CA2190502A1 - Methods and compositions for the dry powder formulation of interferons - Google Patents
Methods and compositions for the dry powder formulation of interferonsInfo
- Publication number
- CA2190502A1 CA2190502A1 CA002190502A CA2190502A CA2190502A1 CA 2190502 A1 CA2190502 A1 CA 2190502A1 CA 002190502 A CA002190502 A CA 002190502A CA 2190502 A CA2190502 A CA 2190502A CA 2190502 A1 CA2190502 A1 CA 2190502A1
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- CA
- Canada
- Prior art keywords
- interferon
- composition
- dry powder
- spray
- carrier
- 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.)
- Abandoned
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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
- A61K9/0012—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/215—IFN-beta
-
- 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
-
- 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
- A61K9/1611—Inorganic compounds
-
- 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
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
According to the present invention, methods and compositions are provided for spray-dried, interferon-based dry powder composit patticularly interferon-beta. The compositions are useful for treating conditions in humans that are responsive to treatment with interfe? ln pardcular, the methods of the present invention rely on spray drying to produce stable. high-potency dry powder formulation interferonns, including but not limited to IFN-beta. Surprisingly, it has been found that IFN can be prepared in high potency, dry po? formulations by spray drying. Such dry powder formulations find particular utility in the pulmonary delivery of INF.
Description
wo 95131479 2 ~ 90 5 0 2 . ~
.
S METEIODS AND COMPOSITIONS FOR TEIE DRY POWDER
n ~TION OF 11~ ~ONS
J
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a in I of co-pending U.S. Patent Application 08/246,034, filed May 18, 1994.
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates generally to methods and . for the dry powder formulation of cytokines, especially interferons. More particularly, the present invention relates to the spray drying of interferons (IFNs) to produce dry powder ~ ' ' of high potency.
.
S METEIODS AND COMPOSITIONS FOR TEIE DRY POWDER
n ~TION OF 11~ ~ONS
J
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a in I of co-pending U.S. Patent Application 08/246,034, filed May 18, 1994.
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates generally to methods and . for the dry powder formulation of cytokines, especially interferons. More particularly, the present invention relates to the spray drying of interferons (IFNs) to produce dry powder ~ ' ' of high potency.
2. Description of the Background Art Interferons are cytokines useful in the treatment of a variety- of human diseases ramging from camcer to immune system; ' Interferons are commonly formulated as isotonic aqueous solutions for parenteral ' Recently, cliniciams have sought alternative routes of ' for interferons more suitable to long term use by patients. Particularly, aerosol r ~ '- of interferons have been produced for pulmonary delivery as described in WO 91/16038. The formulation is dispersed by VuldiliL.liiul. of a liquid propellent. The patent teaches adding a surfactant or the like to improve the ~ - "~ ;ly of a human interferon from a freon delivery system.
Methods amd . , for the preparation of solid polypeptide ulJa.Li.,~ as a l~h ~ aerosol formulation are disclosed in WO 91/16038 wherein IFN-beta was prepared in dry powder form by Iyophili~ing an aqueous solution of IFN and jet milling followmg Iy-~ The purification of proteins of molecular weight in excess of 12,000, including human IFN is disclosed in U.S. Patent Nû.: 4,503,035. Low pH
of " ' IFN-beta are disclosed in WO 89/05158.
Because interferons are fairly expensive compounds, it is highly desirable to have r ~ '' of high potency with improved flow ~ h ~ that can be used with high efficiency in dry powder inhalers to produce 1~l. ' ' '- doses for pulmonary delivery.
_ .. . _ .. ... ..... .......... . ,,,,,, , . _ _ .. . . . . . .
w09sl31479 ~ ~i?!D5~2 An object of the present invention is to provide an interferon containing ~ , suitable for long-term pulmonary ' to a patient in need thereof. Another object of this invention is to provide an il~terferon-containing powdered , that is ' by inhalation in a manner that is free of a liquid propellant such as a FREON
5 or carbon dioxide.
Another object of this invention is to provide am interferon-containing powderedthat cam be easily r ' ~d by a method that maintains a high percentage of interferon activity.
Still another object of this invention is to provide an interferon-containing 10 composition that exhibits a high level of stability of the interferon over time.
Otber objects may be apparent to Qne of ordinary skill upon reviewing the following - and claims.
SUMI~ARY OF THE INVF.NTION
One aspect of this invention is an interferon-based dry powder ~ ~ for pulmonary delivery, said composition comprising a . '1~ effective amount of mterferon in ~ ' with a 1' 'Iy acceptable carrier.
Another aspect of this invention is a unit dosage form for pulmonary delivery ofinterferon, which dosage form comprises a unit receptacle containing the interferon-based dry powder composition of this invention.
A tbird aspect of this invelltion is a method of treating a disease state responsive to treatment by interferon, which method comprises ' _ a yh~ , effective amount of the interferon-based dry powder composition to tbe pulmonary region of the lung of a subject im need thereof.
Still another aspect of this invention is a method for aerosolizing the interferon-based dry powder composition tbat comprise dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing tbe aerosol in a chamber having a moutbpiece for subsequent inbalation by a patient.
Still anotber aspect of tbis invention is a metbod for preparing the interferon-based dry powder , that comprises spray-drying an aqueous mixture of tbe interferon and tbe carrier under conditions to provide a respirable dry powder.
DF~fRlPTlON OF ~PECIFIC EMBODIMENTS
WO95131479 21 ~ 2 ~ c The preseM invention is based at least m part on the higher potency and improvedflow ~ of interferon-based dry powder . produced by spray drying æcording to the present invention. Higher potency means that the resulting interferon-based , has a higher peKentage of 1~ 'og "~, ætive interferon than 5 . . prepared by other methods. The ~ of the invention are readily aerosolized and rapidly absorbed through the lungs of a host when delivered by a dry powder inhaler.
DEFINITIONS
In interpreting the claims to the various aspects of this invention, there are several important definitions that should be considered.
Tbe term "interferon" is meant to include the family of naturally-occurring or IC ' 1~, prepared small proteins and ~ u~,.utu;..~ (sometimes referred to as cytokines) with molecular weight between ~ 15,000 and 27,000 daltons and having interferon-like ætivity. Generally, such activity is exerted by binding to specific membrane receptors on a cell surface. Once bound, interferons initiate a complex series of " ' events that vary among tbe various interferons. Interferons are useful in the treatment of a variety of human conditions varying from cancer to immune system suppression. Naturally occurring interferons are produced and secreted by cells in response to viral infections and to synthetic and biological inducers. Some interferons are modified versions of the naturally occurring material and are prepared using ' DNA
tcchnology. Interferon is sometimes abbreviated as "IFN" and shall be so abbreviated in this application. Examples of interferons include, e.g. IFN-alpha-2A l ' (RoferonD A-Roche 1. ' ~), IFN-alpha-2B 1~ ' antronl A-Shering), IFN-alpha-N3 human leukocyte derived (Alferonl N-Purdue Frederick), IFN-gamma-lB
(Actimmune~-Genentech), IFN-beta ' (Betaseron~-Chiron, Berlex), IFN-beta naturally occurring aFeron~-Toray, ~apan), and the like. U.S. Patent 4,503,035 issued March 5, 1985 to Pestka and Rubinstein gives examples of human leukocyte IFNs. For purposes of this invention IFN-beta is preferred, particularly naturally occurring IFN-beta.
The term "powder" means a . that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an irlhalation device and ' . '~, inhaled by a subject so that the particles reæh the lungs to permit penetration into the alveoli. Thus, the powder is said to be "respirable." Preferæbly the average particle size is less than ~out 10 microns (~m) in diameter with a relatively WO95131479 2~ q~502 ~ 6 uniform spheroidal shape " ' More preferably the diameter is less than about 7.5ym and most preferably less than about 5.0 ym. Usually the particle size distribution is between about 0.1 ym and about 5ym in diameter, particularly about 2 ym to about 5 ym.
The term "dry" meams that the . . has a moisture content such that the particles are readily dispersable in an inhalation device to form an aerosol. This moisture content is generally below about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w.
The term "~ ly e~fective amount" is the amount present in t~hie .
that is needed to provide tbe desired level of interferon in tbe subject to be treated to give 10 the anticipated l,h~.iolo~,k,al respollse. Tbis amount is determined for each interferon on a ""._ hJ c~ . basis. Guidelines are given hereafter.
The term ''~,h.~Diulo~h,~lly effective amount" is tbat amount delivaed to a subject to give the desired palliative or curative effect. Tbis amount is specific for each interferon and its ultimate approved dosage level. Guidelines are given hereafter.
