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WO2001049336A1 - Hydrogel biocompatible et procede de production - Google Patents

Hydrogel biocompatible et procede de production Download PDF

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Publication number
WO2001049336A1
WO2001049336A1 PCT/IT1999/000428 IT9900428W WO0149336A1 WO 2001049336 A1 WO2001049336 A1 WO 2001049336A1 IT 9900428 W IT9900428 W IT 9900428W WO 0149336 A1 WO0149336 A1 WO 0149336A1
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WO
WIPO (PCT)
Prior art keywords
acrylamide
bis
hydrogel
ethylene
water
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.)
Ceased
Application number
PCT/IT1999/000428
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English (en)
Inventor
Vladislav Lopatine
Grigori Matiachvili
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PROGEN Srl
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PROGEN Srl
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Publication date
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Priority to AU20019/00A priority Critical patent/AU2001900A/en
Priority to PCT/IT1999/000428 priority patent/WO2001049336A1/fr
Publication of WO2001049336A1 publication Critical patent/WO2001049336A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

  • the invention relates to a composition and a method of producing a biologically compatible hydrogel on the basis of cross-linked copolymer of acrylamide with a linking agent, which can be used as medical purpose material, e.g.: for endoprosthetics by means of purposeful injection of hydrogel.
  • a linking agent which can be used as medical purpose material, e.g.: for endoprosthetics by means of purposeful injection of hydrogel.
  • hydrogel for plastics of soft facial tissue, mammal gland, penis, sural muscle, cords and other tissues fitting hydrogel consistence; as a filling agent for endoprostheses including mammal gland endopro- stheses; as medicine depot for protracted medication of tumors and abscesses (for example).
  • Acrylamide-based hydrogels can be used as such a material.
  • GB Patent No 21 14578 describes hydrogel on the basis of copolymer of acrylamid with methylene-bis-acrylamide as a linking agent assigned for lens manufacture. Said hydrogel containes 1 1 % wt of copolymer (with acrylamide to methylene-bis-acrylamide mass ratio 100:2,26) and 89 wt per cent of physio- logical salt solution.
  • Method of producing such a hydrogel described in the patent mentioned consists in copolymerization of acrylamide and methylene-bis-acrylamide as a linking agent in physiological salt solution in the presence of copolymerization initiators (tetramethylethylenediamine is one of them) with subsequent washing out of unreacted monomers from the end product. Copolymerization is conducted in a single stage at room temperature.
  • hydrogel thus obtained is unfit for soft tissue plastics because of its high consistence. Besides, due to a single stage process, this gel contains a lot of monomers and free radicals causing negative tissue response of organism.
  • Biocompatible hydrogel described in Claim EP No 742022 contains 3.5 to 9.0% wt of cross-linked copolymer of acrylamide with methylene-bis- acrylamide as a linking agent inaqueous medium.
  • Method of producing this hydrogel described in the Claim consists in acrylamide with methylene-bis-acrylamide copolymerization in inaqueous medium in the presence of peroxide initiators. Reaction mass is maintained at room temperature for 20 minutes for cross-linking a polymer. Copolymeriza- tion process in this case is also a single- stage one, mixture of persulphate and tetramethylethylenediaminebeing used as peroxide initiator of copolymerization. Apirogenic water or sodium chloride solution is taken as aqueous medium. Thus obtained hydrogel has inadequate degree of cross-linking due to low copolymeryzation process temperature and its single-stageness.
  • hydrogel containes unbound tetramethylethylenediamine molecules, free NH 2 radicals and acrylamide monomers in the amount of 1.0-1.2 ⁇ g per lg of gel (1.0-1.2 ppm).
  • Biocompatible hydrogel described in RU Patent No.2127129 contains
  • hydrogel does not contain unbound tetramethylethylene- diamine molecules, contains minimal quantity of free NH 2 radicals and acrylamide monomers in the amount of 0.6-0.8 ⁇ g per lg of gel (1.0-1.2 ppm). Furthermore, after implanting this material to a patient's body it shrinks to 12-15% of the initial level thus reducing cosmetic effect of plastic surgery. In some cases additional material injection is needed.
