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WO1995035093A1 - In situ gel-forming delivery vehicle for bio-affecting substances, and method of use - Google Patents

In situ gel-forming delivery vehicle for bio-affecting substances, and method of use Download PDF

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Publication number
WO1995035093A1
WO1995035093A1 PCT/US1995/007333 US9507333W WO9535093A1 WO 1995035093 A1 WO1995035093 A1 WO 1995035093A1 US 9507333 W US9507333 W US 9507333W WO 9535093 A1 WO9535093 A1 WO 9535093A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
delivery vehicle
polyacid
composition
ionic polymer
Prior art date
Application number
PCT/US1995/007333
Other languages
French (fr)
Inventor
Kenneth J. Himmelstein
Bert O. Haglund
Original Assignee
University Of Nebraska Board Of Regents
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 Nebraska Board Of Regents filed Critical University Of Nebraska Board Of Regents
Priority to JP8502346A priority Critical patent/JPH10501814A/en
Priority to EP95921627A priority patent/EP0802787A4/en
Priority to AU26387/95A priority patent/AU2638795A/en
Publication of WO1995035093A1 publication Critical patent/WO1995035093A1/en

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    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • Patent 5,252,3108 which discloses an aqueous composition containing effective concentrations of a stable combination of at least one thermally-sensitive gelling polymer and at least one pH-sensitive gelling polymer, that can be formulated to undergo a specific sol-gel transition over pre-determined temperature and pH ranges, thus making the compositions useful as drop-in ⁇ tillable aqueous wetting agents and drug delivery systems.
  • These aqueous compositions are low viscosity liquids at ambient temperature and a pH range of 2.5 to 6.5, but are transformed to high viscosity, semi-solid gels when exposed to physiological pH and a temperature of 37°C.
  • U.S. Patent 5,292,517 is concerned with a sustained-release drug delivery vehicle comprising a liquid solution of poly(methylvinylether/maleic acid) copoly er with a therapeutic or diagnostic agent incorporated therein, which reversibly gels in response to changes in pH. These compositions are said to be useful as dropable or injectable drug delivery systems for the sustained delivery of pharmaceutical compounds.
  • the interpolymer complex which is initially a gum-like mass at low pH, is converted to a clear liquid upon solubilization in the aforementioned solvent.
  • the resultant liquid is readily extruded through the cannula of a conventional hypodermic syringe.
  • the liquid When introduced into a physiological environment, e.g., by subcutaneous or intramuscular injection, the liquid forms a semi-solid gel which errodes slowly over a period of several days.
  • the present invention further provides a method for sustained delivery of a therapeutic agent to a patient.
  • the method involves administering to the patient, preferably by injection, the gel-forming delivery vehicle described immediately above, including an effective amount of a therapeutic or diagnostic agent.
  • the gel-forming delivery vehicle of the invention can be used with a wide range of bio- affecting substances of varying molecular weight, and in particular those substances for which systemic distribution is undesired, such as chemotherapeutic agents or analogous diagnostic agents, which may be injected directly into tumors.
  • the gel-forming delivery vehicle and its method of use in accordance with the present invention offer several notable advantages over in situ gel- forming drug delivery systems and methods of the prior art, particularly those utilizing cross-linked polymer hydrogels.
  • the ratio of polyacid to non-ionic polymer in the delivery vehicle should generally be in the range of 5:1 to 1:5. Preferably, this ratio should be on the order of 2:1 to 1:2, with a ratio of 1:1 being most preferred.
  • the polyacid and non-ionic polymer form a stable interpolymer complex having an insoluble gel structure in water at acidic pH, presumably due to a combination of van der Waal forces, hydrogen-bonding and hydrophobic interaction between the polymer chains. It appears that non-ionized carboxyl groups are necessary for cooperative hydrogen-bonding to occur. When acidic conditions are not maintained, the interpolymer complex tends to break down, the reason apparently being that there is inadequate non-ionized carboxyl groups for complexation to occur. Specific complex-forming polyacid-non-ionic polymer pairs have characteristic pH maximums, above which complexation will not occur.
  • the pharmaceutical composition of the invention will contain, based on the total weight of the composition, an effective amount of the therapeutic agent, typically from about 0.01 to about 40%, about 4 to about 60% of at least one pharmaceutically acceptable polyacid, about 2 to about 30% of at least one pharmaceutically acceptable water- soluble non-ionic polymer capable of forming an interpolymer complex under the above-stated conditions, about 5%-50% water and about 5%-75% of a pharmaceutically acceptable alcohol which functions to solubilize the interpolymer complex in the manner described above.
  • the above-stated amounts may be varied to increase or decrease the dosage schedule, as appropriate.
  • the term "therapeutic agent” refers to a substance used in treating or ameliorating a disease or a medical condition.
  • urinary tract disinfectives such as sulfamethoxyazole, trimethoprim, nitrofurantoin, norfloxacin and the like;
  • mu ⁇ cle relaxant ⁇ such as succinylcholine chloride, danbrolene, cyclobenzaprine, methocarbomol, diazepa and the like;
  • the therapeutic or diagnostic agent is water-soluble.
  • some therapeutic or diagnostic agents will show greater solubility in the delivery vehicle than others.
  • Co-solvents may be beneficially used to enhance drug solubility; however, some therapeutic or diagnostic agents may be insoluble. These can often be suspended in the delivery vehicle with the aid of suitable suspending or viscosity enhancing agents. It has been found that incorporating certain polymeric drugs, e.g., proteins or peptides, into the drug delivery vehicle of the invention can re ⁇ ult in phase separation. This is a common phenomenon for polymers of different polarity.
  • a pharmaceutically acceptable compatibility promoting agent may be included in the composition, up to about 50% by weight, to enhance the ability of the components to remain in close association for a prolonged period of time.
  • Glycerin has been found to be a good compatability promoting agent for enhancing the iscibility of the delivery vehicle with polymeric drugs. Citric acid i ⁇ advantageou ⁇ ly u ⁇ ed in conjunction with the glycerin to maintain the pH below the critical value within the gel, rendering it stable for a longer period of time.
  • composition of the invention would contain from about 0.01 to about 40% by weight of the therapeutic agent, as previou ⁇ ly noted. Thu ⁇ , from 1 gm of the compo ⁇ ition, which is about 1.0 ml of solution, there would be obtained about 0.1 mg to about 400 mg of therapeutic agent.
  • the compo ⁇ ition of the invention When used to deliver drug ⁇ by injection, the compo ⁇ ition of the invention will be admini ⁇ tered as a liquid by means of an appropriate syringe equipped with the appropriate delivery tube or needle.
