WO1998047536A1 - Controlled release of ophthalmic compositions - Google Patents
Controlled release of ophthalmic compositions Download PDFInfo
- Publication number
- WO1998047536A1 WO1998047536A1 PCT/NZ1998/000051 NZ9800051W WO9847536A1 WO 1998047536 A1 WO1998047536 A1 WO 1998047536A1 NZ 9800051 W NZ9800051 W NZ 9800051W WO 9847536 A1 WO9847536 A1 WO 9847536A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclodextrin
- drug
- conjugate
- patient
- ophthalmic
- Prior art date
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Definitions
- This invention relates to carboxylic acid containing polymer - cyclodextrin conjugates, the use of such conjugates in the preparation of ophthalmic compositions, and to methods of treating ophthalmic conditions using these ophthalmic compositions.
- Localised delivery means that limited amounts of a therapeutic composition can be provided directly to the target site. Localised delivery therefore has significant benefits over systemic delivery which is untargeted, uses larger amounts of the therapeutic composition to be delivered, and results in lower levels of the therapeutic composition in the eye than is the case with localised delivery.
- compositions administered show low bioavailability, commonly in the order of only one to two percent, and also exhibit considerable variability in the amount of composition delivered at any given time.
- residence time for compositions in the eye tends to be very short, and this is problematic especially for those compositions with a short half life.
- frequent dosing is required which is generally inconvenient and undesirable from a patient's perspective.
- bioadhesive polymers have been used as platforms for drug delivery to various mucosal membranes of the body including those of the eye, nose, mouth, vagina, rectum and gastro-intestinal tract.
- bioadhesive polymers can exert some control over the rate and amount of drug being released.
- their ability to control drug release is limited and control is often more a function of the drug than the polymer. Consequently, for some drugs, enhanced retention of the delivery platform at the adsorption site is achieved but the drug is poorly retained.
- Carboxylic acid containing polymers have been used as bioadhesive polymers.
- carboxylic acid containing polymers include polyacrylic acid (PAA), carboxymethyl cellulose and hyaluronic acid.
- PAA polyacrylic acid
- carboxymethyl cellulose carboxymethyl cellulose
- hyaluronic acid polyacrylic acid polymers are described as having the ability to interact with mucous membranes and so form a drug delivery platform.
- Cyclodextrin inclusion complexes have also been described. Cyclodextrins are cyclic oligosaccharides which have a hydrophobic core and a hydrophilic exterior. The hydrophobic core enables cyclodextrins to form inclusion complexes with a wide range of drug molecules. The inclusion complex formed is not permanent, rather, it is in equilibrium with the free drug. Thus, if the free drug is removed from the system, the complex will disassociate to re-establish the equilibrium. Additionally, cyclodextrins are not absorbed across biological membranes. These two properties render cyclodextrins particularly useful in drug delivery as they can act as a drug reservoir, continuously replenishing the supply of free drug.
- Cyclodextrin polymers are disclosed in Cyclodextrin Containing Polymers, Harada. A et al, Macromolecules 5 (1976) 701-704. Conjugates of polyacrylic acid and cyclodextrin are also disclosed in Sustained-Release of Drugs from Cyclodextrin-Containing Hydrogels, Chino.M et al; Proceed.Intern.Symp. Control. Rel.Bioact. Mater. 18 (1992), Controlled Release Society Inc. at pages 98 and 99.
- Carboxylic acid containing polymer-cyclodextrin conjugates (CACP-CD) and more particularly polyacrylic acid - cyclodextrin (PAA-CD) conjugates, can be used to enable the controlled release of drugs.
- CACP-CD polymer-cyclodextrin conjugates
- PAA-CD polyacrylic acid - cyclodextrin
- CACP-CD conjugates when administered to the eye(s) of a patient can be used to increase bioavailability of an ophthalmically administrable drug encapsulated within the cyclodextrin portion of the CACP-CD conjugate. It is this general finding upon which the present invention is based.
- the object of the present invention is therefore to provide a pharmaceutical composition comprising a carboxylic acid containing polymer - cyclodextrin drug encapsulating conjugate composition which is formulated for ophthalmic administration, or at least to provide the public with a useful choice.
