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WO1997026869A1 - Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee 'sans eclatement' - Google Patents

Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee 'sans eclatement' Download PDF

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Publication number
WO1997026869A1
WO1997026869A1 PCT/US1996/019440 US9619440W WO9726869A1 WO 1997026869 A1 WO1997026869 A1 WO 1997026869A1 US 9619440 W US9619440 W US 9619440W WO 9726869 A1 WO9726869 A1 WO 9726869A1
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Prior art keywords
microcapsules
release
uncapped
emulsion
capped
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PCT/US1996/019440
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English (en)
Inventor
Ramasubbu Jeyanthi
John F. Van Hamont
Phil Friden
Robert H. Reid
F. Donald Roberts
Charles E. Mcqueen
Jean A. Setterstrom
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United States Department of the Army
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United States Department of the Army
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Priority to NZ325561A priority Critical patent/NZ325561A/xx
Priority to AU14104/97A priority patent/AU722884B2/en
Priority to BRPI9607752-2A priority patent/BR9607752B1/pt
Priority to KR1019970706833A priority patent/KR100511215B1/ko
Priority to APAP/P/1997/001088A priority patent/AP665A/en
Application filed by United States Department of the Army filed Critical United States Department of the Army
Priority to CA002216371A priority patent/CA2216371C/fr
Priority to JP9526833A priority patent/JPH11509862A/ja
Priority to EP96944247A priority patent/EP0817619A4/fr
Priority to BRPI9607752A priority patent/BRPI9607752B8/pt
Publication of WO1997026869A1 publication Critical patent/WO1997026869A1/fr
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    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • 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
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to providing novel biocompatible and biodegradable microspheres for burst-free programmable sustained release of biologically active agents, inclusive of polypeptides, over a period of up to 100 days in an aqueous physiological environment.
  • PLGA poly(lactide/glycolides)
  • L/G lactide/glycolide
  • Further prior art preparations of PLGA utilized fillers or additives in the inner aqueous layer to improve the stability and encapsulation efficency and/or to increase the viscosity of the aqueous layer, thereby modulating polymer hydrolysis and the biologically active agent or polypeptide release.
  • PLGA copoly ers were end-capped, in that the terminal carboxyl end groups were blocked.
  • the icrocapsule preparations exhibited a low to moderate burst release of - 10-40% of the entrapped polypeptide in the first 24 hours after placement in an aqueous physiological environment. In part, these characteristics are due to the use of fillers in the inner aqueous phase. Further, a 1-month release of polypeptide is known with the use of a 75/25 co-polymer of PLGA of Mw * ⁇ 20,000.
  • This invention provides biocompatible and biodegradable microspheres that have been designed for novel, burst free, programmable sustained release of biologically active agents, including polypeptides over a period of up to 100 days in an aqueous physiological environment.
  • burst-free, programmable sustained release is achieved through the use of a unique blend of the *uncapped' and end-capped forms of poly(lactide/glycolide) polymer in the molecular weight range of 2,000 to 60,000 daltons.
  • microspheres described in this invention are produced by a unique emulsification technique wherein an inner water-in-oil (w/o) emulsion is stabilized by dispersing in a solvent-saturated aqueous phase containing an emulsion stabilizer. A ternary w/o/w emulsion is then formed by emulsifying the above w/o emulsions in an external pre-coo ed aqueous phase containing an o/w emulsifier.
  • w/o water-in-oil
  • a ternary w/o/w emulsion is then formed by emulsifying the above w/o emulsions in an external pre-coo ed aqueous phase containing an o/w emulsifier.
  • the inner w/o emulsion is comprised of an aqueous layer containing from - 2 to about 20% (w/w) of the active agent to be entrapped and an oil layer containing poly(lactide/glycolide) copolymer in concentrations ranging from - 5 to about— 50% (w/w oil phase) .
  • the copolymer includes molecular weight ranging from 2,000 to about 60,000 daltons, with molar composition of lactide/glycolide from 90/10 to 40/60 and a blend of its uncapped and end-capped forms in a ratio of 100/0 to 1/99. Very high encapsulation efficiencies of about 80 to 100% are achieved depending on polymer molecular weight and structural form.
  • Programmable release of active core over variable durations between 1-100 days is achieved by a judicious selection of process parameters such as polymer concentration, peptide concentration and the aqueous/oil phase ratio.
  • This invention is particularly suitable for high encapsulation efficiencies and burst-free, continuous programmable release of polypeptides of molecular weights ranging from 1,000 to about 250,000 daltons, and also other biologically active agents over a period of 1-100 days.
  • a uniqueness of the invention is that when using a 100/0 blend of the uncapped and capped polymer, the final phase of active core release is concurrent with the complete solubilization of the polymer to innocuous components, such as lactic and glycolic acids. This is a significant advantage over the currently available 30 day - release systems wherein a major regulatory concern is about toxicity of residual polymer at the site of administration, long after release of the active core.
