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EP0802787A1 - VECTEUR D'APPORT DE SUBSTANCES BIO-EFFICACES A GELIFICATION $i(IN SITU) ET METHODE D'UTILISATION - Google Patents

VECTEUR D'APPORT DE SUBSTANCES BIO-EFFICACES A GELIFICATION $i(IN SITU) ET METHODE D'UTILISATION

Info

Publication number
EP0802787A1
EP0802787A1 EP95921627A EP95921627A EP0802787A1 EP 0802787 A1 EP0802787 A1 EP 0802787A1 EP 95921627 A EP95921627 A EP 95921627A EP 95921627 A EP95921627 A EP 95921627A EP 0802787 A1 EP0802787 A1 EP 0802787A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
delivery vehicle
polyacid
composition
ionic polymer
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Withdrawn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
EP95921627A
Other languages
German (de)
English (en)
Other versions
EP0802787A4 (fr
Inventor
Kenneth J. Himmelstein
Bert O. Haglund
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 Nebraska Lincoln
University of Nebraska System
Original Assignee
University of Nebraska Lincoln
University of Nebraska System
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 Lincoln, University of Nebraska System filed Critical University of Nebraska Lincoln
Publication of EP0802787A1 publication Critical patent/EP0802787A1/fr
Publication of EP0802787A4 publication Critical patent/EP0802787A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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

  • 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.
  • 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.
  • Tetronic® polyols ethylenediamine
  • 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.
  • 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.
  • 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 5,252,3108 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 5,292,516 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 interpol
  • 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 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.
  • 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) ; ⁇ represents PEG of 8,000 MW; 0 represents PEG of 18,500 MW) .
  • D represents polyethylene glycol (PEG) of 4,600 molecular weight (MW) ;
  • ⁇ 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; ⁇ represents PEG of 8,000 MW; O represents PEG of 18,500 MW) .
  • 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.
  • 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.
  • 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.
  • 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 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 insoluble gel structure of the interpolymer complex 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.
  • 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.
  • 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.
  • 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:
  • Analgesics such as aspirin, acetaminophen, difluni ⁇ al and the like;
  • anesthetics such as lidocaine, procaine, benzocaine, xylocaine and the like
  • antiarthritics such as phenylbutazone, indomethacin, sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazine probenecid and the like;
  • antiasthma drugs such as theophylline, ephedrine, beclomethasone dipropionate, epinephrine and the like;
  • urinary tract disinfectives such as sulfamethoxyazole, trimethoprim, nitrofurantoin, norfloxacin and the like;
  • anticoagulants such as heparin, bishydroxy coumarin, warfarin and the like;
  • anticonvulsants such as diphenylhydantoin, diazepan and the like;
  • antidepressants such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine, doxepin and the like;
  • antidiabetics such as insulin, tolbutamide, somatostatin and its analogs, tolazanide, acetohexamide, chlorpropamide and the like;
  • antineoplastics such as adriamycin, flurouracil, methotrexate, asparaginase and the like;
  • antipsychotics such as prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine, amitriptyline, triflupromazine and the like;
  • antihypertensives such as ⁇ pironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, ti olol, propranolol, metoprolol, prazosin hydrochloride, reserpine and the like;
  • mu ⁇ cle relaxant ⁇ such as succinylcholine chloride, danbrolene, cyclobenzaprine, methocarbomol, diazepa and the like;
  • proteins and peptides such as atrial natriuretic factor, calcitonin-gene related factor, leutinizing hormone, releasing hormone, neurotensin, vasoactive intestinal peptide, vasopres ⁇ in, cyclo ⁇ porine, interferon, ⁇ ub ⁇ tance P enkephalin ⁇ , epidermal growth factor, fibronectin, insulin-like growth factor and mesoder al growth factor;
  • immuno ⁇ uppressive agents and anti- metabolites such as methotrexate, cyclopho ⁇ phamide, 6-mercaptopurine and azathiopirine;
  • anti-bacterial substances such as beta-lacta antibiotics, tetracyclines, chloroamphenicol, neomycin, gramicidin, bacitracin, sulfonamide, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid and analog ⁇ , the antimicrobial combination of fludalanine/pentizidone and the like; antihistaminics/decongestants, such as perilamine, chlorpheniramine, tetrahydrozoline, antazoline, and the like; antiflammatory drugs, such a ⁇ corti ⁇ one, hydrocorti ⁇ one, betametha ⁇ one, dexametha ⁇ one, fluocortolone, prednisolone, triamcinolone, indomethacin, ⁇ ulindac and it ⁇ ⁇ alts and corresponding ⁇ ulfide, and the like; anti- para ⁇
  • Representative diagnostic agents that may be incorporated in the drug delivery vehicle of the present invention include contrast agents, dyes and radiotracers.
  • 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 pre ⁇ ervative, if desired.
  • 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 particular drug used in the pharmaceutical composition of this invention i ⁇ the type which a patient would require for pharmacological treatment of the condition from which the patient is suffering.
  • 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 chains have about the same length as those of polymethylacrylic acid having molecular weight of 15,000, and since the gain es ⁇ entially ha ⁇ reached it ⁇ maximum at a monomer ratio equal to unity, the rule of one-on-one ⁇ toichio etry is upheld.
  • 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.
  • polymethacrylic acid of 15,000 molecular weight, as the sodium salt, and polyethylene glycol of 18,500 molecular weight 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 wa ⁇ vigorou ⁇ ly ⁇ tirred. The mixture became turbid, but after approximately 5 minutes it cleared up leaving a gum-like mass.
  • the mas ⁇ wa ⁇ recovered, weighed, placed in a ⁇ eparate beaker and dissolved in the smallest possible amount of absolute, dehydrated ethanol (McCormick Distilling Co., Inc., We ⁇ ton, MO).
  • the water content of the resultant solution wa ⁇ determined using a thermogravimetric instrument, Shimadsu TGA-150, and the weight of water wa ⁇ determined to be about one-third the weight of the ⁇ olution.
  • the yield of interpolymer complex wa ⁇ over 95%.
  • Fig. 3 shows the re ⁇ ult ⁇ of thi ⁇ ⁇ tudy.
  • an area wa ⁇ identified wherein the gel at the bottom of the vial ⁇ wa ⁇ unaffected by heating and shaking.
  • a region was ⁇ een wherein the gel particle ⁇ were dispersed by shaking of the vial ⁇ , cau ⁇ ing turbidity.
  • the solution ⁇ were clear and a lower con ⁇ olute temperature wa ⁇ ob ⁇ erved at 17°C and 75% ethanol.
  • clear solutions could not be obtained.
  • 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 po ⁇ ition ⁇ and temperature ⁇ did not affect the pha ⁇ e tran ⁇ formation.
  • 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.
  • Rhodamine B was detected at a wavelength of 555 nm and the polymeric sub ⁇ tance at 271.5 nm, where it had an ab ⁇ orption 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.
  • rhodamine B which is an inten ⁇ ely colored sub ⁇ tance, allowed ob ⁇ ervation of any burst effects. No such effects were ob ⁇ erved.
  • a skin-like structure appeared on the ⁇ urface of the gel, delaying the relea ⁇ e during the fir ⁇ t few hour ⁇ . Except for ⁇ ome initial ⁇ welling, the water-gel area wa ⁇ con ⁇ tant during the experiment. Since apparently all the model substance was released before the gel wa ⁇ di ⁇ olved, it appears that the release mechanism was by diffusion.