- the present invention can broadly be said to consist in an ophthalmically acceptable pharmaceutical composition
- an ophthalmically acceptable pharmaceutical composition comprising:
- the carboxylic acid containing polymer is a polyacrylic acid.
- Particularly preferred polyacrylic acids are Carbopol 934P, or polyacrylic acid having a molecular weight of 450,000.
- a preferred cyclodextrin is ⁇ -cyclodextrin, or a derivative thereof, particularly a hydroxypropyl derivative of ⁇ -cyclodextrin.
- the present invention relates to the use of a carboxylic acid containing polymer - cyclodextrin conjugate in the preparation of an ophthalmic solution suitable for ophthalmic administration to treat a medical condition in a patient, said medicament being in a form such that an ophthalmically administrable drug is encapsulated within the cyclodextrin portion of the conjugate.
- the present invention provides a method of treating a medical condition in a patient comprising the step of administering an ophthalmic composition as described above to the eye(s) of a patient in need thereof.
- the medical condition to be treated will be an ophthalmic medical condition.
- patient refers to human and non-human animal patients.
- Figure 1 is a graph illustrating the comparative bioavailability of hydrocortisone in a suspension formulation and as encapsulated in a cyclodextrin-Carbopol 934P conjugate in the cornea following topical application of 25 ⁇ l of a hydrocortisone formulation.
- Figure 2 is a graph illustrating the comparative bioavailability of hydrocortisone in a suspension formulation and as encapsulated in a cyclodextrin-Carbopol 934P conjugate in the aqueous humor following topical application of 25 ⁇ l of a hydrocortisone formulation.
- the present invention provides an ophthalmically acceptable pharmaceutical liquid composition incorporating a carboxylic acid containing polymer - cyclodextrin (CACP-CD) conjugate.
- CACP-CD carboxylic acid containing polymer - cyclodextrin
- the carboxylic acid containing polymer used in the formation of the conjugate may comprise any known carboxylic acid containing polymer. It is however currently preferred that the polymer be one already approved for human or animal uses and which is in the molecular weight range 1000 to 10 million.
- carboxylic acid containing polymers examples include hyaluronic acids, polyacrylic acids, polymethacrylic acids, polyethacrylic acids, carboxymethylcelluloses, and hydroxypropylmethylcellulose phthalate amongst others.
- polyacrylic acids especially Carbopol 934P, (available from B F Goodrich Co., Cleveland, Ohio, U.S.A.) and polyacrylic acid (Aldrich; MW 450,000 available from Aldrich Chemical Co., Milwaukee, Wisconsin, U.S.A.).
- Carbopol is the Registered Trade Mark of the Goodrich Company.
- Cyclodextrins used in the formation of the conjugate may comprise ⁇ -, ⁇ - or ⁇ - cyclodextrin or functionally equivalent variants or derivatives thereof.
- Cyclodextrins useful in the present invention include hydroxypropyl, hydroxyethyl, glucosyl, multosyl and multotryosol derivatives amongst others.
- a particularly preferred cyclodextrin is ⁇ -cyclodextrin available from the American Maize Products Co., Hammond, Indianapolis, U.S.A. Also preferred is the hydroxypropyl derivative of ⁇ -cyclodextrin.
- a preferred CACP-CD conjugate is a polyacrylic acid (PAA)- ⁇ -cyclodextrin conjugate, or a conjugate of a PAA and a hydroxypropyl derivative of ⁇ -cyclodextrin.
- the CACP-CD conjugates used in the invention may be prepared by conjugating a selected CACP to a selected CD using any conventional method known in the art.
- a preferred preparative method is to add a predetermined amount of a selected polyacrylic acid to a solution of dimethyl formamide containing N,N'- carbonyldiimidazoyl and 4-pynx>Hdinopyridine followed by the addition of a selected cyclodextrin in an appropriate ratio.
- the solution is then mixed for an extended period of time (in the order of two to five days).
- the PAA-CD conjugate is then isolated by standard precipitation techniques, followed by centrifugation. The conjugate produced is then purified.
- the ratio of cyclodextrin to polyacrylic acid is based on the number of cyclodextrin molecules present relative to the carboxylic acid groups on the polyacrylic acid.