  • the delivery vehicle of the invention may al ⁇ o be u ⁇ ed for microencapsulation of therapeutic or diagnostic agents for parenteral administration or for implantation of wound healing drugs, e.g., after surgery.
  • Fig. 1 The co- ⁇ olvent wa ⁇ 60:40 ethanol-water.
  • the curve ⁇ represent the apparent viscosity of the mixtures
  • An aqueous solution of complex aggregates are known to have a compact globular structure due, in part, to hydrophobic interaction ⁇ , and for ⁇ uch low concentration ⁇ that there are no interaction ⁇ between the complex aggregate ⁇ , the gain can a ⁇ ume values much lower than unity.
  • the complexes pre ⁇ u ably have an expanded fiber ⁇ tructure. The stickiness of these solution ⁇ tends to corroborate this as ⁇ umption. Deviation from ⁇ pheric ⁇ tructure ha ⁇ a ⁇ trong effect on the vi ⁇ co ⁇ ity, and hence, the gain depend ⁇ on the length of the fiber ⁇ .
  • the model substance ⁇ were rhodamine-B, having a molecular weight of 444, and a hydrophilic polymeric substance having a molecular weight of 7,400.
  • the composition ⁇ of the delivery vehicle including the model ⁇ ub ⁇ tance ⁇ are set forth in Table I.
  • composition Compositioni Composition Composition
  • Model compound 0.1 10 a Product of Sigma Chemical Co. , St. Louis, MO b Product of Fisher Scientific i Co., Fair Lawn, NJ
  • 1 gm of the delivery vehicle ⁇ olution wa ⁇ depo ⁇ ited in a cylindrical pla ⁇ tic cap having an approximate volume of 1 ml with an inner diameter of 0.7 cm and a depth of 0.7 cm.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Preparation (AREA)

Abstract

An interpolymer complex of a polyacid and a water-soluble, non-ionic polymer, preferably polymethacrylic acid and polyethyleneglycol, which forms a stable, insoluble complex in water at acidic pH, and which is converted to an extrudable liquid upon addition of an appropriate amount of a complex solubilizer, preferably ethanol. The resultant complex is particularly useful as an injectable, sustained release delivery vehicle for bio-affecting substances, including therapeutic agents.

Description

IN SITU GEL-FORMING DELIVERY VEHICLE FOR BIO-AFFECTING SUBSTANCES, AND METHOD OF USE
BACKGROUND OF THE INVENTION
The present invention relates to compositions and methods for sustained delivery of bio-affecting substances and in particular to injectable pharmaceutical compositions which transform to a slowly erodible gel following introduction into a physiological environment.
Various methods have been proposed for efficient delivery of a therapeutic agent to its site of action. Early efforts to develop a sustained release drug delivery system were directed toward incorporating therapeutic agents into solid or semi- solid vehicles for application to or implantation under the patient's skin. A number of semi-solid ointments or gels have been shown to be effective for increasing drug retention times in the case of ophthalmic drug delivery. See, for example, U.S. Patents Nos. 3,700,451, 3,944,427 and 4,100,271.
More recently, attempts have been made to develop gelling drug delivery systems capable of administration via injection. One such system utilizes a polymeric delivery vehicle that is liquid at room temperature, but forms a semi-solid gel when warmed to body temperature. In U.S. Patent 4,188,373, for example, a gel-forming drug delivery system is disclosed which utilizes proprietary non-ionic difunctional polyoxyalkylene derivatives of propylene glycol (known as Pluronic® polyolε) as the thermally gelling polymer. The desired sol-gel transition temperature is said to be obtained by appropriate adjustment of the polymer concentration. Specifically, the lower the concentration of polymer, the higher the sol-gel transition temperature; a gel will not form below a critical minimum concentration. U.S. Patent 4,474,752 discloses an injectable sustained release drug delivery system, based on proprietary non-ionic tetrafunctional polyoxyalkylene derivatives of ethylenediamine (known as Tetronic® polyols) , which gel at temperatures from about 30°-100°C. The sol-gel transition temperature and rigidity of the gel are said to be capable of modification by changes in polymer concentration combined with the pH and ionic strength of the solution.
Although effective for increasing drug retention times, these thermally formed gels dissolve relatively rapidly due to their weak gel structure. U.S. Patent 5,124,151 discloses injectable compositions for sustained drug delivery utilizing thermo-irreversible gels as delivery vehicles. The compositions comprise mixtures of a polyoxyalkylene polymer and an ionic polysaccharide, and a latent counter-ion, the release of which causes the polysaccharide to gel. At ambient temperature, the compositions are low viscosity liquids, but upon administration to the patient the counter-ion is released to gel the polysaccharide, which forms a semi-solid gel of high viscosity. Reversibly gelling compositions useful as drug delivery vehicles are the subject of U.S. Patent 5,252,318, which discloses an aqueous composition containing effective concentrations of a stable combination of at least one thermally-sensitive gelling polymer and at least one pH-sensitive gelling polymer, that can be formulated to undergo a specific sol-gel transition over pre-determined temperature and pH ranges, thus making the compositions useful as drop-inεtillable aqueous wetting agents and drug delivery systems. These aqueous compositions are low viscosity liquids at ambient temperature and a pH range of 2.5 to 6.5, but are transformed to high viscosity, semi-solid gels when exposed to physiological pH and a temperature of 37°C.
U.S. Patent 5,292,516 relates to the use of isotonic, iso-osmotic, pH-balanced thermoreversible gels containing polyoxyalkylene copolymers as vehicles for drug delivery to a body cavity of a mammal.
U.S. Patent 5,292,517 is concerned with a sustained-release drug delivery vehicle comprising a liquid solution of poly(methylvinylether/maleic acid) copoly er with a therapeutic or diagnostic agent incorporated therein, which reversibly gels in response to changes in pH. These compositions are said to be useful as dropable or injectable drug delivery systems for the sustained delivery of pharmaceutical compounds.
Various cross-linked polymer hydrogels have also been proposed for achieving sustained release of various therapeutic agents. Hydrogel-based drug delivery systems frequently involve surgical implantation in the patient. Furthermore, the cross- linking agents used are often toxic substances, thus requiring that the hydrogel undergo extensive purification. Cross-linked polymer hydrogels are also relatively difficult to sterilize.
Interpolymer complexes formed between polyacids and water-soluble non-ionic polymers, e.g., polymethylacrylic acid and polyethyleneglycol, as well as their properties, have been the subject of extensive investigation, the results of which have been widely published. See, for example, E. Bekturov and L. Bimendina, Adv. Polym. Sci., 4.1: 99-147 (1981), and references cited therein. Potential practical applications of such interpolymer complexes include films for uses including transparent and electroconductive plates for illuminating and heating purposes, battery separators, wearing apparel, wallcoverings, and dialysis and ultrafiltration systems. Hydrogels from these polymer complexes have also been proposed for use as contact lenses, tissue substitutes and prosthetic devices. Insofar as is known, however, such interpolymer complexes have never been proposed heretofore for use as delivery vehicles for sustained release of bio-affecting substances.