  • the task of dimi- nishing tissue response of an organism to the implant by reducing a number of free radicals and monomers in a hydrogel is also set.
  • biocompatible hydrogel for endoprosthetics containing cross-linked acrylamide copolymer with a linking agent and water contains mixture of N, N'- methylene-bis-acrylamide and N, N'-ethylene-bis-acrylamide, with acrylamide to N, N'-methylene-bis-acrylamide and N, N'-ethylene-bis- acrylamide mass ratio being 95.0-99.5 : 0.4-4,5 : 0.1-0,5 respectively.
  • Said hydrogel can contain as a linking agent a mixture of N, N'- methylene-bis-acrylamide, N, N'-ethylene-bis-acrylamide and ethylene-bis- (oxyethylene nitril)-tetracetic oxide or ethylene-bis-(oxyethylene nitril)tetracetic acid with mass ratio of acrylamide, N, N'-methylene-bis- acrylamide, N,N'-efhylene-bis-acrylamide and ethylene-bis-(oxyethylene nitril)-tetraacetic oxide or ethylene-bis-(oxyethylene nitril)-tetracetic acid being 95.0-99.5 : 0,4-4,5 : 0.08-0.4 : 0.02-0.1.
  • Said hydrogel has pH 4.5-7.5.
  • Cross-linked copolymer makes up 2.0 to 15% of the total hydrogel by weight.
  • Biocompatible hydrogel's distinctive feature is that it is obtained by copolymeryzation of acrylamide, N, N'-methylene-bis-acrylamide and N,N'- efhylene-bis-acrylamide with their mass ratio 95.0-99.5 : 0.4-4,5 : 0.1-0,5 respectively, in aqueous dispersing medium in the presence of peroxide polymerization initiator with reaction mass incubation at 20-90 °C for 2-24 hours and then at 115-130°C for 1-1.5 hours, with washing of semi-product in hot water at 90-100°C for 4-6 hours following the incubation at 20-90 °C.
  • Said hydrogel can be also produced by copolymerization of acrylamide with N, N'-methylene-bis-acrylamide, N,N'-ethylene-bis-acrylamide and ethylene-bis-(oxyethylene nitril)-tetracetic oxide with their mass ratio 95.0- 99.5 : 0,4-4,5 : 0.08-0.4 : 0.02-0.1 in aqueous medium in the presence of peroxide polymerization initiator with reaction mass incubation at 20-90°C for 2-24 hours and then at 1 15-130°C for 1 -1.5 hours, with semi-product wash- ing in hot water at 90-100°C for 4-6 hours which follows reaction mass incubation at 20-90°C.
  • the problems set are being solved by a method of producing biocompatible hydrogel by means of acrylamide and linking agent copoly- merization in aqueous dispersive medium in the presence of peroxide copolymerization initiator with reaction mass incubation promoting copolymer' s cross-linking in two stages.
  • the first stage is carried out at 20-90 °C for 2-24 hours, mixture of N, N'-methylene-bis-acrylamide and N, N'-ethylene-bis- acrylamide is taken as a linking agent, the second stage of incubation is held at 1 15-130°C for 1-1.5 h, the first incubation is followed by stock washing in hot water at 90-100°C during 4-6 h.
  • mass ratio of acrylamide to N, N'-methylene-bis-acrylamide and N, N'-ethylene-bis-acrylamide is 95.0- 99.5 : 0.4-4,5 : 0.1-0,5.
  • Method is also valid if mixture of N, N'-methylene-bis-acrylamide, N,N'-ethylene-bis-acrylamide and ethylene-bis-(oxyethylene nitril)-tetracetic oxide or ethylene-bis-(oxyethylene nitril)-tetracetic acid is used as a linking agent.
  • mass ratio of acrylamide, N, N'-methylene-bis- acrylamide, N,N'-ethylene-bis-acrylamide and ethylene-bis-(oxyethylene nitril)-tetracetic oxide or ethylene-bis-(oxyethylene nitril)-tetracetic acid is 95.0-99.5 : 0,4-4,5 : 0.08-0.4 : 0.02-0.1.
