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WO1992000718A1 - Systemes d'administration intragingivale pour le traitement de maladies parodontales - Google Patents

Systemes d'administration intragingivale pour le traitement de maladies parodontales Download PDF

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Publication number
WO1992000718A1
WO1992000718A1 PCT/US1990/003762 US9003762W WO9200718A1 WO 1992000718 A1 WO1992000718 A1 WO 1992000718A1 US 9003762 W US9003762 W US 9003762W WO 9200718 A1 WO9200718 A1 WO 9200718A1
Authority
WO
WIPO (PCT)
Prior art keywords
accordance
polymer
pharmaceutical composition
delivery system
tissue
Prior art date
Application number
PCT/US1990/003762
Other languages
English (en)
Inventor
Richard L. Dunn
Arthur J. Tipton
Ronald J. Harkrader
Jack A. Rogers
Original Assignee
Vipont Pharmaceutical, Inc.
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 Vipont Pharmaceutical, Inc. filed Critical Vipont Pharmaceutical, Inc.
Priority to CA002065156A priority Critical patent/CA2065156A1/fr
Priority to PCT/US1990/003762 priority patent/WO1992000718A1/fr
Priority to EP90911129A priority patent/EP0489743A1/fr
Publication of WO1992000718A1 publication Critical patent/WO1992000718A1/fr

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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0063—Periodont