SUMMARY OF THE INVENTION The present invention provides improved pharmaceutical compositions capable of sustained release of therapeutic agents and diagnostic agents, wherein the improvement comprises a gel-forming delivery vehicle comprising a solution of at least one pharmaceutically acceptable polyacid and at least one pharmaceutically acceptable water-soluble, non-ionic polymer, the polyacid and the non-ionic polymer forming a stable, insoluble interpolymer complex in water at acidic pH, in an aqueous solvent including a pharmaceutically acceptable complex solubilizer, the amount of the complex solubilizer being effective to solubilize such insoluble interpolymer complex.
The interpolymer complex, which is initially a gum-like mass at low pH, is converted to a clear liquid upon solubilization in the aforementioned solvent. The resultant liquid is readily extruded through the cannula of a conventional hypodermic syringe. When introduced into a physiological environment, e.g., by subcutaneous or intramuscular injection, the liquid forms a semi-solid gel which errodes slowly over a period of several days.
The gel-forming property of the delivery vehicle of the invention makes it well suited for administration of numerous therapeutic and diagnostic agents via injection to achieve improved bioavailability and sustained release of the therapeutic and diagnostic agents. The delivery vehicle of the invention may also be beneficially used, if desired, for microencapsulation of therapeutic or diagnostic agents for parenteral administration or for implantation of wound healing drugs, e.g., after surgery.
The components of the delivery vehicle are water soluble, non-toxic substances that are readily eliminated via the kidneys due to their low molecular weight.
The present invention further provides a method for sustained delivery of a therapeutic agent to a patient. The method involves administering to the patient, preferably by injection, the gel-forming delivery vehicle described immediately above, including an effective amount of a therapeutic or diagnostic agent. The gel-forming delivery vehicle of the invention can be used with a wide range of bio- affecting substances of varying molecular weight, and in particular those substances for which systemic distribution is undesired, such as chemotherapeutic agents or analogous diagnostic agents, which may be injected directly into tumors. The gel-forming delivery vehicle and its method of use in accordance with the present invention offer several notable advantages over in situ gel- forming drug delivery systems and methods of the prior art, particularly those utilizing cross-linked polymer hydrogels. The starting materials for the drug delivery vehicle of this invention are available from various commercial sources and are easily formulated into the desired pharmaceutical composition according to relatively simple procedures. Moreover, the starting materials used to prepare the gel-forming delivery vehicle according to the present invention do not require the use of cross-linking agents, thus eliminating a potentially toxic component from the composition. Furthermore, according to a preferred embodiment of the present invention in which ethanol of appropriate concentration is used as the interpolymer complex solubilizer, sterilization of the delivery vehicle occurs as a matter of course in the process of its preparation.
The gel-forming delivery vehicle described herein has a relatively strong gel structure, thereby providing enhanced duration of the therapeutic or diagnostic agents incorporated therein. Also, because the gel components are readily eliminated from the body due to their low molecular weights, the need for chemical degradation in the body is obviated.
Additional advantages and features of the present invention are set forth in, and will be apparent to those skilled in the art from the detailed description of the invention presented below considered in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical illustration showing the specific viscosity of the delivery vehicle as a function of the ratio of polyethylene glycol to total polymer concentration for different molecular weights of polyethylene glycol (D represents polyethylene glycol (PEG) of 4,600 molecular weight (MW) ; Δ represents PEG of 8,000 MW; 0 represents PEG of 18,500 MW) .
FIG. 2 is a graphical illustration showing the gain (ratio for viscosity change due to complexation) as a function of polyacid to non-ionic polymer ratio for a preferred drug delivery vehicle of the present invention (D represents PEG of 4,600 MW; Δ represents PEG of 8,000 MW; O represents PEG of 18,500 MW) .
FIG. 3 is a graphical illustration of the results of a study of solution-gel transformation as a function of temperature and solvent compositions for a preferred drug delivery vehicle of the invention (FR=Formulation range for best syringability) .
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, it has now been discovered that certain complex-forming pharmaceutically acceptable macromolecules are capable of functioning as an in-situ gelling delivery vehicle for administration of various bio-affecting substances, including therapeutic agents and diagnostic agents, preferably via injection, thereby enabling sustained release of the bio-affecting substance.
As used herein with reference to the several components of the gel-forming delivery vehicle of the invention, the expression "pharmaceutically acceptable" refers to substances which do not adversely affect the activity or efficacy of the bio- affecting substance included in the delivery vehicle and which are not in themselves toxic to the recipient.
The complex-forming macromolecules include pharmaceutically acceptable polyacids and water- soluble, non-ionic polymers that form a stable interpolymer complex in water under acidic conditions. Representative polyacids include polyacrylic acid, polymethacrylic acid, co-polymers of acrylic acid with acrylic acid esters, e.g., ethylacrylate, or with methacrylic acid esters, e.g., ethylmethacrylate and co-polymers of methacrylic acid with acrylic acid esters or with methacrylic acid esters. Representative water-soluble, non-ionic polymers that form interpolymer complexes with the aforementioned polyacids include hydrogen bond acceptors from the group of polyether glycols, such as polyethylene glycol or polypropylene glycol, polyvinylpyrollidone polyoxyalkylene derivatives of ethylene diamine or polyoxyalkylene derivatives of propylene glycol.
The molecular weight of the individual polymeric components of the delivery vehicle of the invention should be less than about 50,000 to allow for elimination of these components by glomerular filtration. Preferably, the polyacid has a weight average molecular weight of from about 4,000 to about 40,000 and the non-ionic polymer has a weight average molecular weight from about 2,000 to about 40,000.
The ratio of polyacid to non-ionic polymer in the delivery vehicle, based on the number of repeat units in each polymer, should generally be in the range of 5:1 to 1:5. Preferably, this ratio should be on the order of 2:1 to 1:2, with a ratio of 1:1 being most preferred.
The polyacid and non-ionic polymer form a stable interpolymer complex having an insoluble gel structure in water at acidic pH, presumably due to a combination of van der Waal forces, hydrogen-bonding and hydrophobic interaction between the polymer chains. It appears that non-ionized carboxyl groups are necessary for cooperative hydrogen-bonding to occur. When acidic conditions are not maintained, the interpolymer complex tends to break down, the reason apparently being that there is inadequate non-ionized carboxyl groups for complexation to occur. Specific complex-forming polyacid-non-ionic polymer pairs have characteristic pH maximums, above which complexation will not occur. For example, breakdown of polymethacrylic acid-polyethylene glycol and polyacrylic acid-polyethylene glycol complexes occur if the pH is increased beyond 5.7 and 4.8, respectively. The characteristic pH maximum for any specific polyacid-non-ionic polymer pair can easily be determined by routine experimentation. For the reason already indicated, these characteristic pH maximums depend essentially on the polyacid.
The insoluble gel structure of the interpolymer complex, as noted above, can be eliminated by including in the aqueous solution of the complex an amount of a complex solubilizer that is effective to solubilize the insoluble interpolymer complex. Alcohols have been shown to be effective for this purpose. The ability of alcohols to eliminate the gel structure varies directly according to alkyl chain length; the longer the chain length, the greater the solubilizing effect at a given concentration. The addition of the complex solubilizer yields a clear, viscous liquid which is readily extruded through the cannula of a conventional hypodermic syringe, making the resultant composition useful in injectable, sustained release drug delivery systems.
The amount of alcohol added to the delivery vehicle solution to function as a complex solubilizer in the manner described above is generally in the range of 5-90%, based on the weight of the solution. Particularly good results have been obtained using approximately equal amounts of water and alcohol as the solvent for the delivery vehicle of the invention.
Where sustained release of a therapeutic agent is desired, the pharmaceutical composition of the invention will contain, based on the total weight of the composition, an effective amount of the therapeutic agent, typically from about 0.01 to about 40%, about 4 to about 60% of at least one pharmaceutically acceptable polyacid, about 2 to about 30% of at least one pharmaceutically acceptable water- soluble non-ionic polymer capable of forming an interpolymer complex under the above-stated conditions, about 5%-50% water and about 5%-75% of a pharmaceutically acceptable alcohol which functions to solubilize the interpolymer complex in the manner described above. Depending on the condition of the patient, the above-stated amounts may be varied to increase or decrease the dosage schedule, as appropriate. As used herein, the term "therapeutic agent" refers to a substance used in treating or ameliorating a disease or a medical condition.
If desired, the delivery vehicle of the invention may also contain a buffering agent and preservative, in addition to the therapeutic or diagnostic agent. Suitable water-soluble buffering agents include alkali metal or alkaline earth metal carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and tromethamine (TRIS) . These buffering agents may be present in amounts sufficient to maintain the composition at a pH between 1 to 6, and preferably 4 to 5.5. As such, the buffering agent may be as much as 20% by weight of the total composition, the exact amount depending on the chemical nature of the interpolymer complex and the pH value sought to be maintained. Suitable water-soluble preservatives include sodium bisulfite, sodium thiosulfate, ascorbate, benzalkoniu chloride, chlorobutanol, thimerosal, phenylmercuric, borate, parabens, benzylalcohol and phenylethanol. These agents may be present, generally, in amounts of about 0.001% to about 5% by weight and, preferably, in the amount of about 0.01 to about 2%. Virtually any therapeutic agent or diagnostic agent capable of administration using the in situ-gelling compositions of the prior art can be administered using the sustained-release delivery vehicle of the present invention. The following drugs can be administered via injection using the delivery vehicle described herein:
(1) Analgesics such as aspirin, acetaminophen, difluniεal and the like;
(2) anesthetics such as lidocaine, procaine, benzocaine, xylocaine and the like; (3) antiarthritics such as phenylbutazone, indomethacin, sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazine probenecid and the like;
(4) antiasthma drugs such as theophylline, ephedrine, beclomethasone dipropionate, epinephrine and the like;
(5) urinary tract disinfectives such as sulfamethoxyazole, trimethoprim, nitrofurantoin, norfloxacin and the like;
(6) anticoagulants such as heparin, bishydroxy coumarin, warfarin and the like;
(7) anticonvulsants such as diphenylhydantoin, diazepan and the like;
(8) antidepressants such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine, doxepin and the like;
(9) antidiabetics such as insulin, tolbutamide, somatostatin and its analogs, tolazanide, acetohexamide, chlorpropamide and the like;
(10) antineoplastics such as adriamycin, flurouracil, methotrexate, asparaginase and the like;
(11) antipsychotics such as prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine, amitriptyline, triflupromazine and the like; (12) antihypertensives such as εpironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, ti olol, propranolol, metoprolol, prazosin hydrochloride, reserpine and the like;
(13) muεcle relaxantε such as succinylcholine chloride, danbrolene, cyclobenzaprine, methocarbomol, diazepa and the like;
(14) proteins and peptides such as atrial natriuretic factor, calcitonin-gene related factor, leutinizing hormone, releasing hormone, neurotensin, vasoactive intestinal peptide, vasopresεin, cycloεporine, interferon, εubεtance P enkephalinε, epidermal growth factor, fibronectin, insulin-like growth factor and mesoder al growth factor;
(15) immunoεuppressive agents and anti- metabolites, such as methotrexate, cyclophoεphamide, 6-mercaptopurine and azathiopirine; and
(16) oligonucleotideε and DNA fragments; and
(17) various mixtures of the foregoing therapeutic agents, e.g., in combination therapy.
Other suitable drugs which can be administered using the drug delivery vehicle of the present invention are anti-bacterial substances, such as beta-lacta antibiotics, tetracyclines, chloroamphenicol, neomycin, gramicidin, bacitracin, sulfonamide, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid and analogε, the antimicrobial combination of fludalanine/pentizidone and the like; antihistaminics/decongestants, such as perilamine, chlorpheniramine, tetrahydrozoline, antazoline, and the like; antiflammatory drugs, such aε cortiεone, hydrocortiεone, betamethaεone, dexamethaεone, fluocortolone, prednisolone, triamcinolone, indomethacin, εulindac and itε εalts and corresponding εulfide, and the like; anti- paraεitic compoundε, such as invermectin and the like; anti-viral compounds, such as acyclovir, interferon, and the like; carbonic anhydraεe solubilizers, such as acetazolamide, dichlorphena ide, 2-(p- hydroxypheny1)thio-5-thiophenesulfonamide, 6-hydroxy-2-benzothiazolesulfonamide, 6-pivaloyloxy-2- benzothiazolesulfonamide, and the like.
Representative diagnostic agents that may be incorporated in the drug delivery vehicle of the present invention include contrast agents, dyes and radiotracers.
The foregoing listing of suitable bio- affecting agents is exemplary only and is not intended to limit the scope of the present invention.
The delivery vehicle may also contain co- solvents, suspending agents, viscosity enhancing agents, ionic strength and ismolality regulating agents and various excipients, in addition to the bio- affecting agent, buffering agent and/or preεervative, if desired.
