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WO1996010395A1 - Preparations pharmaceutiques a liberation lente - Google Patents

Preparations pharmaceutiques a liberation lente Download PDF

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Publication number
WO1996010395A1
WO1996010395A1 PCT/AU1995/000648 AU9500648W WO9610395A1 WO 1996010395 A1 WO1996010395 A1 WO 1996010395A1 AU 9500648 W AU9500648 W AU 9500648W WO 9610395 A1 WO9610395 A1 WO 9610395A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically active
pharmaceutical preparation
active compound
water
soluble pharmaceutically
Prior art date
Application number
PCT/AU1995/000648
Other languages
English (en)
Inventor
John Cooper Cox
Original Assignee
Csl Limited
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 Csl Limited filed Critical Csl Limited
Priority to AU35999/95A priority Critical patent/AU3599995A/en
Publication of WO1996010395A1 publication Critical patent/WO1996010395A1/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds

Definitions

  • This invention relates to pharmaceutical preparations, and in particular it relates to pharmaceutical preparations which contain a pharmaceutically active ingredient which is released from the preparation in a controlled- or delayed-release manner.
  • Such pharmaceutical preparations will be referred to herein as "controlled-release" pharmaceutical preparations.
  • controlled- or delayed-release vaccine preparations which are in stable particulate form, the particles being microspherical particles which comprise a continuous matrix of biodegradable polymer (such as polylactic acid, polyglycolic acid and copolymers thereof), with one or more discrete, immunogen-containing regions (optionally also containing an adjuvant) dispersed throughout the continuous matrix.
  • biodegradable polymer such as polylactic acid, polyglycolic acid and copolymers thereof
  • These vaccine preparations may be produced either by forming an emulsion of an aqueous suspension comprising the immunogen and optionally the adjuvant in a continuous organic phase having the biodegradable polymer dissolved therein and subsequently spray-drying the water-in-oil emulsion to form the microspherical particles, or by forming a suspension of a particulate immunogen-containing material in a continuous organic phase having the biodegradable polymer dissolved therein and then spray-drying the suspension to form the microspherical particles.
  • microparticles were shown to generate greater and longer lasting immune responses than the identical liquid vaccine from which they were prepared, possibly due to an increased persistence of these microparticles at the injection site, thus minimising inactivation of immunogen by Kuppfer cells of the liver and maximising time of exposure to immune effector cells; i.e. the microparticulate nature of the vaccine component was generating a short-term controlled release.
  • controlled-release pharmaceutical preparations of the present invention have particular utility in that they enable water-soluble pharmaceutically active compounds to be formulated in a manner which does not result in modification of the active compounds, which results for example from exposure to organic solvents used in the solubilisation of polymeric materials. This is of special importance where the pharmaceutically active compounds are for example proteins which might lose activity on modification of their structure.
  • a controlled- release pharmaceutical preparation comprising at least one water-soluble pharmaceutically active compound in stable, dry particulate form, said particles being microparticles prepared by spray-drying and comprising a calcium or aluminium salt having said pharmaceutically active compound(s) adsorbed thereon.
  • the particles are microparticles of a calcium or aluminium salt gel, more preferably a calcium phosphate or aluminium phosphate gel.
  • This invention also provides a method for the production of a controlled-release pharmaceutical preparation as described above, which comprises the steps of contacting the water-soluble pharmaceutically active compound(s) with a calcium or aluminium salt gel, and subsequently spray-drying the preparation to form microparticles of said calcium or aluminium salt having said pharmaceutically active compound(s) adsorbed thereon.
  • the microparticles may, for example, have a size in the range of from 1-3 ⁇ m up to 20-30 ⁇ m in diameter.