The term ''l ' "~, acceptable" carrier means that the carrier can be taken into tbe lungs witb no significamt adverse l- ,; .IAg!~ ~1 effects on thie lungs.
COMPO!~ITIONS OF THE INVENTION
One aspect of this inventiorl is an interferon-based dry powder composition for 20 pulmonary delivery, the . . comprising a Ih- '`I " i~ lly effective amount of interferon in ' with a l,h ~ lly acceptable carrier.
In general, the . of this invention have a higher IFN p~tency and greater ily than other interferon ~ known in the art. In the dry shte IFN is an amorphous forln. The IFNs suihble for use in the composition of this invention include 25 the various IFN alphas, IFN behs and IFN gammas ~ . ' by tbe broad definition of IFN. The IFN alphas and IFN behs are preferred, with IFN beh being patticularly preferred. The . is particularly valuable for naturally occurring IFN beh~ for example that available through Toray Industries, Inc. in Japam.
A i' ~ "~, effective amount of IFN will vary in the composition dependimg on 30 the biological activity of the IFN employed and the amount needed im a unit dosage form.
Because IFN is so highly active it ~nust be r ' U;l in a unh basis in a malmer that allows for ready , ' by the formulator and by the consumer. This generally means that a unit dosage will be between about 0.5 mg and 15 mg of tohl material in the dry powder ~ . , preferably between about 2 mg and 10 mg. Generally, the WO 95/31479 2 !1, qQ F~ ~ ~ p~""~
amouDt of IFN in the . will vary from about ~0.05%w to about 5.0%w. Most preferably the . will be about 0.2% to about 2.0%w IFN.
The amount of the ~,h_.,... _ t;~ ,~lly acceptable carrier is that amount needed to provide the necessary stability, d;.~J.,.g;l,iliLy, consistency and bulking ~ toS ensnre a uniform pulmonary delivery of the composition to a subject in need thereof.
, the amount may be from about 95.0%w to abont 99.95%w, depending on the activity of the IFN being employed. Preferably about 9$%w to about 99.8%w will be used.
The carrier may be one or a ' of two or more, ' ' excipients, but will generally be ' "~, free of any "penetration enhancers." "Penetration enhancers" are surfaoe active compounds which promote penetration of a drug through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug ' ' Exemplary penetration enhancers include bile salts, e.g., , ' ' , ~Iyl ' ' , and ~Ay, ' ' , fusidates, e.g., i u~i~,hyJ~ and b;.J. .- ~ detergents, e.g., Tweens, Laureth-9, and ihe like. The use of penetration enbancers in ' ' for the lungs, however, is generally undesirable because of theepithelial blood barrier in the lung can be adversely affected by such surface active compounds. The dry powder . of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
The types of l ' ' excipients that are useful as carriers in this invention mclude stabilizers such as human serum albumin (HSA), bulking agents such as uhJ~' amino acids and puly~ ikl~D~ pH adjusters or buffers; salts such as sodiumcbloride; amd the like. These carriers may be in a crystalline or amorphous form or may be a miAture of the two.
It has been found that HSA is particularly vaiuable as a carrier in that it provideg eAxcellent ctshiii7stjnn of IFN in solution.
Bulking agents that are particularly vaiuable include compatible ~ ully~' ,uly~ ,tid g, amino acids or ~ ' thereof. Suitable ~buhr~ include such as gaiactose, D-mannose, sorbose, and the like; ~i: - h_ i l'-, sucb as lactose, trehaiose, and tbe like; ~y~ , such as 2 h~ ' y~u~l ,5~y~,lùd~,AL~
amd puly~- h_ ;~i. `, such a raffinose, ' ' , dextrans, and the like; aiditols, such as mannitol, xylitol, and the iike. A preferred group of u~ubuhy~' includes lactose, threhaiose, raffinose ' ' and marmitol. Suitable pul~Li~i.,g include aspartame.
Amino acids include aianine and glycine, with glycine being preferred.
WO9~/31479 2 1 ~ ~5 0 2 T_l/u~ .
Additives, which are minor components of tbe composition of tbis invention, may be included for ~ ' stability during spray drying amd for improving Ai,,.. .~ y of tbe po~der. These additives include h~l., . ' ' amino acids such tryptophan, tyrosme, lucine, l' ,' ' , and the like.
Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred.
The unit dosage form, method of treatment, and process of preparation of this invention are described hereafter.
Unit D Fsrm Another aspect of this invention is a unit dosage form for pulmonary delivery ofinterferon, which dosage form comprises a unit dosage re~eptacle containing an interferon-based dry powder . which composition comprises a ~ , effective amount of an interferon in ' with a l ' 'l~, acceptable carrier.
In this aspect of the invention, the composition of tbis invention (as discussedr t) iS placed within a suitable dosage receptacle in an amount sufficient to provide a subject with }FN for a unit dosage treatment. The dosage re~eptacle is one that fits within a suitable inhalation device to allow for the ~lo~uli4aLiu~ of the interferon-based dry powder ~ . by dispersion into a gas stream to form an aerosol and then captnrimgtbe aerosol so produced in a chamber having a mouthpiece attached for subsequentinhalation by a subject in need of treatment. Such a dosage receptacle includes amy container enclosing the . ' ' known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the contamer to disperse the dry powder . Such containers are exempliffed by those shown in U.S. Patents 4,227,522 issued October 14, 1980; 4,192,309 issued March 11, 1980; and 4,105,027 issued August 8, 1978. Suitable containers also include those used in conjunction with Glaxo's Ventolin Rotohaler brand powder inhaler or Fison's Spinhaler bramd powder inhaler. Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate. The IFN-beta powder is fflled by weight or by volume into the depression in the formable foil and ~ ",ysealed with a covering foil-plastic laminate. Such a container for use with a powder inhalation device is described in U.S. Patent 4,778,054 and is used with Glaxo's DiskhaleP
W09513t479 ~I gQ5~)2 I~
.
(U.S. Patent~s 4,627,432; 4,811,73i; and 5,035,237). All of these references are ' herein by reference.
~ ' ' ' of Treating a Disease ,c Another aspect of this invention is a method of treating a condition responsive to treatment by interferon, which method comprises l ' '~ ' v to a subject in need thereof a ~hJ~;ulu~;i.,~lly effective amount of an interferon-based dry powder that comprises a i' ~ ; "y effective amount of an interferon m with a l,l~ dl.y acceptable carrier.
Conditions that may be treated by the , of this invention include those conditions that are responsive generally to treatment with IFN. For example, IFN alpha is used to treat hepatitis B and C, Hairy Cell Leukemia, chronic hepatitis Non A, Non B/C
and Kaposi's Sarcoma; IFN beta is used to trea~ multiple sclerosis, brain tumor, skin cancer and hepatitis B and C; and IFN gamma is used to treat cllronic v ' dise~se.
The l,h~,;olog;v~lly effective amount ne~ded to treat a particular condition or disease state will depend on the individual, the condition, length of treatment, the regularity of treatment, the type of IFN, and other fætors, but can be determined by one of ordinary skill in the medicinal arts. The dosage may range from .25 x 106 IU to 50 x 10~ IU per person per day depending on the prescribing doctor's diagnosis. For example an induction dosage of IFN alpha ll ' (Roferon~A-Roche I . ' ) for treatment of hairy cell leukemia may be 3 x 10~ IU daily for 16-24 weeks with a dose of 3 x 10 IU three times per week. Other dosage regimes may be determined through clinical trials amd reference to the Physicians Desk Reference~ for 1994 as ,, ' It is presently believed that the effective absorption by a host of dry powder interferon æcording to the present invention results from a rapid dissolution in the ultra-thin (< 0.1 fm) fluid layer of the alveolar lining of the lung. The particles of the present invention thus have a meam size which is from 10 to 50 times larger tham the lung fluid layer, making it unexpected that the particles are dissolved and the interferon systemically absorbed in a rapid malmer for either local lung or systemic treatment. An, of the precise mechanism, however, is not necessary for practicing the present invention as described herein.
