US20020114843A1 - Preparation of microparticles having improved flowability - Google Patents

Preparation of microparticles having improved flowability Download PDF

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Publication number
US20020114843A1
US20020114843A1 US09/748,136 US74813600A US2002114843A1 US 20020114843 A1 US20020114843 A1 US 20020114843A1 US 74813600 A US74813600 A US 74813600A US 2002114843 A1 US2002114843 A1 US 2002114843A1
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Prior art keywords
microparticles
polymer
active agent
solvent
conditioning temperature
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J. Ramstack
Steven Wright
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ALKEMES CONTROLLED THERAPEUTICS Inc II
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ALKEMES CONTROLLED THERAPEUTICS Inc II
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Application filed by ALKEMES CONTROLLED THERAPEUTICS Inc II filed Critical ALKEMES CONTROLLED THERAPEUTICS Inc II
Priority to US09/748,136 priority Critical patent/US20020114843A1/en
Assigned to ALKEMES CONTROLLED THERAPEUTICS INC. II reassignment ALKEMES CONTROLLED THERAPEUTICS INC. II ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RAMSTACK, J. MICHAEL, WRIGHT, STEVEN G.
Priority to EP01991188A priority patent/EP1345682B1/en
Priority to AU2002230930A priority patent/AU2002230930B2/en
Priority to US10/022,859 priority patent/US7247319B2/en
Priority to PCT/US2001/048711 priority patent/WO2002051535A2/en
Priority to PT1991188T priority patent/PT1345682E/en
Priority to ES01991188T priority patent/ES2404279T3/en
Priority to JP2002552670A priority patent/JP4248237B2/en
Priority to DK01991188.2T priority patent/DK1345682T3/en
Priority to CA002432279A priority patent/CA2432279C/en
Publication of US20020114843A1 publication Critical patent/US20020114843A1/en
Priority to US11/812,697 priority patent/US20070260038A1/en
Priority to CY20131100224T priority patent/CY1113803T1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F6/00—Post-polymerisation treatments
    • C08F6/001—Removal of residual monomers by physical means
    • C08F6/005—Removal of residual monomers by physical means from solid polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/12—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
    • C09K23/38—Alcohols, e.g. oxidation products of paraffins

Definitions

  • the present invention relates to preparation of microparticles containing an active agent. More particularly, the present invention relates to microparticles having improved flowability, and to a method for the preparation of such microparticles.
  • a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall-forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other active agents.
  • a biocompatible, biodegradable wall-forming material e.g., a polymer
  • the material to be encapsulated is generally dissolved, dispersed, or emulsified in a solvent containing the wall forming material. Solvent is then removed from the microparticles to form the finished microparticle product.
  • Tice et al. in U.S. Pat. No. 4,389,330 describe the preparation of microparticles containing an active agent by using a two-step solvent removal process.
  • the active agent and the polymer are dissolved in a solvent.
  • the mixture of ingredients in the solvent is then emulsified in a continuous-phase processing medium that is immiscible with the solvent.
  • a dispersion of microparticles containing the indicated ingredients is formed in the continuous-phase medium by mechanical agitation of the mixed materials.
  • the organic solvent can be partially removed in the first step of the solvent removal process.
  • the dispersed microparticles are isolated from the continuous-phase processing medium by any convenient means of separation. Following the isolation, the remainder of the solvent in the microparticles is removed by extraction. After the remainder of the solvent has been removed from the microparticles, they are dried by exposure to air or by other conventional drying techniques.
  • U.S. Pat. No. 5,407,609 Another conventional method of microencapsulating an agent to form a microencapsulated product is disclosed in U.S. Pat. No. 5,407,609.
  • This method includes: (1) dissolving or otherwise dispersing one or more agents (liquids or solids) in a solvent containing one or more dissolved wall-forming materials or excipients (usually the wall-forming material or excipient is a polymer dissolved in a polymer solvent); (2) dispersing the agent/polymer-solvent mixture (the discontinuous phase) into a processing medium (the continuous phase which is preferably saturated with polymer solvent) to form an emulsion; and (3) transferring all of the emulsion immediately to a large volume of processing medium or other suitable extraction medium, to immediately extract the solvent from the microdroplets in the emulsion to form a microencapsulated product, such as microcapsules or microspheres.
  • U.S. Pat. No. 5,650,173 discloses a process for preparing biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible polymeric binder and a biologically active agent, wherein a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons, are used to dissolve both the agent and the polymer.
  • the solvent blend containing the dissolved agent and polymer is dispersed in an aqueous solution to form droplets.
  • the resulting emulsion is added to an aqueous extraction medium preferably containing at least one of the solvents of the blend, whereby the rate of extraction of each solvent is controlled, whereupon the biodegradable, biocompatible microparticles containing the biologically active agent are formed.
  • Active agents suitable for encapsulation by this process include, but are not limited to, norethindrone, risperidone, and testosterone, and a preferred solvent blend is one comprising benzyl alcohol and ethyl acetate.
  • U.S. Pat. No. 5,654,008 describes a microencapsulation process that uses a static mixer.
  • a first phase comprising an active agent and a polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the active agent.
  • Microparticles having poor flow properties tend to “arch” or “bridge” and then may “rat hole” or stop completely when discharged from the hopper. In this case further processing must be abandoned. None of the documents discussed above discloses a specific method for preparing microparticles that have improved flowability.
  • the present invention relates to a method for preparing microparticles that have improved flowability.
  • a method for processing a quantity of microparticles comprises placing, the quantity of microparticles into a container, and maintaining the microparticles at a conditioning temperature for a period of time.
  • the conditioning temperature and the period are selected so that an angle of repose of the quantity of microparticles is less than about 28°.
  • a method for preparing microparticles having improved flowability comprises: preparing an emulsion that comprises a first phase and a second phase, the first phase comprising an active agent, a polymer, and a solvent for the polymer; extracting the solvent from the emulsion to form microparticles containing the active agent; and maintaining the microparticles at a conditioning temperature for a period of time, the conditioning temperature and the period being selected so that an angle of repose of the microparticles is less than about 28°.
  • microparticles having improved flowability are provided.
  • Such microparticles may be prepared by any of the methods described and disclosed herein, including a method comprising: preparing an emulsion that comprises a first phase and a second phase, the first phase comprising an active agent, a polymer, and a solvent for the polymer; extracting the solvent from the emulsion to form microparticles containing the active agent; and allowing crystal growth of active agent present on a surface of the microparticles.
  • the crystal growth of active agent on the surface of the microparticles takes place while the microparticles are maintained at a conditioning temperature for a period of time, the conditioning temperature and the period being selected so that an angle of repose of the microparticles is less than about 28°.
  • a feature of the present invention is that it provides microparticles having improved flowability. More particularly, the present invention advantageously provides microparticles having significantly improved flowability to facilitate processing in certain automated equipment, such as certain automated vial filling machines and tabletting machines.