Definitions

  • Periodontal disease or gum disease as it is often called can be defined as an infection and inflammation of the gingiva or gums and loss of underlying alveolar bone support. There are varying levels of severity of the disease. The mildest cases are clinically termed gingivitis (inflamed and bleeding gums) . More severe cases are clinically known as periodontitis and can involve loss of bone support. Gingivitis is reversible and can often be eliminated with a thorough dental prophylaxis followed by improved personal oral hygiene procedures. If gingivitis is not controlled, the disease often progresses into periodontitis.
  • Periodontitis is not only characterized by bacterial infection and inflammation, it is also accompanies by the formation of periodontal pockets (spaces between the teeth and gums) and bone deterioration which can lead to tooth loss. Periodontitis is recurring, progressive, and episodic. There is no cure at this time. Effective treatment is to apply professional intervention to halt disease progression.
  • Nonsurgical treatment consists of periodic professional scaling, root planing, and soft tissue curettage, in combination with conscientious home care by brushing and flossing on the part of the patient.
  • Surgical treatment involves gingivectomy and flap surgery to recontour the soft and hard tissue around the diseased areas.
  • the shape of the pocket or potential space is not regular, but often contoured based upon the shape of the tooth and the extent of the disease.
  • placement of a film or fiber within the pocket requires careful fitting to fill the pocket but not extend beyond the gingival margin. Any material extending outside the pocket will be removed by normal oral hygiene procedures unless the material is either adhered to the tissue or tooth or covered by a periodontal dressing.
  • Periodontal dressings are also adhesives and their adhesions to wet surfaces such as a tooth or gum tissue is difficult; and most periodontal dressings do not adhere long within the mouth. In addition, they are uncomfortable to the wearer and they tend to collect food particles and bacteria.
  • chemotherapeutic agents when placed within the periodontal pocket will kill the bacteria there, but these agents will not penetrate the gingival tissue to destroy the bacteria located intragingivally. These bacteria subsequently repopulate the periodontal pocket after the chemotherapeutic agent has been totally released or exhausted. There is therefore a need for a local delivery system that will destroy not only the periodontal pathogens within the periodontal pocket but also within the gingival tissues.
  • the present invention relates to the use of controlled release systems for the delivery of chemotherapeutic agents to localized sites in the mouth for the treatment of periodontal disease.
  • the method of treatment involves the placement of a polymeric delivery system directly into the gingival tissue that is infected rather than into the periodontal pocket that is formed between the infected tissue and the tooth.
  • the polymeric delivery system may consist of microspheres, microcapsules, liposomes, fibers, rods, films, or spheres. They may be fabricated from either biodegradable or nonbiodegradable polymers, although delivery systems fabricated from biodegradable polymers are preferred because they do not require removal after the chemotherapeutic agent has been released. Also preferred are the delivery systems in the form of microspheres, microcapsules, nano-particles, and liposomes which can be injected directly into the gingival tissue. Liquid polymeric systems that can be injected into the gingival tissue to form solid implants are also preferred delivery systems.
  • the polymeric delivery systems When injected into the gingival tissue, the polymeric delivery systems release the bioactive agent directly into the infected tissue.
  • the bioactive agent is released by diffusion or dissolution from the polymer or if the polymer is bioerodible the agent can be released as the polymeric device erodes or biodegrades.
  • the release of the agent creates a high concentration of active material within the gingival tissue. If the agent released is antimicrobial, the local concentration is sufficient to destroy the bacteria causing the infection. If the agent is an anti-inflammatory drug, the concentration is sufficient to reduce the inflammation within the tissue. Because the gingival crevicular fluid in the periodontal pocket is formed from serum from within the gingival tissue, the active agent is transported to the periodontal pocket as the serum flows out of the tissue.
  • the intragingival delivery system can achieve concentrations of drug sufficient to kill the bacteria both within the tissue as well as in the periodontal pocket.
  • This system provides a significant advantage over delivery systems placed within the periodontal pocket where the outward flow of crevicular fluid tends to remove the active agent from the pocket as it is released. This loss of active agent has been alleviated to some extent by the placement of periodontal dressings over the opening of the pocket or the use of adhesives or sutures to close the pocket. Because of the outward flow of the crevicular fluid and the poor penetration of most active agents into tissue, the drugs released into the periodontal pocket from a delivery system placed within the pocket or outside the pocket are unable to achieve an effective concentration of drug within the infected gingival tissue.
