EP1003555A1 - Liberation controlee de compositions ophtalmiques - Google Patents

Liberation controlee de compositions ophtalmiques

Info

Publication number
EP1003555A1
EP1003555A1 EP98917817A EP98917817A EP1003555A1 EP 1003555 A1 EP1003555 A1 EP 1003555A1 EP 98917817 A EP98917817 A EP 98917817A EP 98917817 A EP98917817 A EP 98917817A EP 1003555 A1 EP1003555 A1 EP 1003555A1
Authority
EP
European Patent Office
Prior art keywords
cyclodextrin
drug
conjugate
patient
ophthalmic
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.)
Withdrawn
Application number
EP98917817A
Other languages
German (de)
English (en)
Inventor
Kerrie Setiawan
Nigel Davies
Ian Tucker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Otago
Original Assignee
University of Otago
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by University of Otago filed Critical University of Otago
Publication of EP1003555A1 publication Critical patent/EP1003555A1/fr
Withdrawn legal-status Critical Current

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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nanotechnology (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions ophtalmiques qui libèrent dans l'oeil d'un patient, avec une biodisponibilité accrue, un médicament acceptable sur le plan ophtalmique. Ces compositions renferment un polymère contenant de l'acide carboxylique, conjugué à une cyclodextrine, le médicament étant encapsulé dans la partie cyclodextrine du conjugué.
EP98917817A 1997-04-23 1998-04-23 Liberation controlee de compositions ophtalmiques Withdrawn EP1003555A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NZ31466497 1997-04-23
NZ31466497 1997-04-23
PCT/NZ1998/000051 WO1998047536A1 (fr) 1997-04-23 1998-04-23 Liberation controlee de compositions ophtalmiques

Publications (1)

Publication Number Publication Date
EP1003555A1 true EP1003555A1 (fr) 2000-05-31

Family

ID=19926215

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98917817A Withdrawn EP1003555A1 (fr) 1997-04-23 1998-04-23 Liberation controlee de compositions ophtalmiques

Country Status (4)

Country Link
EP (1) EP1003555A1 (fr)
JP (1) JP2001524097A (fr)
AU (1) AU743204B2 (fr)
WO (1) WO1998047536A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6656456B2 (en) * 1998-11-23 2003-12-02 The Procter & Gamble Company Skin deodorizing compositions
CN1328443A (zh) * 1998-11-23 2001-12-26 宝洁公司 皮肤除臭和卫生消毒组合物
WO2000033885A1 (fr) * 1998-12-04 2000-06-15 California Institute Of Technology Complexes supramoleculaires contenant des agents therapeutiques
TWI321054B (en) 2000-12-19 2010-03-01 California Inst Of Techn Compositions containing inclusion complexes
KR20140070676A (ko) 2002-09-06 2014-06-10 인설트 테라페틱스, 인코퍼레이티드 공유결합된 치료제 전달을 위한 사이클로덱스트린-기초 중합체
BR0315198A (pt) 2002-10-09 2005-08-30 Insert Therapeutics Inc Materiais e composições à base de ciclodextrina e usos relacionados aos mesmos
US20080176958A1 (en) 2007-01-24 2008-07-24 Insert Therapeutics, Inc. Cyclodextrin-based polymers for therapeutics delivery
WO2014055493A1 (fr) 2012-10-02 2014-04-10 Cerulean Pharma Inc. Procédés et systèmes s'appliquant à la précipitation de polymères et à la génération de particules
CN117257979A (zh) * 2022-12-30 2023-12-22 江苏云视药物科技有限公司 地塞米松/环糊精骨架复合物及其制备方法与应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5227372A (en) * 1990-03-07 1993-07-13 Children's Medical Center Corporation Method for retaining ophthalmological agents in ocular tissues
JP3569065B2 (ja) * 1996-02-08 2004-09-22 株式会社ノエビア 皮膚及び口腔用組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9847536A1 *

Also Published As

Publication number Publication date
JP2001524097A (ja) 2001-11-27
WO1998047536A1 (fr) 1998-10-29
AU743204B2 (en) 2002-01-24
AU7087398A (en) 1998-11-13

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