  • a controlled-release pharmaceutical preparation comprising at least one water-soluble pharmaceutically active compound in stable, dry particulate form, said particles being microspherical particles prepared by spray-drying and comprising a continuous matrix of biodegradable polymer containing one or more discrete regions comprising said water- soluble pharmaceutically active compound(s).
  • the invention provides a controlled-release pharmaceutical preparation comprising at least one water-soluble pharmaceutically active compound and at least one lipid-soluble pharmaceutically active compound in stable, dry particulate form, said particles being microspherical particles prepared by spray-drying and comprising a continuous matrix of biodegradable polymer with said lipid-soluble pharmaceutically active compound(s) therein, said matrix containing one or more discrete regions comprising said water-soluble pharmaceutically active compound(s).
  • the invention also provides a method for the production of a controlled-release pharmaceutical preparation in stable, dry particulate form as described above, which comprises the steps of forming an emulsion of an aqueous phase comprising the water-soluble pharmaceutically active compound(s) in a continuous organic phase having said biodegradable polymer dissolved therein, and subsequently spray-drying the water-in-oil emulsion to form microspherical particles which comprise a continuous matrix of polymer containing one or more discrete regions comprising the water-soluble pharmaceutically active compound(s).
  • controlled-release pharmaceutical preparation also comprises lipid- soluble pharmaceutically active compound(s)
  • these compounds are dissolved with the biodegradable polymer in the continuous organic phase prior to spray-drying the emulsion.
  • the microspherical particles may have a size in the range of from 10-30 ⁇ m in diameter, preferably in the range of 20-30 ⁇ m.
  • the present invention also extends to a pharmaceutical composition
  • a pharmaceutical composition comprising a controlled-release pharmaceutical preparation as described above, together with a pharmaceutically or veterinarily acceptable carrier or diluent.
  • This invention also extends to a method of treating a human or other animal patient, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition as described above.
  • pharmaceutical preparation and “pharmaceutical composition” are to be understood as including both preparations and compositions for use in treatment of humans and preparations and compositions for use in treatment of other animals.
  • the water-soluble pharmaceutically active compound(s) in the controlled-release pharmaceutical preparations of the invention may, if desired, be stabilised with a stabiliser, in particular a sugar or sugar derivative such as trehalose, lactose, dextrose, mannitol or glucosamine.
  • a stabiliser in particular a sugar or sugar derivative such as trehalose, lactose, dextrose, mannitol or glucosamine.
  • water-soluble pharmaceutically active compound(s) are present in discrete regions in a continuous matrix of biodegradable polymer, they may be adsorbed on a solid carrier such as a calcium or aluminium phosphate gel.
  • the water-soluble pharmaceutically active compounds which may be formulated in accordance with this invention include all water-soluble pharmaceutical or veterinary drugs, as well as water-soluble proteins which are therapeutically active in humans and other animals such as erythropoietin, GM-CSF and other CSFs, any member of the extensive family of cytokines, e.g. IL-1, IL-2, IFN- ⁇ , and the like, blood factors and the like, and growth factors such as bovine somatotrophin, (BST), porcine somatotrophin (PST), and the like. Other compounds include hormones such as testosterone, oestradiol and the like, and antibiotics and antimalarial drugs.
  • the water-soluble vitamins may also be formulated in accordance with this invention (and water-insoluble or lipid-soluble vitamins may be included in the polymeric continuous matrix).
  • the biodegradable polymer used in the present invention may be any polymer substance which is capable of existing in a nonaqueous phase, which is biocompatible and which is capable of delayed breakdown in vivo.
  • Suitable polymers include, for example polyesters, polyorthoesters, polyanhydrides and cyanoacrylates, as well as various natural polymers including some proteins and polysaccharides.
  • Particularly suitable polymers for use in accordance with the present invention include homopolymers of D-, L- and DL-polylactic acids (D-PLA; L-PLA; DL-PLA) and polyglycolic acid (PGA), and various polylactide coglycolide (PLG) copolymers thereof.