  • aqueous dispersive medium and total amount of acrylamide and linking agents must be taken, with initial water to monomers' mixture ratio being 85.0-98.0 : 2.0-15.0 mass parts.
  • Stock washing is carried out at mass ratio of semi-product to water 1 :8- 10.
  • Hydrogen peroxide and/or ammonium persulfate are taken as polymerization initiators, in the amount not exceeding 0.3% wt.
  • Twice-distilled apyrogenic water is taken as aqueous medium.
  • Hydrogel material on the basis of copolymer of acrylamide and linking agents is known to constitute a three-dimensional net, in this particular case, of cross-linked copolymer of acrylamid, N, N'-methylene-bis-acrylamide
  • methylene-bis-acrylamide and N, N'-ethylene-bis-acrylamide or cross- linked copolymer of acrylamid, N, N'-methylene-bis-acrylamide (methylene- bis-acrylamide), N, N'-ethylene-bis-acrylamide and ethylene-bis- (oxyethylene nitril)-tetracetic oxide or ethylene-bis-(oxyethylene nitril)- tetracetic acid.
  • Aqueous medium is retained within the net sells, cernain un- defined amount of unbound polymerization initiator is, in turn, retained within the aqueous medium.
  • Essense of invention consists in experimental selection of conditions for biocompatible hydrogel production, which allowed reducing amount of unbound amides, free NH 2 radicals and unsaturated double bonds.
  • linkage degree has been increased due to structural groups formation (HC- NH-CH), (-CO-NH-CR-O-R), (-CO-NH-NH-CO-), (H-COR-NH-CR-O-R), (-
  • Bromation level of thus produced hydrogel does not exceed 2.0 mg Br/1 and monomers content is not more than 0.4 ppm.
  • assessment of known hydrogel according to RU patent No. 2127129 shows bromation level of 3.0 mg Br/1 and monomers content of 0.6-0.8 ppm.
  • N,N'-methylene-bis-acrylamide C 7 H 10 N 2 O 2 , mol.wt - 154,16, white odourless crystal powder, melting point is 185 °C, produced by Sigma Co. (USA); N,N'- ethylene-bis-acrylamide produced by Aldrich Co. (USA);
  • Ammonium persulfate (NH 4 ) 2 S 2 O 8 , mol. wt - 228.19, flat colourless crystals; decomposition point is 120°C; produced by Sigma Co. (USA); All above-mentioned monomers must be fit for biological use and they must not need additional purification.
  • Aqueous solution of acrylamide and linking agents N, N'-methylene- bis-acrylamide and N, N'-ethylene-bis-acrylamide (taken in mass ratio 95 :
  • Polymerization initiators hydrogen peroxide in the amount of 0.1-0.3 % wt or ammonium persulfate in the amount of 0.0006-0.03 % wt or their mixture in any ratio in the amount not exceeding their total maximum are put to the solution.
  • hydrogen peroxide and ammonium persulfate amounts By varying hydrogen peroxide and ammonium persulfate amounts a material of desirable pH is obtained.
  • Finished reaction mass is filtrated through polymer bactericidal filters of F8273 brand with pore size of 0.45 mm CA/CN (producer - Sigma Co.(USA) and is incubated at 20-90°C for 2-24 h. After the incubation semi-product of gel-like appearance must be washed with hot water.
  • hydrogel characteristics have been measured: refractive index (by the technique described in "Physical Chemistry Workshop", M., 1974, pp.86-97); pH ( by the technique described in “Methodical Guideline For Sanita- tion Assessment of Rubber and Latex Goods of Medical Application", Moscow, 1988, pp.18, 19); bromation level (by the technique described in “Transactions of Guid- ing Materials On Toxicology Study of Polymer Materials and Goods of Medical Application", M. Ministry of Health of the USSR, 1987., pp.27-29); monomers content (by unpublished technique developed by the authors for evaluation of monomers content in water-containing polymers).
  • the claimed hydrogel has the following physicochemical characteristics: appearance - colorless gel; refractive index - 1.328-1.360; density - 0.9-1.2 g/cm 2 ; pH - 4.5-7.5; monomers content - ⁇ 0,4 ppm; bromation level - ⁇ 2.0 mg Br/1.