  • Another feature of the method of the present invention is that it produces microparticles in stable form that should remain unchanged during normal storage conditions.
  • the present invention specifically provides for crystal growth of active agent on the surface of the microparticles.
  • An advantage of the present invention is that the process call be carried out in readily available, completely closed containers eliminating the need for further processing or product transfers, thereby preserving the sterility of the microparticles. In this manner, there is no need for further sterilization.
  • Another advantage of the present invention is that the process can be carried out at a temperature much lower than the glass transition temperature T g of the polymer. Processing at such a temperature advantageously minimizes the product agglomeration and instability that typically occurs at temperatures nearer to or above the polymer T g .
  • the present invention advantageously avoids reformulation or redesign of established formulations, processes, and equipment.
  • FIG. 1 depicts measurement of angle of repose for microparticles
  • FIGS. 2A and 2B show micrographs of microparticles prior to carrying out one embodiment of a process of the present invention.
  • FIGS. 3A and 3B show micrographs of microparticles after carrying out one embodiment of a process of the present invention.
  • the present invention relates to microparticles having improved flowability, and to methods for the preparation of such microparticles.
  • Flowability refers to the ability of microparticles to flow. Microparticles exhibiting poor flowability stick to one another, and “bridge” together such as when they are processed through certain automated filling equipment and hoppers. Conversely, microparticles exhibiting good flowability flow freely, and can be processed in automated filling or tabletting equipment without significant occurrence of bridging or hold-up.
  • angle of repose of the microparticles can be used to characterize the flowability of the microparticles.
  • angle of repose refers to the limiting angle of incline, ⁇ r , at which a body on the incline will remain at rest.
  • the frictional force f may have any value up to a maximum ⁇ s N, where ⁇ s is the coefficient of static friction and N is the normal force.
  • the angle of repose, ⁇ r is related to ⁇ s by the equation:
  • microparticles processed in accordance with the methods of the present invention flowed freely and demonstrated angles of repose less than about 28°.
  • microparticles not subject to the conditioning process of the present invention bridged in filling hoppers and demonstrated angles of repose greater than about 35°.
  • a conditioning process is carried out on the microparticles.
  • the conditioning process is carried out on a finished microparticle product, prior to any filling operation.
  • finished microparticles can be prepared using emulsion-based methods of preparing microparticles.
  • phase separation methods can be used to prepare finished microparticles. Suitable methods of preparing a finished microparticle product are disclosed in, for example, the following U.S. patents, the entirety of each of which is incorporated herein by reference: U.S. Pat. Nos. 3,737,337; 4,389,330; 5,407,609; 5,650,173; 5,654,008; 5,792,477; 5,916,598; and 6,110,503.
  • the method of the present invention comprises placing a batch or other quantity of microparticles into a closed container.
  • the closed container is maintained at a conditioning temperature for a period of time.
  • the conditioning temperature and the period are selected so that an angle of repose of the batch of microparticles is less than about 28°.
  • the closed container is rotated or inverted during the period to provide mixing, thereby reducing or eliminating any temperature gradient that may be present.
  • the batch of microparticles can be transferred to a vial filling machine to fill vials with the microparticles, or to a tabletting machine or the like for further processing.
  • the microparticles are made using an emulsion-based process.
  • the method of the present invention includes preparing an emulsion that comprises a first phase and a second phase.
  • the first phase preferably comprises an active agent, a polymer, and a solvent for the polymer.
  • the second phase is a continuous phase, preferably an aqueous phase.
  • the solvent is extracted from the emulsion to firm microparticles containing the active agent.
  • the microparticles are maintained at a conditioning temperature for a period of time. The conditioning temperature and the period are selected so that an angle of repose of the microparticles is less than about 28°.
  • microparticles solid particles that contain an active agent or other substance dispersed or dissolved within a polymer that serves as a matrix or binder of the particle.
  • the polymer is preferably biodegradable and biocompatible.
  • biodegradable is meant a material that should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body.
  • biocompatible is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues.
  • body preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body.
  • weight % or “% by weight” is meant parts by weight per hundred parts total weight of microparticle.
  • 10 wt. % active agent would mean 10 parts active agent by weight and 90 parts polymer by weight. Unless otherwise indicated to the contrary, percentages (%) reported herein are by weight.
  • controlled release microparticle or “sustained release microparticle” is meant a microparticle from which an active agent or other type of substance is released as a function of time.
  • mass median diameter is meant the diameter at which half of the distribution (volume percent) has a larger diameter and half has a smaller diameter.
  • the present invention provides a method to improve flowability of a microparticle product, preferably a microparticle comprised of an active agent and a biodegradable polymer.
  • the flowability of the microparticle product is improved to allow processing in conventional hoppers and automated vial filling equipment. Without the method of the present invention, poor microparticle flow characteristics result in bridging in powder hoppers and subsequent inability to process the microparticle product in automated equipment.
  • a conditioning process is carried out on a finished microparticle product, such as a batch or quantity of microparticles prepared by the process disclosed and described in U.S. Pat. Nos. 5,654,008 and 5,650,173.
  • the batch of microparticles is maintained at a conditioning temperature for a period of time.
  • the conditioning temperature and the period are selected so that an angle of repose of the batch of microparticles is less than about 28°.
  • This conditioning process is preferably carried out at a temperature below the T g of the polymer to avoid product agglomeration.
  • the conditioning process is preferably carried out in an open container so that the microparticles may be exposed to elevated humidity or moisture vapor.
  • the conditioning process is carried out in a closed container with a dry product.
  • the conditioning process may be carried out in a completely closed container, which is placed in a controlled-temperature chamber. The temperature in the chamber, and the length of time the container is in the chamber, are both controlled.
  • the container is rotated or inverted while it is in the chamber to provide mixing. Processing the material in a closed container preserves the sterility of the microparticle product, avoids yield losses and contamination associated with handling and product transfers, and minimizes moisture pick-up by avoiding atmospheric contact.
  • a 16.7 wt. % polymer solution was prepared by dissolving 12 kg of MEDISORB® 7525 DL polymer (Alkermes, Inc., Blue Ash, Ohio) in ethyl acetate.
  • a 24 wt. % drug solution was prepared by dissolving 8 kg of risperidone (Janssen Pharmaceutica, Beerse, Belgium) in benzyl alcohol.
  • An active agent/polymer solution (organic phase) was prepared by mixing the drug solution into the polymer solution. The active agent/polymer solution was maintained at a temperature of 25 ⁇ 5° C.
  • the second, continuous phase was prepared by preparing a 600 liter solution of 1% PVA, the PVA acting as an emulsifier. To this was added 42 kg of ethyl acetate to form a 6.5 wt. % solution of ethyl acetate. The two phases were combined using a static mixer such as a 1′′ Kenics static mixer available from Chemineer, Inc., North Andover, Mass.
  • the emulsion was transferred to a solvent extraction medium.
  • the solvent extraction medium was 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10° C.
  • the volume of the solvent extraction medium is 0.25 L per gram of batch size.