Preferably, the therapeutic or diagnostic agent is water-soluble. Of course, some therapeutic or diagnostic agents will show greater solubility in the delivery vehicle than others. Co-solvents may be beneficially used to enhance drug solubility; however, some therapeutic or diagnostic agents may be insoluble. These can often be suspended in the delivery vehicle with the aid of suitable suspending or viscosity enhancing agents. It has been found that incorporating certain polymeric drugs, e.g., proteins or peptides, into the drug delivery vehicle of the invention can reεult in phase separation. This is a common phenomenon for polymers of different polarity. In order to avoid phase separation, a pharmaceutically acceptable compatibility promoting agent may be included in the composition, up to about 50% by weight, to enhance the ability of the components to remain in close association for a prolonged period of time. Glycerin has been found to be a good compatability promoting agent for enhancing the iscibility of the delivery vehicle with polymeric drugs. Citric acid iε advantageouεly uεed in conjunction with the glycerin to maintain the pH below the critical value within the gel, rendering it stable for a longer period of time.
In the case of administration of therapeutic agents, the composition of the invention would contain from about 0.01 to about 40% by weight of the therapeutic agent, as previouεly noted. Thuε, from 1 gm of the compoεition, which is about 1.0 ml of solution, there would be obtained about 0.1 mg to about 400 mg of therapeutic agent.
The particular drug used in the pharmaceutical composition of this invention iε the type which a patient would require for pharmacological treatment of the condition from which the patient is suffering.
When used to deliver drugε by injection, the compoεition of the invention will be adminiεtered as a liquid by means of an appropriate syringe equipped with the appropriate delivery tube or needle. As previously noted, although injection is the preferred mode of adminiεtration, the delivery vehicle of the invention may alεo be uεed for microencapsulation of therapeutic or diagnostic agents for parenteral administration or for implantation of wound healing drugs, e.g., after surgery.
Although the process by which the delivery vehicle of the invention slowly erodes upon contact with a physiological environment has not been thoroughly elucidated, it iε believed that a delivery vehicle-phyεiological fluid interface is formed at the site of injection, over which the complex solubilizer migrates out, while phyεiological fluid migrates in, causing immediate formation of the soft, semi-solid gel.
The following examples are provided to describe the invention in further detail. These examples are intended merely to illustrate specific embodiments of the delivery vehicle of the invention and should in no way be construed as limiting the invention.
EXAMPLE 1 Determination of Specific Viscosity of Delivery Vehicle as a Function of Varying Polymer Ratios
Given the utility discovered for the interpolymer complexes deεcribed herein, the interactionε between the macromoleculeε forming the complexeε took on considerable interest and, therefore, formulation range concentrations of the polymers were investigated. Specific viscosities of solutions, initially containing a preferred polyacid, polymethacrylic acid (20% by weight) were measured while polyethylene glycol (also 20% by weight) was added in increments and mixed in a viscometer. In three different experimentε, polyethylene glycol having molecular weightε of 4,600 (Carbowax 4600 NF, Union Carbide Corp., Danbury, CT) , 8,000 (Carbowax 8000 NF, Union Carbide, Corp., Danbury, CT) and 18,500 (Polyεcienceε, Inc., Warrington, PA) were uεed. All the solutions had a solvent content of 60% ethanol. To enεure optimal complex formation, pH waε adjuεted to a value of 2. An Ubbelohde-type viεcometer with a wide capillary waε uεed, and the experiments were carried out at 25°C. The εpecific viεcoεity in centipoiεe versus the ratio of polyethylene glycol to total polymer concentration (20% by weight) is shown in Fig. 1. The co-εolvent waε 60:40 ethanol-water. The curveε represent the apparent viscosity of the mixtures,
'.Miture while the lines show calculated viεcoεitieε, ηPEG + TJP AΛ, aε if no complex were formed. For normalization of the data with reεpect to the calculated viεcosity, a parameter gain, was utilized, which waε determined according to the following equation.
Gain = η Mixture
V PLG + V PMA
The gain iε the ratio for viεcosity change due to complexation. An aqueous solution of complex aggregates are known to have a compact globular structure due, in part, to hydrophobic interactionε, and for εuch low concentrationε that there are no interactionε between the complex aggregateε, the gain can aεεume values much lower than unity. In ethanolic solutionε, where the interactionε giving rise to globular complex formation are eliminated, the complexes preεu ably have an expanded fiber εtructure. The stickiness of these solutionε tends to corroborate this asεumption. Deviation from εpheric εtructure haε a εtrong effect on the viεcoεity, and hence, the gain dependε on the length of the fiberε. A graph plotting gain verεuε monomer ratio iε shown in Fig. 2. For polyethylene glycol having molecular weight of 8,000, the chains have about the same length as those of polymethylacrylic acid having molecular weight of 15,000, and since the gain esεentially haε reached itε maximum at a monomer ratio equal to unity, the rule of one-on-one εtoichio etry is upheld. In the caεe of polyethylene glycol having molecular weight of 4,600, two polyethylene glycol chainε can fit on each polymethacrylic acid molecule, and ideally the length of the complex aggregateε would be the same as with polyethylene glycol having 8,000 molecular weight, but since a lower gain was observed, it waε concluded that the strength of these complexes waε weaker. In the case of polyethylene glycol having 18,500 molecular weight, two polymethacrylic chains can fit on each polyethylene glycol molecule, making the complex aggregates twice as long, and explaining the greater gain observed in this caεe.
EXAMPLE 2 Preparation of Gel-Forming Delivery Vehicle A delivery vehicle was prepared utilizing an interpolymer complex composed of polymethacrylic acid and polyethylene glycol. Since the monomer weight for polymethacrylic acid is close to twice that for polyethylene glycol, the rule of one-on-one stoichiometry requires the weight concentration for polymethylacrylic acid to be twice that for polyethylene glycol. Accordingly, polymethacrylic acid of 15,000 molecular weight, as the sodium salt, and polyethylene glycol of 18,500 molecular weight (both obtained from Polyscienceε, Inc.) were mixed in amounts of 10% and 20%, by weight, respectively, in a beaker until a clear solution was obtained and HCl(lOM) was added slowly while the mixture waε vigorouεly εtirred. The mixture became turbid, but after approximately 5 minutes it cleared up leaving a gum-like mass. The masε waε recovered, weighed, placed in a εeparate beaker and dissolved in the smallest possible amount of absolute, dehydrated ethanol (McCormick Distilling Co., Inc., Weεton, MO). The water content of the resultant solution waε determined using a thermogravimetric instrument, Shimadsu TGA-150, and the weight of water waε determined to be about one-third the weight of the εolution. The yield of interpolymer complex waε over 95%.
When the reεultant solution was diluted to twice itε volume with an ethanol-water (1:1) solvent mixture, the solution waε extrudable through a 20 gauge needle. Uεe of an ethanol concentration above 60% will εerve to sterilize the compoεition.
A εolution of the complex in ethanol-water (75:25) solvent was found to be very sticky and yard- long thin threads were easily drawn upon handling. It thus appears that in addition to eliminating the globular structure of the interpolymer complex, the addition of ethanol cauεeε the complex aggregateε to aεεume an expanded, fibrous structure.
EXAMPLE 3 Temperature-Solvent Composition Studies The εolution-gel tranεformation waε studied at different temperatureε and εolvent compoεitions in the manner described herein. Ten solutions, each containing 10% by weight of the polymer complex prepared in accordance with the procedure described in Example 2 above, in different water-εoluble ethanol εolvent compositions were prepared in 20 ml vials with screwcaps. The εolution pH waε adjuεted uεing HC1 or NaOH, aε appropriate. Each vial waε heated on a water bath to 80°C, and after εhaking, allowed to cool. Phaεe tranεformationε were obεerved during cooling.
Fig. 3 shows the reεultε of thiε εtudy. At low ethanol content, an area waε identified wherein the gel at the bottom of the vialε waε unaffected by heating and shaking. At ethanol contents of 18-50%, a region was εeen wherein the gel particleε were dispersed by shaking of the vialε, cauεing turbidity. In an area between 50 and 90% ethanol content, the solutionε were clear and a lower conεolute temperature waε obεerved at 17°C and 75% ethanol. Finally, above 90% ethanol content, clear solutions could not be obtained. At physiological temperature (37°C) , the solution-to-gel transformation occurs between 48% and 18% ethanol content. Variation in pH between 2 and 5 at particular co poεitionε and temperatureε did not affect the phaεe tranεformation.
EXAMPLE 4 Release Profiles of Model Substances Release profiles were generated for two model subεtanceε, to evaluate the delivery of therapeutic and diagnoεtic agents with substantially different molecular weights. The model substanceε were rhodamine-B, having a molecular weight of 444, and a hydrophilic polymeric substance having a molecular weight of 7,400. The compositionε of the delivery vehicle including the model εubεtanceε are set forth in Table I.
TABLE I
Rhodamine-B Polymeric substance
SUBSTANCE Overall Solvent Overall Solvent
Composition Compositioni Composition Composition
Water 30.7 47.0 22.1 35.5
Ethanol 35.0 53.0 17.7 28.4
Glycerol" 22.5 36.1
Citric acidb 18.0 20.5
PEG-PMA complex 16.2 16.2
Model compound 0.1 10 a Product of Sigma Chemical Co. , St. Louis, MO b Product of Fisher Scientific i Co., Fair Lawn, NJ In carrying out this experiment, 1 gm of the delivery vehicle εolution waε depoεited in a cylindrical plaεtic cap having an approximate volume of 1 ml with an inner diameter of 0.7 cm and a depth of 0.7 cm. The cap waε i merεed in 200 ml εtirred buffer (phosphate buffered saline) with pH maintained at 7.4 during the experiment. Samples were withdrawn at appropriate time intervalε until the gel had diεεolved. The samples were analyzed in a Shimadsu UV 160U spectrophotometer. Rhodamine B was detected at a wavelength of 555 nm and the polymeric subεtance at 271.5 nm, where it had an abεorption maximum. At the latter wavelength, the polymer component of the delivery vehicle also had some absorption that was measured separately and substracted from that of the samples.
It was found that while the pH of the aqueous medium in which the delivery vehicle was immersed was maintained at 7.4, the gel eroded slowly with a rate dependent on the availability of buffer ionε at the gel- medium interface. Stirring and the addition of NaOH at appropriate intervalε maintained the pH and the buffer εtrength constant at the interface.
The use of rhodamine B, which is an intenεely colored subεtance, allowed obεervation of any burst effects. No such effects were obεerved. On the contrary, a skin-like structure appeared on the εurface of the gel, delaying the releaεe during the firεt few hourε. Except for εome initial εwelling, the water-gel area waε conεtant during the experiment. Since apparently all the model substance was released before the gel waε diεεolved, it appears that the release mechanism was by diffusion.
In the experiment with the polymeric model subεtance, a higher degree of εwelling waε obεerved, eεtimated to be about 40%. The model εubεtance waε releaεed with eεεentially a conεtant rate over a period of about 3-1/2 days, and it waε concluded that the releaεe mechaniεm was by erosion from the gel surface, which may be explained in part because of the slower diffusion of the higher molecular weight model substance in the gel.
While certain embodiments of the present invention have been described and/or exemplified above, various other embodimentε will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to the particular embodiments described and/or exemplified, but is capable of considerable variation and modification without departure from the scope of the amended claims.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical compoεition including a therapeutic agent and a εuεtained-releaεe delivery vehicle, wherein the improvement compriεeε a gelable delivery vehicle comprising a solution of at least one pharmaceutically acceptable polyacid and at least one pharmaceutically acceptable water-soluble, non-ionic polymer, said polyacid and εaid non-ionic polymer forming a εtable insoluble interpolymer complex in water at acidic pH, in an aqueous solvent including a pharmaceutically acceptable complex solubilizer, the amount of said εolubilizer being effective to solubilize said inεoluble interpolymer complex.
2. A pharmaceutical compoεition aε claimed in claim 1, wherein εaid pharmaceutically acceptable polyacid iε selected from the group consiεting of polymerε of acrylic acid, polymers of methacrylic acid, co-polymers of acrylic acid with an eεter of acrylic acid or an eεter of methacrylic acid and co-polymers of methacrylic acid with an ester of acrylic acid or an ester of methacrylic acid, and said pharmaceutically acceptable water-soluble, non-ionic polymer is selected from the group consisting of polyether glycol, polyvinylpyrollidone, polyoxyalkylene derivatives of ethylene diamine or polyoxyalkylene derivatives of propylene glycol.
3. A composition as claimed in claim 1, wherein said complex solubilizer is an alcohol.
4. A composition aε claimed in claim 1, wherein the amount of said alcohol in εaid εolution is in the range of 5-90%, based on the weight of said solution.
5. A composition aε claimed in claim 1, wherein the average molecular weight of each of said polyacid and said water-soluble non-ionic polymer is less than about 50,000.
6. A composition as claimed in claim 5, wherein the average molecular weight of said polyacid is from about 4,000 to about 40,000.
7. A compoεition as claimed in claim 5, wherein the average molecular weight of said non-ionic polymer is from about 2,000 to about 40,000.
8. A composition as claimed in claim 1, wherein the ratio of polyacid to non-ionic polymer, based on the number of repeat units in each said polymer, is in the range of 5:1 to 1:5.
9. A composition aε claimed in claim 8, wherein εaid ratio of polyacid to non-ionic polymer is about 1:1.
10. A composition as claimed in claim 10, wherein said εolution optionally includes up to about 50% by weight of a pharmaceutically acceptable compatability promoting agent which renders said therapeutic agent and said delivery vehicle compatible.
11. A composition aε claimed in claim 10, wherein εaid compatability promoting agent comprises glycerin.
12. A composition as claimed in claim 11, wherein said compatability promoting agent further compriεeε citric acid.
13. The composition of claim 11 in the form of a injectable preparation.
14. An injectable, gel-forming delivery vehicle, for suεtained release of a therapeutic or diagnostic agent, compriεing, baεed on the total weight of εaid vehicle, about 10 to about 60% of at leaεt one pharmaceutically acceptable polyacid, about 5 to about 30% of a pharmaceutically acceptable water-soluble non- ionic polymer, said polyacid and εaid non-ionic polymer forming a εtable inεoluble interpolymer complex in water at acidic pH, about 5% to 50% of water and about 5% to 75% of a pharmaceutically acceptable alcohol which solubilizeε εaid inεoluble interpolymer complex.
15. A delivery vehicle aε claimed in claim 14, wherein εaid pharmaceutically acceptable polyacid is selected from the group consiεting of polymerε of acrylic acid, polymerε of methacrylic acid, co-polymers of acrylic acid with an ester of acrylic acid or an ester of methacrylic acid and co-polymers of methacrylic acid with an eεter of acrylic acid or an ester of methacrylic, and said pharmaceutically acceptable water- soluble, non-ionic polymer is selected from the group consiεting of polyether glycol, polyvinylpyrollidone, polyoxyalkylene derivativeε of ethylene diamine or polyoxyalkylene derivativeε of propylene glycol.
16. A delivery vehicle as claimed in claim 14, wherein εaid polyacid comprises polymethacrylic acid of 15,000 average molecular weight and said non-ionic polymer comprises polyethylene glycol of 18,500 average molecular weight.
17. A delivery vehicle as claimed in claim 14, further compriεing a diagnoεtically effective amount of a diagnoεtic agent.
18. A delivery vehicle as claimed in claim 14, further comprising a therapeutically effective amount of a therapeutic agent.
19. A delivery vehicle as claimed in claim
18, which further includes up to about 50% by weight of a compatability promoting agent which renders said therapeutic agent and said delivery vehicle compatible.
20. A delivery vehicle aε claimed in claim
19, wherein said compatability promoting agent comprises glycerin.
21. A delivery vehicle as claimed in claim 20, wherein said compatability promoting agent further comprises citric acid.
22. A method for sustained delivery of a therapeutic agent to a patient, said method comprising administering to said patient an injectable, gel-forming pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent and a sustained- release delivery vehicle comprising, based on the weight of said composition, about 4% to about 60% of at least one pharmaceutically acceptable polyacid, about 2 to about 30% of at leaεt one pharmaceutically acceptable water-soluble non-ionic polymer, said polyacid and said non-ionic polymer forming a stable, insoluble interpolymer complex in water at acidic pH, about 5% to 50% of water, about 5% to 75% of a pharmaceutically acceptable alcohol which solubilizeε εaid inεoluble interpolymer complex, and up to 50% of a pharmaceutically acceptable compatability promoting agent which renderε said therapeutic agent and said delivery vehicle compatible.
23. A method as claimed in claim 22, wherein said pharmaceutically acceptable polyacid is selected from the group conεiεting of polymers of acrylic acid, polymers of methacrylic acid, co-polymerε of acrylic acid with an eεter of acrylic acid or an ester of methacrylic acid and co-polymers of methacrylic acid with an ester of acrylic acid or an ester of methacrylic, and said pharmaceutically acceptable water- soluble, non-ionic polymer is selected from the group consisting of polyether glycol, polyvinylpyrollidone, polyoxyalkylene derivatives of ethylene diamine or polyoxyalkylene derivatives of propylene glycol.
24. A method aε claimed in claim 22, wherein said composition is adminiεtered subcutaneously.
25. A method as claimed in claim 22, wherein said composition is administered intramuεcularly.
26. A method aε claimed in claim 22, wherein εaid composition is adminiεtered intaperitoneally.
27. An injectable, gel-forming εustained release pharmaceutical composition for injection into a body for pharmacological treatment of a condition requiring such treatment, said compoεition compriεing an effective amount of a drug having activity againεt εaid condition and a delivery vehicle for said drug, said vehicle comprising, based on the weight of said composition, about 4 to about 60% of at least one pharmaceutically acceptable polyacid, about 2 to about 30% of at least one pharmaceutically acceptable, water- soluble, non-ionic polymer, said polyacid and said non- ionic polymer forming a stable complex interpolymer in water at acidic pH, about 5% to about 50% of water, about 5% to 75% of ethanol, and up to 50% of a pharmaceutically acceptable compatability promoting agent which renderε εaid drug and said delivery vehicle compatible.
28. A pharmaceutical composition as claimed in claim 27, wherein εaid pharmaceutically acceptable polyacid iε εelected from the group conεisting of polymers of acrylic acid, polymers of methacrylic acid, co-polymers of acrylic acid with an ester of acrylic acid or an ester of methacrylic acid and co-polymers of methacrylic acid with an ester of acrylic acid or an ester of methacrylic, and said pharmaceutically acceptable water-soluble, non-ionic polymer iε selected from the group conεisting of polyether glycol, polyvinylpyrollidone, polyoxyalkylene derivatives of ethylene diamine or polyoxyalkylene derivatives of propylene glycol.
29. A pharmaceutical composition as claimed in claim 27, wherein said polyacid comprises polymethacrylic acid and said non-ionic polymer comprises polyethylene glycol.
30. A pharmaceutical composition aε claimed in claim 27, wherein εaid drug is selected from the group consiεting of analgeεicε, anti-arthritics, anti- aεthmaticε, anti-coagulants, anti-convulsantε, anti- depreεεantε, anti-diabeticε, anti-neoplaεtidε, anti- pεychotics, anti-hypertensive agentε, muεcle relaxants, proteins, peptides, anti-bacterial εubstances, anti- histamines and decongestantε, anti-inflammatories, anti- cholinergicε, anti-paraεiticε, anti-viral compoundε, carbonic anhydrase inhibitors, chelating agents, immunosuppreεεive agents, anti-metabolites, amoebacidal compoundε, trichomonacidal agentε, and combinationε of said drugs.
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19701912C1 (en) * 1997-01-10 1998-05-14 Jenapharm Gmbh Implant for controlled drug release
WO1999014259A1 (en) * 1997-09-12 1999-03-25 Shearwater Polymers Degradable poly(ethylene glycol) hydrogels with controlled half-life and precursors therefor
WO1999029174A1 (en) * 1997-12-05 1999-06-17 Bell Thomas A Compositions and methods for controlling ectoparasitic insects
EP1173517A1 (en) * 1999-04-26 2002-01-23 California Institute of Technology In situ forming hydrogels
US6627217B1 (en) * 1998-12-28 2003-09-30 Taisho Pharmaceutical Co., Ltd. External preparation
EP0841897B2 (en) † 1995-08-04 2004-06-30 Sederma S.A. Physically active antimicrobial gel for cosmetic products
US7018624B2 (en) 1996-11-06 2006-03-28 Debio Recherche Pharmaceutique S.A. Delivery of poly(ethylene glycol)-modified molecules from degradable hydrogels
WO2006084153A2 (en) 2005-02-04 2006-08-10 Repros Therapeutics Inc. Methods and materials with trans-clomiphene for the treatment of male infertility
US7173064B2 (en) 2001-07-09 2007-02-06 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene for treating wasting and lipodystrophy
US7368480B2 (en) 2001-07-09 2008-05-06 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene
US7737185B2 (en) 2001-07-09 2010-06-15 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene
EP2392322A2 (en) 2005-03-22 2011-12-07 Repros Therapeutics Inc. Dosing regimes for trans-clomiphene
US8092682B2 (en) 2003-09-19 2012-01-10 Ge Healthcare Bio-Sciences Ab Matrix for separation of polyethers and method of separation
WO2013020017A1 (en) 2011-08-04 2013-02-07 Repros Therapeutics Inc. Trans-clomiphene metabolites and uses thereof
US8372887B2 (en) 2007-10-16 2013-02-12 Repros Therapeutics Inc. Trans-clomiphene for metabolic syndrome
WO2016170531A1 (en) * 2015-04-20 2016-10-27 Botanocap Ltd. Liquid and solid core microcapsules formed by interpolymeric complexation
US9687458B2 (en) 2012-11-02 2017-06-27 Repros Therapeutics Inc. Trans-clomiphene for use in cancer therapy
WO2020033677A1 (en) 2018-08-08 2020-02-13 Johnson Lanny Leo Methods of diagnosing and treating infected implants

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ADVANCES IN POLYMER SCIENCE, Volume 41, issued 05 May 1981, E.A. BEKTUROV et al., "Interpolymer Complexes", pages 99-147. *
See also references of EP0802787A4 *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0841897B2 (en) † 1995-08-04 2004-06-30 Sederma S.A. Physically active antimicrobial gel for cosmetic products
US7964217B2 (en) 1996-09-13 2011-06-21 Nektar Therapeutics Degradable poly(ethylene glycol) hydrogels with controlled half-life and precursors therefor
US7018624B2 (en) 1996-11-06 2006-03-28 Debio Recherche Pharmaceutique S.A. Delivery of poly(ethylene glycol)-modified molecules from degradable hydrogels
WO1998030245A2 (en) * 1997-01-10 1998-07-16 Jenapharm Gmbh & Co. Kg Injection implant
WO1998030245A3 (en) * 1997-01-10 1998-09-11 Jenapharm Gmbh Injection implant
DE19701912C1 (en) * 1997-01-10 1998-05-14 Jenapharm Gmbh Implant for controlled drug release
US6303137B1 (en) 1997-01-10 2001-10-16 Jenapharm Gmbh & Co. Kg Injectable implant
WO1999014259A1 (en) * 1997-09-12 1999-03-25 Shearwater Polymers Degradable poly(ethylene glycol) hydrogels with controlled half-life and precursors therefor
US6596291B2 (en) 1997-12-05 2003-07-22 Thomas A. Bell Compositions and methods for treating surfaces infected with ectoparasitic insects
WO1999029174A1 (en) * 1997-12-05 1999-06-17 Bell Thomas A Compositions and methods for controlling ectoparasitic insects
US6627217B1 (en) * 1998-12-28 2003-09-30 Taisho Pharmaceutical Co., Ltd. External preparation
EP1173517A1 (en) * 1999-04-26 2002-01-23 California Institute of Technology In situ forming hydrogels
EP1173517A4 (en) * 1999-04-26 2006-06-28 California Inst Of Techn HYDROGELE THROUGH SITU SHAPES
US7368480B2 (en) 2001-07-09 2008-05-06 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene
US7173064B2 (en) 2001-07-09 2007-02-06 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene for treating wasting and lipodystrophy
US7737185B2 (en) 2001-07-09 2010-06-15 Repros Therapeutics Inc. Methods and compositions with trans-clomiphene
US7759360B2 (en) 2001-07-09 2010-07-20 Repros Therapeutics Inc. Methods and materials for the treatment of testosterone deficiency in men
US8618176B2 (en) 2001-07-09 2013-12-31 Repros Therapeutics Inc. Methods and materials for the treatment of testosterone deficiency in men
US8092682B2 (en) 2003-09-19 2012-01-10 Ge Healthcare Bio-Sciences Ab Matrix for separation of polyethers and method of separation
WO2006084153A2 (en) 2005-02-04 2006-08-10 Repros Therapeutics Inc. Methods and materials with trans-clomiphene for the treatment of male infertility
EP2392322A2 (en) 2005-03-22 2011-12-07 Repros Therapeutics Inc. Dosing regimes for trans-clomiphene
US8247456B2 (en) 2005-03-22 2012-08-21 Repros Therapeutics Inc. Dosing regimes for trans-clomiphene
US8372887B2 (en) 2007-10-16 2013-02-12 Repros Therapeutics Inc. Trans-clomiphene for metabolic syndrome
US8377991B2 (en) 2007-10-16 2013-02-19 Repros Therapeutics Inc. Trans-clomiphene for metabolic syndrome
EP2826475A1 (en) 2007-10-16 2015-01-21 Repros Therapeutics Inc. Trans-clomiphene for treating diabetes in hypogonadal men
WO2013020017A1 (en) 2011-08-04 2013-02-07 Repros Therapeutics Inc. Trans-clomiphene metabolites and uses thereof
US9981906B2 (en) 2011-08-04 2018-05-29 Repros Therapeutics Inc. Trans-clomiphene metabolites and uses thereof
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WO2020033677A1 (en) 2018-08-08 2020-02-13 Johnson Lanny Leo Methods of diagnosing and treating infected implants

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CA2192708A1 (en) 1995-12-28

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