  • hydrogel extract did not display hemo- lytic effect 'in vitro' tests with isolated erythrocytes of rabbits. 0.04%o hemol- ysis occured with admissible level of 2%.
  • Test mouses autopsy indicated that tissue at gel injection point, regional glands, viscuses (liver, kidneys, and spleen) were within the physiological norm and control.
  • Tissue response to the claimed hydrogel implantation was studies dur- ing experimental and morphological and clinical morphological trials (see
  • Test was carried out on 160 male rats of August line, 200 g in weight and 10 dogs.
  • tissue blocks were fixed in 96° alcohol or neutral formalin and put in paraffin. Sections were colored with hematoxiline-eosin, picrofuxin by Van Gizon, silvering by Gomory to study fibrous components, with toluidine blue for acid glycosamineglycanes. PAS response to glycogen and glycoproteins as well as Brashe response to RNA were studied.
  • the capsulus In the capsular thickness as well as in the zone between the capsular and cellular tissue small fragments of hydrogel surrounded by macrophages and isolated giant multinucleous cells can be seen. 1 -3 months after the implantation the capsulus is still thin. It consists of mature conjunctive tissue with reduced number of fibroplasts, the remaining cells have lesser RNA content. There are hydrogel fragments in the transcapsular area which are resorbed by macrophages . Interior surface of the capsular is still coated with macrophages .
  • Tissue response at later terms was studied by subcutaneous implantation of gel to dogs.
  • a narrow lysis zone of the hydrogel can be seen.
  • the hydrogel is resorbed by macrophages and germinated with fibroplast bars in that zone.
  • Signs of lime sediments in the hydrogel can be found neither in dogs nor in rats.
  • Dystrophic cell changes in tissue surrounding the implant which could indicate toxic effect of the hydrogel, are not found.
  • hydrogel remained mostly homogeneous and conjunctive tissue germinated only near the capsular.
  • tissue response to the gel is feebly marked.
  • "Old" fibros capsular is in backward development in nearly all parts.
  • the implant is surrounded by a thin conjunctive tissue capsular having no interior myofibroplastic layer which takes place in case of silicone prosthesis.
  • small lympho-macrophagal infiltrates without inflammatory neutrophilic response can be seen in a "new" capsular.
  • Capsular's vasa are not numerous; there are no dystrophic changes and lime salt deposites in the capsular.
  • a superficial germination of thin conjunctive tissue bars (fibroplasts, macrophags and thin immature collagen fibers) into the hydrogel can be seen in a vicinity of the capsular.
  • Some macrophages have a big foamy cytoplasm
  • hydrogel It is significant that there was no deep invasion of macrophages and microphages into the hydrogel. It proves its stability to resorption in organ- ism. At the same time hydrogel does not reduce functional activity of cells and does not cause their dystrophy. This proves lack of migration of toxic substanses from gel to tissue. There is no calcification of hydrogel and surrounding tissues.
  • the biologically compatible hydrogel claimed causes no tissue response, no organism sensitization, it is not mutagenic, it causes no dystrophic and necrotic changes and can be used for endoprosthetics and contour soft tissue plastics.
  • hydrogel 19 g of acrylamide, 0.9 g of N,N' -methylene-bis- acrylamide and 0.1 g of N,N'-ethylene-bis-acrylamide suitable for biological application dissolved in 400 ml of twice-distilled apyrogenic water with a pH of 5.6. 0.04 g of ammonium persufate and 2 ml of 30% hydrogen peroxide were added to the solution.
  • the mixture obtained was filtrated through polymer bactericidal filter of F8273 brand with pore size 0.45 mm CA/CN (producer - Sigma Co. (USA) and placed in the vessel which was put to a water bath for incubation at 30 °C for 22 hours.
  • the gel like semi-product was washed in hot water with water to gel ratio 10: 1 at temperature of 90 °C for 4 hours and was further incubated for 1 hour at temperature not exceeding 125 °C.
