WO2001058428A1 - Procede de preparation d'une composition a liberation prolongee - Google Patents

Procede de preparation d'une composition a liberation prolongee Download PDF

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Publication number
WO2001058428A1
WO2001058428A1 PCT/US2001/003165 US0103165W WO0158428A1 WO 2001058428 A1 WO2001058428 A1 WO 2001058428A1 US 0103165 W US0103165 W US 0103165W WO 0158428 A1 WO0158428 A1 WO 0158428A1
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Prior art keywords
biologically active
active agent
composition
water soluble
solvent
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PCT/US2001/003165
Other languages
English (en)
Inventor
Kevin L. Ward
Mark A. Tracy
Original Assignee
Alkermes Controlled Therapeutics, Inc.
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Publication date
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Priority to AU2001233180A priority Critical patent/AU2001233180A1/en
Publication of WO2001058428A1 publication Critical patent/WO2001058428A1/fr

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    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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)

Definitions

  • sustained release devices can exhibit high release of active agent over the first twenty-four hours, often referred to as a burst. In some instances this burst can result in unacceptably high levels of biologically active agne and minimal relase of agent thereafter. Therefore, a need exists to exert additional control over release kinetica by reducing the burst of active agent.
  • the present invention is based upon the discovery that burst of biologically active agent from the sustained release composition of the invention can be controlled by reducing the particle size of the biologically active agent which is dispersed in the polymer matrix of the composition.
  • the present invention relates to a sustained release composition and a method of preparing and administering the sustained release composition.
  • the method of the invention for preparing a composition for the sustained release of a biologically active agent comprises the steps of: a) forming a dispersed system comprising a biologically active agent, a water soluble polymer and a first solvent for the water soluble polymer; (b) atomizing the dispersed system to form droplets; (c) freezing the droplets to produce frozen droplets;
  • the method can further comprise the step of forming droplets of the mixture after fragmenting but prior to removal of the second solvent. Further, the method can comprise freezing the droplets prior to removal of the second solvent.
  • the droplets can be microdroplets.
  • the second solvent can be removed by an evaporation and/or extraction process. Phase separation is also a suitable method for removing the second solvent.
  • the composition for sustained release of a biologically active agent is likewise prepared according to the method of the invention as described above.
  • composition for the sustained release of biologically active agent as described herein is a composition prepared by the method comprising the steps of: a) forming a dispersed system comprising a biologically active agent, a water soluble polymer and a first solvent for the water soluble polymer;
  • the sustained release composition of the present invention can be used in a method for providing a therapeutically, prophylactically, or diagnostically effective amount of a biologically active agent to a subject for a sustained period.
  • the invention therefore also relates to a method for providing a therapeutically, prophylactically or diagnostically effective amount of a biologically active agent to a subject for a sustained period, having a reduced initial release of agent comprising administering a dose of the sustained release composition prepared as described herein to a subject over a therapeutically useful period of time.
  • the fragmented biologically active agent once formed can, without isolation, be further processed to prepare a composition for the sustained release of the biologically active agent.
  • the sustained release compositions which are prepared according to the claimed method, exhibit lower initial release of biologically active agent when compared to same compositions absent the water soluble surfactant in the dried substance resulting from the removal of the first solvent from the frozen droplets.
  • the compositions provide increased therapeutic benefits by reducing fluctuations in active agent concentration in blood levels, by providing a more desirable release profile and by potentially lowering the total amount of biologically active agent needed to provide a therapeutic benefit.
  • the Figure is a graph of percentage of drug released in 24 hours from microparticles containing biologically active agent differing in volume median particle size from about 2 to about 5 microns.
  • the present invention relates to a sustained release composition and a method of preparing and administering the sustained release composition.
  • the method of the invention for preparing a composition for the sustained release of a biologically active agent comprises the steps of: a) forming a dispersed system comprising a biologically active agent, a water soluble polymer and a first solvent for the water soluble polymer;
  • the method can further comprise the step of forming droplets of the mixture after fragmenting but prior to removal of the second solvent. Further, the method can comprise freezing the droplets prior to removal of the second solvent.
  • the droplets can be microdroplets.
  • the second solvent can be removed by an evaporation and/or extraction process. Phase separation is also a suitable method for removing the second solvent.
  • the composition for sustained release of a biologically active agent is likewise prepared according to the method of the invention as described above.