  • the intragingival delivery system described in the present invention provides a reliable method for retention of the delivery system at the site of infection.
  • the delivery system is retained by the gingival tissue until it is surgically removed or the polymer has degraded. Being located within the tissue, the intragingival delivery system (unlike a periodontal pocket delivery system) is not subject to untimely removal by the gingival crevicular fluid or the normal dental hygiene procedures such as brushing, flossing, or rinsing.
  • the location of the delivery system within the gingival tissue does not interfere with the reattachment of tissue to the tooth once the bacteria have been destroyed or the inflammation has been eliminated.
  • a periodontal pocket delivery system prevents tissue reattachment unless it is removed or unless the delivery system degrades in a short time.
  • An added advantage of the intragingival delivery system of this invention is that its retention and non-interference properties allow the active agent to be delivered for much longer times than those possible with a periodontal-pocket-delivery system.
  • the present invention relates to a method for treating periodontal disease by the use of an intragingival polymeric controlled delivery system.
  • the polymeric delivery system in the form of microspheres, microcapsules, nanoparti ⁇ les, or liposomes are injected directly into the infected gingival tissue where they release an active agent such as an antimicrobic or antibiotic to destroy bacteria or an anti-inflammatory agent to eliminate inflammation.
  • the preferred delivery system consists of a biodegradable polymer such that the delivery system does not require removal once the drug has been depleted.
  • the polymeric delivery system can also be in the form of a fiber, film, or rod which is surgically placed within the gingival tissue, but the preferred systems are those which can be injected into the tissue.
  • a liquid polymeric system that forms a solid implant that forms a solid implant after injection into the tissue is preferred.
  • nonbiodegradable polymers can be used in this application, the biodegradable polymers are preferred because they do not require removal after drug depletion.
  • biodegradable polymers which can be used in this application are polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates , polyphosphazenes , polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, pol (malic acid), poly(amino acids) , polyvinylpyrrolidone, polyethylene glycol, hydroxycellulose, methylcellulose, chitin, chitosan, gelatin, collagen, and copolymers,
  • drug or bioactive agent includes, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body.
  • Representative drugs and biologically active agents to be used in this application include antimicrobials, antibiotics, anti- inflammoratory agents, anti-infectives, peptide drugs, protein drugs, bone and tissue growth factors, analgesics, antigens, biological response modifiers, vaccines, and the benzophenanthridine alkaloids.
  • other drugs or bioactive agents that can be released in an aqueous environment can be utilized in the described intragingival delivery system.
  • various forms of the drugs or bioactive agents may be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc. , which are biologically activated when injected into the body.
  • the amount of drug or bioactive agent incorporated into the intragingival delivery system depends upon the desired release profile, the concentration of drug required for a biological effect, and the length of time that the drug has to be released for treatment. There is no critical upper limit on the amount of drug incorporated into the delivery system except for the local tissue irritation or the toxicity of the drug. The lower limit of drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for treatment.
  • the drug With certain drugs and polymers, the drug will be released by diffusion from the polymer matrix. The rate of release will be described by Fick's Law of
  • the release rate will be first-order in which there is a burst of drug initially followed by a gradually declining rate. If a reservoir device is used, the release rate will be zero-order in which there is a constant rate of release until the drug has been depleted.
  • the drug will be released by simple dissolution in which the loading of drug and the porosity of the polymeric delivery system will control the rate of delivery.
  • the release will depend upon the degradation rate of the polymer. The molecular weight of these drugs are so high that they will not diffuse through the matrix polymer and the only way for them to be released is for the polymer to erode or fragment due to biodegradation.
  • the drug and the polymer can be blended together using a variety of methods.
  • the intimacy of mixing, particle size, and particle shape can be varied according to the intended use.
  • High homogeneity can be obtained by mixing the components in the molten state, cooling and grinding the resulting solid.
  • the same type of homogeneity can be achieved if both components are dissolved in a common solvent, the solvent removed to give a film, and the film ground into a powder.
  • These particles can be sieved to obtain the desired particle size for injection and for drug release.
  • These particles as prepared constitute a monolithic delivery system in which the drug is distributed within the polymer matrix. As such the rate of release will be first order.
  • the particles can be converted to reservoir systems by coating them with a layer of polymer which serves as a rate-controlling membrane.