  • microcapsules described in this invention are suitable for administration via several routes such as parenteral
  • FIG. 1 shows a comparison of drug release from a conventional system versus a controlled release system. Peak and valley levels from conventional administrations are shown, in contrast to the steady therapeutic levels from the controlled release administration.
  • FIG. 2 shows a scanning electron micrograph of PLGA microspheres prepared by the process described in the invention using 50/50 uncapped polymer of Mw 8-12k dalton and shows superior sphere morphology, sphere integrity, and narrow size distribution.
  • FIG. 2a shows a scanning electron micrograph of PLGA microspheres prepared by conventional solvent evaporation method using a 50/50 12k uncapped polymer of Mw 8-12k dalton.
  • FIG. 3 shows cumulative Histatin release from PLGA microspheres, wherein release profiles from several batches are prepared using 50/50, uncapped polymer (of Mw 8-l2k dalton) and wherein the process parameters are varied to modulate release between 1 and 35 days.
  • FIG. 4 shows a scanning electron micrograph of solid, smooth spherical surfaces of PLGA microspheres prepared by the method of in the invention using 50/50, end-capped polymer (of Mw 30-40k dalton) .
  • FIG. 5 shows cumulative Histatin release from PLGA microspheres, wherein the release profiles are from several batches prepared using 50/50, uncapped and end-capped polymer of Mw 30-4Ok daltons, and wherein the process parameters are varied to modulate release between 28 to 60 days.
  • FIG. 6 shows cumulative Histatin release from PLGA microspheres, wherein combined release profiles from several batches have been prepare ⁇ using 50/50, uncapped and end-capped polymer of Mw 8-40k daltons, while varying the process parameters to modulate release between 1 and 60 days.
  • FIG. 7 shows a cumulative percent release of LHRH from PLGA microspheres prepared using uncapped polymer of Mw 8-12 daltons.
  • This invention relates to the design of biocompatible and biodegradable microspheres for novel, programmable sustained release of biologically active agents, including polypeptides over a period of up to 100 days in an aqueous physiological environment with little or no burst release.
  • this invention achieves high encapsulation efficiency and *burst-free' release without the use of any additive.
  • burst-free, programmable sustained release is achieved through the use of a unique blend of the 'uncapped' and end- capped forms of poly (lactide/glycolide) polymer.
  • the 'uncapped' form refers to "poly(lactide/glycolide) with free carboxyl end groups" which renders the polymer more hydrophilic compared to the routinely used end-capped form.
  • Currently used 'end-capped' polymer hydrates between 4-12 weeks depending on the molecular weight, resulting in an intermediate 'no release' or a 'lag phase'.
  • the uncapped polymer hydrates typically between 5 to 60 days depending on the molecular weight, thus releasing its core continuously without a lag phase.
  • a careful blend of the two forms and appropriate molecular weights and L/G ratios results in a continuous release between 1 to 100 days.
  • release within this time is programmable by a judicious selection of process parameters such as polymer concentration, peptide concentration and the aqueous/oil phase ratio.
  • the coploymer in this invention includes molecular weight ranging from 2,000 to 60,000 daltons, a lactide/glycolide ratio of 90/10 to 40/60 and a blend of the uncapped/capped forms in the ratio of 100/0 to 1/99.
  • the molecular weight of the polypeptide may be in the range of 1000 to 250,000 daltons while that of other biologically active agents may range from 100 to 100,000 daltons.
  • Microcapsules described in this invention are prepared by a unique aqueous emulsification techinique which has been developed for use with the uncapped polymer to provide superior sphere morphology, sphere integrity and narrow size distribution. This is accomplished by first preparing an inner water-in-oil (w/o) by mixing the solutions of polymer in an organic solvent such as methylene chloride and the biologically active agent in water.
  • an organic solvent such as methylene chloride
  • a ternary emulsion is then formed by emulsifying the w/o emulsion in an external aqueous phase containing the same emulsifier as above at concentrations ranging from 0.25 - 1% w/v.
  • Microcapsules are hardened upon solvent removal by evaporation, rinsed to remove residual emulsifier and lyophilized. Low temperature is used both at the time of primary emulsification (w/o emulsion formation) and during the formation of the final w/o/w emulsion to achieve stable emulsion and superior sphere characteristics.
  • a biologically active agent is any water-soluble hormone drugs, antibiotics, antitumor agents, antiinflammatory agents, antipyretics, analgesics, antitussives, expectorants, sedatives, muscle relaxants, antiepileptics, antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythmic drugs, vasodilators, antihypertensives, diuretics, anticoagulants, antinarcotics, etc. More precisely, applicants have discovered a pharmaceutical composition and process with the following itemized features:
  • biodegradable poly(lactide/glycolide) is a blend of uncapped and capped forms, in ratios ranging from 100/0 to 1/99.