- An appropriate ratio of the cyclodextrin to the carboxylic acids of the polyacrylic acid is from substantially 1: 1 to 1: 100.
- Preferred ratios of cyclodextrin to polyacrylic acid carboxylic acids are 1:50 and 1:60.
- the degree of substitution of the cyclodextrin is the number of carboxylic acid groups reacted with each cyclodextrin molecule.
- An appropriate ratio is 1: 1 to 1: 14.
- the solution is preferably mixed for approximately three days before precipitation.
- organic (e.g. ether) or acid precipitation is preferred.
- the conjugate once precipitated may be purified either by repeated washings with an acid, or by standard dialysis, ion-exchange and ultra filtration procedures.
- the product is additionally freeze-dried and ground prior to use.
- an ophthalmically administrable drug is encapsulated within the cyclodextrin portion of the PAA-CD conjugate formed above. Encapsulation of the selected drug may be achieved using conventional encapsulation techniques.
- a preferred encapsulation technique is to dissolve a selected PAA-CD conjugate in an appropriate solvent and to mix it with a selected ophthalmically acceptable drug. If the formulation is not to be used immediately it can optionally be freeze dried. If the formulation is freeze dried then the ophthalmic composition of the invention is subsequently prepared by dissolving the PAA-CD conjugate with encapsulated drug in an ophthalmically acceptable diluent or carrier such as water. Optionally, additional ophthalmically acceptable agents may be included in the formulation. Examples of such agents include buffers, salts to adjust tonicity, anti-microbial agents and chelating agents.
- the ophthalmic composition of the invention is prepared by mixing the PAA- CD conjugate with the drug to be encapsulated, a carrier or diluent, and optionally one or more ophthalmically acceptable agents as identified above, in a single process.
- the drug encapsulation step and preparation of the ophthalmic composition is accomplished by mixing a suspension of the PAA-CD conjugate with the drug to be encapsulated in water. The mixture is then probe sonicated for a short period (in order of 1 to 20 minutes) followed by a longer period of rotation (in the order of 12 to 36 hours) at a temperature of between substantially 25 to 45°C, and at a rotation rate of between about 15 and 75 rpm.
- the mixture is probe sonicated for approximately 2 minutes, followed by rotation end-over-end in a bottle for 24 hours at 33°C and at 45 rpm.
- the composition is for administration to the eye it is important that it be provided in a sterile condition. This can be achieved by preparing the composition under aseptic conditions or alternatively by sterilising the composition once produced. Suitable sterilisation techniques include radiation treatment, autoclaving, and filtration (for low MW conjugates) amongst others. The composition may then be stored at room temperature until required.
- drug is used in a broad sense to refer to compounds or compositions useful in methods of human and veterinary therapy.
- ophthalmically acceptable drugs for incorporation into the PAA-CD conjugate include antibacterials, antifungals, antivirals, anti-inflammatories, mydriatics, cycloplegics, miotics, beta-blockers, local anaesthetics, carbonic anhydrase inhibitors and immunosuppressants.
- the amount of the drug present in the formulation can of course be varied on a percentage w/v basis as desired. Generally the drug will be present in the formulation in a range of from 0.01 % to 5 % w/v formulation.
- the present invention relates to the use of a CACP-CD conjugate as described above in the preparation of an ophthalmic medicament suitable for opthalmic administration to treat a medical condition in a patient.
- the present invention relates to a method of treating a medical condition in a human or animal patient comprising the step of administering an ophthalmic composition of the invention to the eye(s) of a patient in need thereof.
- the medical condition to be treated will most usually be an ophthalmic condition such as bacterial, fungal or viral eye infections or inflammatory states.
- ophthalmic condition such as bacterial, fungal or viral eye infections or inflammatory states.
- conditions amenable to treat with the composition of the invention include glaucoma and conjunctivitis.
- the compositions may also be formatted as anaesthetics.
- an ophthalmic composition prepared as described above is instilled into the eye(s) of the patient using any conventional means such as an eye dropper, or squeeze bottle, or may be administered in the form of a gel, spray or insert.
- the amount of composition administered may of course vary with the drug being administered and according to the condition to be treated. For a solution such as a spray or eye drop it is anticipated that the amount administered would not exceed 50 ⁇ l (or 1 drop), for a gel it is anticipated that the amount administered would be in the order of 50-100 mg.