  • the particles can be coated by several methods including spray drying, fluid-bed coating, or microencapsulation.
  • microencapsulation can be used to coat drug/polymer particles already formed, it can also be used directly to form microspheres or microcapsules containing drug using a variety of methods known to those skilled in the art. These include solvent evaporation, phase separation, interfacial polymerization, hot melt, and spray drying.
  • the type of polymer used for the coating, the uniformity of the coating, the thickness of the coating, and the size of the microspheres or microcapsules can be used to control the release of drug.
  • liposomes Other small particles which can be used for injection include liposomes. These drug delivery forms are formed by encapsulating various drugs in lipid bylayers. The liposomes formed are extremely small and can be injected easily into the body or the blood stream. The other particles or microcapsules are injected as fluid suspensions from syringes into subcutaneous or muscular tissue. Water or aqueous solutions of sodium chloride or sodium carboxymethyl cellulose can be used for these injections. Oils such as sesame or peanut may also be used for injection.
  • the drug also dissolved or dispersed in the polymer solution may be injected directly into the body to form a solid implant.
  • the polymer is injected into the body as a liquid prepolymer and then polymerizes further or crosslinks to form a solid, then the drug dispersed in the liquid prepolymer can be injected to form a solid implant.
  • a surgical incision or the use of a trochar is needed for implantation.
  • These solid implants may be in the form of fibers, films, rods, cylinders, and pellets.
  • the fibers can be formed by melt extrusion if the drug is stable at the melt-spinning temperature or by solution spinning where polymer is soluble in a solvent that is compatible with the drug.
  • Rods and cylinders can be formed by the same method or they can be formed by injection molding or compression molding. Pellets can also be formed by compression molding or injection molding.
  • EXAMPLE 1 Poly(DL-1actide) (DL-PLA) with an inherent viscosity of 0.26 dL/g and a theoretical molecular weight of approximately 10,000 daltons was prepared by the ring-opening polymerization of DL-lactide using lauryl alcohol as the initiator and stannous chloride as the catalyst. The polymer was dissolved in N-methyl-2- pyrrolidone to give a 74% by weight solution. Sanguinarine hydrochloride as an orange powder was added to the polymer solution to give a 5% by weight dispersion of the drug in the polymer solution. The dispersion when added to water or saline solution formed a deep orange-colored solid precipitate which released the active drug over a period of two weeks.
  • EXAMPLE 2 Ethoxydihydrosanguinarine, the ethoxy ester of sanguinarine, was added to the same DL-PLA solution as described in Example 1 to give a 5% by weight solution of the drug. The light brown solution when injected into water or a saline solution gave a slightly orange- colored solid precipitate which released the drug as sanguinarine over a period of two weeks.
  • EXAMPLE 3 The two formulations described in Example 1 and 2 were place in 1-mL disposable syringes fitted with 21 gauge, 1.5-inch needles. Each formulation was then injected into the gingival tissue of healthy beagle dogs with artificially-created periodontal pockets. The needle was placed so that the formulation penetrated through the tissue into the periodontal pocket.
  • Tetracycline hydrochloride was added to the same DL-PLA solution as described in Example 1 to give a 5% by weight dispersion of drug in the solution. After standing overnight, the drug had dissolved completely into the polymer solution to give a light yellow solution. When injected into an aqueous or saline solution, the polymer coagulated to form a solid which slowly released tetracycline over a time of several weeks.
  • EXAMPLE 5 Poly(DL-lactide-co-glycolide) was prepared by the ring-opening polymerization of a mixture of DL- lactide and glycolide using lauryl alcohol as the initiator and stannous chloride as the catalyst. The proportions of the two monomers were adjusted so that the final copolymer (DL-PLG) had a 50:50 ratio of the two monomers as determined by nuclear magnetic resonance spectrophotometry. The initiator was also adjusted to give a copolymer with a theoretical molecular weight of 1500 daltons. The copolymer was dissolved in N-methyl- 2-pyrrolidone to give a 70% by weight polymer solution.
  • Tetracycline as the free base was added to the polymer solution to give a 2.4% by weight solution of the drug in the polymer solution.
  • the light yellow solution when added to water or saline formed a solid matrix as the polymer coagulated.
  • the drug was released from the polymeric matrix over a period of two weeks.
  • Tetracycline hydrochloride was added to the same DL-PLG solution as described in Example 5 to give a 2% by weight dispersion. After standing overnight, the drug dissolved completely in the polymer solution. The solid that formed when the solution was added to water or saline released the drug at a controlled rate for a time of two weeks.
  • the dispersion was poured into a shallow dish and the methylene chloride evaporated to form a film with the particles of drug dispersed uniformly within the polymer matrix.
  • the film was then ground to give small particles of polymer/drug which could be suspended in an aqueous injection vehicle and injected directly into tissue using a standard syringe and needle.