The ærosolized interferon-based dry powders of this invention are particularly useful in place of parenteral delivery. Thus, the methods and , of the present invention will be particularly valuable in chronic treatment protocols where a patient can WO9~/31479 21 9~r~ r ", c., .~
.
sclf ~ ' Tbe patient carl æhieve a desired dosage by inhaling an appropriate arnount of interferon, as just described. The efficiency of systemic interferon delivery via the method as just described will typically be in the range from about 15% to 50%, with individuai dosages (on a per iMaiation basis), typicaily being in the range from about 3 million IU to about 50 million IU during a single respiratory ' Thus, the deslred dosage may be effected by the patient taicing from I breath to 5 bteaths.
r~ for Aern~r~li7i~ ' Powder Stiil another aspect of this invention is a method for aerosolizing am interferon-based dry powder , that comprises a i' , "~! effective amount of am interferon in ' - with a 1 ' "~, acceptable carrier, which method comprises dispersing an amount of the dry powder composition in a gas stream to form an aerosol amd capturing the aerosol in a chamber having a mouthpiece for subsequent iMaiatiOn by a patient.
A further detaiied description of this method is found in pending U.S. Patent Applications Ser. Nos. 071910,048 amd 08/207,472, both of which are . ' herein by reference.
Preparin~ the t' Still amother aspect of this invention is a method for preparing an interferon-based dry powder ~ . of this invention that comprises spray-drying an aqueous mixture of the interferon and a ~ ly acceptable carrier having an interferon pH under conditions to provide a respirable dry powder Spray drying is a process in which a 1~ aqueous mixture of IFN and the carrier is introduced via a no~le (e.g., a two fluid no_zle), SpiMing disc or an equivalent device into a hot gas stream to atomi7e the solution to form fine droplets. The aqueous mixture may be a solution, suspension, slurry, or the iiice, but needs to be 1- O to ensure uniform distribution of the components in tbe mixture and ultimately the powdered Preferably the aqueous mixture is a solution. The solvent, generaily water, rapidly evaporates from the droplets producing a flne dry powder having particles I to 5 ~Lm in diameter. S , ~'~" the protein is not degraded when it is exposed to the hot drying gas, and the interferon powders can be prepared having suffcient purity for , 1 -- . ---: ,~ use. An acceptable purity is defined as less than 5% degradation products and , preferably les~ tilam 3 % amd most preferably less than 1% .
WO95/31479 21 qO 502 r~l"~ , .
The spray drying is done under conditions that result in ' '~, amorphous powder of I " constitution having a particle size that is respirable, a low moisture content and flow ~ GlG~t~ Li~,~ that ailow for ready G_lU~UIi~iiUII. Preferably the particle size of the resulting powder is such that more than about 98 % of the mass is in particles having a diameter of about 10 ~m or less with about 90% of the mass being in particles having a diameter less than 5 ~m. Alternatively, about 95% (preferably more than 95%) of the mass will have particles with a diameter of less than 10 ~m with about 80% (preferably more tham 80%) of the mass of tbe particles having a diameter of less tban 5 ym.According to the methods of the present invention, interferon dry powders of higher potency and improved flow ~ are prepared by spray drying, where, bulk mterferon, preferabiy IFN-beta but suitably other forms of interferon, is prepared in solution to have a a~iull from 0.0005% by weight to 0.02% by weight, usuaily from 0.001% to 0.005%. The solutions may contain a stabilizer to maintain the chemicai stability of the IFN-beta in solution such as HSA in a from 0.01~ to 1.0% by weight and preferably 0.05% to 0.25% by weight and may contain other materiai such as a sait or p- G ~GI ~ d i ~ _ that is present as a result of the preparation of bulk IFN . The solutions may then be sprayeo dried in ,u..~ tiOIldi spray drying equipment from commerciai suppliers, such as Buchi, Niro, Yamato Chemicai Co., ~kawara Kakoki Co., amd the like, resulting in a ' "~ amorphous particulate product.
For the spraying process, such spraying methods as rotary pressure atomization and two-fluid atomization can be used. Examples of the devices used in these processes include "Pulvis Mini-Spray GA-32" and "Pulvis Spray Drier DL~I", r ' G~i by Yamato Chemicai Co., or "Spray Drier CL-8," "Spray Drier L-8," "SprayDrier FL-12," "Spray Drier FL-16" or "Spray Drier FL-20," r ' e,d by Okawara Kakoki Co., cam be used for the method of spraying using rotary-disk atomizer.
While no speciai restrictions are placed on the nozzle of the atomizer used in the process of spraying, it is ' ' to use a nozzle which can produce a spray-dry rn~rn~;rinn with a gr~un diameter suitable for nasai, pharyngeai or pulmonary _' For example, nozzle types "IA," "1," "2A," "2," "3" and the like, r ' G~i by Yamato Chemicai Co., can be used for the dbU._: ' spray-drier, r ' ~ by the same company. In addition, disics type "MC-50," "MC~5" or "MC-85," r Gd by Okawara Kakoki Co., can be use~i as rotary disics of the spray-orier atomizer, r ' ~ by the same company.
WO95/31479 2 1 9 ~5 02 I~I/L.~ _ G
Wbile no particular restrictions are placed on tbe gas used to dry the sprayed materiai, it is ,~ ' ' to use air, nitrogen gas or am inert gas. The temperature of the iniet of the gas used to dry the sprayed materiais such that it does not cause heat deactivation of the sprayed materiai. The range of i . ~ may vary between about 50CC to about 200C, preferable between about 50C and 100C. The temperature of the outiet gas used to dry the sprayed materiai, may vary between about 0C amd about 150, preferably between 0C and 90C, and even more preferably between 0C and 60C. The fact that iniet amd outlet L...,,. ci:~ above about 55C can be used is surprising in view of the fact that IFN starts deactivating at that temperature, with nearly complete deactivation 10 occurring at about 70C.
By minimizing the amount of stabilizer in the solution, high potency iFN powder cam be prepared such that the number of inhaiations required to deliver even high dosages of IFN can be ' "~, reduced, often to oniy a single inhaiation.
Interferon dry powders suitable for use in the present invention are ' "~
15 amorphous, esseDtiaily lacicing any crystaiiine structure. Dry powder interferons are prepared by spray drying under conditions which result in a ' "~, amorphous powder having a particle size within the above-stated range. Accordmg to the method of ti~e present invention, bulic interferon, preferably IFN-,~ but suitably other forms of imterferon, is first dissolved in a ~Ih~ 'o" "~,-acceptable aqueous solution typicaily 20 containing sodium chloride, optionally with a buffer, having a pH in the ramge from about 2 to 9. The interferon is dissolved at a ~ from 0.01% by weight to 1% by weight, usuaily from 0.1% to 0.2%. The solutions may then be spray dried in Cu..~ iU..di spray drying equipment from commerciai suppliers, such as Buchi, Niro Yamato, Okawara Kaicoici amd the liice, resulting in a ' ''~ amorphous particulate product.
The interferon dry powders of the present invention may optionaily be combined with ~ carriers or excipients which are suitable for respiratory and pulmonary - ' Such carriers may serve simply as bulicing agents when it is desired to reduce the interferon in the powder which is being delivered to a patient, but may aiso serve to enhance the stabiliy of the interferon , amd to improve the ~ y of the powder within a powder dispersion device in order to provide more efficient and l~-uJu~ delivery of the interferon and to improve handling . .-- A. t ;~
of the interferon such as flowabiliy and consistency to facilitate r and powder fiiling.
.
W095131479 ~ a 2 r~l, 5Cf ~r Such carrier materials may be combined with the interferon prior to spray drying, i e., by adding the carrier material to the purifled bulk solution. In that way, the carrier particles will be formed ' '~, with the IFN particles to produce a I
powder. Alternatively, the carriers may be separately prepared in a dry powder form and 5 combined with the dry powder interferon by blending. ~he powder carriers will usually be crystalline (to avoid water absorption), but might in som~ cases be amorphous or mixtures of crystallme and amorphous. The size of the carrier particles may be selected to improve the flowability of the IFN powder, typically being in the range from 25 ~Lm to 100 ILm. A
preferred carrier material is cryst~lline lactose having a size in the above-stated range.
EXPERIMENTAL
Examvl~ l This example sets forth a method of preparing a composition of this invention.
A~",., 'y 50 mL of 10 mM sodium chloride solution of natnral human IFN-15 beta comprising rr ' ' ~12 mg/ml HSA was prepared.
The resnlting aqueous mixtnre is fed to a Buchi Laboratory Spray Dryer under the following conditions to give a ~ . of this invention:
Temperature of the aqueous mixture 4C-10C
Inlet temperature 115C-125C
Feed rate 6 mL/mirl Outlet temperature 60C-70C
Once the aqueous mixture is consumed, the outlet temperature is maintained at about 70C for about 15 minutes by slowly decreasing the inlet i . This provides a 25 secondary drying to give an IFN-based dry powder composition having a water content of less than 3% as measured by a coulombic Karl Fischer method. In this case the (%w based on total solids) is constituted as follows:
I .9%w IFN-beta 98.1%w Carrier (75.8% HSA, 22.3 NaCI) Exam~le 11 By following the procedure of Example 1, but increasing the outdet tcmperature to 75C-80C during the secondary drying stage, one obtains a composition of this invention 35 having less than I %w water.