  • composition for the sustained release of biologically active agent as described herein is a composition prepared by the method comprising the steps of: a) forming a dispersed system comprising a biologically active agent, a water soluble polymer and a first solvent for the water soluble polymer;
  • the sustained release composition of the present invention can be used in a method for providing a therapeutically, prophylactically, or diagnostically effective amount of a biologically active agent to a subject for a sustained period.
  • a sustained release of biologically active agent is a release of the biologically active agent which occurs over a period of time longer than that which would be obtained following direct administration. It is preferred that a sustained release be a release of biologically active agent which occurs over a period of greater than two days, more preferably one week and most preferably two or more weeks.
  • the sustained release profile of the present invention is superior in that the amount of biologically active agent initially released over the first twenty- four hours following administration is reduced due to the reduced particle size of the incorporated biologically active agent.
  • the reduced particle size of the biologically active agent is a result of the presence of a water soluble polymer in the dried substance which is employed in the process described herein.
  • the invention therefore also relates to a method for providing a therapeutically, prophylactically or diagnostically effective amount of a biologically active agent to a subject for a sustained period, comprising administering a dose of the sustained release composition prepared as described herein to a subject over a therapeutically useful period of time.
  • the term “a or an” refers to one or more.
  • the term “particle size” refers to a volume median particle size as determined by conventional particle size measuring techniques known to those skilled in the art, such as, laser diffraction, photon correlation spectroscopy, sedimentation field flow fractionation, disk centrifugation or electrical sensing zone. Laser diffraction is preferred.
  • the "volume median particle size” is the median diameter of the volume weighted size distribution, also referred to as D v 50 .
  • the term “microparticles” refers to particles having a volume median particle size of between about 1 and 1000 microns.
  • the term "dispersed system” refers to a suspension, a dispersion, a colloidal system or a solution of biologically active agent and water soluble polymer in a first solvent which solubilizes the water soluble polymer.
  • the first solvent of the dispersed system can act to substantially dissolve the water soluble polymer and to dissolve completely or dissolve a substantial portion of the biologically active agent. Complete dissolution of both the polymer and active agent is preferred.
  • the biologically active agent can be a stabilized biologically active agent as described herein. As this is the case, stabilizing agents and other excipients can also be present in the dispersed system.
  • the first solvent is an aqueous solvent.
  • Water, aqueous buffers and mixtures thereof are suitable choices. The choice of first solvent can be determined for the particular water soluble polymer and biologically active agent being used and the type of dispersed system desired.
  • a preferred aqueous solvent is a buffer, which can remain in or be partially or completely removed in preparation of the dried substance. Buffers include, for example, ammonium salts, such as ammonium bicarbonate and sodium salts, such as sodium bicarbonate and sodium acetate.
  • Other suitable first solvents include, methylene chloride, dimethylformamide, dimethylsulfoxide, alcohols such as methanol, ethanol, propanol, mixtures thereof and mixtures with aqueous solvents.
  • the term "non-solvent for a substance" refers to a material which does not substantially dissolve that substance.
  • a "water soluble polymer” as defined herein is any polymer which is soluble in water or an aqueous-based system.
  • the water soluble polymer is also soluble in the solvent for the biocompatible polymer used in the process for preparing the sustained release composition described herein.
  • Water soluble polymers suitable for use in the invention include water soluble polysaccharides, for example, ficoll and polymer surfactants, in particular, nonionic polymer surfactants.
  • Suitable nonionic polymer surfactants include poloxamers, which are polyethylenepolypropyleneglycol polymers commonly referred to as Pluronics.
  • poloxamer 407 sold under the trademark PLURONIC F127
  • poloxamer 188 sold under the trademark PLURONIC F68 (available from BASF Wyandotte) and combinations thereof.
  • Polysorbates are another type of nonionic surfactant often referred to as polyoxyethylene sorbitan esters.
  • Polysorbate 80 sold under the trademark TWEEN ® 80
  • polysorbate 20 sold under the trademark TWEEN ® 20 and combinations thereof are suitable polysorbates for use as the water soluble polymer of the invention.
  • Other water soluble nonionic polymer surfactants suitable for use in the invention include, but are not limited to, polyethylene glycol polymers, polyvinylpyrrolidones, and any combinations of any of the above.
  • Dry substance as that term is used herein is the substance which results from removing the solvent from the frozen droplets produced from the dispersed system.
  • the dried substance comprises a biologically active agent and a water soluble polymer.