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  • Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un système d'administration régulée à base de polymères est utilisé dans le traitement de maladies parodontales. Le système d'administration, sous différentes formes, est placé directement dans le tissu gingival infecté où l'agent chimiothérapeutique est lentement libéré dans les tissus et dans la poche parodontale infectée par l'intermédiaire du fluide de la crevasse gingivale provenant du tissu gingival.
PCT/US1990/003762 1990-07-03 1990-07-03 Systemes d'administration intragingivale pour le traitement de maladies parodontales WO1992000718A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002065156A CA2065156A1 (fr) 1990-07-03 1990-07-03 Systemes de liberation intragingival pour le traitement d'une maladie periodontique
PCT/US1990/003762 WO1992000718A1 (fr) 1990-07-03 1990-07-03 Systemes d'administration intragingivale pour le traitement de maladies parodontales
EP90911129A EP0489743A1 (fr) 1990-07-03 1990-07-03 Systemes d'administration intragingivale pour le traitement de maladies parodontales

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1990/003762 WO1992000718A1 (fr) 1990-07-03 1990-07-03 Systemes d'administration intragingivale pour le traitement de maladies parodontales

Publications (1)

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WO1992000718A1 true WO1992000718A1 (fr) 1992-01-23

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CA (1) CA2065156A1 (fr)
WO (1) WO1992000718A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023018A1 (fr) * 1992-05-20 1993-11-25 Agence Conseil 3 P Compositions sous forme de film pour le traitement des parodontolyses et procede de fabrication
US5384333A (en) * 1992-03-17 1995-01-24 University Of Miami Biodegradable injectable drug delivery polymer
US5423337A (en) * 1994-03-24 1995-06-13 Ahlert; Gary Medicated dental floss
WO1995028124A3 (fr) * 1994-04-08 1996-02-15 Atrix Lab Inc Systeme auxiliaire de polymeres pour dispositif medical
WO1996013253A1 (fr) * 1994-11-01 1996-05-09 Dong Kook Pharmaceutical Co., Ltd. Preparation biodegradable a liberation prolongee destinee au traitement de la desmodontite
US5525330A (en) * 1992-12-16 1996-06-11 Colgate Palmolive Company Antiplaque antigingivitis, anticaries oral composition
EP0591392B1 (fr) * 1991-06-21 1996-09-11 Genetics Institute, Inc. Compositions pharmaceutiques de proteines osteogeniques
US5607686A (en) * 1994-11-22 1997-03-04 United States Surgical Corporation Polymeric composition
US5736152A (en) * 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5889110A (en) * 1992-05-28 1999-03-30 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US6130200A (en) * 1996-12-20 2000-10-10 Alza Corporation Gel composition and methods
US6589511B1 (en) 1997-03-18 2003-07-08 Sunstar, Inc. Composition for forming solid particles
US8153148B2 (en) 2002-03-14 2012-04-10 Degradable Solutions Ag Porous biocompatible implant material and method for its fabrication
US8163030B2 (en) 2004-05-06 2012-04-24 Degradable Solutions Ag Biocompatible bone implant compositions and methods for repairing a bone defect
US8865198B2 (en) 2010-10-25 2014-10-21 Dexcel Pharma Technologies Ltd. Method for treating a periodontal disease
US9375558B2 (en) 2013-03-14 2016-06-28 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit
DE102016101280A1 (de) 2016-01-26 2017-07-27 Frank Bröseler Pharmazeutische Zusammensetzung
CN116172983A (zh) * 2022-12-13 2023-05-30 首都医科大学附属北京朝阳医院 一种牙周塞治膜及其制作工艺

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JPS60184027A (ja) * 1984-03-01 1985-09-19 Lion Corp 歯周疾患予防治療剤
EP0244118A1 (fr) * 1986-04-29 1987-11-04 Pharmetrix Corporation Système à libération contrôlée de drogues pour la poche périodontale
US4774091A (en) * 1983-10-14 1988-09-27 Sumitomo Pharmaceuticals Company, Ltd. Long-term sustained-release preparation
EP0297535A2 (fr) * 1987-06-30 1989-01-04 Vipont Pharmaceutical, Inc. Systèmes libérant des médicaments
EP0330180A1 (fr) * 1988-02-24 1989-08-30 Biomaterials Universe, Inc. Microsphères du type acide polylactique contenant des substances physiologiquement actives et leur procédé de préparation
WO1990003768A1 (fr) * 1988-10-03 1990-04-19 Southern Research Institute Implants biodegradables a formation in situ
EP0375127A1 (fr) * 1988-11-02 1990-06-27 Genentech, Inc. Composition en vue du traitement des maladies periodontiques

Patent Citations (7)

* Cited by examiner, † Cited by third party
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US4774091A (en) * 1983-10-14 1988-09-27 Sumitomo Pharmaceuticals Company, Ltd. Long-term sustained-release preparation
JPS60184027A (ja) * 1984-03-01 1985-09-19 Lion Corp 歯周疾患予防治療剤
EP0244118A1 (fr) * 1986-04-29 1987-11-04 Pharmetrix Corporation Système à libération contrôlée de drogues pour la poche périodontale
EP0297535A2 (fr) * 1987-06-30 1989-01-04 Vipont Pharmaceutical, Inc. Systèmes libérant des médicaments
EP0330180A1 (fr) * 1988-02-24 1989-08-30 Biomaterials Universe, Inc. Microsphères du type acide polylactique contenant des substances physiologiquement actives et leur procédé de préparation
WO1990003768A1 (fr) * 1988-10-03 1990-04-19 Southern Research Institute Implants biodegradables a formation in situ
EP0375127A1 (fr) * 1988-11-02 1990-06-27 Genentech, Inc. Composition en vue du traitement des maladies periodontiques