WO 95/31479 2 1 q ~ 5 G 2 ~ cr F ' 111 This example sets forth a method of preparing a . . of this invention whaein the carrier includes a bulking agent, i.e., mammitol.
Mannitol is dissolved in natural human IFN-beta described rn Example 1. The S I of mannitol was 5.75 mg/mL.
The resulting aqueous mixture is fed to a Buchi Laboratory Spray Dryer under thefollowing conditions:
Temperature of the aqueous mixture 4CC-10C
Inlet temperature 115C-125C
Feed rate 5 mL/min Outlet temperature 60C-70C
Secondary drying- 15 minutes at 70C
Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of, ' " ~ it will be obvious that certain changes and ~ ~ may be practiced within the scope of the appended claims.
F ' IV
This example sets forth a method for preparing a composition of this invention wherein no bul~ing agent is prese~t in the ~ .
A~",., 'y 100 ml of 10 mM sodium chloride solution of natural humam mterferon (obtained by culturing human normal diploid fibroblasts) (~ 1y 7 x 10'IUlml) comprising ~ ,., 'y 2 mg/ml human serum albumin (HSA) were prepared, and spray-dried using the commercial spray-drier "13ulvis Mini-Spray GA-32,"
r ' cd by Yamato Chemical Co. The spray nozzle used was a IA nozzle (~ 0.4 mm) and the inlet temperature and the outlet temperature of the drying gas were 100C amd 60C, respectively. In addition, tlle spray pressure was I kg/cm2, the flow capacity of the hot air was 0.40 to 0.42 m3/min and the rate of solution i was 4.3 ml/min.
After ,1~ 'y 20 min. of spray-drying, the dry powder, which was collected into achamber using a cyclone, was recovered, and the interferon (IFN) activity was measured.
The interferon activity was measured using an enzyme J (EIA) involving an amti-humam interferon 3 antibody (S. Yamazal~i et al., ~ " 10, 57(1989)). The activity of the dry powder was measured by dissolvrng the dry powder using distilled water WO95/31479 ~ l 9~ 5 02 y~uv ~ ~
and comparing its interteron activity, ~ . ' v to the light absorption at 280 mm, with the interferon activity prior to the spray-drying process. The results are shown in Table 1.
The ~ were repeated three times, and the average values were used for the ~r~n~p jcnn The error in the relative activity in the table is a standard error (i SE).
Table I
Natural human interferon ,~ activity before and after spray-dr,ving Relative activity aU/A 280 unit) Remaining activity (%) Before spray-drying 4.11 i 0.11 100 After spray-drying 3.14 i 0.04 74.8 After the spray-drying process, the natnral human interferon ~ showed an interferon activity which was 74.8% of its activity prior to the spray-drying process, indicating that it can be spray-dried while maintaining its activity. These results are surprising because a similar natnral human interferon ,~ solution comprising a similar quantity of HSA will start 15 deactivating at "~", ly 55C, with complete deactivation occuring at 70C.
The dry powder obtained by the process of this invention was subjected to platinum coating and the shape of its grains was examined using a field emission scan electron microscope (model S-8000, r ' vd by Hitachi Co.). A~ 90% of the grains examined were grains with relatively smooth and large dents and protrusions in the 20 grain surface, and with a grain diameter of ,Iy~ 101~m. In addition, the resulting powder exhibited a moisture content of 5.6 wt% using the Karl Fischer method (coulometric titration r ' ~ CA-06, ~ vd by Mitsubishi Kasei Co.).
ExamDle V
25 This example sets forth a method for preparing an IFN/HSA/mannitol c~ inn A,. l~, 100 ml of lOmM sodium chloride solution of natnral human interferon comprising 150 mg/ml mannitol and ~.., 'y 2 mg/ml human serum albumin aHSA) were prepared. The proportion of the mannitol to the total solutes in this solutlon was ~ , 90 wt%.
30 The above solution was spray-dried using the same method and the same conditlons as In Example IV, and the interferon activity of the dry powder obtained was measured using the same method as in Example IV. The results are shown in Table 2.
Table 2 Natural human interferon ,~ activity before and after spray-drying WO95131479 2 i 9 C5~2 Relative activity aU/A 280 unit) Remaining activity (%) Before spray-drying 5.59 + 0.51 100 Afterspray-drying 4.53 + 0.13 81.0 5 After the spray-drying process, the natural human interferon ,~ maintained 81.0% of its activity compared with its activity prior to the spray-drying process. As in Example IV, these results are surprising because a similar aqueous solution of the same quantity of natural human interferon ,~, HSA and mannitol started to deactivate at ~ , 55C,witb almost complete deactivation occurring at 70C.
10 While the IFN-based powder from Example IV and V are dispersible, the powder obtained from Example V was more readily dispersed than the powder obtained in Example IV.
When the grain shape was examined by subjecting the powder to platinum coating and using a field emission scan electron microscope (model S-8000, r ' ed by Elitachi Co.), the grains were found to have a size similar to those of Example IV but a shape more 15 rounded compared with the powder particles obtained in Example IV. In addition, when the distribution of the grain diameter of the powder was measured by dispersing it in ethanol anhydride amd using a gran~lation amalyzer (Microtrac FRA, r ' ~ by Ni~lciso Co.), it was found that ~ , 90% of the grains were distributed within the range of 1.6 to 9.3 ~m. The moisture content was 0.74 %wt, as measured by the Karl 20 Fischer method of Example IV
All publications and patent applications mentioned in this 5, "- - are herein . ~ by reference to the same extent as if each individual publication or patent application wa~ specifically and individually indicated to be . ' by reference.
The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes amd, ~ ., can be made thereto without departing from the spirit or scope of the appended claims.
Methods amd . , for the preparation of solid polypeptide ulJa.Li.,~ as a l~h ~ aerosol formulation are disclosed in WO 91/16038 wherein IFN-beta was prepared in dry powder form by Iyophili~ing an aqueous solution of IFN and jet milling followmg Iy-~ The purification of proteins of molecular weight in excess of 12,000, including human IFN is disclosed in U.S. Patent Nû.: 4,503,035. Low pH
of " ' IFN-beta are disclosed in WO 89/05158.
Because interferons are fairly expensive compounds, it is highly desirable to have r ~ '' of high potency with improved flow ~ h ~ that can be used with high efficiency in dry powder inhalers to produce 1~l. ' ' '- doses for pulmonary delivery.
_ .. . _ .. ... ..... .......... . ,,,,,, , . _ _ .. . . . . . .
w09sl31479 ~ ~i?!D5~2 An object of the present invention is to provide an interferon containing ~ , suitable for long-term pulmonary ' to a patient in need thereof. Another object of this invention is to provide an il~terferon-containing powdered , that is ' by inhalation in a manner that is free of a liquid propellant such as a FREON
5 or carbon dioxide.
Another object of this invention is to provide am interferon-containing powderedthat cam be easily r ' ~d by a method that maintains a high percentage of interferon activity.
Still another object of this invention is to provide an interferon-containing 10 composition that exhibits a high level of stability of the interferon over time.
Otber objects may be apparent to Qne of ordinary skill upon reviewing the following - and claims.
SUMI~ARY OF THE INVF.NTION
One aspect of this invention is an interferon-based dry powder ~ ~ for pulmonary delivery, said composition comprising a . '1~ effective amount of mterferon in ~ ' with a 1' 'Iy acceptable carrier.
Another aspect of this invention is a unit dosage form for pulmonary delivery ofinterferon, which dosage form comprises a unit receptacle containing the interferon-based dry powder composition of this invention.
A tbird aspect of this invelltion is a method of treating a disease state responsive to treatment by interferon, which method comprises ' _ a yh~ , effective amount of the interferon-based dry powder composition to tbe pulmonary region of the lung of a subject im need thereof.
Still another aspect of this invention is a method for aerosolizing the interferon-based dry powder composition tbat comprise dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing tbe aerosol in a chamber having a moutbpiece for subsequent inbalation by a patient.
Still anotber aspect of tbis invention is a metbod for preparing the interferon-based dry powder , that comprises spray-drying an aqueous mixture of tbe interferon and tbe carrier under conditions to provide a respirable dry powder.