  • the hydrogel obtained was sterilised by autoclaving (at temperature of
  • Bromation level - 0.1 (mg Br per 1L);
  • the hydrogel produced was injected to a female patient L-ya, aged 55, to replace a silicone prosthesis which had been used for primary mammaplasty 8 years before and caused coarse fibrosis of both mammals.
  • the patient was being seen for 8 months' post-operative period with monthly examinations. Fibrosis recurrence was not detected. Positive result was obtained: mammals' shape and size fit patient's constitution, their elasticity was typical for tissue of healthy mammal.
  • hydrogel 24.5 g of acrylamide, 0.375 g of N,N' -methylene- bis-acrylamide, 0.1 g of N,N'-ethylene-bis-acrylamide and 0.025 g of ethylene-bis-(oxyethylene nitril)-tetracetic oxide or ethylene-bis-
  • the hydrogel obtained was sterilised as described in example 1.
  • the produced material had the following physicochemical characteristics:
  • hydrogel 77.6 g of acrylamide, 2.08 g of N,N'-methylene- bis-acrylamide and 0.32 g of N,N'-ethylene-bis-acrylamide dissolved in 1000 ml of twice-distilled apyrogenic water with a pH of 5.6. Then 0.03 g of ammonium persufate was added to the solution. The mixture obtained was fil- trated as described in example 1 and put to incubation at 60 °C for 12 hours.
  • the gel was washed in hot water at 100°C for 4.5 hours and was further incubated for 1.5 hours at temperature of 120°C.
  • the hydrogel obtained was sterilised as described in example 1.
  • Bromation level - 0.05 (mg Br per 1L).
  • the hydrogel obtained was used for sural muscle plasty.
  • 150 g of hy- drogel was implanted into each sural muscle of a patient S., aged 47. The patient was being seen for 12 months' post-operative period with periodic examinations of every 3 months. Inflammatory and allergic effects were not detected. Desirable cosmetic effect was obtained.
  • hydrogel 23.75 g of acrylamide, 1.075 g of N, N'- methylene-bis-acrylamide, 0.045 g of N,N'-ethylene-bis-acrylamide and 0.005 g of ethylene-bis-(oxyethylene nitril)-tetracetic oxide or ethylene-bis- (oxyethylene nitril)-tetracetic acid dissolved in 400 ml of twice-distilled apyrogenic water with a pH of 5.6. Then 0.02 g of ammonium persufate and
  • the hydrogel produced was injected to a female patient L-ya, aged 26, to replace a silicone prosthesis which had been used for primary mammaplasty 3 years before and caused fibrosis of both mammals 7 months after the operation.
  • Surgery was performed to remove silicone prosthesis with open capsulotomy and delayed injection of 180 g of hydrogel to each mammal. 3 months later another 100 g of the same hydrogel was injected to each mammal.
  • the patient was being seen for 7 months' post-operative period with once-every-two-months examinations. Fibrosis recurrence was not detected.
  • mammals' shape and size fit patient's constitu- tion their elasticity was typical for tissue of healthy mammal. A desirable cosmetic effect was obtained.
  • examples given prove possibility of producing biocompatible hydrogel and of using it for plastics of soft tissues.
  • a hydrogel can also be used as a filling agent for endoprostheses comprising a cover and a filling agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition et un procédé de production d'un hydrogel biologiquement compatible destiné à l'endoprothétique, contenant un copolymère réticulé d'acrylamide avec un agent de liaison et de l'eau, ledit agent de liaison pouvant être un mélange d'acrylamide, de N,N'-méthylène-bis-acrylamide, de N,N'-éthylène-bis-acrylamide, d'éthylène-bis-(oxyéthylène nitril)-tétracétique oxyde ou d'éthylène-bis-(oxyéthylène nitril)-tétracétique acide.