  • L/G ratio for uncapped and end-capped polymer is 90/10 to 40/60. 5.
  • microcapsules of item 6 wherein said polypeptide is histatin consisting of 12 amino acids and having a molecular weight of 1563.
  • the microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to completely release histatin in an aqueous physiological environment from 1-35 days with a 100/0 blend of uncapped and end-capped poly(lactide/glycolide) having a
  • microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to completely release histatin in an aqueous physiological environment from 18-40 days with a 100/0 blend of uncapped and end-capped poly(lactide/glycolide) having a
  • microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to release up to 90% of the histatin in an aqueous physiological environment from 28-70 days with a 0/100 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 48/52 to 52/48 and a molecular weight range of 10,000-40,000 daltons.
  • microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 characterized by the capacity to release up to 80% of histatin in an aqueous physiological environment from 56-100 days with a 0/100 blend of uncapped and end-capped poly(lactide/glycolide) having a L/G ratio of 75/25 and a molecular weight of ⁇ 15,000 daltons.
  • microcapsules of items 7 or 8 or 9 or 10 or 11 having analogs of histatin with chain lengths of from 11-24 amino acids of molecular weights from 1,500-3,000 daltons and characterized by the following structures:
  • microcapsules of items 1 or 2 or 3 or 4 or 5 wherein the biologically active agent is a polypeptide Leutinizing hormone releasing hormone (LHRH) that is a decapeptide of molecular weight 1182 in its acetate form, and having the structure: p- E H W S Y G L R P G
  • microcapsule of items 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 having a molecular weight of from 1,000 to 250,000 daltons.
  • microcapsules of items 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 wherein release of profiles of variable rates and duration are achieved by blending uncapped and capped polymer in different ratios within the same microshreres.
  • ETEC such as CFA/I,CFA/II,CS1,CS3,CS6 and CS17 and other ETEC- related enterotoxins.
  • microcapsules of items 1 or 2 or 3 or 4 or 5 wherein said biologically active agents are selected from the group consisting of water-soluble hormone drugs, antibiotics, antitumor agents, anti inflammatory agents, antipyretics, analgesics, antitussives, expectorants, sedatives, muscle relaxants, antiepileptic ⁇ , antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythmic drugs, vasodilators, antihypertensives, diuretics, anticoagulants, and antinarcotics, in the molecular weight range of 100-100,000 daltons.
  • said biologically active agents are selected from the group consisting of water-soluble hormone drugs, antibiotics, antitumor agents, anti inflammatory agents, antipyretics, analgesics, antitussives, expectorants, sedatives, muscle relaxants, antiepileptic ⁇ , antiulcer agents, antidepressants, antiallergic drugs, cardiotonics, antiarrhythm
  • microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 wherein said biodegradable poly(lactide/glycolide) is in an oil phase, and is present in about 1-50% (w/w).
  • a process for preparing controlled release microcapsule formulations characterized by burst-free, sustained, programmable release of biologically active agents comprising: Dissolving biodegradable poly (lactide/glycolide) , in uncapped form in methylene chloride, and dissolving a biologically active agent or active core in water; adding the aqueous layer to the polymer solution and emulsifying to provide an inner water-in-oil (w/o) emulsion; stabilizing the w/o emulsion in a solvent-saturated aqueous phase containing a oil-in-water (o/w) emulsifier; adding said w/o emulsion to an external aqueous layer containing oil-in- water emulsifier to form a ternary emulsion; and stirring the resulting water-in-oil-in-water (w/o/w) emulsion for sufficient time to remove said solvent, and rinsing hardened microcapsules with
  • a process for preparing controlled release microcapsule formulations characterized by burst-free, sustained, programmable release of biologically active agents comprising: dissolving biodegradable poly(lactide/glycolide) in end- capped form in methylene chloride, and dissolving a biologically active agent or active core in water; adding the aqueous layer to the polymer solution and emulsifying to provide an inner water- in-oil emulsion; stabilizing the w/o emulsion in a solvent- saturated aqueous phase containing a oil-in-water (o/w) emulsifier; adding said w/o emulsion to an external aqueous layer containing oil-in-water emulsifier to form a ternary emulsion; and stirring a resulting water-in-oil-water (w/o/w) emulsion for sufficient time to remove said solvent; and rinsing hardened microcapsules with water; and lyophilizing said
  • microcapsules of items 6 or 7 or 8 or 9 or 10 or 11 wherein, when entrapped polypeptide such as histatin is inactive at a low pH, a non-ionic surfactant such as polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60 and Tween 20) and polyoxyethylene - polyoxypropylene block copolymers (Pluronics) is added to the inner aqueous phase to maintain biological activity of the released polypeptide.