  • one or more emulsifiers are used, and suitable emulsifiers include, for example, Tween 80 and Span 85 and mixtures thereof.
  • the water-soluble pharmaceutically active compound(s) is/are adsorbed to a calcium or aluminium salt gel, a sugar stabiliser is added if desired, and the preparation is spray-dried.
  • an aqueous phase is prepared including the water-soluble compound(s) and emulsifier(s), and this aqueous phase is then emulsified into a continuous organic phase which consists of the biodegradable polymer (and, if desired, the lipid-soluble compound(s)) dissolved in an organic solvent such as chloroform or dichloromethane.
  • the emulsion may comprise 1 part aqueous phase : 9 parts organic phase, by volume.
  • the resultant water-in-oil emulsion is then spray-dried under suitable conditions, to generate the microspherical particles of the preparation of the invention.
  • the water-soluble active compound(s) in this emulsion may be free in solution or adsorbed to a calcium or aluminium salt gel prior to emulsification.
  • the controlled-release preparations of this invention may be administered to a human or animal patient by any appropriate route, for example, parenterally by injection in an acceptable pharmaceutical or veterinary carrier or diluent.
  • the preparation may be administered in the form of a solid pellet or implant using a solid carrier for subcutaneous or similar use.
  • Suitable pharmaceutically acceptable carriers and/or diluents include any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art, and it is described, by way of example, in Remington 's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions of the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the human or other animal patients to be treated; each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical or veterinary carrier and/or diluent.
  • the specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active ingredient and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active ingredient for the particular treatment.
  • a variety of administration routes are available for the controlled-release preparations of this invention.
  • the particular mode selected will depend, of course, upon the particular condition being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practised using any mode of administration that is acceptable in the fields of human or other animal medicine, meaning any mode that produces therapeutic levels of the active component of the invention without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, topical, nasal, transdermal or parenteral (e.g. subcutaneous, intramuscular and intravenous) routes.
  • Formulations for oral administration include discrete units such as capsules, tablets, lozenges and the like.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the active component into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active component into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation containing the active component, which is preferably isotonic with the blood of the recipient.
  • This aqueous preparation may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in polyethylene glycol and lactic acid.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • sustained release delivery systems can include sustained release delivery systems.
  • Preferred sustained release delivery systems are those including a solid carrier which can provide for release of the active component in sustained release implants, pellets or capsules.
  • the active component is administered in therapeutically effective amounts.
  • a therapeutically effective amount means that amount necessary at least partly to attain the desired effect, or to delay the onset of, inhibit the progression of, or halt altogether, the onset or progression of the particular condition being treated. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition and individual patient parameters including age, physical condition, size, weight and concurrent treatment. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgement. It will be understood by those of ordinary skill in the art, however, that a lower dose or tolerable dose may be administered for medical reasons, psychological reasons or for virtually any other reasons.
  • the present invention provides for the formulation of water-soluble pharmaceutically active compounds such as proteins, with or without additional water-insoluble (or lipid-soluble) active compounds, into a controlled-release microspherical, injectable preparation.