DF~fRlPTlON OF ~PECIFIC EMBODIMENTS
WO95131479 21 ~ 2 ~ c The preseM invention is based at least m part on the higher potency and improvedflow ~ of interferon-based dry powder . produced by spray drying æcording to the present invention. Higher potency means that the resulting interferon-based , has a higher peKentage of 1~ 'og "~, ætive interferon than 5 . . prepared by other methods. The ~ of the invention are readily aerosolized and rapidly absorbed through the lungs of a host when delivered by a dry powder inhaler.
DEFINITIONS
In interpreting the claims to the various aspects of this invention, there are several important definitions that should be considered.
Tbe term "interferon" is meant to include the family of naturally-occurring or IC ' 1~, prepared small proteins and ~ u~,.utu;..~ (sometimes referred to as cytokines) with molecular weight between ~ 15,000 and 27,000 daltons and having interferon-like ætivity. Generally, such activity is exerted by binding to specific membrane receptors on a cell surface. Once bound, interferons initiate a complex series of " ' events that vary among tbe various interferons. Interferons are useful in the treatment of a variety of human conditions varying from cancer to immune system suppression. Naturally occurring interferons are produced and secreted by cells in response to viral infections and to synthetic and biological inducers. Some interferons are modified versions of the naturally occurring material and are prepared using ' DNA
tcchnology. Interferon is sometimes abbreviated as "IFN" and shall be so abbreviated in this application. Examples of interferons include, e.g. IFN-alpha-2A l ' (RoferonD A-Roche 1. ' ~), IFN-alpha-2B 1~ ' antronl A-Shering), IFN-alpha-N3 human leukocyte derived (Alferonl N-Purdue Frederick), IFN-gamma-lB
(Actimmune~-Genentech), IFN-beta ' (Betaseron~-Chiron, Berlex), IFN-beta naturally occurring aFeron~-Toray, ~apan), and the like. U.S. Patent 4,503,035 issued March 5, 1985 to Pestka and Rubinstein gives examples of human leukocyte IFNs. For purposes of this invention IFN-beta is preferred, particularly naturally occurring IFN-beta.
The term "powder" means a . that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an irlhalation device and ' . '~, inhaled by a subject so that the particles reæh the lungs to permit penetration into the alveoli. Thus, the powder is said to be "respirable." Preferæbly the average particle size is less than ~out 10 microns (~m) in diameter with a relatively WO95131479 2~ q~502 ~ 6 uniform spheroidal shape " ' More preferably the diameter is less than about 7.5ym and most preferably less than about 5.0 ym. Usually the particle size distribution is between about 0.1 ym and about 5ym in diameter, particularly about 2 ym to about 5 ym.
The term "dry" meams that the . . has a moisture content such that the particles are readily dispersable in an inhalation device to form an aerosol. This moisture content is generally below about 10% by weight (%w) water, usually below about 5%w and preferably less than about 3%w.
The term "~ ly e~fective amount" is the amount present in t~hie .
that is needed to provide tbe desired level of interferon in tbe subject to be treated to give 10 the anticipated l,h~.iolo~,k,al respollse. Tbis amount is determined for each interferon on a ""._ hJ c~ . basis. Guidelines are given hereafter.
The term ''~,h.~Diulo~h,~lly effective amount" is tbat amount delivaed to a subject to give the desired palliative or curative effect. Tbis amount is specific for each interferon and its ultimate approved dosage level. Guidelines are given hereafter.
The term ''l ' "~, acceptable" carrier means that the carrier can be taken into tbe lungs witb no significamt adverse l- ,; .IAg!~ ~1 effects on thie lungs.
COMPO!~ITIONS OF THE INVENTION
One aspect of this inventiorl is an interferon-based dry powder composition for 20 pulmonary delivery, the . . comprising a Ih- '`I " i~ lly effective amount of interferon in ' with a l,h ~ lly acceptable carrier.
In general, the . of this invention have a higher IFN p~tency and greater ily than other interferon ~ known in the art. In the dry shte IFN is an amorphous forln. The IFNs suihble for use in the composition of this invention include 25 the various IFN alphas, IFN behs and IFN gammas ~ . ' by tbe broad definition of IFN. The IFN alphas and IFN behs are preferred, with IFN beh being patticularly preferred. The . is particularly valuable for naturally occurring IFN beh~ for example that available through Toray Industries, Inc. in Japam.
A i' ~ "~, effective amount of IFN will vary in the composition dependimg on 30 the biological activity of the IFN employed and the amount needed im a unit dosage form.
Because IFN is so highly active it ~nust be r ' U;l in a unh basis in a malmer that allows for ready , ' by the formulator and by the consumer. This generally means that a unit dosage will be between about 0.5 mg and 15 mg of tohl material in the dry powder ~ . , preferably between about 2 mg and 10 mg. Generally, the WO 95/31479 2 !1, qQ F~ ~ ~ p~""~
amouDt of IFN in the . will vary from about ~0.05%w to about 5.0%w. Most preferably the . will be about 0.2% to about 2.0%w IFN.
The amount of the ~,h_.,... _ t;~ ,~lly acceptable carrier is that amount needed to provide the necessary stability, d;.~J.,.g;l,iliLy, consistency and bulking ~ toS ensnre a uniform pulmonary delivery of the composition to a subject in need thereof.
, the amount may be from about 95.0%w to abont 99.95%w, depending on the activity of the IFN being employed. Preferably about 9$%w to about 99.8%w will be used.
The carrier may be one or a ' of two or more, ' ' excipients, but will generally be ' "~, free of any "penetration enhancers." "Penetration enhancers" are surfaoe active compounds which promote penetration of a drug through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug ' ' Exemplary penetration enhancers include bile salts, e.g., , ' ' , ~Iyl ' ' , and ~Ay, ' ' , fusidates, e.g., i u~i~,hyJ~ and b;.J. .- ~ detergents, e.g., Tweens, Laureth-9, and ihe like. The use of penetration enbancers in ' ' for the lungs, however, is generally undesirable because of theepithelial blood barrier in the lung can be adversely affected by such surface active compounds. The dry powder . of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
The types of l ' ' excipients that are useful as carriers in this invention mclude stabilizers such as human serum albumin (HSA), bulking agents such as uhJ~' amino acids and puly~ ikl~D~ pH adjusters or buffers; salts such as sodiumcbloride; amd the like. These carriers may be in a crystalline or amorphous form or may be a miAture of the two.
It has been found that HSA is particularly vaiuable as a carrier in that it provideg eAxcellent ctshiii7stjnn of IFN in solution.
Bulking agents that are particularly vaiuable include compatible ~ ully~' ,uly~ ,tid g, amino acids or ~ ' thereof. Suitable ~buhr~ include such as gaiactose, D-mannose, sorbose, and the like; ~i: - h_ i l'-, sucb as lactose, trehaiose, and tbe like; ~y~ , such as 2 h~ ' y~u~l ,5~y~,lùd~,AL~
amd puly~- h_ ;~i. `, such a raffinose, ' ' , dextrans, and the like; aiditols, such as mannitol, xylitol, and the iike. A preferred group of u~ubuhy~' includes lactose, threhaiose, raffinose ' ' and marmitol. Suitable pul~Li~i.,g include aspartame.
Amino acids include aianine and glycine, with glycine being preferred.
WO9~/31479 2 1 ~ ~5 0 2 T_l/u~ .
Additives, which are minor components of tbe composition of tbis invention, may be included for ~ ' stability during spray drying amd for improving Ai,,.. .~ y of tbe po~der. These additives include h~l., . ' ' amino acids such tryptophan, tyrosme, lucine, l' ,' ' , and the like.
Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred.
The unit dosage form, method of treatment, and process of preparation of this invention are described hereafter.
Unit D Fsrm Another aspect of this invention is a unit dosage form for pulmonary delivery ofinterferon, which dosage form comprises a unit dosage re~eptacle containing an interferon-based dry powder . which composition comprises a ~ , effective amount of an interferon in ' with a l ' 'l~, acceptable carrier.