PCT/IT1999/000428 1999-12-29 1999-12-29 Hydrogel biocompatible et procede de production Ceased WO2001049336A1 (fr)

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AU20019/00A AU2001900A (en) 1999-12-29 1999-12-29 Biocompatible hydrogel and method of its production
PCT/IT1999/000428 WO2001049336A1 (fr) 1999-12-29 1999-12-29 Hydrogel biocompatible et procede de production

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PCT/IT1999/000428 WO2001049336A1 (fr) 1999-12-29 1999-12-29 Hydrogel biocompatible et procede de production

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016453A1 (fr) * 2000-08-25 2002-02-28 Contura S.A. Hydrogel de polyacrylamide et son utilisation comme endoprothese
WO2003087170A1 (fr) * 2002-04-10 2003-10-23 Gradipore Limited Hydrogels polyacrylamides
US7186419B2 (en) 2000-08-25 2007-03-06 Contura Sa Polyacrylamide hydrogel for arthritis
US7238761B2 (en) 2002-04-10 2007-07-03 Obschestvos Organichennoy Otvetstvennostyu “Vitagel” Multifunctional biocompatible hydrophilic gel and the method of gel manufacture
US7294348B2 (en) * 2001-09-28 2007-11-13 Biopharma Development, Ltd. Polyfunctional biocompatible hydrogel and method for the production thereof
US7678146B2 (en) 2000-08-25 2010-03-16 Contura A/S Polyacrylamide hydrogel and its use as an endoprosthesis
US8496943B2 (en) * 2003-03-31 2013-07-30 Durect Corporation Non-aqueous single phase vehicles and formulations utilizing such vehicles
US11083796B2 (en) 2005-07-26 2021-08-10 Durect Corporation Peroxide removal from drug delivery vehicle
US11400019B2 (en) 2020-01-13 2022-08-02 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
US12433877B2 (en) 2021-01-12 2025-10-07 Durect Corporation Sustained release drug delivery systems and related methods

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RU2127129C1 (ru) * 1996-05-28 1999-03-10 Владислав Викторович Лопатин Способ получения гелеобразного материала для пластики мягких тканей
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7935361B2 (en) 2000-08-25 2011-05-03 Contura A/S Polyacrylamide hydrogel as a soft tissue filler endoprosthesis
US8216561B2 (en) 2000-08-25 2012-07-10 Contura A/S Polyacrylamide hydrogel for the treatment of incontinence and vesicouretal reflex
EP1564230A2 (fr) 2000-08-25 2005-08-17 Contura S.A. Hydrogel de polyacrylamide et son utilisation comme endoprothèse
US7186419B2 (en) 2000-08-25 2007-03-06 Contura Sa Polyacrylamide hydrogel for arthritis
WO2002016453A1 (fr) * 2000-08-25 2002-02-28 Contura S.A. Hydrogel de polyacrylamide et son utilisation comme endoprothese
EP1564230A3 (fr) * 2000-08-25 2009-12-09 Contura A/S Hydrogel de polyacrylamide et son utilisation comme endoprothèse
US7678146B2 (en) 2000-08-25 2010-03-16 Contura A/S Polyacrylamide hydrogel and its use as an endoprosthesis
US7780958B2 (en) 2000-08-25 2010-08-24 Contura Sa Polyacrylamide hydrogel for the treatment of incontinence and vesicouretal reflux
US7790194B2 (en) 2000-08-25 2010-09-07 Contura A/S Polyacrylamide hydrogel as a soft tissue filler endoprosthesis
US7294348B2 (en) * 2001-09-28 2007-11-13 Biopharma Development, Ltd. Polyfunctional biocompatible hydrogel and method for the production thereof
US7238761B2 (en) 2002-04-10 2007-07-03 Obschestvos Organichennoy Otvetstvennostyu “Vitagel” Multifunctional biocompatible hydrophilic gel and the method of gel manufacture
WO2003087170A1 (fr) * 2002-04-10 2003-10-23 Gradipore Limited Hydrogels polyacrylamides
US8496943B2 (en) * 2003-03-31 2013-07-30 Durect Corporation Non-aqueous single phase vehicles and formulations utilizing such vehicles
US11083796B2 (en) 2005-07-26 2021-08-10 Durect Corporation Peroxide removal from drug delivery vehicle
US11400019B2 (en) 2020-01-13 2022-08-02 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
US11771624B2 (en) 2020-01-13 2023-10-03 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
US12433877B2 (en) 2021-01-12 2025-10-07 Durect Corporation Sustained release drug delivery systems and related methods

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