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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0591392B1 (fr) * 1991-06-21 1996-09-11 Genetics Institute, Inc. Compositions pharmaceutiques de proteines osteogeniques
US5597897A (en) * 1991-06-21 1997-01-28 Genetics Institute, Inc. Pharmaceutical formulations of osteogenic proteins
US5384333A (en) * 1992-03-17 1995-01-24 University Of Miami Biodegradable injectable drug delivery polymer
FR2691360A1 (fr) * 1992-05-20 1993-11-26 3P Agence Conseil Compositions pharmaceutiques destinées en particulier au traitement des poches parondontales et procédé de fabrication.
WO1993023018A1 (fr) * 1992-05-20 1993-11-25 Agence Conseil 3 P Compositions sous forme de film pour le traitement des parodontolyses et procede de fabrication
US6034175A (en) * 1992-05-28 2000-03-07 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US5889110A (en) * 1992-05-28 1999-03-30 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US5525330A (en) * 1992-12-16 1996-06-11 Colgate Palmolive Company Antiplaque antigingivitis, anticaries oral composition
US5423337A (en) * 1994-03-24 1995-06-13 Ahlert; Gary Medicated dental floss
WO1995028124A3 (fr) * 1994-04-08 1996-02-15 Atrix Lab Inc Systeme auxiliaire de polymeres pour dispositif medical
US5707647A (en) * 1994-04-08 1998-01-13 Atrix Laboratories, Inc. Adjunctive polymer system for use with medical device
US5717030A (en) * 1994-04-08 1998-02-10 Atrix Laboratories, Inc. Adjunctive polymer system for use with medical device
WO1996013253A1 (fr) * 1994-11-01 1996-05-09 Dong Kook Pharmaceutical Co., Ltd. Preparation biodegradable a liberation prolongee destinee au traitement de la desmodontite
US5855904A (en) * 1994-11-01 1999-01-05 Dong Kook Pharmaceutical Co., Ltd. Biodegradable sustained release preparation for treating periodontitis
US5607686A (en) * 1994-11-22 1997-03-04 United States Surgical Corporation Polymeric composition
US5736152A (en) * 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5888533A (en) * 1995-10-27 1999-03-30 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US6120789A (en) * 1995-10-27 2000-09-19 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US6468961B1 (en) 1996-12-20 2002-10-22 Alza Corporation Gel composition and methods
US6331311B1 (en) 1996-12-20 2001-12-18 Alza Corporation Injectable depot gel composition and method of preparing the composition
US6130200A (en) * 1996-12-20 2000-10-10 Alza Corporation Gel composition and methods
US6673767B1 (en) 1996-12-20 2004-01-06 Alza Corporation Gel composition and methods
US6589511B1 (en) 1997-03-18 2003-07-08 Sunstar, Inc. Composition for forming solid particles
US8153148B2 (en) 2002-03-14 2012-04-10 Degradable Solutions Ag Porous biocompatible implant material and method for its fabrication
US8163030B2 (en) 2004-05-06 2012-04-24 Degradable Solutions Ag Biocompatible bone implant compositions and methods for repairing a bone defect
US8865198B2 (en) 2010-10-25 2014-10-21 Dexcel Pharma Technologies Ltd. Method for treating a periodontal disease
US9278064B2 (en) 2010-10-25 2016-03-08 Dexcel Pharma Technologies Ltd. Method for treating a periodontal disease
US9889090B2 (en) 2010-10-25 2018-02-13 Dexcel Pharma Technologies Ltd. Method for treating a periodontal disease
US9375558B2 (en) 2013-03-14 2016-06-28 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit
US9498612B2 (en) 2013-03-14 2016-11-22 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit
US10456568B2 (en) 2013-03-14 2019-10-29 Hallux, Inc. Method of treating infections, diseases or disorders of nail unit
DE102016101280A1 (de) 2016-01-26 2017-07-27 Frank Bröseler Pharmazeutische Zusammensetzung
EP3199144A1 (fr) 2016-01-26 2017-08-02 Frank Bröseler Composition pharmaceutique
CN116172983A (zh) * 2022-12-13 2023-05-30 首都医科大学附属北京朝阳医院 一种牙周塞治膜及其制作工艺

Also Published As

Publication number Publication date
CA2065156A1 (fr) 1992-01-04
EP0489743A1 (fr) 1992-06-17

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