- the ophthalmic composition is administered to the eye(s) of a patient in need thereof. It has been found that some of the compositions of the invention when administered to the eye(s) surprisingly form a gel. This gel potentially assists in enhancing drug bioavailability.
- bioavailability of a drug from the PAA-CD conjugate may be increased from substantially 2 to substantially 10 times that of the availability of the drug from a suspension formulation of the drug alone. This increase in bioavailability was found to occur to varying degrees in all ocular tissues including the aqueous humour, cornea and iris/ciliary bodies.
- cyclodextrin-Carbopol 934P polymer Approximately 1.2g of the cyclodextrin-Carbopol 934P polymer was recovered. The product was found to contain 20% w/w ⁇ -cyclodextrin. This composition was confirmed by elemental analysis. The analyses suggests that one cyclodextrin molecule interacts with an average of 3.5 carboxylic acid groups of the poly (acrylic acid). The binding of the cyclodextrin to the polymer backbone is stable as determined by ultrafiltration.
- the product was then dissolved in water to a concentration of 3.3% w/v and stirred over a cation-exchange resin (amberlite IR20) for 30 minutes. The solution was adjusted to pH 5 and decanted. The product was further purified by ultrafiltration through a 10,000 molecular weight cutoff membrane washing 5 times with purified water. The product was finally isolated by freeze-drying. The product was found to contain 20% w/w ⁇ -cyclodextrin and had an aqueous solubility in excess of 25mg/ml.
- a cation-exchange resin amberlite IR20
- Example 4 Comparison of Ocular Bioavailability of a Hydrocortisone Formulated as a Suspension and as a Complex with a Carbopol 934P-Cyclodextrin Conjugate
- aqueous humour bioavailability (as determined by the area under the concentration time profile over the first 3 hours) of the 0.3% w/v formulation containing the cyclodextrin Carbopol 934P polymer was found to be 6-fold higher than that of the suspension formulation (see Figure 2).
- a similar increase in bioavailability was observed for the cornea (see Figure 1) and the iris/ciliary body. Bioavailabilities in all other ocular tissues were also increased to various magnitudes (at least 2-fold) by the cyclodextrin-Carbopol 934P polymer.
- an ophthalmic composition which enables the controlled release of an ophthalmically administrable drug and at bioavailability levels significantly enhanced from the bioavailability levels in cases where the drug is administered in a suspension or solution formulation by itself.
- the ophthalmic composition of the invention therefore provides advantages in treating medical and particularly ophthalmic conditions more effectively or at least provides an alternate and potentially superior mode of administration.
- the ophthalmic compositions of the present invention targeted localised delivery is achieved with prolonged drug residence times, reducing the need for frequent dosing. It is believed that adverse reactions, side effects and variability in amount of drug delivered should be reduced using the ophthalmic composition of the invention. Cost reductions are also possible in the treatment of ophthalmic conditions by being able to produce more effective drug formulations.
- drugs other than hydrocortisone can be readily encapsulated in the composition for delivery to the eye.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nanotechnology (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Biotechnology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Medical Informatics (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU70873/98A AU743204B2 (en) | 1997-04-23 | 1998-04-23 | Controlled release of ophthalmic compositions |
JP54553198A JP2001524097A (en) | 1997-04-23 | 1998-04-23 | Controlled release of ophthalmic compositions |
EP98917817A EP1003555A1 (en) | 1997-04-23 | 1998-04-23 | Controlled release of ophthalmic compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ31466497 | 1997-04-23 | ||
NZ314664 | 1997-04-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998047536A1 true WO1998047536A1 (en) | 1998-10-29 |
Family
ID=19926215
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NZ1998/000051 WO1998047536A1 (en) | 1997-04-23 | 1998-04-23 | Controlled release of ophthalmic compositions |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1003555A1 (en) |
JP (1) | JP2001524097A (en) |
AU (1) | AU743204B2 (en) |
WO (1) | WO1998047536A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030600A1 (en) * | 1998-11-23 | 2000-06-02 | The Procter & Gamble Company | Skin deodorizing compositions |
WO2000030599A1 (en) * | 1998-11-23 | 2000-06-02 | The Procter & Gamble Company | Skin deodorizing and sanitizing compositions |
JP2002531530A (en) * | 1998-12-04 | 2002-09-24 | カリフォルニア インスティテュート オブ テクノロジー | Supramolecular complexes containing therapeutic agents |
JP2010031284A (en) * | 2000-12-19 | 2010-02-12 | California Inst Of Technology | Composition containing inclusion complex |
US8252276B2 (en) | 2002-09-06 | 2012-08-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8357377B2 (en) | 2002-10-09 | 2013-01-22 | Suzie Hwang Pun | Cyclodextrin-based materials, compositions and uses related thereto |
US8497365B2 (en) | 2007-01-24 | 2013-07-30 | Mark E. Davis | Cyclodextrin-based polymers for therapeutics delivery |
US11464871B2 (en) | 2012-10-02 | 2022-10-11 | Novartis Ag | Methods and systems for polymer precipitation and generation of particles |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7139691A (en) * | 1990-03-07 | 1991-09-12 | Children's Medical Center Corporation | Method for retaining ophthalmological agents in ocular tissues |
JPH09216810A (en) * | 1996-02-08 | 1997-08-19 | Noevir Co Ltd | Composition for skin and oral cavity application |
-
1998
- 1998-04-23 WO PCT/NZ1998/000051 patent/WO1998047536A1/en not_active Application Discontinuation
- 1998-04-23 AU AU70873/98A patent/AU743204B2/en not_active Ceased
- 1998-04-23 JP JP54553198A patent/JP2001524097A/en active Pending
- 1998-04-23 EP EP98917817A patent/EP1003555A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7139691A (en) * | 1990-03-07 | 1991-09-12 | Children's Medical Center Corporation | Method for retaining ophthalmological agents in ocular tissues |
JPH09216810A (en) * | 1996-02-08 | 1997-08-19 | Noevir Co Ltd | Composition for skin and oral cavity application |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030600A1 (en) * | 1998-11-23 | 2000-06-02 | The Procter & Gamble Company | Skin deodorizing compositions |
WO2000030599A1 (en) * | 1998-11-23 | 2000-06-02 | The Procter & Gamble Company | Skin deodorizing and sanitizing compositions |
US6656456B2 (en) | 1998-11-23 | 2003-12-02 | The Procter & Gamble Company | Skin deodorizing compositions |
JP2002531530A (en) * | 1998-12-04 | 2002-09-24 | カリフォルニア インスティテュート オブ テクノロジー | Supramolecular complexes containing therapeutic agents |
JP2010031284A (en) * | 2000-12-19 | 2010-02-12 | California Inst Of Technology | Composition containing inclusion complex |
US7807198B2 (en) | 2000-12-19 | 2010-10-05 | California Institute Of Technology | Compositions containing inclusion complexes |
US7968123B2 (en) | 2000-12-19 | 2011-06-28 | California Institute Of Technology | Complexing agents for compositions containing inclusion complexes |
US8092833B2 (en) | 2000-12-19 | 2012-01-10 | California Institute Of Technology | Compositions containing inclusion complexes |
JP2014210810A (en) * | 2000-12-19 | 2014-11-13 | カリフォルニア インスティテュート オブテクノロジー | Composition containing inclusion complexes |
US8277846B2 (en) | 2000-12-19 | 2012-10-02 | California Institute Of Technology | Complexing agents for compositions containing inclusion complexes |
US8404662B2 (en) | 2002-09-06 | 2013-03-26 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8580244B2 (en) | 2002-09-06 | 2013-11-12 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8389499B2 (en) | 2002-09-06 | 2013-03-05 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8399431B2 (en) | 2002-09-06 | 2013-03-19 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8314230B2 (en) | 2002-09-06 | 2012-11-20 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8475781B2 (en) | 2002-09-06 | 2013-07-02 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US9550860B2 (en) | 2002-09-06 | 2017-01-24 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8518388B2 (en) | 2002-09-06 | 2013-08-27 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8580242B2 (en) | 2002-09-06 | 2013-11-12 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8252276B2 (en) | 2002-09-06 | 2012-08-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8580243B2 (en) | 2002-09-06 | 2013-11-12 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8603454B2 (en) | 2002-09-06 | 2013-12-10 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8609081B2 (en) | 2002-09-06 | 2013-12-17 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8680202B2 (en) | 2002-09-06 | 2014-03-25 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutics delivery |
US8357377B2 (en) | 2002-10-09 | 2013-01-22 | Suzie Hwang Pun | Cyclodextrin-based materials, compositions and uses related thereto |
US8497365B2 (en) | 2007-01-24 | 2013-07-30 | Mark E. Davis | Cyclodextrin-based polymers for therapeutics delivery |
US9610360B2 (en) | 2007-01-24 | 2017-04-04 | Ceruliean Pharma Inc. | Polymer drug conjugates with tether groups for controlled drug delivery |
US11464871B2 (en) | 2012-10-02 | 2022-10-11 | Novartis Ag | Methods and systems for polymer precipitation and generation of particles |
Also Published As
Publication number | Publication date |
---|---|
AU743204B2 (en) | 2002-01-24 |
AU7087398A (en) | 1998-11-13 |
EP1003555A1 (en) | 2000-05-31 |
JP2001524097A (en) | 2001-11-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Di Colo et al. | Effect of chitosan and of N-carboxymethylchitosan on intraocular penetration of topically applied ofloxacin | |
Chaudhari et al. | Supramolecular cyclodextrin complex: Diversity, safety, and applications in ocular therapeutics | |
Maged et al. | Nano spray drying technique as a novel approach to formulate stable econazole nitrate nanosuspension formulations for ocular use | |
Shinde et al. | Development of dorzolamide loaded 6-O-carboxymethyl chitosan nanoparticles for open angle glaucoma | |
Fini et al. | The role of chitosan in drug delivery: current and potential applications | |
BRPI0613234A2 (en) | system that includes nanoparticles for the release of biologically active molecules, pharmaceutical composition, cosmetic composition, vaccine, procedure for obtaining a system for the controlled release of biologically active molecule, procedure for obtaining nanoparticles and use of a system | |
AU757786B2 (en) | Formulations of fexofenadine | |
Wang et al. | Cyclodextrin-based ocular drug delivery systems: A comprehensive review | |
Manchanda et al. | Topical delivery of acetazolamide by encapsulating in mucoadhesive nanoparticles | |
Jansook et al. | Self-assembled γ-cyclodextrin as nanocarriers for enhanced ocular drug bioavailability | |
AU743204B2 (en) | Controlled release of ophthalmic compositions | |
JPH08502761A (en) | Topical ophthalmic pharmaceutical vehicle | |
EP0807434A1 (en) | Anti-inflammatory eyedrops | |
EP2042166A1 (en) | Nanocapsules for oral delivery of proteins | |
Gharge et al. | Recent trends in chitosan based nanotechnology: a reference to ocular drug delivery system | |
WO2005060945A2 (en) | Intranasal compositions comprising zolpidem | |
Deng et al. | Development of a chitosan-based nanoparticle formulation for ophthalmic delivery of honokiol | |
Pardeshi et al. | Novel crosslinked nanoparticles of chitosan oligosaccharide and dextran sulfate for ocular administration of dorzolamide against glaucoma | |
Sha et al. | In situ gels: The next new frontier in ophthalmic drug delivery system | |
NZ514568A (en) | Ophthalmic compositions comprising carboxylic acid polymer-cyclodextrin conjugate like PAA-CD (polyacrylic acid cyclodextrin) and active drug | |
EP2994109B1 (en) | Aqueous ophthalmic formulations based on azithromycin | |
CN111686075B (en) | In-situ hydrogel composition taking nano-micelle as cross-linking agent and application thereof | |
US20100056476A1 (en) | Pharmaceutical compositions comprising peranhydrocyclodextrin | |
Subramanian et al. | Chitosan and its derivatives in clinical use and applications | |
EP4356929A1 (en) | Antifibrotic formulation for ophthalmic treatment |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1998 545531 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 500911 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 70873/98 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998917817 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09402611 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1998917817 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: CA |
|
WWG | Wipo information: grant in national office |
Ref document number: 70873/98 Country of ref document: AU |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1998917817 Country of ref document: EP |