In this aspect of the invention, the composition of tbis invention (as discussedr t) iS placed within a suitable dosage receptacle in an amount sufficient to provide a subject with }FN for a unit dosage treatment. The dosage re~eptacle is one that fits within a suitable inhalation device to allow for the ~lo~uli4aLiu~ of the interferon-based dry powder ~ . by dispersion into a gas stream to form an aerosol and then captnrimgtbe aerosol so produced in a chamber having a mouthpiece attached for subsequentinhalation by a subject in need of treatment. Such a dosage receptacle includes amy container enclosing the . ' ' known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the contamer to disperse the dry powder . Such containers are exempliffed by those shown in U.S. Patents 4,227,522 issued October 14, 1980; 4,192,309 issued March 11, 1980; and 4,105,027 issued August 8, 1978. Suitable containers also include those used in conjunction with Glaxo's Ventolin Rotohaler brand powder inhaler or Fison's Spinhaler bramd powder inhaler. Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate. The IFN-beta powder is fflled by weight or by volume into the depression in the formable foil and ~ ",ysealed with a covering foil-plastic laminate. Such a container for use with a powder inhalation device is described in U.S. Patent 4,778,054 and is used with Glaxo's DiskhaleP
W09513t479 ~I gQ5~)2 I~
.
(U.S. Patent~s 4,627,432; 4,811,73i; and 5,035,237). All of these references are ' herein by reference.
~ ' ' ' of Treating a Disease ,c Another aspect of this invention is a method of treating a condition responsive to treatment by interferon, which method comprises l ' '~ ' v to a subject in need thereof a ~hJ~;ulu~;i.,~lly effective amount of an interferon-based dry powder that comprises a i' ~ ; "y effective amount of an interferon m with a l,l~ dl.y acceptable carrier.
Conditions that may be treated by the , of this invention include those conditions that are responsive generally to treatment with IFN. For example, IFN alpha is used to treat hepatitis B and C, Hairy Cell Leukemia, chronic hepatitis Non A, Non B/C
and Kaposi's Sarcoma; IFN beta is used to trea~ multiple sclerosis, brain tumor, skin cancer and hepatitis B and C; and IFN gamma is used to treat cllronic v ' dise~se.
The l,h~,;olog;v~lly effective amount ne~ded to treat a particular condition or disease state will depend on the individual, the condition, length of treatment, the regularity of treatment, the type of IFN, and other fætors, but can be determined by one of ordinary skill in the medicinal arts. The dosage may range from .25 x 106 IU to 50 x 10~ IU per person per day depending on the prescribing doctor's diagnosis. For example an induction dosage of IFN alpha ll ' (Roferon~A-Roche I . ' ) for treatment of hairy cell leukemia may be 3 x 10~ IU daily for 16-24 weeks with a dose of 3 x 10 IU three times per week. Other dosage regimes may be determined through clinical trials amd reference to the Physicians Desk Reference~ for 1994 as ,, ' It is presently believed that the effective absorption by a host of dry powder interferon æcording to the present invention results from a rapid dissolution in the ultra-thin (< 0.1 fm) fluid layer of the alveolar lining of the lung. The particles of the present invention thus have a meam size which is from 10 to 50 times larger tham the lung fluid layer, making it unexpected that the particles are dissolved and the interferon systemically absorbed in a rapid malmer for either local lung or systemic treatment. An, of the precise mechanism, however, is not necessary for practicing the present invention as described herein.
The ærosolized interferon-based dry powders of this invention are particularly useful in place of parenteral delivery. Thus, the methods and , of the present invention will be particularly valuable in chronic treatment protocols where a patient can WO9~/31479 21 9~r~ r ", c., .~
.
sclf ~ ' Tbe patient carl æhieve a desired dosage by inhaling an appropriate arnount of interferon, as just described. The efficiency of systemic interferon delivery via the method as just described will typically be in the range from about 15% to 50%, with individuai dosages (on a per iMaiation basis), typicaily being in the range from about 3 million IU to about 50 million IU during a single respiratory ' Thus, the deslred dosage may be effected by the patient taicing from I breath to 5 bteaths.
r~ for Aern~r~li7i~ ' Powder Stiil another aspect of this invention is a method for aerosolizing am interferon-based dry powder , that comprises a i' , "~! effective amount of am interferon in ' - with a 1 ' "~, acceptable carrier, which method comprises dispersing an amount of the dry powder composition in a gas stream to form an aerosol amd capturing the aerosol in a chamber having a mouthpiece for subsequent iMaiatiOn by a patient.
A further detaiied description of this method is found in pending U.S. Patent Applications Ser. Nos. 071910,048 amd 08/207,472, both of which are . ' herein by reference.
Preparin~ the t' Still amother aspect of this invention is a method for preparing an interferon-based dry powder ~ . of this invention that comprises spray-drying an aqueous mixture of the interferon and a ~ ly acceptable carrier having an interferon pH under conditions to provide a respirable dry powder Spray drying is a process in which a 1~ aqueous mixture of IFN and the carrier is introduced via a no~le (e.g., a two fluid no_zle), SpiMing disc or an equivalent device into a hot gas stream to atomi7e the solution to form fine droplets. The aqueous mixture may be a solution, suspension, slurry, or the iiice, but needs to be 1- O to ensure uniform distribution of the components in tbe mixture and ultimately the powdered Preferably the aqueous mixture is a solution. The solvent, generaily water, rapidly evaporates from the droplets producing a flne dry powder having particles I to 5 ~Lm in diameter. S , ~'~" the protein is not degraded when it is exposed to the hot drying gas, and the interferon powders can be prepared having suffcient purity for , 1 -- . ---: ,~ use. An acceptable purity is defined as less than 5% degradation products and , preferably les~ tilam 3 % amd most preferably less than 1% .
WO95/31479 21 qO 502 r~l"~ , .
The spray drying is done under conditions that result in ' '~, amorphous powder of I " constitution having a particle size that is respirable, a low moisture content and flow ~ GlG~t~ Li~,~ that ailow for ready G_lU~UIi~iiUII. Preferably the particle size of the resulting powder is such that more than about 98 % of the mass is in particles having a diameter of about 10 ~m or less with about 90% of the mass being in particles having a diameter less than 5 ~m. Alternatively, about 95% (preferably more than 95%) of the mass will have particles with a diameter of less than 10 ~m with about 80% (preferably more tham 80%) of the mass of tbe particles having a diameter of less tban 5 ym.According to the methods of the present invention, interferon dry powders of higher potency and improved flow ~ are prepared by spray drying, where, bulk mterferon, preferabiy IFN-beta but suitably other forms of interferon, is prepared in solution to have a a~iull from 0.0005% by weight to 0.02% by weight, usuaily from 0.001% to 0.005%. The solutions may contain a stabilizer to maintain the chemicai stability of the IFN-beta in solution such as HSA in a from 0.01~ to 1.0% by weight and preferably 0.05% to 0.25% by weight and may contain other materiai such as a sait or p- G ~GI ~ d i ~ _ that is present as a result of the preparation of bulk IFN . The solutions may then be sprayeo dried in ,u..~ tiOIldi spray drying equipment from commerciai suppliers, such as Buchi, Niro, Yamato Chemicai Co., ~kawara Kakoki Co., amd the like, resulting in a ' "~ amorphous particulate product.
For the spraying process, such spraying methods as rotary pressure atomization and two-fluid atomization can be used. Examples of the devices used in these processes include "Pulvis Mini-Spray GA-32" and "Pulvis Spray Drier DL~I", r ' G~i by Yamato Chemicai Co., or "Spray Drier CL-8," "Spray Drier L-8," "SprayDrier FL-12," "Spray Drier FL-16" or "Spray Drier FL-20," r ' e,d by Okawara Kakoki Co., cam be used for the method of spraying using rotary-disk atomizer.
While no speciai restrictions are placed on the nozzle of the atomizer used in the process of spraying, it is ' ' to use a nozzle which can produce a spray-dry rn~rn~;rinn with a gr~un diameter suitable for nasai, pharyngeai or pulmonary _' For example, nozzle types "IA," "1," "2A," "2," "3" and the like, r ' G~i by Yamato Chemicai Co., can be used for the dbU._: ' spray-drier, r ' ~ by the same company. In addition, disics type "MC-50," "MC~5" or "MC-85," r Gd by Okawara Kakoki Co., can be use~i as rotary disics of the spray-orier atomizer, r ' ~ by the same company.
WO95/31479 2 1 9 ~5 02 I~I/L.~ _ G
Wbile no particular restrictions are placed on tbe gas used to dry the sprayed materiai, it is ,~ ' ' to use air, nitrogen gas or am inert gas. The temperature of the iniet of the gas used to dry the sprayed materiais such that it does not cause heat deactivation of the sprayed materiai. The range of i . ~ may vary between about 50CC to about 200C, preferable between about 50C and 100C. The temperature of the outiet gas used to dry the sprayed materiai, may vary between about 0C amd about 150, preferably between 0C and 90C, and even more preferably between 0C and 60C. The fact that iniet amd outlet L...,,. ci:~ above about 55C can be used is surprising in view of the fact that IFN starts deactivating at that temperature, with nearly complete deactivation 10 occurring at about 70C.