  • water-soluble pharmaceutically active compounds such as proteins
  • additional water-insoluble (or lipid-soluble) active compounds into a controlled-release microspherical, injectable preparation.
  • biodegradable polymers for example by using different ratios of polylactide coglycolide (PLG), and with different inherent viscosities, preparations with different release characteristics can be produced. These preparations may then be mixed in appropriate proportions to achieve an end product having the desired final release characteristics.
  • the final release characteristics of the end product may be further modified by incorporation of a further component having initial short-term release characteristics and which comprises stable, dry particles comprising water-soluble pharmaceutically active compound(s) adsorbed onto microparticles of a calcium or aluminium salt.
  • copolymers of polylactide coglycolide were sourced from Birmingham Polymers Ltd, Birmingham, Alabama, USA:
  • the copolymers were solubilised to 5% w/v dissolution in either chloroform or dichloromethane.
  • an emulsion was produced which comprised: a) 88 parts polymer solution b) 2 parts of a 50:50 mixture of Tween 80 and Span 85 c) 10 parts of an aqueous solution of GM-CSF in trehalose (50mg/ml).
  • the mixture was vigorously agitated using either an ultrasonic probe or a high speed blender (e.g. a Siverson blender) to produce a stable water-in-oil emulsion with a milk-like consistency and appearance.
  • the mean diameter of the discrete (aqueous) phase of this emulsion was around 0.5 to 1.0 ⁇ m.
  • This emulsion was spray-dried using a Drytec Compact Laboratory Spray Dryer equipped with a 40/100/120 concentric-type nozzle at an atomising pressure of 30 psi and an outlet temperature of 35°C.
  • the resultant microspheres had a size range around 20 to 30 ⁇ m and were collected as a free- flowing powder. Traces of remaining organic solvent were removed in vacuo and the product was stored in a dry environment at 4°C.
  • EXAMPLE 2 Production of a moderate-release preparation of mouse-recombinant GM-CSF.
  • GM-CSF was separately absorbed to gels of aluminium phosphate and calcium phosphate by slow addition of the cytokine to the appropriate gel at the optimal pH and ionic strength whilst continuously stirring overnight.
  • the gel was spray-dried in a Drytec Compact Laboratory Spray Dryer equipped with a 40/100/120 concentric-type nozzle. Two different preparations were made for each gel. The first used an atomising pressure of 80 psi and an outlet temperature of 60°C to achieve particles in the range 1 to 3 ⁇ m. The second used an atomising pressure of 30 psi and an outlet temperature of 60°C to achieve particles in the range of 20 to 30 ⁇ m. All microparticles were stored at 4°C in a dry environment.
  • Preparations as described in Examples 1 and 2 were placed in buffered saline containing 2 mg/ml casein and 0.1%(w/v) sodium azide and held at 37°C . At intervals of days to weeks, depending upon the expected release characteristics of the preparation, samples of the supernatant were removed for estimation of GM-CSF content by enzyme immunoassay (El A). Fresh diluent was added to replace the aliquot removed. Based on the results of these experiments, calculated weights of the appropriate preparations are mixed to give a formulation with zero order release characteristics over a desired time interval.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparations pharmaceutiques à libération lente, se présentant sous une forme particulaire stable et obtenues par séchage par pulvérisation. Cette préparation à libération lente peut comprendre un ou plusieurs composés hydrosolubles pharmaceutiquement actifs, adsorbés dans des microparticules de sel de calcium ou d'aluminium. Selon une variante, la préparation à libération lente peut comprendre des particules microsphériques constituées d'une matrice continue d'un polymère biodégradable contenant une ou plusieurs régions séparées comprenant un ou plusieurs composés hydrosolubles pharmaceutiquement actifs.
PCT/AU1995/000648 1994-10-04 1995-10-04 Preparations pharmaceutiques a liberation lente WO1996010395A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35999/95A AU3599995A (en) 1994-10-04 1995-10-04 Controlled-release pharmaceutical preparations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPM8551A AUPM855194A0 (en) 1994-10-04 1994-10-04 Controlled-release pharmaceutical preparations
AUPM8551 1994-10-04