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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)
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  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

Un complexe interpolymère d'un polyacide et d'un polymère soluble dans l'eau et non-ionique, de préférence l'acide polyméthacrylique et le polyéthylénéglycol forme un complexe stable non-soluble dans l'eau à un pH acide, et est transformé en liquide extrudable par adjonction d'une quantité appropriée d'agent de solubilisation, de préférence de l'éthanol. Le complexe ainsi obtenu est particulièrement utile comme vecteur injectable et à libération prolongée de substances bio-efficaces, et notamment d'agents thérapeutiques.
EP95921627A 1994-06-17 1995-06-09 VECTEUR D'APPORT DE SUBSTANCES BIO-EFFICACES A GELIFICATION -i(IN SITU) ET METHODE D'UTILISATION Withdrawn EP0802787A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26173194A 1994-06-17 1994-06-17
US261731 1994-06-17
PCT/US1995/007333 WO1995035093A1 (fr) 1994-06-17 1995-06-09 Vecteur d'apport de substances bio-efficaces a gelification in situ et methode d'utilisation

Publications (2)

Publication Number Publication Date
EP0802787A1 true EP0802787A1 (fr) 1997-10-29
EP0802787A4 EP0802787A4 (fr) 1998-09-02

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Country Status (5)

Country Link
EP (1) EP0802787A4 (fr)
JP (1) JPH10501814A (fr)
AU (1) AU2638795A (fr)
CA (1) CA2192708A1 (fr)
WO (1) WO1995035093A1 (fr)

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FR2737406B1 (fr) † 1995-08-04 1997-10-24 Sederma Sa Gel a activite physique pour produits cosmetiques
US20020064546A1 (en) 1996-09-13 2002-05-30 J. Milton Harris Degradable poly(ethylene glycol) hydrogels with controlled half-life and precursors therefor
US6258351B1 (en) 1996-11-06 2001-07-10 Shearwater Corporation Delivery of poly(ethylene glycol)-modified molecules from degradable hydrogels
DE19701912C1 (de) * 1997-01-10 1998-05-14 Jenapharm Gmbh Injizierbares Implantat
US6596291B2 (en) 1997-12-05 2003-07-22 Thomas A. Bell Compositions and methods for treating surfaces infected with ectoparasitic insects
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WO1995035093A1 (fr) 1995-12-28
JPH10501814A (ja) 1998-02-17
EP0802787A4 (fr) 1998-09-02
AU2638795A (en) 1996-01-15
CA2192708A1 (fr) 1995-12-28

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