By minimizing the amount of stabilizer in the solution, high potency iFN powder cam be prepared such that the number of inhaiations required to deliver even high dosages of IFN can be ' "~, reduced, often to oniy a single inhaiation.
Interferon dry powders suitable for use in the present invention are ' "~
15 amorphous, esseDtiaily lacicing any crystaiiine structure. Dry powder interferons are prepared by spray drying under conditions which result in a ' "~, amorphous powder having a particle size within the above-stated range. Accordmg to the method of ti~e present invention, bulic interferon, preferably IFN-,~ but suitably other forms of imterferon, is first dissolved in a ~Ih~ 'o" "~,-acceptable aqueous solution typicaily 20 containing sodium chloride, optionally with a buffer, having a pH in the ramge from about 2 to 9. The interferon is dissolved at a ~ from 0.01% by weight to 1% by weight, usuaily from 0.1% to 0.2%. The solutions may then be spray dried in Cu..~ iU..di spray drying equipment from commerciai suppliers, such as Buchi, Niro Yamato, Okawara Kaicoici amd the liice, resulting in a ' ''~ amorphous particulate product.
The interferon dry powders of the present invention may optionaily be combined with ~ carriers or excipients which are suitable for respiratory and pulmonary - ' Such carriers may serve simply as bulicing agents when it is desired to reduce the interferon in the powder which is being delivered to a patient, but may aiso serve to enhance the stabiliy of the interferon , amd to improve the ~ y of the powder within a powder dispersion device in order to provide more efficient and l~-uJu~ delivery of the interferon and to improve handling . .-- A. t ;~
of the interferon such as flowabiliy and consistency to facilitate r and powder fiiling.
.
W095131479 ~ a 2 r~l, 5Cf ~r Such carrier materials may be combined with the interferon prior to spray drying, i e., by adding the carrier material to the purifled bulk solution. In that way, the carrier particles will be formed ' '~, with the IFN particles to produce a I
powder. Alternatively, the carriers may be separately prepared in a dry powder form and 5 combined with the dry powder interferon by blending. ~he powder carriers will usually be crystalline (to avoid water absorption), but might in som~ cases be amorphous or mixtures of crystallme and amorphous. The size of the carrier particles may be selected to improve the flowability of the IFN powder, typically being in the range from 25 ~Lm to 100 ILm. A
preferred carrier material is cryst~lline lactose having a size in the above-stated range.
EXPERIMENTAL
Examvl~ l This example sets forth a method of preparing a composition of this invention.
A~",., 'y 50 mL of 10 mM sodium chloride solution of natnral human IFN-15 beta comprising rr ' ' ~12 mg/ml HSA was prepared.
The resnlting aqueous mixtnre is fed to a Buchi Laboratory Spray Dryer under the following conditions to give a ~ . of this invention:
Temperature of the aqueous mixture 4C-10C
Inlet temperature 115C-125C
Feed rate 6 mL/mirl Outlet temperature 60C-70C
Once the aqueous mixture is consumed, the outlet temperature is maintained at about 70C for about 15 minutes by slowly decreasing the inlet i . This provides a 25 secondary drying to give an IFN-based dry powder composition having a water content of less than 3% as measured by a coulombic Karl Fischer method. In this case the (%w based on total solids) is constituted as follows:
I .9%w IFN-beta 98.1%w Carrier (75.8% HSA, 22.3 NaCI) Exam~le 11 By following the procedure of Example 1, but increasing the outdet tcmperature to 75C-80C during the secondary drying stage, one obtains a composition of this invention 35 having less than I %w water.
WO 95/31479 2 1 q ~ 5 G 2 ~ cr F ' 111 This example sets forth a method of preparing a . . of this invention whaein the carrier includes a bulking agent, i.e., mammitol.
Mannitol is dissolved in natural human IFN-beta described rn Example 1. The S I of mannitol was 5.75 mg/mL.
The resulting aqueous mixture is fed to a Buchi Laboratory Spray Dryer under thefollowing conditions:
Temperature of the aqueous mixture 4CC-10C
Inlet temperature 115C-125C
Feed rate 5 mL/min Outlet temperature 60C-70C
Secondary drying- 15 minutes at 70C
Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of, ' " ~ it will be obvious that certain changes and ~ ~ may be practiced within the scope of the appended claims.
F ' IV
This example sets forth a method for preparing a composition of this invention wherein no bul~ing agent is prese~t in the ~ .
A~",., 'y 100 ml of 10 mM sodium chloride solution of natural humam mterferon (obtained by culturing human normal diploid fibroblasts) (~ 1y 7 x 10'IUlml) comprising ~ ,., 'y 2 mg/ml human serum albumin (HSA) were prepared, and spray-dried using the commercial spray-drier "13ulvis Mini-Spray GA-32,"
r ' cd by Yamato Chemical Co. The spray nozzle used was a IA nozzle (~ 0.4 mm) and the inlet temperature and the outlet temperature of the drying gas were 100C amd 60C, respectively. In addition, tlle spray pressure was I kg/cm2, the flow capacity of the hot air was 0.40 to 0.42 m3/min and the rate of solution i was 4.3 ml/min.
After ,1~ 'y 20 min. of spray-drying, the dry powder, which was collected into achamber using a cyclone, was recovered, and the interferon (IFN) activity was measured.
The interferon activity was measured using an enzyme J (EIA) involving an amti-humam interferon 3 antibody (S. Yamazal~i et al., ~ " 10, 57(1989)). The activity of the dry powder was measured by dissolvrng the dry powder using distilled water WO95/31479 ~ l 9~ 5 02 y~uv ~ ~
and comparing its interteron activity, ~ . ' v to the light absorption at 280 mm, with the interferon activity prior to the spray-drying process. The results are shown in Table 1.
The ~ were repeated three times, and the average values were used for the ~r~n~p jcnn The error in the relative activity in the table is a standard error (i SE).
Table I
Natural human interferon ,~ activity before and after spray-dr,ving Relative activity aU/A 280 unit) Remaining activity (%) Before spray-drying 4.11 i 0.11 100 After spray-drying 3.14 i 0.04 74.8 After the spray-drying process, the natnral human interferon ~ showed an interferon activity which was 74.8% of its activity prior to the spray-drying process, indicating that it can be spray-dried while maintaining its activity. These results are surprising because a similar natnral human interferon ,~ solution comprising a similar quantity of HSA will start 15 deactivating at "~", ly 55C, with complete deactivation occuring at 70C.
The dry powder obtained by the process of this invention was subjected to platinum coating and the shape of its grains was examined using a field emission scan electron microscope (model S-8000, r ' vd by Hitachi Co.). A~ 90% of the grains examined were grains with relatively smooth and large dents and protrusions in the 20 grain surface, and with a grain diameter of ,Iy~ 101~m. In addition, the resulting powder exhibited a moisture content of 5.6 wt% using the Karl Fischer method (coulometric titration r ' ~ CA-06, ~ vd by Mitsubishi Kasei Co.).
ExamDle V
25 This example sets forth a method for preparing an IFN/HSA/mannitol c~ inn A,. l~, 100 ml of lOmM sodium chloride solution of natnral human interferon comprising 150 mg/ml mannitol and ~.., 'y 2 mg/ml human serum albumin aHSA) were prepared. The proportion of the mannitol to the total solutes in this solutlon was ~ , 90 wt%.
30 The above solution was spray-dried using the same method and the same conditlons as In Example IV, and the interferon activity of the dry powder obtained was measured using the same method as in Example IV. The results are shown in Table 2.
Table 2 Natural human interferon ,~ activity before and after spray-drying WO95131479 2 i 9 C5~2 Relative activity aU/A 280 unit) Remaining activity (%) Before spray-drying 5.59 + 0.51 100 Afterspray-drying 4.53 + 0.13 81.0 5 After the spray-drying process, the natural human interferon ,~ maintained 81.0% of its activity compared with its activity prior to the spray-drying process. As in Example IV, these results are surprising because a similar aqueous solution of the same quantity of natural human interferon ,~, HSA and mannitol started to deactivate at ~ , 55C,witb almost complete deactivation occurring at 70C.
10 While the IFN-based powder from Example IV and V are dispersible, the powder obtained from Example V was more readily dispersed than the powder obtained in Example IV.