Publications (1)

Publication Number Publication Date
WO1996010395A1 true WO1996010395A1 (fr) 1996-04-11

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PCT/AU1995/000648 WO1996010395A1 (fr) 1994-10-04 1995-10-04 Preparations pharmaceutiques a liberation lente

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AU (1) AUPM855194A0 (fr)
WO (1) WO1996010395A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013502A3 (fr) * 1995-10-12 1997-10-02 Immunex Corp Liberation prolongee de facteurs stimulant les colonies de granulocytes-macrophages (gm-csf)
DE19847252A1 (de) * 1998-10-02 2000-04-13 Jenapharm Gmbh Verwendung von Testosteronestern und/oder Testosteron zur Herstellung von bukkal applizierbaren bioadhäsiven Systemen mit zeitgesteuerter Arzneistoffwirkung
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof
US6911204B2 (en) 2000-08-11 2005-06-28 Favrille, Inc. Method and composition for altering a B cell mediated pathology
WO2010066203A1 (fr) * 2008-12-10 2010-06-17 Anhui Zhongren Technology Co., Ltd. Composition à libération contrôlée
WO2010020518A3 (fr) * 2008-08-18 2010-10-14 Unilever Plc Améliorations concernant des compositions de nanodispersion

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990001949A1 (fr) * 1988-08-18 1990-03-08 The Australian National University Compositions a base d'inuline gamma
US5219577A (en) * 1990-06-22 1993-06-15 The Regents Of The University Of California Biologically active composition having a nanocrystalline core
WO1994015636A1 (fr) * 1993-01-08 1994-07-21 Csl Limited Preparations de vaccins
EP0486959B1 (fr) * 1990-11-22 1996-08-28 Vectorpharma International S.P.A. Composition pharmaceutique contenant des microparticules avec libération contrÔlée et son procédé de fabrication

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990001949A1 (fr) * 1988-08-18 1990-03-08 The Australian National University Compositions a base d'inuline gamma
US5219577A (en) * 1990-06-22 1993-06-15 The Regents Of The University Of California Biologically active composition having a nanocrystalline core
EP0486959B1 (fr) * 1990-11-22 1996-08-28 Vectorpharma International S.P.A. Composition pharmaceutique contenant des microparticules avec libération contrÔlée et son procédé de fabrication
WO1994015636A1 (fr) * 1993-01-08 1994-07-21 Csl Limited Preparations de vaccins

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
INTERNATIONAL JOURNAL OF PHARMACEUTICS, Volume 95, 1993, pages 77-83, LUCY S.C. WAN et al., "Influence of Hydrophile-Lipophile Balance on Alginate Microspheres". *
JOURNAL OF CONTROLLED RELEASE, Volume 26, 1993, pages 229-238, P.K. GUPTA et al., "In Vitro and in Vivo Evaluation of Clarithromycin/Poly(Lactic Acid)Microspheres for Intramuscular Drug Delivery". *
JOURNAL OF CONTROLLED RELEASE, Volume 32, 1994, pages 79-85, SHIGEYUKI TAKADA et al., "Preparation and Characterization of Copoly (Dl-Lactic/Glycolic Acid) Microparticles for Sustained Release of Thyrotropin Releasing Hormone by Double Nozzle Spray Drying Method". *
JOURNAL OF PHARMACY AND PHARMACOLOGY, Volume 40, 1988, pages 754-757, ROLAND BODMEIER et al., "Preparation of Biodegradable Poly(+/-) Lactide Microparticles Using a Spray-Drying Technique". *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013502A3 (fr) * 1995-10-12 1997-10-02 Immunex Corp Liberation prolongee de facteurs stimulant les colonies de granulocytes-macrophages (gm-csf)
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof
DE19847252A1 (de) * 1998-10-02 2000-04-13 Jenapharm Gmbh Verwendung von Testosteronestern und/oder Testosteron zur Herstellung von bukkal applizierbaren bioadhäsiven Systemen mit zeitgesteuerter Arzneistoffwirkung
DE19847252B4 (de) * 1998-10-02 2004-02-12 Jenapharm Gmbh & Co. Kg Bukkal applizierbare bioadhäsive Systeme mit zeitlich gesteuerter Wirkstofffreisetzung enthaltend Testosteronester und fakultativ zusätzlich Testosteron
US6911204B2 (en) 2000-08-11 2005-06-28 Favrille, Inc. Method and composition for altering a B cell mediated pathology
US8114404B2 (en) 2000-08-11 2012-02-14 Mmrglobal, Inc. Method and composition for altering a B cell mediated pathology
US8133486B2 (en) 2000-08-11 2012-03-13 Mmrglobal, Inc. Method and composition for altering a B cell mediated pathology
US8637638B2 (en) 2000-08-11 2014-01-28 Mmrglobal, Inc. Method and composition for altering a B cell mediated pathology
WO2010020518A3 (fr) * 2008-08-18 2010-10-14 Unilever Plc Améliorations concernant des compositions de nanodispersion
WO2010066203A1 (fr) * 2008-12-10 2010-06-17 Anhui Zhongren Technology Co., Ltd. Composition à libération contrôlée
US9498431B2 (en) 2008-12-10 2016-11-22 Jianjian Xu Controlled releasing composition

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