  • Other components which can be present in the dried substance include buffer salts which can remain after removal of the first solvent and other excipients which can be added to maintain the potency and/or stability of the biologically active agent.
  • the amount of water soluble polymer which can be added to the first solvent of the dispersed system is based on a percentage by weight of the total solids added to the first solvent.
  • the water soluble polymer will represent at least about 0.5% (w/w) of the total solids added to the first solvent, preferably between about 0.5% (w/w) to about 60% (w/w). In a specific embodiment, the range is from about 5.0% (w/w) to about 30% (w/w) of the total solids added to the first solvent.
  • the amount of water soluble polymer which can be present in the dried substance is preferably at least about 0.5% (w/w), more preferably between 0.5% (w/w) to about 60% (w/w) of the dry weight of the dried substance. In a specific embodiment, the range is from about 5.0% (w/w) to about 30% (w/w).
  • the amount of water soluble polymer present in the final sustained release composition can be optimized based on the load of biologically active agent desired.
  • the amount of water soluble polymer which can be present in the sustained release composition is preferably at least about 0.01% (w/w), more preferably between 0.05%(w/w) to about 60% (w/w) of the dry weight of the sustained release composition. In a specific embodiment the range is from about 0.5% (w/w) to about 30% (w/w).
  • additional water soluble polymers can be present in the sustained release composition and can be added into the process following preparation of the dried substance.
  • Atomization of the dispersed system can be carried out in an apparatus which includes an atomizing means.
  • means for atomizing the suspension to form droplets include directing the dispersed system through an ultrasonic nozzle, pressure nozzle, Rayleigh jet, or by other known means for creating droplets from a solution. Both single fluid and multifluid atomization are suitable. Multifluid atomization refers to atomization which employs more than one fluid in the atomization process. For example, the dispersed system and an atomization gas.
  • the droplets are then frozen by a suitable means.
  • Means suitable for freezing droplets include directing the droplets into or near a cryogenic fluid such as a liquified gas, for example liquid argon or liquid nitrogen to form frozen droplets which can then be collected and dried by removing the solvent.
  • the solvent is removed from the frozen droplets by drying means known to those skilled in the art.
  • the solvent can be removed by lyophilization.
  • the lyophilization cycle is designed to avoid nearing or exceeding the lowest T coordinate of the components of the dried substance.
  • a mixture of the dried substance comprising a biologically active agent and a water soluble polymer, a biocompatible polymer and a second solvent for the water soluble polymer and the biocompatible polymer which is also a non-solvent for the biologically active agent is prepared.
  • the biologically active agent of the mixture is then fragmented.
  • the biologically active agent is a protein
  • the biocompatible polymer is poly(lactide-co-glycolide) and the water soluble polymer is poloxamer 407
  • a suitable solvent for the polymers which is also a non-solvent for the biologically active agent can include for example methylene chloride, chloroform, acetone, ethyl acetate, anisole, methyl acetate, hexafluoroisopropanol, tetrahydrofuran or any combination thereof.
  • Such mixtures were prepared as described in Example 1 using dried substances comprising varying concentrations of ⁇ -IFN, the amino acid glutamate or aspartate, the disaccharide trehalose and a variety of water soluble polymers, and a poly(lactide-co-glycolide) polymer with a 50:50 lactide:glycolide ratio, a 10 kD molecular weight with esterified end groups, and methylene chloride as the second solvent for the polymers and non-solvent for the biologically active agent.
  • Fragmentation can be accomplished by means known to those skilled in the art, for example by ultrasonic probe sonication, homogenization, mechanical shear, fluidization, comminution, ultrasonic nozzle and milling. Fragmentation is performed under conditions and for a period of time which does not deleteriously effect the biological activity of the biologically active agent.
  • a suitable fragmentation temperature can be determined based on the biologically active agent present. For example, fragmentation can be conducted at a temperature of about 37°C. Preferably, the fragmentation is conducted at a temperature of less than about 30°C and more preferably at a temperature of about 10°C.
  • fragmenting is conducted using probe sonication. Typical sonication times can range from about 0.5 to about 5 minutes at microtip limit for the sonicator.
  • the particle can also be fragmented using high pressure homogenization, for example, operating at about 10,000 psi with one or multiple passes.
  • fragmentation is conducted on a mixture which does not include the biocompatible polymer.
  • the biocompatible polymer is added to the mixture following fragmenting.
  • biologically active agent is an agent, or its pharmaceutically acceptable salt, which when released in vivo, possesses the desired biological activity, for example therapeutic, diagnostic and/or prophylactic properties in vivo. It is understood that the term includes stabilized biologically active agents as described herein.
  • a sustained release composition of the invention can contain from about 0.01% (w/w) to about 90% (w/w) of active agent (dry weight of composition). The amount of agent can vary depending upon the desired effect of the agent, the planned release levels, and the time span over which the agent is to be released.
  • a preferred range of agent loading is between about 0.1% (w/w) to about 30% (w/w).
  • a more preferred range of agent loading is between about 0.5% (w/w) to about 20%
  • suitable biologically active agents include proteins, muteins and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g., lymphokines, monokines, chemokines), interleukins, interferons ( ⁇ -IFN, -LFN and ⁇ - rJFN, erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors, insulin, enzymes (e.g.
  • superoxide dismutase tissue plasminogen activator
  • tumor suppressors blood proteins, hormones and hormone analogs (e.g., growth hormone, adrenocorticotropic hormone and luteinizing hormone releasing hormone (LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens), antigens, blood coagulation factors; growth factors; peptides such as protein inhibitors, protein antagonists, and protein agonists; nucleic acids, such as antisense molecules; oligonucleotides; and ribozymes.
  • Small molecular weight agents suitable for use in the invention include, antitumor agents such as bleomycin hydrochloride, carboplatin, methotrexate and adriamycin; antibiotics such as gentamicin, tetracycline hydrochloride and ampicillin; antipyretic, analgesic and anti-inflammatory agents; antitussives and expectorants such as ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride and codeine phosphate; sedatives such as chlorpromazine hydrochloride, prochlorperazine hydrochloride and atropine sulfate; muscle relaxants such as tubocurarine chloride; antiepileptics such as sodium phenytoin and ethosuximide; antiulcer agents such as metoclopramide; antidepressants such as clomipramine; antiallergic agents such as diphenhydramine; cardiotonics such as theophillol; anti
  • the biologically active agent is stabilized.
  • the biologically active agent can be stabilized against degradation, loss of potency and/or loss of biological activity, all of which can occur during formation of the dried substance, during formation of the sustained release composition having the biologically active agent dispersed therein, and/or prior to and during in vivo release of the biologically active agent.
  • stabilization can result in a decrease in the solubility of the biologically active agent, the consequence of which is a reduction in the initial release of biologically active agent, in particular, when release is from a sustained release composition.
  • the period of release of the biologically active agent can be prolonged.
  • Stabilization of the biologically active agent can be accomplished, for example, by the use of a stabilizing agent or a specific combination of stabilizing agents.
  • the stabilizing agent can be present in the dispersed system or can be added to the mixture either before or after fragmentation of the biologically active agent.
  • "Stabilizing agent" is any agent which binds or interacts in a covalent or non-covalent manner or is included with the biologically active agent. Stabilizing agents suitable for use in the invention are described in U.S. Patent Nos. 5,716,644, 5,674,534, 5,654,010, 5,667,808, and 5,711,968, and co-pending U.S. Patent Applications 08/934,830 to Burke et al, filed on September 22, 1997 and 09/104,549 to Burke, filed on June 25, 1998 the entire teachings of which are incorporated herein by reference.
  • a metal cation can be complexed with the biologically active agent, or the biologically active agent can be complexed with a polycationic complexing agent such as protamine, albumin, spermidine and spermine, or associated with a "salting-out" salt.
  • a specific combination of stabilizing agents and/or excipients may be needed to optimize stabilization of the biologically active agent.
  • the biologically active agent in the dispersed system is an acid-stable or free sulfhydryl- containing protein such as ⁇ -IFN
  • a particular combination of stabilizing agents which includes a disaccharide and an acidic excipient can be added to the dispersed system along with the water soluble polymer. This type of stabilizing formulation is described in detail in U.S. Application Serial No.
  • Suitable metal cations include any metal cation capable of complexing with the biologically active agent.
  • a metal cation-stabilized biologically active agent as defined herein, comprises a biologically active agent and at least one type of metal cation wherein the cation is not significantly oxidizing to the biologically active agent.
  • the metal cation is multivalent, for example, having a valency of +2 or more. It is preferred that the metal cation be complexed to the biologically active agent.
  • Suitable stabilizing metal cations include biocompatible metal cations.
  • a metal cation is biocompatible if the cation is non-toxic to the recipient, in the quantities used, and also presents no significant deleterious or untoward effects on the recipient's body, such as a significant immunological reaction at the injection site.
  • the suitability of metal cations for stabilizing biologically active agents and the ratio of metal cation to biologically active agent needed can be determined by one of ordinary skill in the art by performing a variety of stability indicating techniques such as polyacrylamide gel electrophoresis, isoelectric focusing, reverse phase chromatography, and HPLC analysis on particles of metal cation-stabilized biologically active agents prior to and following particle size reduction and/or encapsulation.
  • the molar ratio of metal cation to biologically active agent is typically between about 1:2 and about 100:1, preferably between about 2:1 and about 12:1.
  • stabilizing metal cations include, but are not limited to, K + , Zn +2 , Mg +2 and Ca +2 .
  • Stabilizing metal cations also include cations of transition metals, such as Cu +2 .
  • Combinations of metal cations can also be employed.
  • Zn +2 is used as a stabilizing metal cation for rhGH at a zinc cation component to hGH molar ratio of about 4:1 to about 100:1.
  • the zinc cation component to hGH molar ratio is about 4:1 to about 12:1, and most preferably 10:1.
  • the biologically active agent can also be stabilized with at least one polycationic complexing agent.
  • Suitable polycationic complexing agents include, but are not limited to, protamine, spermine, spermidine and albumin.
  • the suitability of polycationic complexing agents for stabilizing biologically active agents can be determined by one of ordinary skill in the art in the manner described above for stabilization with a metal cation. An equal weight ratio of polycationic complexing agent to biologically active agent is suitable.
  • excipients can be added to maintain the potency of the biologically active agent over the duration of release and modify polymer degradation.
  • the excipients can be added to the dispersed system which is then atomized or can be added to the mixture which is subjected to fragmenting either before or after fragmentation of the dried substance to achieve particles of biologically active agent.
  • Suitable excipients include, for example, carbohydrates, amino acids, fatty acids, surfactants, and bulking agents, and are known to those skilled in the art. An acidic or a basic excipient is also suitable.
  • the amount of excipient used is based on ratio to the biologically active agent, on a weight basis.
  • the ratio of carbohydrate to biologically active agent is typically between about 1 :10 and about 20: 1.
  • the ratio of surfactant to biologically active agent is typically between about 1 : 1000 and about 2:1.
  • the surfactant ia a "water soluble surfactant" as defined herein and is added to the dispersed system the specific concentrations described earlier are employed.
  • Bulking agents typically comprise inert materials. Suitable bulking agents are known to those skilled in the art.
  • the excipient can also be a metal cation component which is separately dispersed within the polymer matrix.
  • This metal cation component acts to modulate the release of the biologically active agent and is not complexed with the biologically active agent.
  • the metal cation component can optionally contain the same species of metal cation, as is contained in the metal cation stabilized biologically active agent, if present, and/or can contain one or more different species of metal cation.
  • the metal cation component acts to modulate the release of the biologically active agent from the polymer matrix of the sustained release composition and can enhance the stability of the biologically active agent in the composition.
  • a metal cation component used in modulating release typically comprises at least one type of multivalent metal cation.
  • metal cation components suitable to modulate release include or contain, for example, Mg(OH) 2 , MgCO 3 (such as 4MgCO 3 .Mg(OH) 2 .5H 2 O), MgSO 4 , Zn(OAc) 2 , Mg(OAc) 2 , ZnCO 3 (such as 3Zn(OH) 2 2ZnCO 3 )ZnSO 4 , ZnCl 2 , MgCl 2 ,
  • a suitable ratio of metal cation component to polymer is between about 1 :99 to about 1 :2 by weight. The optimum ratio depends upon the polymer and the metal cation component utilized.
  • a polymer matrix containing a dispersed metal cation component to modulate the release of a biologically active agent from the polymer matrix is further described in U.S. Patent
  • At least one pore forming agent such as a water soluble salt, sugar or amino acid
  • a sustained release composition can be included in the sustained release composition to modify the microstructure.
  • the proportion of pore forming agent added to the suspension comprising submicron particles of biologically active agent dispersed in a solution comprising at least one biocompatible polymer and at least one polymer solvent, is between about 1% (w/w) to about 30% (w/w). It is prefe ⁇ ed that at least one pore forming agent be included in a nonbiodegradable polymer matrix of the present invention.
  • sustained release composition as defined herein, comprises a biocompatible polymer, particles of biologically active agent and a water soluble polymer dispersed throughout the biocompatible polymer (also referred to herein as a "polymer/biologically active agent matrix”).
  • the polymers of the invention are biocompatible. Suitable biocompatible polymers, can be either biodegradable or non- biodegradable polymers or blends or copolymers thereof, as described herein.
  • a polymer, or polymer matrix is biocompatible if the polymer, and any degradation products of the polymer, are substantially non-toxic to the recipient and also present no significant deleterious or untoward effects on the recipient's body, such as a significant immunological reaction at the site of administration.
  • Biodegradable as defined herein, means the composition will degrade or erode in vivo to form smaller chemical species. Degradation can result, for example, by enzymatic, chemical and/or physical processes.
  • Suitable biocompatible, biodegradable polymers include, for example, poly(lactides), poly(glycolides), poly(lactide-co- glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetals, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylates)s, copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethanes, blends and copolymers thereof.
  • Biocompatible, non-biodegradable polymers suitable for a sustained release device include non-biodegradable polymers selected from the group consisting of polyacrylates, polymers of ethylene-vinyl acetates and acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly( vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, polypropylene oxide, blends and copolymers thereof.
  • non-biodegradable polymers selected from the group consisting of polyacrylates, polymers of ethylene-vinyl acetates and acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly( vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, polypropylene oxide, blends and copoly
  • terminal functionalities or pendant groups of the polymers can be modified, for example, to modify hydrophobicity, hydrophilicity and/or provide, remove or block moieties which can interact with the active agent (via, for example, ionic or hydrogen bonding).
  • Acceptable molecular weights for polymers used in this invention can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical properties such as mechanical strength, and rate of dissolution of polymer in solvent. Typically, an acceptable range of molecular weights is of about 2,000 Daltons to about 2,000,000 Daltons.
  • the polymer is a biodegradable polymer or copolymer.
  • the polymer is a poly(lactide-co-glycolide) (hereinafter "PLGA”) with a lactide: glycolide ratio of about 1 :1 and a molecular weight of about 5,000 Daltons to about 70,000 Daltons.
  • the molecular weight of the PLGA used in the present invention has a molecular weight of about 5,000 Daltons to about 42,000 Daltons.
  • the sustained release composition of this invention can be formed into many shapes such as a film, a pellet, a cylinder, a wafer, a disc or microparticles.
  • Microparticles can have a generally spherical, non-spherical or irregular shape.
  • the microparticle will be of a size suitable for injection.
  • a preferred size range for microparticles is from about 1 to about 250 microns in diameter.
  • the sustained release device in the form of a wafer or disc for example, will typically be of a size suitable for implantation and, for example, can be manufactured by compressing microparticles.
  • the release profile and amount of biologically active agent released can be affected by the loading of biologically active agent, selection of excipients to produce the desired effect and/or by other conditions such as the type of polymer used, the fabrication process employed and the ultimate geometry of the device.
  • Prefe ⁇ ed methods for forming a composition for the sustained release of biologically active agent from the fragmented mixture are described in U.S. Patent No. 5,019,400, issued to Gombotz et al, and U.S. Patent No. 5,912, 253 issued to Herbert et al, the teachings of which are incorporated herein by reference in their entirety.
  • This method of formation as compared with other methods such as phase separation, can reduce the amount of biologically active agent required to produce a sustained release composition with a specific biologically active agent content.
  • the fragmented mixture is processed to create droplets, wherein at least a significant portion of the droplets contains biocompatible polymer, water soluble polymer, polymer solvent and particles of biologically active agent.
  • the biologically active agent can be completely or substantially insoluble in the polymer solution.
  • the droplets are then frozen by a suitable means.
  • suitable means for processing the suspension to form droplets include directing the dispersion through an ultrasonic nozzle, pressure nozzle, Rayleigh jet, or by other known means for creating droplets from a solution.
  • Means suitable for freezing droplets include directing the droplets into or near a liquified gas, such as liquid argon or liquid nitrogen to form frozen microdroplets which are then separated from the liquid gas.
  • a liquified gas such as liquid argon or liquid nitrogen
  • the frozen microdroplets are then exposed to a liquid or solid non-solvent, such as ethanol, hexane, ethanol mixed with hexane, heptane, ethanol mixed with heptane, pentane or oil.
  • the solvent in the frozen microdroplets is extracted as a solid and/or liquid into the non-solvent to form a polymer/biologically active agent matrix comprising a biocompatible polymer, particles of a biologically active agent and a water soluble polymer.
  • a polymer/biologically active agent matrix comprising a biocompatible polymer, particles of a biologically active agent and a water soluble polymer.
  • Mixing ethanol with other non-solvents, such as hexane, heptane or pentane can increase the rate of solvent extraction, above that achieved by ethanol alone, or prevent extraction of advantageous excipients which are soluble in ethanol from certain polymers, such as poly(lactide-co-glycolide) polymers.
  • a wide range of sizes of sustained release compositions can be made by varying the droplet size, for example, by changing the ultrasonic nozzle frequency. If the sustained release composition is in the form of microparticles, and very large microparticles are desired, the microparticles can be extruded, for example, through a syringe directly into the cold liquid. Increasing the viscosity of the polymer solution can also increase microparticle size. The size of the microparticles which can be produced by this process ranges, for example, from greater than about 1000 to about 1 micrometers in diameter.
  • the particles may be isolated from the extraction solvent by filtration and may be dried by evaporation to further remove the remaining solvent.
  • the particles may be sized by passing them through an appropriate sized mesh.
  • Yet another method of forming a sustained release composition, from a suspension comprising a biocompatible polymer and a dried substance includes film casting, such as in a mold, to form a film or a shape. For instance, after putting the suspension into a mold, the polymer solvent is then removed by means known in the art, or the temperature of the polymer suspension is reduced, until a film or shape, with a consistent dry weight, is obtained. Film casting of a polymer solution, is further described in U.S. Patent No. 5,656,297, the teachings of which are incorporated herein by reference in their entirety.
  • the release of the biologically active agent can occur by two different mechanisms.
  • the biologically active agent can be released by diffusion through aqueous filled channels generated in the polymer matrix, such as by the dissolution of the biologically active agent, or by voids created by the removal of the polymer solvent during the preparation of the sustained release composition.
  • a second mechanism is the release of the biologically active agent, due to degradation of the polymer. The rate of degradation can be controlled by changing polymer properties that influence the rate of hydration of the polymer.
  • These properties include, for instance, the ratio of different monomers, such as lactide and glycolide, comprising a polymer; the use of the L-isomer of a monomer instead of a racemic mixture; and the molecular weight of the polymer.
  • These properties can affect hydrophilicity and crystallinity, which control the rate of hydration of the polymer.
  • the contributions of diffusion and/or polymer degradation to biologically active agent release can be controlled. For example, increasing the glycolide content of a poly(lactide-co-glycolide) polymer and decreasing the molecular weight of the polymer can enhance the hydrolysis of the polymer and thus, provides an increased biologically active agent release from polymer erosion.
  • composition of this invention can be administered in vivo, for example, to a human, or to an animal, by injection, implantation (e.g., subcutaneously, intramuscularly, intraperitoneally, intracranially, and intradermally), administration to mucosal membranes (e.g., intranasally, intravaginally, intrapulmonary, buccally or by means of a suppository), or in situ delivery (e.g., by enema or aerosol spray) to provide the desired dosage of biologically active agent based on the known parameters for treatment with the particular agent of the various medical conditions.
  • injection implantation
  • mucosal membranes e.g., intranasally, intravaginally, intrapulmonary, buccally or by means of a suppository
  • in situ delivery e.g., by enema or aerosol spray
  • a “therapeutically effective amount”, “prophylactically effective amount” or “diagnostically effective amount” is the amount of the biologically active agent or of the sustained release composition of biologically active agent needed to elicit the desired biological, prophylactic or diagnostic response following administration.
  • Formation of a mixture comprising the dried substance, a biocompatible polymer and a second solvent for the biocompatible polymer and water soluble polymer of the dried substance which is a non-solvent for the biologically active agent of the dried substance. Fragmentation of the dried substance of the mixture.
  • Atomization of the fragmented mixture and freezing of the droplets by contact with liquid nitrogen Atomization of the fragmented mixture and freezing of the droplets by contact with liquid nitrogen.
  • Extraction of the solvent for the biocompatible and water soluble polymers into an extraction solvent e.g., -80°C ethanol
  • an extraction solvent e.g., -80°C ethanol
  • the dried substances listed in the Table were prepared as follows. Dispersed systems comprising an aqueous solution of ⁇ -EFN, the water soluble polymer indicated in the Table and the other excipients listed were prepared. The dispersed system was then spray freeze dried to form the dried substance. Spray freeze drying of the dispersed system was accomplished by atomizing the dispersed system to form liquid droplets, contacting the liquid droplets with a freezing medium to produce frozen droplets, removing the solvent from the frozen droplets by lyophilization to form the dried substance. The dried substance was then mixed in a 10% w/v solution of the indicated biocompatible polymer and methylene chloride. The dried substance was formulated as 10% of the microparticle or 1% (w/v) in the methylene chloride solution.
  • Dried substance batch 7 in the Table contained no water soluble polymer. However, 2% (w/v) of F 127 was added to the methylene chloride solution of the biocompatible polymer and the solid of batch 7 (no water soluble polymer present). It is noted that the reduction in particle size was significantly less than that seen with the dried substance.
  • EXAMPLE 2 IN VITRO RELEASE OF BIOLOGICALLY ACTIVE AGENT FROM MICROPARTICLES
  • the polymer used in this example was purchased from Alkermes, Inc. of
  • the dried substances listed in the Table were incorporated into microparticles of po ⁇ y(lactide-co-glycolide) (PLG) by the process detailed above, using a 10% w/v solution of the PLG in methylene chloride, and a 1% w/v suspension of the dried substance in the polymer solution.
  • the microparticles thus formed were then tested for in vitro release properties.
  • About 25 mg of microparticles were incubated in 500 ⁇ L of phosphate buffer (50 mM sodium phosphate, pH 7.2, 100 mM NaCl, and 0.02% w/v sodium azide) at 37°C. After incubation for about 24 hours a sample of the buffer was removed and ⁇ -LFN concentration determined by SEC. The percent released was calculated by dividing the amount of agent released by the amount originally present in the microparticles.

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Abstract

La présente invention porte sur une composition à libération prolongée et sur un procédé de préparation et d'administration de cette composition. Le procédé de préparation de la composition permettant la libération prolongée d'un agent biologiquement actif consiste à : (a) former un système dispersé comprenant un agent biologiquement actif, un polymère soluble dans l'eau et un premier solvant destiné à ce polymère ; (b) pulvériser le système dispersé sous forme de gouttelettes ; (c) congeler les gouttelettes ; (d) retirer au moins une partie du premier solvant des gouttelettes congelées afin d'obtenir une substance séchée comprenant l'agent biologiquement actif et le polymère soluble dans l'eau ; (e) préparer un mélange comprenant la substance séchée, un polymère biocompatible et un second solvant destiné à ce polymère et au polymère soluble dans l'eau qui n'est pas un solvant pour l'agent biologiquement actif ; (f) fragmenter l'agent biologiquement actif du mélange ; (g) retirer le second solvant du mélange afin d'obtenir une matrice polymère biocompatible solide dans laquelle sont dispersés l'agent biologiquement actif et le polymère soluble dans l'eau.
PCT/US2001/003165 2000-02-10 2001-01-31 Procede de preparation d'une composition a liberation prolongee WO2001058428A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089287A2 (fr) * 2003-04-04 2004-10-21 Genteric Inc. Systemes et procedes de coacervation et de sechage par pulverisation
US7807680B2 (en) 2003-10-23 2010-10-05 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US9457026B2 (en) 2007-07-31 2016-10-04 Otsuka Pharmaceutical Co., Ltd. Methods for producing aripiprazole suspension and freeze-dried formulation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589167A (en) * 1993-02-23 1996-12-31 Genentech, Inc. Excipient stabilization of polypeptides treated with organic solvents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589167A (en) * 1993-02-23 1996-12-31 Genentech, Inc. Excipient stabilization of polypeptides treated with organic solvents

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089287A2 (fr) * 2003-04-04 2004-10-21 Genteric Inc. Systemes et procedes de coacervation et de sechage par pulverisation
WO2004089287A3 (fr) * 2003-04-04 2006-11-16 Genteric Inc Systemes et procedes de coacervation et de sechage par pulverisation
US7807680B2 (en) 2003-10-23 2010-10-05 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8030313B2 (en) 2003-10-23 2011-10-04 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8722679B2 (en) 2003-10-23 2014-05-13 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8952013B2 (en) 2003-10-23 2015-02-10 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US9763935B2 (en) 2003-10-23 2017-09-19 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US9457026B2 (en) 2007-07-31 2016-10-04 Otsuka Pharmaceutical Co., Ltd. Methods for producing aripiprazole suspension and freeze-dried formulation

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