  • the microparticles were collected, de-watered, and dried. The temperature was maintained at less than about 15° C.
  • microparticles were then re-slurried in a re-slurry tank using a 25% ethanol solution.
  • the temperature in the re-slurry tank was in the range of about 0° C. to about 15° C.
  • the microparticles were then transferred back to the solvent extraction tank for washing with another extraction medium (25% ethanol solution) that was maintained at preferably 25° ⁇ 1° C.
  • microparticles were collected, de-watered, and dried. The temperature was warmed to greater than about 20° C. but below 40° C.
  • the conditioning process of the present invention improves the flowability of microparticles.
  • Table 1 below shows the effect of the conditioning process on angle of repose for samples of risperidone microparticles prepared in the manner described above.
  • the angle of repose was measured in the following manner.
  • a standard 100 mm Nalgene funnel was positioned in a ring stand so that the funnel discharge was at a height of approximately three inches above a level horizontal surface.
  • Approximately 100 g of microparticles were weighed out.
  • the microparticles were placed in the funnel, which was fitted with a stopper to block discharge. The stopper was removed, and the microparticles were allowed to flow through the funnel until all material was discharged.
  • the discharged microparticles formed a pile having an angle of repose characteristic of the microparticles forming the pile.
  • a pile 100 of microparticles is depicted in FIG. 1.
  • ⁇ r is the angle of incline at which the microparticles forming pile 100 remain at rest. Microparticles that are poor flowing have a higher angle of repose (i.e., form a taller pile with greater height (h)) than microparticles that have greater flowability. Conversely, microparticles with improved flowability have a lower angle of repose (i.e., form a shorter and wider pile with lower height (h)) than microparticles having poorer flowability.
  • the parameter (d) provided additional qualitative information about flowability. As can be seen from FIG. 1, if (d) is not equal to twice the width (w), then a truncated cone (pointed top of cone is truncated) has been formed. It was observed that microparticles having good flowability tended to form a truncated cone, while microparticles having poorer flowability tended to form a more defined cone with (d) substantially equal to twice the width (w).
  • Table 1 shows for each sample the treatment, or conditioning process, to which the sample of microparticles was subjected, the angle of repose, and an assessment of the flowability or flow property.
  • the first two samples exhibiting poor flowability were not subjected to the conditioning process of the present invention.
  • the angle of repose for these microparticles was greater than 35°.
  • the sample exhibiting good flowability was maintained at a conditioning temperature of 72° F. for a period of 24 hours; the angle of repose for these microparticles was between about 25.6° and 27.6°.
  • the flowability of the microparticles improved to excellent by maintaining the microparticles for one week at 72° F., as shown by the last sample in Table 1.
  • the angle of repose for the last sample in Table 1 was between about 21.3° and 23.7°.
  • Table 2 shows the angle of repose and flow property as a function of the number of days the microparticles are maintained at a conditioning temperature in the range of 20-25° C. At zero ( ⁇ ) days, corresponding to no conditioning process, the flowability of the microparticles was poor, and the angle of repose was about 42°. As the length of the conditioning period (days at 20-25° C.) increased, the flowability of the microparticles improved. The improved flowability is characterized by a decrease in the angle of repose. Acceptable flowability for processing of the microparticles in automated filling equipment is characterized by an angle of repose in the range of from about 18° to about 28°. However, it should be understood that the present invention is not limited to angles in this range. It is preferred to have the angle of repose as low as possible below about 28°.
  • AFM atomic force microscopy
  • AFM micrographs were prepared for samples of microparticles from the batches reported in Table 1 and another batch of risperidone microparticles prepared in the manner described above.
  • One set of micrographs was prepared on “pre-conditioned” microparticles, i.e., prior to carrying out the conditioning process of the present invention.
  • the pre-conditioned micrographs are presented in FIGS. 2A and 2B.
  • the micrographs of FIGS. 2A and 2B exhibit large dark-phase patches 200 of what appear to be nanocrystalline or amorphous material.
  • FIGS. 3A and 3B Another set of micrographs was prepared on “post-conditioned” microparticles, i.e., after carrying out the conditioning process of the present invention.
  • the post-conditioned micrographs are presented in FIGS. 3A and 3B.
  • the micrographs of FIGS. 3A and 3B exhibit larger (up to several microns in length) and much more numerous crystals 300 than were present on the pre-conditioned micrographs of FIGS. 2A and 2B.
  • the microparticles included active agent (in this case risperidone) on the surface largely in amorphous form.
  • active agent in this case risperidone
  • the post-conditioned micrographs of FIGS. 3A and 3B through the conditioning process of the present invention, the active agent on the surface of the microparticles is converted to largely crystalline form.
  • the post-conditioned microparticles with the surface active agent in crystalline form exhibited improved flowability as discussed above.
  • microparticles having improved flowability can be prepared in accordance with the present invention.
  • the crystal growth of risperidone on the surface of the microparticles occurred during the conditioning process of the present invention.
  • the conditioning process was carried out at a conditioning temperature in the range of from about 20° C. to about 25° C. These temperatures are also much less than the polymer T g (approximately 45° C.), which is preferred since it avoids the possibility of product agglomeration.
  • Preferred active agents that can be encapsulated by the process of the present invention include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles.
  • the most preferred active agents of this kind for treatment by the process of the present invention are 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (“risperidone”) and 3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (“9-hydroxyrisperidone”) and the pharmaceutically acceptable salts thereof.
  • Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is most preferred. Risperidone can be prepared in accordance with the teachings of U.S. Pat. No. 4,804,663, the entirety of which is incorporated herein by reference. 9-hydroxyrisperidone can be prepared in accordance with the teachings of U.S. Pat. No. 5,158,952, the entirety of which is incorporated herein by reference.
  • polymer matrix materials include poly(glycolic acid), poly(d,1-lactic acid), poly(1-lactic acid), copolymers of the foregoing, and the like.
  • Various commercially available poly(lactide-co-glycolide) materials may be used in the method of the present invention.
  • poly (d,1-lactic-co-glycolic acid) is commercially available from Alkermes, Inc. (Blue Ash,, Ohio).
  • a suitable product commercially available from Alkermes, Inc. is a 50:50 poly(d,1-lactic-co-glycolic acid) known as MEDISORB® 5050 DL. This product has a mole percent composition of 50% lactide and 50% glycolide.
  • the most preferred polymer for use in the practice of the invention is the copolymer, poly(d,1-lactide-co-glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 85:15 to about 50:50.
  • the molecular weight of the polymeric matrix material is of some importance.
  • the molecular weight should be high enough to permit the formation of satisfactory polymer coatings, i.e., the polymer should be a good film former.
  • a satisfactory molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 daltons.
  • the molecular weight of the polymer is also important from the point of view of its influence upon the biodegradation rate of the polymer.
  • the polymer should remain intact until all of the drug is released from the microparticles and then degrade.
  • the drug can also be released from the microparticles as the polymeric excipient bioerodes.
  • a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in according multiphasic release patterns.
  • the formulation prepared by the process of the present invention contains an active agent dispersed in the microparticle polymeric matrix material.
  • the amount of such agent incorporated in the microparticles usually ranges from about 1 wt. % to about 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %.
  • Other biologically active agents include non-steroidal antifertility agents; parasympathomimetic agents; psychotherapeutic agents; tranquilizers; decongestants; sedative hypnotics; steroids; sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials; anti-migraine agents; anti-Parkinson agents such as L-dopa; anti-spasmodics; anticholinergic agents (e.g.
  • oxybutynin oxybutynin
  • antitussives bronchodilators
  • cardiovascular agents such as coronary vasodilators and nitroglycerin
  • alkaloids such as coronary vasodilators and nitroglycerin
  • analgesics such as codeine, dihydrocodienone, meperidine, morphine and the like
  • non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like
  • opioid receptor antagonists such as naltrexone and naloxone
  • antibiotics such as gentamycin, tetracycline and penicillins
  • anti-cancer agents anti-convulsants
  • anti-emetics antihistamines
  • anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, indomethacin, pheny
  • Still other suitable active agents include estrogens, antibacterials; antifungals; antivirals; anticoagulants; anticonvulsants; antidepressants; antihistamines; and immunological agents.
  • Suitable biologically active agents include peptides and proteins, analogs, muteins, and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g. lymphokines, monokines, chemokines), blood clotting factors, hemopoietic factors, interleukins (IL-2, IL-3, IL-4, IL-6), interferons ( ⁇ -IFN, ⁇ -IFN and ⁇ -IFN), erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors (e.g., GCSF, GM-CSF, MCSF), 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
  • Small molecular weight agents suitable for use in the invention include, antitumor agents such as bleomycin hydrochloride, carboplatin, methotrexate and adriamycin; antipyretic and analgesic 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; antiarrhythmic agents such as propranolol hydrochloride; vasodilators such as dil

Abstract

Methods for preparing microparticles having improved flowability to facilitate processing in automated equipment. Microparticles are maintained at a conditioning temperature for a period of time. The conditioning temperature and period are selected so that the angle of repose of the microparticles is less than about 28°.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • The present invention relates to preparation of microparticles containing an active agent. More particularly, the present invention relates to microparticles having improved flowability, and to a method for the preparation of such microparticles. [0002]
  • 2. Related Art [0003]
  • Various methods are known by which compounds can be encapsulated in the form of microparticles. It is particularly advantageous to encapsulate a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall-forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other active agents. In these methods, the material to be encapsulated (drugs or other active agents) is generally dissolved, dispersed, or emulsified in a solvent containing the wall forming material. Solvent is then removed from the microparticles to form the finished microparticle product. [0004]
  • An example of a conventional microencapsulation process is disclosed in U.S. Pat. No. 3,737,337 wherein a solution of a wall or shell forming polymeric material in a solvent is prepared. The solvent is only partially miscible in water. A solid or core material is dissolved or dispersed in the polymer-containing solution and, thereafter, the core-material-polymer-containing solution is dispersed in an aqueous liquid that is immiscible in the organic solvent in order to remove solvent from the microparticles. [0005]
  • Tice et al. in U.S. Pat. No. 4,389,330 describe the preparation of microparticles containing an active agent by using a two-step solvent removal process. In the Tice et al. process, the active agent and the polymer are dissolved in a solvent. The mixture of ingredients in the solvent is then emulsified in a continuous-phase processing medium that is immiscible with the solvent. A dispersion of microparticles containing the indicated ingredients is formed in the continuous-phase medium by mechanical agitation of the mixed materials. From this dispersion, the organic solvent can be partially removed in the first step of the solvent removal process. After the first stage, the dispersed microparticles are isolated from the continuous-phase processing medium by any convenient means of separation. Following the isolation, the remainder of the solvent in the microparticles is removed by extraction. After the remainder of the solvent has been removed from the microparticles, they are dried by exposure to air or by other conventional drying techniques. [0006]
  • Another conventional method of microencapsulating an agent to form a microencapsulated product is disclosed in U.S. Pat. No. 5,407,609. This method includes: (1) dissolving or otherwise dispersing one or more agents (liquids or solids) in a solvent containing one or more dissolved wall-forming materials or excipients (usually the wall-forming material or excipient is a polymer dissolved in a polymer solvent); (2) dispersing the agent/polymer-solvent mixture (the discontinuous phase) into a processing medium (the continuous phase which is preferably saturated with polymer solvent) to form an emulsion; and (3) transferring all of the emulsion immediately to a large volume of processing medium or other suitable extraction medium, to immediately extract the solvent from the microdroplets in the emulsion to form a microencapsulated product, such as microcapsules or microspheres. [0007]
  • U.S. Pat. No. 5,650,173 discloses a process for preparing biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible polymeric binder and a biologically active agent, wherein a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons, are used to dissolve both the agent and the polymer. The solvent blend containing the dissolved agent and polymer is dispersed in an aqueous solution to form droplets. The resulting emulsion is added to an aqueous extraction medium preferably containing at least one of the solvents of the blend, whereby the rate of extraction of each solvent is controlled, whereupon the biodegradable, biocompatible microparticles containing the biologically active agent are formed. Active agents suitable for encapsulation by this process include, but are not limited to, norethindrone, risperidone, and testosterone, and a preferred solvent blend is one comprising benzyl alcohol and ethyl acetate. [0008]
  • U.S. Pat. No. 5,654,008 describes a microencapsulation process that uses a static mixer. A first phase, comprising an active agent and a polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the active agent. [0009]
  • The documents described above all disclose methods that can be used to prepare microparticles that contain an active agent. However, flowability of these microparticles immediately after processing and recovery may be poor. Good flowability is characterized by steady, controlled flow similar to dry sand. Poor flowability, on the other hand, is characterized by uncontrolled, erratic flow similar to wet sand. In this case the entire bulk tries to move in a solid mass. This last condition is termed “floodable” flow and is most characteristic of cohesive, sticky powders. Flowability is an important consideration in large-scale processing when invariably these powders or microparticles must be moved from place to place. It is a particularly important consideration when using automated filling equipment where material must flow from a hopper. Microparticles having poor flow properties tend to “arch” or “bridge” and then may “rat hole” or stop completely when discharged from the hopper. In this case further processing must be abandoned. None of the documents discussed above discloses a specific method for preparing microparticles that have improved flowability. [0010]
  • Thus, there is a need in the art for a method for preparing microparticles having improved flowability. There is a further need in the art for a method for preparing microparticles with improved flowability so that such microparticles can be processed in automated powder filling equipment. The present invention, the description of which is fully set forth below, solves the need in the art for such methods. [0011]
    • SUMMARY OF THE INVENTION
  • The present invention relates to a method for preparing microparticles that have improved flowability. In one aspect, a method for processing a quantity of microparticles is provided. The method comprises placing, the quantity of microparticles into a container, and maintaining the microparticles at a conditioning temperature for a period of time. The conditioning temperature and the period are selected so that an angle of repose of the quantity of microparticles is less than about 28°. [0012]
  • In another aspect of the present invention, a method for preparing microparticles having improved flowability is provided. The method comprises: preparing an emulsion that comprises a first phase and a second phase, the first phase comprising an active agent, a polymer, and a solvent for the polymer; extracting the solvent from the emulsion to form microparticles containing the active agent; and maintaining the microparticles at a conditioning temperature for a period of time, the conditioning temperature and the period being selected so that an angle of repose of the microparticles is less than about 28°. [0013]
  • In yet another aspect of the present invention, microparticles having improved flowability are provided. Such microparticles may be prepared by any of the methods described and disclosed herein, including a method comprising: preparing an emulsion that comprises a first phase and a second phase, the first phase comprising an active agent, a polymer, and a solvent for the polymer; extracting the solvent from the emulsion to form microparticles containing the active agent; and allowing crystal growth of active agent present on a surface of the microparticles. In a preferred aspect of the present invention, the crystal growth of active agent on the surface of the microparticles takes place while the microparticles are maintained at a conditioning temperature for a period of time, the conditioning temperature and the period being selected so that an angle of repose of the microparticles is less than about 28°. [0014]
  • Features and Advantages [0015]
  • A feature of the present invention is that it provides microparticles having improved flowability. More particularly, the present invention advantageously provides microparticles having significantly improved flowability to facilitate processing in certain automated equipment, such as certain automated vial filling machines and tabletting machines. [0016]
  • Another feature of the method of the present invention is that it produces microparticles in stable form that should remain unchanged during normal storage conditions. Advantageously, the present invention specifically provides for crystal growth of active agent on the surface of the microparticles. [0017]
  • An advantage of the present invention is that the process call be carried out in readily available, completely closed containers eliminating the need for further processing or product transfers, thereby preserving the sterility of the microparticles. In this manner, there is no need for further sterilization. [0018]
  • Another advantage of the present invention is that the process can be carried out at a temperature much lower than the glass transition temperature T[0019] g of the polymer. Processing at such a temperature advantageously minimizes the product agglomeration and instability that typically occurs at temperatures nearer to or above the polymer Tg.
  • Poor flowability often results from conventional formulation and processing techniques for microparticles. By solving the poor flowability problem as a final processing step, the present invention advantageously avoids reformulation or redesign of established formulations, processes, and equipment.[0020]
    • BRIEF DESCRIPTION OF THE FIGURES
  • The present invention is described with reference to the accompanying drawings. In the drawings, like reference numbers indicate identical or functionally similar elements. Additionally, the left-most digit of a reference number identifies the drawing in which the reference number first appears. [0021]
  • FIG. 1 depicts measurement of angle of repose for microparticles; [0022]
  • FIGS. 2A and 2B show micrographs of microparticles prior to carrying out one embodiment of a process of the present invention; and [0023]
  • FIGS. 3A and 3B show micrographs of microparticles after carrying out one embodiment of a process of the present invention.[0024]
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • Overview [0025]
  • The present invention relates to microparticles having improved flowability, and to methods for the preparation of such microparticles. “Flowability” refers to the ability of microparticles to flow. Microparticles exhibiting poor flowability stick to one another, and “bridge” together such as when they are processed through certain automated filling equipment and hoppers. Conversely, microparticles exhibiting good flowability flow freely, and can be processed in automated filling or tabletting equipment without significant occurrence of bridging or hold-up. [0026]
  • The angle of repose of the microparticles can be used to characterize the flowability of the microparticles. As known to one skilled in the art, “angle of repose” refers to the limiting angle of incline, θ[0027] r, at which a body on the incline will remain at rest. For the body at rest on the incline, the frictional force f may have any value up to a maximum μsN, where μs is the coefficient of static friction and N is the normal force. The angle of repose, θr, is related to μs by the equation:
  • tan θr=μs
  • Particularly, as will be described in more detail below, microparticles processed in accordance with the methods of the present invention flowed freely and demonstrated angles of repose less than about 28°. In contrast, microparticles not subject to the conditioning process of the present invention bridged in filling hoppers and demonstrated angles of repose greater than about 35°. [0028]
  • In one embodiment of the present invention, a conditioning process is carried out on the microparticles. The conditioning process is carried out on a finished microparticle product, prior to any filling operation. It should be readily apparent to one skilled in the art, that the present invention is not limited to any particular method of preparing a finished microparticle product. For example, finished microparticles can be prepared using emulsion-based methods of preparing microparticles. Alternatively, phase separation methods can be used to prepare finished microparticles. Suitable methods of preparing a finished microparticle product are disclosed in, for example, the following U.S. patents, the entirety of each of which is incorporated herein by reference: U.S. Pat. Nos. 3,737,337; 4,389,330; 5,407,609; 5,650,173; 5,654,008; 5,792,477; 5,916,598; and 6,110,503. [0029]
  • In one aspect, the method of the present invention comprises placing a batch or other quantity of microparticles into a closed container. The closed container is maintained at a conditioning temperature for a period of time. The conditioning temperature and the period are selected so that an angle of repose of the batch of microparticles is less than about 28°. Preferably, the closed container is rotated or inverted during the period to provide mixing, thereby reducing or eliminating any temperature gradient that may be present. After the period, the batch of microparticles can be transferred to a vial filling machine to fill vials with the microparticles, or to a tabletting machine or the like for further processing. [0030]
  • In one preferred embodiment of the present invention, the microparticles are made using an emulsion-based process. In such a preferred embodiment, the method of the present invention includes preparing an emulsion that comprises a first phase and a second phase. The first phase preferably comprises an active agent, a polymer, and a solvent for the polymer. The second phase is a continuous phase, preferably an aqueous phase. The solvent is extracted from the emulsion to firm microparticles containing the active agent. The microparticles are maintained at a conditioning temperature for a period of time. The conditioning temperature and the period are selected so that an angle of repose of the microparticles is less than about 28°. [0031]
  • To ensure clarity of the description that follows, the following definitions are provided. By “microparticles” or “microspheres” is meant solid particles that contain an active agent or other substance dispersed or dissolved within a polymer that serves as a matrix or binder of the particle. The polymer is preferably biodegradable and biocompatible. By “biodegradable” is meant a material that should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body. By “biocompatible” is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues. As used herein, “body” preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body. By “weight %” or “% by weight” is meant parts by weight per hundred parts total weight of microparticle. For example, 10 wt. % active agent would mean 10 parts active agent by weight and 90 parts polymer by weight. Unless otherwise indicated to the contrary, percentages (%) reported herein are by weight. By “controlled release microparticle” or “sustained release microparticle” is meant a microparticle from which an active agent or other type of substance is released as a function of time. By “mass median diameter” is meant the diameter at which half of the distribution (volume percent) has a larger diameter and half has a smaller diameter. [0032]
  • Methods of the Present Invention [0033]
  • The present invention provides a method to improve flowability of a microparticle product, preferably a microparticle comprised of an active agent and a biodegradable polymer. The flowability of the microparticle product is improved to allow processing in conventional hoppers and automated vial filling equipment. Without the method of the present invention, poor microparticle flow characteristics result in bridging in powder hoppers and subsequent inability to process the microparticle product in automated equipment. [0034]
  • In accordance with the present invention, a conditioning process is carried out on a finished microparticle product, such as a batch or quantity of microparticles prepared by the process disclosed and described in U.S. Pat. Nos. 5,654,008 and 5,650,173. The batch of microparticles is maintained at a conditioning temperature for a period of time. The conditioning temperature and the period are selected so that an angle of repose of the batch of microparticles is less than about 28°. This conditioning process is preferably carried out at a temperature below the T[0035] g of the polymer to avoid product agglomeration. To promote crystal growth of the active agent on the surface of the microparticle (described in detail below), the conditioning process is preferably carried out in an open container so that the microparticles may be exposed to elevated humidity or moisture vapor. However, use of an open container and exposure of the microparticles to moisture vapor may compromise the sterility and stability of the final product. Therefore, to ensure sterility and stability of the microparticles, the conditioning process is carried out in a closed container with a dry product. For example, the conditioning process may be carried out in a completely closed container, which is placed in a controlled-temperature chamber. The temperature in the chamber, and the length of time the container is in the chamber, are both controlled. Preferably, the container is rotated or inverted while it is in the chamber to provide mixing. Processing the material in a closed container preserves the sterility of the microparticle product, avoids yield losses and contamination associated with handling and product transfers, and minimizes moisture pick-up by avoiding atmospheric contact.
  • Batches of microparticles containing risperidone were prepared at the twenty-kilogram scale using the following process. The 20 Kg process (8 kg of active agent and 12 kg of polymer) provides a theoretical drug loading of the microparticles of 40% (8 kg/20 kg×100%). [0036]
  • A 16.7 wt. % polymer solution was prepared by dissolving 12 kg of MEDISORB® 7525 DL polymer (Alkermes, Inc., Blue Ash, Ohio) in ethyl acetate. A 24 wt. % drug solution was prepared by dissolving 8 kg of risperidone (Janssen Pharmaceutica, Beerse, Belgium) in benzyl alcohol. An active agent/polymer solution (organic phase) was prepared by mixing the drug solution into the polymer solution. The active agent/polymer solution was maintained at a temperature of 25±5° C. [0037]
  • The second, continuous phase was prepared by preparing a 600 liter solution of 1% PVA, the PVA acting as an emulsifier. To this was added 42 kg of ethyl acetate to form a 6.5 wt. % solution of ethyl acetate. The two phases were combined using a static mixer such as a 1″ Kenics static mixer available from Chemineer, Inc., North Andover, Mass. [0038]
  • The emulsion was transferred to a solvent extraction medium. The solvent extraction medium was 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10° C. The volume of the solvent extraction medium is 0.25 L per gram of batch size. [0039]
  • After completion of the solvent extraction step, the microparticles were collected, de-watered, and dried. The temperature was maintained at less than about 15° C. [0040]
  • The microparticles were then re-slurried in a re-slurry tank using a 25% ethanol solution. The temperature in the re-slurry tank was in the range of about 0° C. to about 15° C. The microparticles were then transferred back to the solvent extraction tank for washing with another extraction medium (25% ethanol solution) that was maintained at preferably 25°±1° C. [0041]
  • The microparticles were collected, de-watered, and dried. The temperature was warmed to greater than about 20° C. but below 40° C. [0042]
  • As will be demonstrated below, the conditioning process of the present invention, wherein the microparticles are maintained at a conditioning temperature for a period of time, improves the flowability of microparticles. Table 1 below shows the effect of the conditioning process on angle of repose for samples of risperidone microparticles prepared in the manner described above. [0043]
  • The angle of repose was measured in the following manner. A standard 100 mm Nalgene funnel was positioned in a ring stand so that the funnel discharge was at a height of approximately three inches above a level horizontal surface. Approximately 100 g of microparticles were weighed out. The microparticles were placed in the funnel, which was fitted with a stopper to block discharge. The stopper was removed, and the microparticles were allowed to flow through the funnel until all material was discharged. The discharged microparticles formed a pile having an angle of repose characteristic of the microparticles forming the pile. A [0044] pile 100 of microparticles is depicted in FIG. 1. The height of the pile (h), the diameter of the pile (d), and the width (w) where the height of the pile was measured, were all recorded. The angle of repose was calculated from the recorded dimensions in accordance with the following formula: θ r = tan - 1 ( height ( h ) width ( w ) )
    Figure US20020114843A1-20020822-M00001
  • θ[0045] r is the angle of incline at which the microparticles forming pile 100 remain at rest. Microparticles that are poor flowing have a higher angle of repose (i.e., form a taller pile with greater height (h)) than microparticles that have greater flowability. Conversely, microparticles with improved flowability have a lower angle of repose (i.e., form a shorter and wider pile with lower height (h)) than microparticles having poorer flowability.
  • Although the diameter of the pile (d) was not needed to calculate θ[0046] r, the parameter (d) provided additional qualitative information about flowability. As can be seen from FIG. 1, if (d) is not equal to twice the width (w), then a truncated cone (pointed top of cone is truncated) has been formed. It was observed that microparticles having good flowability tended to form a truncated cone, while microparticles having poorer flowability tended to form a more defined cone with (d) substantially equal to twice the width (w).
    TABLE 1
    Angle of Flow
    Sample Treatment Repose (°) Property
    (unsifted) None 38.7 Poor
    (sifted)1 None 37.5 Poor
    36.9
    (unsifted) 24 hours @ 72° F. 25.6 Good
    27.6
    (sifted)1 1 week @ 72° F. 21.3 Excellent
    23.7
  • Table 1 shows for each sample the treatment, or conditioning process, to which the sample of microparticles was subjected, the angle of repose, and an assessment of the flowability or flow property. The first two samples exhibiting poor flowability were not subjected to the conditioning process of the present invention. The angle of repose for these microparticles was greater than 35°. The sample exhibiting good flowability was maintained at a conditioning temperature of 72° F. for a period of 24 hours; the angle of repose for these microparticles was between about 25.6° and 27.6°. The flowability of the microparticles improved to excellent by maintaining the microparticles for one week at 72° F., as shown by the last sample in Table 1. The angle of repose for the last sample in Table 1 was between about 21.3° and 23.7°. [0047]
  • Another batch of risperidone microparticles was prepared in the manner described above. The effect of conditioning time on angle of repose for this batch of microparticles is shown below in Table 2. [0048]
    TABLE 2
    Days at Angle of Flow
    20-25° C. Repose (°) Property
    0 41.9 Poor
    2 24.8 Good
    3 23.2 Good
    4 23.2 Good
    5 21.8 Excellent
    6 18.4 Excellent
  • Table 2 shows the angle of repose and flow property as a function of the number of days the microparticles are maintained at a conditioning temperature in the range of 20-25° C. At zero () days, corresponding to no conditioning process, the flowability of the microparticles was poor, and the angle of repose was about 42°. As the length of the conditioning period (days at 20-25° C.) increased, the flowability of the microparticles improved. The improved flowability is characterized by a decrease in the angle of repose. Acceptable flowability for processing of the microparticles in automated filling equipment is characterized by an angle of repose in the range of from about 18° to about 28°. However, it should be understood that the present invention is not limited to angles in this range. It is preferred to have the angle of repose as low as possible below about 28°. [0049]
  • In order to more fully characterize the micrographs exhibiting improved flowability, atomic force microscopy (AFM) micrographs were prepared for microparticles prior to the conditioning process of the present invention, and for the same microparticles after carrying out the conditioning process of the present invention. In AFM, a stylus, having a tip diameter on the order of 10-20 nm and a length of about 10μ, scans across the surface of a sample while oscillating vertically or “tapping.” Deflection data of the stylus provides both geometric and compositional information about the surface of the sample. [0050]
  • AFM micrographs were prepared for samples of microparticles from the batches reported in Table 1 and another batch of risperidone microparticles prepared in the manner described above. One set of micrographs was prepared on “pre-conditioned” microparticles, i.e., prior to carrying out the conditioning process of the present invention. The pre-conditioned micrographs are presented in FIGS. 2A and 2B. The micrographs of FIGS. 2A and 2B exhibit large dark-[0051] phase patches 200 of what appear to be nanocrystalline or amorphous material.
  • Another set of micrographs was prepared on “post-conditioned” microparticles, i.e., after carrying out the conditioning process of the present invention. The post-conditioned micrographs are presented in FIGS. 3A and 3B. The micrographs of FIGS. 3A and 3B exhibit larger (up to several microns in length) and much more [0052] numerous crystals 300 than were present on the pre-conditioned micrographs of FIGS. 2A and 2B.
  • As evidenced by the pre-conditioned micrographs of FIGS. 2A and 2B, the microparticles included active agent (in this case risperidone) on the surface largely in amorphous form. As evidenced by the post-conditioned micrographs of FIGS. 3A and 3B, through the conditioning process of the present invention, the active agent on the surface of the microparticles is converted to largely crystalline form. The post-conditioned microparticles with the surface active agent in crystalline form exhibited improved flowability as discussed above. Thus, by allowing crystal growth of the active agent present on a surface of the microparticles, microparticles having improved flowability can be prepared in accordance with the present invention. [0053]
  • As evidenced by FIGS. [0054] 2A-3B, the crystal growth of risperidone on the surface of the microparticles occurred during the conditioning process of the present invention. The conditioning process was carried out at a conditioning temperature in the range of from about 20° C. to about 25° C. These temperatures are also much less than the polymer Tg (approximately 45° C.), which is preferred since it avoids the possibility of product agglomeration.
  • Preferred active agents that can be encapsulated by the process of the present invention include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles. The most preferred active agents of this kind for treatment by the process of the present invention are 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (“risperidone”) and 3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (“9-hydroxyrisperidone”) and the pharmaceutically acceptable salts thereof. Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is most preferred. Risperidone can be prepared in accordance with the teachings of U.S. Pat. No. 4,804,663, the entirety of which is incorporated herein by reference. 9-hydroxyrisperidone can be prepared in accordance with the teachings of U.S. Pat. No. 5,158,952, the entirety of which is incorporated herein by reference. [0055]
  • Preferred examples of polymer matrix materials include poly(glycolic acid), poly(d,1-lactic acid), poly(1-lactic acid), copolymers of the foregoing, and the like. Various commercially available poly(lactide-co-glycolide) materials (PLGA) may be used in the method of the present invention. For example, poly (d,1-lactic-co-glycolic acid) is commercially available from Alkermes, Inc. (Blue Ash,, Ohio). A suitable product commercially available from Alkermes, Inc. is a 50:50 poly(d,1-lactic-co-glycolic acid) known as MEDISORB® 5050 DL. This product has a mole percent composition of 50% lactide and 50% glycolide. Other suitable commercially available products are MEDISORB® 6535 DL, 7525 DL, 8515 DL and poly(d,1-lactic acid) (100 DL). Poly(lactide-co-glycolides) are also commercially available from Boehringer Ingelheim (Germany) under its Resomer® mark, e.g., PLGA 50:50 (Resomer® RG 502), PLGA 75:25 (Resomer® RG 752) and d,1-PILA (Resomer® RG 206), and from Birmingham Polymers (Birmingham, Ala.). These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid. [0056]
  • The most preferred polymer for use in the practice of the invention is the copolymer, poly(d,1-lactide-co-glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 85:15 to about 50:50. [0057]
  • The molecular weight of the polymeric matrix material is of some importance. The molecular weight should be high enough to permit the formation of satisfactory polymer coatings, i.e., the polymer should be a good film former. Usually, a satisfactory molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 daltons. However, since the properties of the film are also partially dependent on the particular polymeric matrix material being used, it is very difficult to specify an appropriate molecular weight range for all polymers. The molecular weight of the polymer is also important from the point of view of its influence upon the biodegradation rate of the polymer. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microparticles and then degrade. The drug can also be released from the microparticles as the polymeric excipient bioerodes. By an appropriate selection of polymeric materials a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in according multiphasic release patterns. [0058]
  • The formulation prepared by the process of the present invention contains an active agent dispersed in the microparticle polymeric matrix material. The amount of such agent incorporated in the microparticles usually ranges from about 1 wt. % to about 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. [0059]
  • Other biologically active agents include non-steroidal antifertility agents; parasympathomimetic agents; psychotherapeutic agents; tranquilizers; decongestants; sedative hypnotics; steroids; sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials; anti-migraine agents; anti-Parkinson agents such as L-dopa; anti-spasmodics; anticholinergic agents (e.g. oxybutynin); antitussives; bronchodilators; cardiovascular agents such as coronary vasodilators and nitroglycerin; alkaloids; analgesics; narcotics such as codeine, dihydrocodienone, meperidine, morphine and the like; non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like; opioid receptor antagonists, such as naltrexone and naloxone; antibiotics such as gentamycin, tetracycline and penicillins; anti-cancer agents; anti-convulsants; anti-emetics; antihistamines; anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like; prostaglandins and cytotoxic drugs. [0060]
  • Still other suitable active agents include estrogens, antibacterials; antifungals; antivirals; anticoagulants; anticonvulsants; antidepressants; antihistamines; and immunological agents. [0061]
  • Other examples of suitable biologically active agents include peptides and proteins, analogs, muteins, and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g. lymphokines, monokines, chemokines), blood clotting factors, hemopoietic factors, interleukins (IL-2, IL-3, IL-4, IL-6), interferons (β-IFN, α-IFN and γ-IFN), erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors (e.g., GCSF, GM-CSF, MCSF), 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); somatostatin; antigens; blood coagulation factors; growth factors (e.g., nerve growth factor, insulin-like growth factor); 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; antipyretic and analgesic 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; antiarrhythmic agents such as propranolol hydrochloride; vasodilators such as diltiazem hydrochloride and bamethan sulfate; hypotensive diuretics such as pentolinium and ecarazine hydrochloride; antidiuretic agents such as metformin; anticoagulants such as sodium citrate and heparin; hemostatic agents such as thrombin, menadione sodium bisulfite and acetomenaphthone; antituberculous agents such as isoniazide and ethanbutol; hormones such as prednisolone sodium phosphate and methimazole. [0062]
  • Conclusion [0063]
  • While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. The present invention is not limited to a particular active agent, polymer or solvent, nor is the present invention limited to a particular scale or batch size. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. [0064]

Claims (27)

What is claimed is:
1. A method for processing a quantity of microparticles, comprising:
(a) placing the quantity of microparticles into a container;
(b) maintaining the microparticles at a conditioning temperature for a period of time, wherein the conditioning temperature and the period are selected so that an angle of repose of the quantity of microparticles is less than about 28°.
2. The method of claim 1, further comprising after step (b):
(c) transferring at least a portion of the quantity of microparticles into a vial filling machine.
3. The method of claim 1, wherein the conditioning temperature is from about 20° C. to about 25° C.
4. The method of claim 3, wherein the period is at least two days.
5. The method of claim 3, wherein the period is at least five days.
6. The method of claim 1, wherein step (b) comprises:
(i) rotating the container.
7. A method for preparing microparticles having improved flowability, comprising:
(a) preparing an emulsion that comprises a first phase and a second phase, wherein the first phase comprises an active agent, a polymer, and a solvent for the polymer;
(b) extracting the solvent from the emulsion to form microparticles containing the active agent;
(c) maintaining the microparticles at a conditioning temperature for a period of time, wherein the conditioning temperature and the period are selected so that an angle of repose of the microparticles is less than about 28°.
8. The method of claim 7, wherein step (b) comprises:
(i) transferring the emulsion to a solvent extraction medium.
9. The method of claim 7, further comprising prior to step (c):
(d) washing the microparticles; and
(e) drying the microparticles.
10. The method of claim 7, wherein step (c) is carried out in a temperature-controlled chamber.
11. The method of claim 7, wherein the conditioning temperature is less than a glass transition temperature (Tg) of the polymer.
12. The method of claim 1, wherein the microparticles comprise a polymer and the conditioning temperature is less than a glass transition temperature (Tg) of the polymer.
13. The method of claim 7, wherein the conditioning temperature is from about 20° C. to about 25° C.
14. The method of claim 7, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
15. The method of claim 14, wherein the solvent comprises benzyl alcohol and ethyl acetate.
16. The method of claim 7, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,1-lactic acid, poly-1-lactic acid, and copolymers of the foregoing.
17. The method of claim 14, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,1-lactic acid, poly-1-lactic acid, and copolymers of the foregoing.
18. A method for preparing microparticles having improved flowability, comprising:
(a) preparing an emulsion that comprises a first phase and a second phase, wherein the first phase comprises an active agent, a polymer, and a solvent for the polymer;
(b) extracting the solvent from the emulsion to form microparticles containing the active agent;
(c) introducing the microparticles into a container; and
(d) maintaining the container at a conditioning temperature for a period of time, wherein the conditioning temperature and the period are selected so that an angle of repose of the microparticles is less than about 28°.
19. The method of claim 18, wherein step (d) comprises:
(i) rotating the container.
20. Microparticles having improved flowability prepared by a method, comprising:
(a) preparing an emulsion that comprises a first phase and a second phase, wherein the first phase comprises an active agent, a polymer, and a solvent for the polymer;
(b) extracting the solvent from the emulsion to form microparticles containing the active agent; and
(c) allowing crystal growth of active agent present on a surface of the microparticles.
21. The microparticles of claim 20, wherein step (c) comprises:
(i) maintaining the microparticles at a conditioning temperature for a period of time, wherein the conditioning temperature and the period are selected so that an angle of repose of the microparticles is less than about 28°.
22. The microparticles of claim 21, wherein the conditioning temperature is less than a glass transition temperature (Tg) of the polymer.
23. The method of claim 18, wherein the conditioning temperature is less than a glass transition temperature (Tg) of the polymer.
24. The microparticles of claim 21, wherein the conditioning temperature is from about 20° C. to about 25° C.
25. The microparticles of claim 20, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
26. The microparticles of claim 25, wherein the solvent comprises benzyl alcohol and ethyl acetate.
27. The microparticles of claim 20, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,1-lactic acid, poly-1-lactic acid, and copolymers of the foregoing.
US09/748,136 2000-12-27 2000-12-27 Preparation of microparticles having improved flowability Abandoned US20020114843A1 (en)

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US09/748,136 US20020114843A1 (en) 2000-12-27 2000-12-27 Preparation of microparticles having improved flowability
CA002432279A CA2432279C (en) 2000-12-27 2001-12-20 Preparation of microparticles having improved flowability
DK01991188.2T DK1345682T3 (en) 2000-12-27 2001-12-20 Preparation of microparticles with improved flowability
PT1991188T PT1345682E (en) 2000-12-27 2001-12-20 Preparation of microparticles having improved flowability
AU2002230930A AU2002230930B2 (en) 2000-12-27 2001-12-20 Preparation of microparticles having improved flowability
US10/022,859 US7247319B2 (en) 2000-12-27 2001-12-20 Preparation of microparticles having improved flowability
PCT/US2001/048711 WO2002051535A2 (en) 2000-12-27 2001-12-20 Preparation of microparticles having improved flowability
EP01991188A EP1345682B1 (en) 2000-12-27 2001-12-20 Preparation of microparticles having improved flowability
ES01991188T ES2404279T3 (en) 2000-12-27 2001-12-20 Preparation of microparticles with improved fluidity
JP2002552670A JP4248237B2 (en) 2000-12-27 2001-12-20 Preparation of fine particles with improved fluidity
US11/812,697 US20070260038A1 (en) 2000-12-27 2007-06-21 Preparation of microparticles having improved flow ability
CY20131100224T CY1113803T1 (en) 2000-12-27 2013-03-14 PREPARATION OF SMOLE PARTICLES WITH IMPROVED FLUIDITY

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US7247319B2 (en) 2007-07-24
AU2002230930B2 (en) 2006-10-12
US20070260038A1 (en) 2007-11-08
CA2432279A1 (en) 2002-07-04
EP1345682A2 (en) 2003-09-24
CY1113803T1 (en) 2016-07-27
DK1345682T3 (en) 2013-05-21
ES2404279T3 (en) 2013-05-27
WO2002051535A3 (en) 2002-10-31
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CA2432279C (en) 2010-03-09

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