  • a non-ionic surfactant such as polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60 and Tween 20) and polyoxyethylene - polyoxypropylene block copolymers (Pluronics) is added to the inner aqueous phase to maintain biological activity of the released polypeptide.
  • microcapsules of item 30 wherein placebo spheres loaded with non-ionic surfactant are coadministered with polypeptide-loaded spheres to maintain biological activity of the released peptide where the addition of non-ionic surfactants in the inner aqueous phase is undesirable for successful encapsulation of the acid pH sensitive polypeptide.
  • microcapsules of items 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 comprising a blend of uncapped and capped polymer, wherein complete solubilization of the copolymer leaves no residual polymer at the site of administration and occurs concurrently with the complete release of the entrapped agent.
  • Ease of administration of the microcapsules in various dosage forms via several routes such as parenteral (intramuscular and sucutaneous), oral, topical, nasal, vaginal, etc.
  • hydrophilic homo-and co-polymers based on D,L-lactide and glycolide contains hydrophilic adjusted homo-and co-polymers with free carboxylic end groups, and is characterized by the formula :
  • FIG. 1 depicts a blood-drug concentration versus time graph that shows conventional drug administration using a series of dosages compared to an ideal controlled release system.
  • drugs have a therapeutic range, above which they are toxic and below which they are ineffective. Oscillating drug levels that are commonly observed following systemic administration causes alternating periods of ineffectiveness and toxicity.
  • a sustained-release encapsulated biologically active agent or polypeptide preparation ideally, will maintain the drug in the desired therapeutic range by means of a single dose, as depicted in the
  • FIG.l THERAPEUTIC RANGE in FIG.l , where the ideal case for controlled release is shown.
  • FIG. 2 there is shown a scanning electron micrograph of PLGA microspheres prepared using 50/50 uncapped polymer of Mw 8- 12k dalton. The uncapped polymer has solid, smooth spherical surfaces, and is suited to provide a "burst free" release system.
  • Table I is a summarization of the microsphere process description for preparing a peptide system (Histatin peptide) having a controlled release over the course of from l to 100 days.
  • Release profiles can be modified by a judicious blend of uncapped and capped polymers either in separate microspheres or in the same microspheres. Release from microcapsule formulations 1 through 21 listed in Table 1, occur independently of each other and hence the cumulative release from blends of these formulations are additive. By blending several formulations of uncapped and end-capped microspheres, release curves of any desired duration can be tailored. In addition, based on the release characteristics of uncapped and end-capped polymers. blending of the two forms in a single formulation comprising different ratios of uncapped to capped polymer, would significantly influence the polymer hydration and hence release of the active core thereby providing release curves of any desirable pattern. Manipulation of polymer hydration and degradation resulting in modulation of release of active core is achieved by the addition of uncapped polymer to end-capped polymer in amounts as low as 1% up to 100%.
  • FIG. 4 a view is provided through a scanning electron micrograph of PLGA microspheres designed for a one to two month release system prepared using end-capped polymer of Mw 30- 0k daltons.
  • FIG. 5 depicts the cumulative Histatin release from PLGA microspheres, in which the release profiles are from several batches prepared using 50/50, uncapped and capped polymer, and varying the process parameters to modulate release between 28 to 60 days.
  • Figure 6 represents cumulative Histatin release from PLGA microspheres these combined release profiles are from several batches prepared using 50/50 uncapped and capped polymer, and varying the process parameters to modulate release between 1-60 days.
  • a biologically active agent is any water-soluble antibiotics, antitumor agents, antipyretics analgesics, anti-inflammatory agents, antitussives, expectorants, sedatives, muscle relaxants, anti epileptics, antiulcer agents, anti-depressants, anti-allergic drugs, cardiotonics, antiarrhythmics drugs, vasodilators, antihypertensives, diuretics, anticoagulants, hormone drugs, anti-narcotics, etc.
  • burst free sustained release delivery of biologically active agents from PLGA microshperes is accomplished in the context of this invention using of 90/10 to 40/60 molar ratios, and ratios of uncapped polymer to end-capped polymer of 100/0 to 1/99.
  • Peptide loads - from 2 to about 40% (w/w polymer) and by using the unique aqueous emulsification method described in the invention.
  • Ease of administration of the microcapsules in various dosages forms via several routes such as parenteral (intramusclar and subcutaneous), oral, topical, nasal, vaginal, etc.
  • Polylactide/glycolide (PLGA) microcapsules are prepared by a unique aqueous emulsification technique which has been developed for use with the uncapped polymer to provide superior sphere morphology, sphere integrity and narrow size distribution (See Figures la and lb) . This is accomplished by dissolving the polymer in a chlorinated hydrocarbon solvent such as methylene chloride and dissolving the biologically active agent in water. A w/o emulsion is then formed by mixing the solutions of polymer and the active agent by sonication, followed by emulsion stabilization in a solvent - saturated aqueous solution containing polyvinyl alcohol.
  • a chlorinated hydrocarbon solvent such as methylene chloride
  • a ternary emulsion is then formed by emulsifying the w/o emulsion in an external, pre-cooled aqueous phase containing polyvinyl alcohol (0.25 - 1% w/v) .
  • Microcapsules are hardened upon removal of solvent by evaporation, rinsed to remove any residual emulsifier, and then lyophilized.
  • Table 1 lists the microcapsule compositions, Nos. 1-21 thus prepared, consisting of a biologically active polypeptide, Histatin (composed of 12 amino acids and a molecular weight of 1563) and blends of uncapped and capped polymer of ratios 100/0 to 1/99, and having a lactide/glycolide ratio of 90/10 to 40/60, and a molecular weight range between 2000 to 60,000 daltons.
  • Example 2
  • Microcapsule compositions are prepared as described in Example 1 wherein the copolymer L/G ratio is 48/52 to 52/48, and the ratio of uncapped/capped polymer is 100/0.
  • the active core is Histatin (Mw 1563), the polymer molecular weight is ⁇ 15,000 and the polymer concentrations vary from 7% to - 40% w/w.
  • Compositions 1,2,4 12-14 and 16-18 are listed in Table 1.
  • Release profiles of the active core from the compositions in an aqueous physiological environment are plotted as cumulative percentage release versus time, and presented in Figure 2.
  • Burst-free, variable release from 1-35 days is achieved by varying the polymer concentration from 7 to - 40% w/w in the oil phase.
  • Microcapsule compositions are prepared as described in Example 2, wherein the aqueous /oil ratio is varied from 1/4 to 1/20 (v/v) .
  • Compositions 1,2,4 and 12 are listed in Table 1.
  • Release profiles of the active core from the compositions in an aqueous physiological environment described in Example 2 are plotted as cumulative percentage release versus time, and presented in Figure 2.
  • Burst-free, continuous release from 1-35 days, with different onset and completion times are achieved by selecting different w/o ratios in the inner core.
  • Example 4 Microcapsule compositions are prepared as described in
  • Example 2 wherein the polymer molecular weight is 28,000-40,000 and polymer concentrations vary from 5% to - 15% w/w.
  • Compositions 19-21 are listed in Table 1. Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2 are plotted as cumulative percentage release versus time and presented in Figure 3. Burst-free, variable release from 18-40 days is achieved by varying the polymer concentration.
  • Example 5 Microcapsule compositions are prepared as described in
  • Example 2 wherein the ratio of uncapped/capped polymer is 1/99 and polymer concentrations vary between 5% to - 12% w/w.
  • Compositions 10 and 11 are listed in Table 1. Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2, and plotted as cumulative percentage release versus time and presented in Figure 2. Burst-free, variable release from 28-70 days is achieved by varying the polymer concentration in the oil phase.
  • Example 6 Microcapsule compositions are prepared as described in
  • Example 5 wherein polymer molecular weight is 28,000-40,000 and polymer concentrations vary between 5% to - 12% w/w.
  • Compositions 5 and 6 are listed in Table 1. Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2 and are plotted as cumulative percentage release versus time, and presented in Figure 3. Burst-free, variable release from 28-70 days is achieved by varying the polymer concentration.
  • Microcapsule compositions are prepared as described in Example 6, wherein the aqueous/oil ratio varies between 1/5 to 1/25 (v/v) .
  • Compositions 3 and 7 are listed in Table 1.
  • Burst-free, variable release from 28-70 days is achieved by varying the aqueous/oil ratios.
  • Microcapsule compositions are prepared as described in Example 5, wherein the copolymer ratio is 75/25 and polymer concentrations vary between 5% to - 25% w/w.
  • Compositions 8 and 9 are listed in Table 1.
  • Release profiles of the active core from the compositions in an aqueous physiological environment are described in Example 2, and are plotted as cumulative percentage release versus time, and presented in Figure 2.
  • Burst-free, variable release from 56- 90 days is achieved by varying the polymer concentration in the oil phase.
  • Microcapsule compositions are described in Example 2, wherein the active core is leutinizing hormone releasing hormone (LHRH, a decapeptide of molecular weight 1182) and the polymer concentration is -40% w/w. Release profiles of the active core from the composition in an aqueous physiological environment is described in Example 2, and is plotted as cumulative percentage release versus time, and presented in Figure 4.
  • LHRH leutinizing hormone releasing hormone
  • Burst-free, continuous and complete release is achieved within 35 days, similar to Histatin acetate.
  • Microcapsule compositions are prepared as described in Example 2, wherein an additive such as sodium salt (carbonate or bicarbonate) is added to the inner aqueous phase at concentrations of 1-10% w/w to maintain the biological activity of the released polypeptide.
  • an additive such as sodium salt (carbonate or bicarbonate) is added to the inner aqueous phase at concentrations of 1-10% w/w to maintain the biological activity of the released polypeptide.
  • Microcapsule compositions are prepared as described in Example 2, wherein an additive such as a nonionic surfactant, polyoxyethylene/polyoxypropylene block copolymer (Pluronics F68 and F127) is added to either the inner oil or the aqueous phase at concentrations from 10-100% w/w, to maintain the biological activity of the released polypeptide.
  • an additive such as a nonionic surfactant, polyoxyethylene/polyoxypropylene block copolymer (Pluronics F68 and F127) is added to either the inner oil or the aqueous phase at concentrations from 10-100% w/w, to maintain the biological activity of the released polypeptide.
  • Burst-free, continuous release from 1-35 days is achieved similar to Examples 2 * 3, and the released polypeptide is bioactive due to the presence of the surfactant.
  • Cumulative histatin release from the microcapsule compositions described in Examples 1 through 11 and release profiles plotted in Figures 2 and 3 show the burst-free, programmable peptide release for variable duration from 1-100 days. Virtually any pattern of cumulative release is achievable over ' a 100 day duration by a judicious blending of several compositions, as shown in these figures.

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Abstract

Nouvelles microcapsules biocompatibles et biodégradables à libération prolongée sans éclatement pouvant être programmées afin de libérer leur noyau actif pendant des durées variables allant de 1 à 100 jours dans un environnement physiologique aqueux. Les microcapsules se composent d'un noyau de polypeptide ou d'un autre agent biologiquement actif encapsulé dans une matrice de copolymères de poly(lactide/glucolide), se présentant sous la forme d'un mélange de formes non coiffées (goupe carboxyle terminal libre) et de formes coiffées dont les rapports sont compris entre 100/0 et 1/99.
PCT/US1996/019440 1996-01-24 1996-11-18 Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee 'sans eclatement' Ceased WO1997026869A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BRPI9607752A BRPI9607752B8 (pt) 1996-01-24 1996-11-18 formulação farmacêutica de microcápsula de liberação controlada.
AU14104/97A AU722884B2 (en) 1996-01-24 1996-11-18 Novel "burst-free" sustained release poly-(lactide/glycolide) microspheres
BRPI9607752-2A BR9607752B1 (pt) 1996-01-24 1996-11-18 formulação farmacêutica de microcápsula de liberação controlada.
KR1019970706833A KR100511215B1 (ko) 1996-01-24 1996-11-18 신규한비-일시방출형서방성폴리(락타이드/글리콜라이드)마이크로캡슐
APAP/P/1997/001088A AP665A (en) 1996-01-24 1996-11-18 Novel "burst free" sustained release poly-(lactide/glycolide microspheres).
NZ325561A NZ325561A (en) 1996-01-24 1996-11-18 Pharmaceutical composition containing an active ingredient and poly(lactide/glycolide) microcapsules which is a burst free controlled release formulation
CA002216371A CA2216371C (fr) 1996-01-24 1996-11-18 Microspheres nouvelles en poly-(lactide-glycolide) a liberation controle« a l'epreuve de l'eclatement »
JP9526833A JPH11509862A (ja) 1996-01-24 1996-11-18 新規「バーストフリー」持続放出型ポリ（ラクチド／グリコリド）微小球
EP96944247A EP0817619A4 (fr) 1996-01-24 1996-11-18 Nouvelles microspheres de poly-(lactide/glucolide) a liberation prolongee "sans eclatement"

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US59097396A 1996-01-24 1996-01-24
US08/590,973 1996-01-24
CNB961947683A CN100391445C (zh) 1996-01-24 1996-11-18 新型的“非突发的”持续释放聚(丙交酯/乙交酯)的微球

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BR (1) BR9607752B1 (fr)
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WO1998047489A1 (fr) * 1997-04-18 1998-10-29 Pharma Biotech Compositions presentant une liberation prolongee et leur procede de preparation
CN1073412C (zh) * 1998-03-19 2001-10-24 中国科学院化学研究所 一种高分子微包囊的制备方法
CN1075945C (zh) * 1998-02-26 2001-12-12 中国科学院化学研究所 一种高分子包囊胰岛素微粒体及其制备方法和用途
WO2004062649A3 (fr) * 2003-01-09 2004-11-04 Allergan Inc Implant oculaire biodegradable
US7033608B1 (en) * 1995-05-22 2006-04-25 The United States Of America As Represented By The Secretary Of The Army “Burst-free” sustained release poly-(lactide/glycolide) microspheres
KR100816065B1 (ko) 2006-11-27 2008-03-24 동국제약 주식회사 초기 방출억제 특성이 우수한 서방출성 마이크로캡슐의제조방법 및 이에 의해 제조되는 마이크로캡슐
US7625582B2 (en) 2000-11-29 2009-12-01 Allergan, Inc. Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
US8048445B2 (en) 2003-01-09 2011-11-01 Allergan, Inc. Ocular implant made by a double extrusion process
WO2013177236A1 (fr) * 2012-05-24 2013-11-28 Ethicon, Inc. Compositions de mélanges de polymères absorbables mécaniquement résistantes présentant des taux d'absorption contrôlables de manière précise, procédés de traitement, et produits obtenus à partir de celle-ci
US8722097B2 (en) 2004-04-30 2014-05-13 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US8900622B1 (en) 2004-04-30 2014-12-02 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US8911768B2 (en) 2004-04-30 2014-12-16 Allergan, Inc. Methods for treating retinopathy with extended therapeutic effect
US9012437B2 (en) 2000-07-05 2015-04-21 Allergan, Inc. Implants and methods for treating inflammation-mediated conditions of the eye
US9326949B2 (en) 2004-04-30 2016-05-03 Allergan, Inc. Method of making oil-in-oil emulsified polymeric implants containing a hypotensive lipid
US9775846B2 (en) 2004-04-30 2017-10-03 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related implants
CN113384536A (zh) * 2020-03-14 2021-09-14 鲁南制药集团股份有限公司 一种注射用双羟萘酸加兰他敏缓释微粒及其制备方法
US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems
USRE49251E1 (en) 2010-01-04 2022-10-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
US12097292B2 (en) 2016-08-28 2024-09-24 Mapi Pharma Ltd. Process for preparing microparticles containing glatiramer acetate
US12370233B2 (en) 2016-08-31 2025-07-29 Mapi Pharma Ltd. Depot systems comprising glatiramer acetate

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GB0517674D0 (en) * 2005-08-31 2005-10-05 Astrazeneca Ab Formulation
GB0517673D0 (en) * 2005-08-31 2005-10-05 Astrazeneca Ab Formulation
CN101007169B (zh) * 2006-01-23 2011-05-25 珠海市嘉族生物科技有限公司 一种鸡卵黄免疫球蛋白微胶囊及其制备方法和应用
US8956641B2 (en) * 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of inflammatory diseases
US8889173B2 (en) * 2008-04-18 2014-11-18 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of pain and/or inflammation
CN101612111B (zh) * 2008-06-24 2011-11-23 上海医药工业研究院 醋酸诺美孕酮或其类似物的缓释微球及其制备方法和用途
KR20100037389A (ko) * 2008-10-01 2010-04-09 연세대학교 산학협력단 다중 약물방출조절이 가능한 솔리드 마이크로구조체 및 이의 제조방법
CN102357080B (zh) * 2011-11-04 2014-07-16 无锡中科光远生物材料有限公司 一种酸性环境中可实现药物快速释放的智能型多功能空心微球及其制备方法
HUE036141T2 (hu) * 2013-06-20 2018-06-28 Pharmathen Sa Szigmoid kibocsátási profillal bíró polilaktid-poliglikolid mikrorészecskék elõállítása
US20170022256A1 (en) * 2015-07-23 2017-01-26 General Biologicals Corporation Anti-fungal and anti-bacterial peptide and therapeutic method using same
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US7033608B1 (en) * 1995-05-22 2006-04-25 The United States Of America As Represented By The Secretary Of The Army “Burst-free” sustained release poly-(lactide/glycolide) microspheres
US6217893B1 (en) 1997-04-18 2001-04-17 Pharma Biotech Sustained-release compositions and method for preparing same
WO1998047489A1 (fr) * 1997-04-18 1998-10-29 Pharma Biotech Compositions presentant une liberation prolongee et leur procede de preparation
CN1075945C (zh) * 1998-02-26 2001-12-12 中国科学院化学研究所 一种高分子包囊胰岛素微粒体及其制备方法和用途
CN1073412C (zh) * 1998-03-19 2001-10-24 中国科学院化学研究所 一种高分子微包囊的制备方法
US10206934B2 (en) 2000-07-05 2019-02-19 Allergan, Inc. Implants and methods for treating inflammation-mediated conditions of the eye
US9012437B2 (en) 2000-07-05 2015-04-21 Allergan, Inc. Implants and methods for treating inflammation-mediated conditions of the eye
US9775849B2 (en) 2000-07-05 2017-10-03 Allergan, Inc. Implants and methods for treating inflammation-mediated conditions of the eye
US7625582B2 (en) 2000-11-29 2009-12-01 Allergan, Inc. Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
US9283178B2 (en) 2000-11-29 2016-03-15 Allergan, Inc. Methods for treating edema in the eye and intraocular implants for use therefor
US9592242B2 (en) 2000-11-29 2017-03-14 Allergan, Inc. Methods for treating edema in the eye and intraocular implants for use therefor
US8048445B2 (en) 2003-01-09 2011-11-01 Allergan, Inc. Ocular implant made by a double extrusion process
US10076526B2 (en) 2003-01-09 2018-09-18 Allergan, Inc. Ocular implant made by a double extrusion process
US10702539B2 (en) 2003-01-09 2020-07-07 Allergan, Inc. Ocular implant made by a double extrusion process
AU2004204744B2 (en) * 2003-01-09 2008-03-13 Allergan, Inc. Biodegradable ocular implant
WO2004062649A3 (fr) * 2003-01-09 2004-11-04 Allergan Inc Implant oculaire biodegradable
US9192511B2 (en) 2003-01-09 2015-11-24 Allergan, Inc. Ocular implant made by a double extrusion process
US9669039B2 (en) 2004-04-30 2017-06-06 Allergan, Inc. Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods
US9750751B2 (en) 2004-04-30 2017-09-05 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US9326949B2 (en) 2004-04-30 2016-05-03 Allergan, Inc. Method of making oil-in-oil emulsified polymeric implants containing a hypotensive lipid
US9393223B2 (en) 2004-04-30 2016-07-19 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US9101583B2 (en) 2004-04-30 2015-08-11 Allergan, Inc. Microparticles manufactured in an oil-in-water process comprising a prostamide
US8911768B2 (en) 2004-04-30 2014-12-16 Allergan, Inc. Methods for treating retinopathy with extended therapeutic effect
US9707238B2 (en) 2004-04-30 2017-07-18 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US10406168B2 (en) 2004-04-30 2019-09-10 Allergan, Inc. Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods
US10398707B2 (en) 2004-04-30 2019-09-03 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related implants
US10328086B2 (en) 2004-04-30 2019-06-25 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US9775846B2 (en) 2004-04-30 2017-10-03 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related implants
US8900622B1 (en) 2004-04-30 2014-12-02 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US10864218B2 (en) 2004-04-30 2020-12-15 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US10064872B2 (en) 2004-04-30 2018-09-04 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US8722097B2 (en) 2004-04-30 2014-05-13 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US9233071B2 (en) 2004-04-30 2016-01-12 Allergan, Inc. Methods for treating retinopathy with extended therapeutic effect
KR100816065B1 (ko) 2006-11-27 2008-03-24 동국제약 주식회사 초기 방출억제 특성이 우수한 서방출성 마이크로캡슐의제조방법 및 이에 의해 제조되는 마이크로캡슐
USRE49251E1 (en) 2010-01-04 2022-10-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
USRE50301E1 (en) 2010-01-04 2025-02-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
WO2013177236A1 (fr) * 2012-05-24 2013-11-28 Ethicon, Inc. Compositions de mélanges de polymères absorbables mécaniquement résistantes présentant des taux d'absorption contrôlables de manière précise, procédés de traitement, et produits obtenus à partir de celle-ci
US10675376B2 (en) 2012-05-24 2020-06-09 Ethicon Llc Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom
RU2652180C2 (ru) * 2012-05-24 2018-04-25 ЭТИКОН, ЭлЭлСи Композиции, включающие смесь механически прочных рассасывающихся полимеров с точно управляемыми скоростями рассасывания, способы их обработки и продукты из них
US9737630B2 (en) 2012-05-24 2017-08-22 Ethicon, Llc Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom
US9737629B2 (en) 2012-05-24 2017-08-22 Ethicon, Llc Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom
US12097292B2 (en) 2016-08-28 2024-09-24 Mapi Pharma Ltd. Process for preparing microparticles containing glatiramer acetate
US12370233B2 (en) 2016-08-31 2025-07-29 Mapi Pharma Ltd. Depot systems comprising glatiramer acetate
US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems
US12343371B2 (en) 2017-03-26 2025-07-01 Mapi Pharma Ltd. Method for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using a sustained release depot formulation comprising glatiramer acetate
CN113384536A (zh) * 2020-03-14 2021-09-14 鲁南制药集团股份有限公司 一种注射用双羟萘酸加兰他敏缓释微粒及其制备方法
CN113384536B (zh) * 2020-03-14 2024-04-02 鲁南制药集团股份有限公司 一种注射用双羟萘酸加兰他敏缓释微粒及其制备方法

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CN1188408A (zh) 1998-07-22
EP0817619A1 (fr) 1998-01-14
NZ325561A (en) 1999-06-29
JPH11509862A (ja) 1999-08-31
AP665A (en) 1998-08-19
AU1410497A (en) 1997-08-20
CN100391445C (zh) 2008-06-04
BR9607752A (pt) 1999-11-30
EP0817619A4 (fr) 1999-02-03
AU722884B2 (en) 2000-08-10
AP9701088A0 (en) 1997-10-31
BR9607752B1 (pt) 2009-05-05

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