When the grain shape was examined by subjecting the powder to platinum coating and using a field emission scan electron microscope (model S-8000, r ' ed by Elitachi Co.), the grains were found to have a size similar to those of Example IV but a shape more 15 rounded compared with the powder particles obtained in Example IV. In addition, when the distribution of the grain diameter of the powder was measured by dispersing it in ethanol anhydride amd using a gran~lation amalyzer (Microtrac FRA, r ' ~ by Ni~lciso Co.), it was found that ~ , 90% of the grains were distributed within the range of 1.6 to 9.3 ~m. The moisture content was 0.74 %wt, as measured by the Karl 20 Fischer method of Example IV
All publications and patent applications mentioned in this 5, "- - are herein . ~ by reference to the same extent as if each individual publication or patent application wa~ specifically and individually indicated to be . ' by reference.
The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes amd, ~ ., can be made thereto without departing from the spirit or scope of the appended claims.
Claims (26)
1. A spray-dried, interferon-based dry powder composition for pulmonary delivery, said composition being prepared from an aqueous solution of the interferon and comprising a therapeutically effective amount of interferon in combination with a pharmaceutically acceptable carrier.
2. The composition of claim 1, wherein the composition is substantially free from penetration enhancers.
3. The composition of claim 2, wherein the carrier comprises human serum albumin.
4. The composition of claim 3, wherein the carrier further comprises a carbohydrate bulking agent.
5. The composition of claim 4, wherein the carrier is mannitol.
6. The composition of claim 4, wherein the carrier is raffinose.
7. The composition of claim 1, wherein about 95 % of the mass of the dry powder composition has a particle size of less than 10 µm.
8. The composition of claim 7, wherein about 80% of the mass of the dry powder composition has a particle size of less than 5µm.
9. The composition of claim 1. wherein the interferon is naturally occurring.
10. The composition of claim 1, wherein the interferon is interferon beta.
11. A unit dosage form for pulmonary delivery of interferon, which dosage form comprises a unit dosage receptacle containing a spray-dried, interferon-based dry powder composition, which composition is prepared from an aqueous solution of the interferon and comprises a therapeutically effective amount of an interferon in with a pharmaceutically acceptable carrier.
12. The unit dosage form of Claim 11, wherein the carrier comprises human serum albumin or human serum albumin and a carbohydrate bulking agent, the composition is substantially free from penetration enhancers and about 95 % of the mass of the dry powder composition has a particle size of less than about 10µm.
13. A method of treating a disease state responsive to treatment by interferon, which method comprises pulmonarily administering to a subject in need thereof a physiologically effective amount of a spray-dried, interferon-based dry powder that is prepared from an aqueous solution of the interferon and that comprises atherapeutically effective amount of an interferon in combination with a pharmaceutically acceptable carrier.
14. The method of Claim 13. wherein the carrier comprises HSA and a carbohydrate bulking agent, the composition is substantially free from penetration enhancers and about 95 % of the mass of the dry powder composition has a particle size of less than about 10µm.
15. A method for aerosolizing a spray-dried, interferon-based dry powder composition that comprises a therapeutically effective amount of an interferon in composition with a pharmaceutically accepted carrier, which method comprises:
dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing the aerosol in a chamber suitable for subsequent inhalation by a patient.
dispersing an amount of the dry powder composition in a gas stream to form an aerosol and capturing the aerosol in a chamber suitable for subsequent inhalation by a patient.
16. The method of claim 15. wherein the carrier comprises HSA and a carbohydrate bulking agent, the composition is substantially free from penetration enhancers and about 95% of the mass of the dry powder composition has a particle size of less than about 10µm.
17. A method for preparing a spray-dried, interferon-based dry powder composition that comprises a therapeutically effective amount of an interferon and a pharmaceutically acceptable carrier, which method comprises spray-drying an aqueous solution of the interferon and the carrier under conditions to provide a respirable dry powder.
18. The method of Claim 17 wherein the composition is substantially free from penetration enhancers.
19. The method of Claim 18, wherein the carrier comprises HSA.
20. The method of Claim 19, wherein the carrier further comprises a carbohydrate bulking agent.
21. The method of Claim 20, wherein the bulking agent is mannitol.
22. The method of Claim 20, wherein the bulking agent is raffinose.
23. The method of Claim 17, wherein 95% of the mass of the spray-dry composition has a particle size less than 10µm.
24. A spray-dried, interferon-based dry powder composition for pulmonary delivery, said composition being prepared from an aqueous solution of the interferon-beta and comprising a therapeutically effective amount of naturally occurring interferon-beta in combination with a pharmaceutically acceptable carrier that comprises human serum albumin or human serum albumin and a carbohydrate bulking agent, wherein the composition is substantially free from penetration enhancers and about 95% of the mass of the dry powder composition has a particle size of less than 10µm.
25. The composition of Claim 24, wherein the bulking agent is mannitol.
26. The composition of Claim 24, wherein the bulking agent is raffinose.
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| US24603494A | 1994-05-18 | 1994-05-18 | |
| US08/246,034 | 1994-05-18 |
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| CA2190502A1 true CA2190502A1 (en) | 1995-11-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002190502A Abandoned CA2190502A1 (en) | 1994-05-18 | 1995-05-15 | Methods and compositions for the dry powder formulation of interferons |
Country Status (13)
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| US (4) | US6231851B1 (en) |
| EP (1) | EP0759939B1 (en) |
| JP (1) | JPH10500672A (en) |
| KR (1) | KR100384353B1 (en) |
| CN (1) | CN1073119C (en) |
| AT (1) | ATE299892T1 (en) |
| AU (1) | AU696387B2 (en) |
| CA (1) | CA2190502A1 (en) |
| DE (1) | DE69534318T2 (en) |
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| MX (1) | MX9605717A (en) |
| NZ (1) | NZ285664A (en) |
| WO (1) | WO1995031479A1 (en) |
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- 1995-05-15 ES ES95919181T patent/ES2245780T3/en not_active Expired - Lifetime
- 1995-05-15 CA CA002190502A patent/CA2190502A1/en not_active Abandoned
- 1995-05-15 AT AT95919181T patent/ATE299892T1/en not_active IP Right Cessation
- 1995-05-15 KR KR1019960706515A patent/KR100384353B1/en not_active IP Right Cessation
- 1995-05-15 JP JP7529809A patent/JPH10500672A/en active Pending
- 1995-05-15 WO PCT/US1995/006008 patent/WO1995031479A1/en active IP Right Grant
- 1995-05-15 MX MX9605717A patent/MX9605717A/en not_active IP Right Cessation
- 1995-05-15 AU AU25142/95A patent/AU696387B2/en not_active Ceased
- 1995-05-15 CN CN95193669A patent/CN1073119C/en not_active Expired - Fee Related
- 1995-05-15 NZ NZ285664A patent/NZ285664A/en not_active IP Right Cessation
- 1995-05-15 US US08/737,724 patent/US6231851B1/en not_active Expired - Fee Related
- 1995-05-15 EP EP95919181A patent/EP0759939B1/en not_active Revoked
-
1999
- 1999-11-22 US US09/444,116 patent/US6123936A/en not_active Expired - Fee Related
-
2000
- 2000-02-17 US US09/506,426 patent/US6479049B1/en not_active Expired - Fee Related
-
2002
- 2002-09-18 US US10/245,704 patent/US20030072718A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR100384353B1 (en) | 2003-10-04 |
| CN1073119C (en) | 2001-10-17 |
| EP0759939A4 (en) | 1998-05-27 |
| US20030072718A1 (en) | 2003-04-17 |
| EP0759939A1 (en) | 1997-03-05 |
| CN1151168A (en) | 1997-06-04 |
| US6231851B1 (en) | 2001-05-15 |
| US6123936A (en) | 2000-09-26 |
| AU2514295A (en) | 1995-12-05 |
| KR970703366A (en) | 1997-07-03 |
| NZ285664A (en) | 1998-07-28 |
| MX9605717A (en) | 1998-05-31 |
| DE69534318T2 (en) | 2006-04-20 |
| ES2245780T3 (en) | 2006-01-16 |
| DE69534318D1 (en) | 2005-08-25 |
| EP0759939B1 (en) | 2005-07-20 |
| WO1995031479A1 (en) | 1995-11-23 |
| ATE299892T1 (en) | 2005-08-15 |
| AU696387B2 (en) | 1998-09-10 |
| US6479049B1 (en) | 2002-11-12 |
| JPH10500672A (en) | 1998-01-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |