US5089181A (en) * | 1987-02-24 | 1992-02-18 | Vestar, Inc. | Method of dehydrating vesicle preparations for long term storage |
FR2611501B1 (en) * | 1987-03-04 | 1991-12-06 | Corbiere Jerome | NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ROUTE BASED ON LYSINE ACETYLSALIELYLATE AND PROCESS FOR OBTAINING SAME |
US4855326A (en) | 1987-04-20 | 1989-08-08 | Fuisz Pharmaceutical Ltd. | Rapidly dissoluble medicinal dosage unit and method of manufacture |
US5387431A (en) * | 1991-10-25 | 1995-02-07 | Fuisz Technologies Ltd. | Saccharide-based matrix |
JP2656944B2 (en) * | 1987-04-30 | 1997-09-24 | クーパー ラボラトリーズ | Aerosolization of protein therapeutics |
US4876241A (en) | 1987-05-22 | 1989-10-24 | Armour Pharmaceutical Company | Stabilization of biological and pharmaceutical products during thermal inactivation of viral and bacterial contaminants |
US4790824A (en) | 1987-06-19 | 1988-12-13 | Bioject, Inc. | Non-invasive hypodermic injection device |
GB8715238D0 (en) | 1987-06-29 | 1987-08-05 | Quadrant Bioresources Ltd | Food process |
US5059587A (en) * | 1987-08-03 | 1991-10-22 | Toyo Jozo Company, Ltd. | Physiologically active peptide composition for nasal administration |
US5139016A (en) | 1987-08-07 | 1992-08-18 | Sorin Biomedica S.P.A. | Process and device for aerosol generation for pulmonary ventilation scintigraphy |
IT1222509B (en) | 1987-08-17 | 1990-09-05 | Miat Spa | INSUFFLATOR FOR THE ADMINISTRATION OF DRUGS IN THE FORM OF PRE-DOSED POWDER IN OPERATIONS |
GB8723846D0 (en) | 1987-10-10 | 1987-11-11 | Danbiosyst Ltd | Bioadhesive microsphere drug delivery system |
US4968607A (en) | 1987-11-25 | 1990-11-06 | Immunex Corporation | Interleukin-1 receptors |
WO1989004838A1 (en) | 1987-11-25 | 1989-06-01 | Immunex Corporation | Interleukin-1 receptors |
US5081228A (en) | 1988-02-25 | 1992-01-14 | Immunex Corporation | Interleukin-1 receptors |
GB8801338D0 (en) | 1988-01-21 | 1988-02-17 | Quadrant Bioresources Ltd | Preservation of viruses |
IT1217890B (en) | 1988-06-22 | 1990-03-30 | Chiesi Farma Spa | DOSED AEROSOL INHALATION DEVICE |
US4919962A (en) | 1988-08-12 | 1990-04-24 | General Foods Corporation | Coffee flakes and process |
EP0360340A1 (en) | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
EP0363060B1 (en) | 1988-10-04 | 1994-04-27 | The Johns Hopkins University | Aerosol inhaler |
JPH02104531A (en) | 1988-10-14 | 1990-04-17 | Toyo Jozo Co Ltd | Physiologically active peptide composition for nasal application |
US4984158A (en) | 1988-10-14 | 1991-01-08 | Hillsman Dean | Metered dose inhaler biofeedback training and evaluation system |
GB8824897D0 (en) | 1988-10-24 | 1988-11-30 | Ici Plc | Biocatalysts |
US4931361A (en) | 1988-11-18 | 1990-06-05 | California Institute Of Technology | Cryoprotective reagents in freeze-drying membranes |
US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US4906476A (en) * | 1988-12-14 | 1990-03-06 | Liposome Technology, Inc. | Novel liposome composition for sustained release of steroidal drugs in lungs |
US5006343A (en) * | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
US5011678A (en) | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
GB8903593D0 (en) | 1989-02-16 | 1989-04-05 | Pafra Ltd | Storage of materials |
IT1228459B (en) | 1989-02-23 | 1991-06-19 | Phidea S R L | INHALER WITH REGULAR AND COMPLETE EMPTYING OF THE CAPSULE. |
GB8904370D0 (en) | 1989-02-25 | 1989-04-12 | Cosmas Damian Ltd | Liquid delivery compositions |
SE466684B (en) | 1989-03-07 | 1992-03-23 | Draco Ab | DEVICE INHALATOR AND PROCEDURE TO REGISTER WITH THE DEVICE INHALATOR MEDICATION |
GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
ES2087911T3 (en) * | 1989-04-28 | 1996-08-01 | Riker Laboratories Inc | DRY DUST INHALATION DEVICE. |
IT1230313B (en) | 1989-07-07 | 1991-10-18 | Somova Spa | INHALER FOR CAPSULES MEDICATIONS. |
GB8918879D0 (en) | 1989-08-18 | 1989-09-27 | Danbiosyst Uk | Pharmaceutical compositions |
US5238920A (en) | 1989-08-22 | 1993-08-24 | Abbott Laboratories | Pulmonary surfactant protein fragments |
US5562608A (en) * | 1989-08-28 | 1996-10-08 | Biopulmonics, Inc. | Apparatus for pulmonary delivery of drugs with simultaneous liquid lavage and ventilation |
IT1237118B (en) | 1989-10-27 | 1993-05-18 | Miat Spa | MULTI-DOSE INHALER FOR POWDER DRUGS. |
GB2237510B (en) * | 1989-11-04 | 1993-09-15 | Danbiosyst Uk | Small particle drug compositions for nasal administration |
HU218654B (en) * | 1989-11-28 | 2000-10-28 | Syntex (U.S.A.) Inc. | Tricyclic compounds, pharmaceutical preparatives containing such compounds and process for their production |
US5376386A (en) | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
GB9001635D0 (en) | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
US5113855A (en) | 1990-02-14 | 1992-05-19 | Newhouse Michael T | Powder inhaler |
DE4004904A1 (en) | 1990-02-16 | 1990-09-13 | Gerhard Brendel | DRUM APPLICATOR |
US5621094A (en) * | 1990-05-14 | 1997-04-15 | Quadrant Holdings Cambridge Limited | Method of preserving agarose gel structure during dehydration by adding a non-reducing glycoside of a straight-chain sugar alcohol |
IT1246350B (en) * | 1990-07-11 | 1994-11-17 | Eurand Int | METHOD FOR OBTAINING A RAPID SUSPENSION OF INSOLUBLE DRUGS IN WATER |
IT1243344B (en) | 1990-07-16 | 1994-06-10 | Promo Pack Sa | MULTI-DOSE INHALER FOR POWDER MEDICATIONS |
US5037912A (en) | 1990-07-26 | 1991-08-06 | The Goodyear Tire & Rubber Company | Polymerization of 1,3-butadiene to trans-1,4-polybutadiene with organolithium and alkali metal alkoxide |
US5230884A (en) | 1990-09-11 | 1993-07-27 | University Of Wales College Of Cardiff | Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations |
AU657492B2 (en) | 1990-09-12 | 1995-03-16 | Hans Bisgaard | An inhaling device |
US5200399A (en) | 1990-09-14 | 1993-04-06 | Boyce Thompson Institute For Plant Research, Inc. | Method of protecting biological materials from destructive reactions in the dry state |
FR2667509B1 (en) | 1990-10-04 | 1995-08-25 | Valois | POWDER INHALER, DEVICE FOR PACKAGING POWDER MICRODOSES IN THE FORM OF BANDS SUITABLE FOR USE IN A POWDER INHALER, AND METHOD FOR MANUFACTURING SUCH BANDS. |
US5149543A (en) | 1990-10-05 | 1992-09-22 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
US5217004A (en) | 1990-12-13 | 1993-06-08 | Tenax Corporation | Inhalation actuated dispensing apparatus |
PT100115B (en) * | 1991-02-08 | 1999-06-30 | Cambridge Neuroscience Inc | SUBSTITUTED GUANIDINES AND ITS UTILITY DERIVATIVES AS NEUROTRANSMITOR RELEASE MODULATORS AND TRACEABILITY ASSAYS FOR NEUROTRANSMITTER RELEASE BLOCKERS |
US5182097A (en) * | 1991-02-14 | 1993-01-26 | Virginia Commonwealth University | Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content |
US5099833A (en) | 1991-02-19 | 1992-03-31 | Baxter International Inc. | High efficiency nebulizer having a flexible reservoir |
WO1992014449A1 (en) * | 1991-02-20 | 1992-09-03 | Nova Pharmaceutical Corporation | Controlled release microparticulate delivery system for proteins |
US5404871A (en) * | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
US5186164A (en) | 1991-03-15 | 1993-02-16 | Puthalath Raghuprasad | Mist inhaler |
WO1992016192A1 (en) * | 1991-03-15 | 1992-10-01 | Amgen Inc. | Pulmonary administration of granulocyte colony stimulating factor |
DE59107894D1 (en) | 1991-03-21 | 1996-07-11 | Ritzau Pari Werk Gmbh Paul | Nebulizers, in particular for use in devices for inhalation therapy |
GB9106648D0 (en) | 1991-03-28 | 1991-05-15 | Rhone Poulenc Rorer Ltd | New inhaler |
KR960002186B1 (en) | 1991-04-15 | 1996-02-13 | 레이라스 오와이 | Device intended for measuring a dose of powdered medicament for |
US5206200A (en) | 1991-04-22 | 1993-04-27 | W. R. Grace & Co.-Conn. | Tin catalysts for hydrolysis of latent amine curing agents |
AU659645B2 (en) * | 1991-06-26 | 1995-05-25 | Inhale Therapeutic Systems | Storage of materials |
US6681767B1 (en) * | 1991-07-02 | 2004-01-27 | Nektar Therapeutics | Method and device for delivering aerosolized medicaments |
ATE359842T1 (en) * | 1991-07-02 | 2007-05-15 | Nektar Therapeutics | DISPENSING DEVICE FOR MIST-FORMED MEDICATIONS |
GB9116610D0 (en) | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
US5161524A (en) | 1991-08-02 | 1992-11-10 | Glaxo Inc. | Dosage inhalator with air flow velocity regulating means |
US5253468A (en) | 1991-09-03 | 1993-10-19 | Robert Raymond | Crop chopping machine |
US6013638A (en) * | 1991-10-02 | 2000-01-11 | The United States Of America As Represented By The Department Of Health And Human Services | Adenovirus comprising deletions on the E1A, E1B and E3 regions for transfer of genes to the lung |
US5124162A (en) | 1991-11-26 | 1992-06-23 | Kraft General Foods, Inc. | Spray-dried fixed flavorants in a carbohydrate substrate and process |
DE69212497T2 (en) | 1991-12-05 | 1996-12-12 | Mallinckrodt Veterinary Inc | GLASS-LIKE CARBOHYDRATE MATRICE FOR THE ADMINISTRATION OF MEDICINES WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES |
US5320094A (en) | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
ATE146359T1 (en) * | 1992-01-21 | 1997-01-15 | Stanford Res Inst Int | IMPROVED METHOD FOR PRODUCING MICRONIZED POLYPEPTIDE DRUGS |
AU660824B2 (en) * | 1992-06-12 | 1995-07-06 | Teijin Limited | Pharmaceutical preparation for intra-airway administration |
EP0611567B1 (en) * | 1992-06-12 | 2002-08-28 | Teijin Limited | Ultrafine powder for inhalation and production thereof |
US5376359A (en) | 1992-07-07 | 1994-12-27 | Glaxo, Inc. | Method of stabilizing aerosol formulations |
US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US6509006B1 (en) * | 1992-07-08 | 2003-01-21 | Inhale Therapeutic Systems, Inc. | Devices compositions and methods for the pulmonary delivery of aerosolized medicaments |
US6673335B1 (en) * | 1992-07-08 | 2004-01-06 | Nektar Therapeutics | Compositions and methods for the pulmonary delivery of aerosolized medicaments |
DE69332105T2 (en) * | 1992-09-29 | 2003-03-06 | Inhale Therapeutic Systems San | PULMONAL DELIVERY OF ACTIVE FRAGMENT OF PARATHORMON |
US5380473A (en) * | 1992-10-23 | 1995-01-10 | Fuisz Technologies Ltd. | Process for making shearform matrix |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
US5558085A (en) | 1993-01-29 | 1996-09-24 | Aradigm Corporation | Intrapulmonary delivery of peptide drugs |
WO1994016756A1 (en) | 1993-01-29 | 1994-08-04 | Miris Medical Corporation | Intrapulmonary delivery of hormones |
US5672581A (en) | 1993-01-29 | 1997-09-30 | Aradigm Corporation | Method of administration of insulin |
US5354934A (en) | 1993-02-04 | 1994-10-11 | Amgen Inc. | Pulmonary administration of erythropoietin |
US5506203C1 (en) | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
GB9314886D0 (en) * | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Production of a biological control agent |
EP0655237A1 (en) * | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medicinal aerosol formulation |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
MX9603936A (en) | 1994-03-07 | 1997-05-31 | Inhale Therapeutic Syst | Methods and compositions for pulmonary delivery of insulin. |
GB2288732B (en) * | 1994-04-13 | 1998-04-29 | Quadrant Holdings Cambridge | Pharmaceutical compositions |
AU711350B2 (en) * | 1994-05-10 | 1999-10-14 | Zoetis Services Llc | Improved modified live BRSV vaccine |
AU696387B2 (en) * | 1994-05-18 | 1998-09-10 | Inhale Therapeutic Systems, Inc. | Methods and compositions for the dry powder formulation of interferons |
US5591453A (en) * | 1994-07-27 | 1997-01-07 | The Trustees Of The University Of Pennsylvania | Incorporation of biologically active molecules into bioactive glasses |
US6290991B1 (en) * | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US5512547A (en) * | 1994-10-13 | 1996-04-30 | Wisconsin Alumni Research Foundation | Pharmaceutical composition of botulinum neurotoxin and method of preparation |
US5705482A (en) * | 1995-01-13 | 1998-01-06 | Novo Nordisk A/S | Pharmaceutical formulation |
US6165463A (en) * | 1997-10-16 | 2000-12-26 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
WO1996032096A1 (en) * | 1995-04-14 | 1996-10-17 | Inhale Therapeutic Systems | Powdered pharmaceutical formulations having improved dispersibility |
US6019968A (en) | 1995-04-14 | 2000-02-01 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
US6190859B1 (en) * | 1995-04-17 | 2001-02-20 | The United States Of America As Represented By The Secretary Of The Army | Method and kit for detection of dengue virus |
GB9508691D0 (en) * | 1995-04-28 | 1995-06-14 | Pafra Ltd | Stable compositions |
US5611344A (en) * | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
JP2001507702A (en) * | 1996-12-31 | 2001-06-12 | インヘイル・セラピューティックス・システムズ・インコーポレテッド | Method for spray drying an aqueous suspension of a hydrophobic drug having a hydrophilic excipient and a composition made by the method |
US20030035778A1 (en) * | 1997-07-14 | 2003-02-20 | Robert Platz | Methods and compositions for the dry powder formulation of interferon |
ATE313318T1 (en) * | 1999-10-29 | 2006-01-15 | Nektar Therapeutics | DRY POWDER COMPOSITIONS WITH IMPROVED DISPERSITY |
-
1995
- 1995-02-07 MX MX9603936A patent/MX9603936A/en unknown
- 1995-02-07 WO PCT/US1995/001563 patent/WO1995024183A1/en active IP Right Grant
- 1995-02-07 DE DE69532884T patent/DE69532884T2/en not_active Revoked
- 1995-02-07 AT AT95909506T patent/ATE264096T1/en not_active IP Right Cessation
- 1995-02-07 CN CN95191910A patent/CN1098679C/en not_active Expired - Fee Related
- 1995-02-07 BR BR9507023A patent/BR9507023A/en not_active Application Discontinuation
- 1995-02-07 DK DK95909506T patent/DK0748213T3/en active
- 1995-02-07 PL PL95316199A patent/PL179443B1/en not_active IP Right Cessation
- 1995-02-07 KR KR1019960704918A patent/KR100419037B1/en not_active IP Right Cessation
- 1995-02-07 PT PT95909506T patent/PT748213E/en unknown
- 1995-02-07 ES ES95909506T patent/ES2218543T3/en not_active Expired - Lifetime
- 1995-02-07 CZ CZ19962600A patent/CZ295827B6/en not_active IP Right Cessation
- 1995-02-07 EP EP95909506A patent/EP0748213B1/en not_active Revoked
- 1995-02-07 JP JP7523456A patent/JPH10501519A/en not_active Withdrawn
- 1995-02-07 ES ES04076082T patent/ES2316917T3/en not_active Expired - Lifetime
- 1995-02-07 EP EP08021259A patent/EP2036541A1/en not_active Withdrawn
- 1995-02-07 NZ NZ281112A patent/NZ281112A/en not_active IP Right Cessation
- 1995-02-07 AT AT04076082T patent/ATE416755T1/en not_active IP Right Cessation
- 1995-02-07 CA CA002183577A patent/CA2183577C/en not_active Expired - Fee Related
- 1995-02-07 AU AU17449/95A patent/AU689217B2/en not_active Ceased
- 1995-02-07 HU HU9602454A patent/HUT75676A/en unknown
- 1995-02-07 DE DE69535897T patent/DE69535897D1/en not_active Expired - Fee Related
- 1995-02-07 EP EP04076082A patent/EP1462096B1/en not_active Expired - Lifetime
- 1995-02-12 IL IL11261895A patent/IL112618A/en not_active IP Right Cessation
- 1995-03-06 MY MYPI95000545A patent/MY124282A/en unknown
-
1996
- 1996-06-17 US US08/668,036 patent/US6685967B1/en not_active Expired - Lifetime
- 1996-09-04 FI FI963468A patent/FI116195B/en active IP Right Grant
- 1996-09-06 NO NO19963745A patent/NO316661B1/en not_active IP Right Cessation
-
1997
- 1997-03-21 US US08/821,493 patent/US5997848A/en not_active Expired - Lifetime
-
2002
- 2002-05-07 US US10/141,028 patent/US6737045B2/en not_active Expired - Fee Related
- 2002-05-07 US US10/141,044 patent/US20020192164A1/en not_active Abandoned
-
2003
- 2003-07-01 US US10/612,376 patent/US7521069B2/en not_active Expired - Fee Related
- 2003-07-01 US US10/613,078 patent/US20040096401A1/en not_active Abandoned
-
2005
- 2005-12-05 JP JP2005350682A patent/JP2006077032A/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2183577C (en) | Methods and compositions for pulmonary delivery of insulin | |
US20090203576A1 (en) | Methods and compositons for pulmonary delivery of insulin | |
JP4195191B2 (en) | Administration of aerosolized active agent | |
US6436902B1 (en) | Therapeutic preparations for inhalation | |
JP2008163033A (en) | Pulmonary delivery of aerosolized medicament | |
AU2003218308B2 (en) | hGH (human growth hormone) formulations for pulmonary administration | |
RU2175556C2 (en) | Methods and compositions for light delivery of insulin | |
TW576750B (en) | Pharmaceutical composition for respiratory/pulmonary delivery of insulin and preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |