US20030211164A1 - Method for preparing microparticles having a selected polymer molecular weight - Google Patents

Method for preparing microparticles having a selected polymer molecular weight Download PDF

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US20030211164A1
US20030211164A1 US10/454,617 US45461703A US2003211164A1 US 20030211164 A1 US20030211164 A1 US 20030211164A1 US 45461703 A US45461703 A US 45461703A US 2003211164 A1 US2003211164 A1 US 2003211164A1
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microparticles
polymer
molecular weight
phase
solution
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Steven Wright
Michael Rickey
J. Ramstack
Shawn Lyons
Joyce Hotz
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Alkermes Controlled Therapeutics Inc II
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647Polyesters, e.g. poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02Making microcapsules or microballoons

Definitions

  • the present invention relates to preparation of microparticles. More particularly, the present invention relates to a method and an apparatus for preparing microparticles having a selected polymer molecular weight.
  • a variety of methods is 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.
  • a biocompatible, biodegradable wall forming material e.g., a polymer
  • the material to be encapsulated is generally dissolved, dispersed or emulsified, using stirrers, agitators, or other dynamic mixing techniques, in one or more solvents containing the wall forming material. Solvent is then removed from the microparticles and thereafter the microparticle product is obtained.
  • One variable that affects the in vitro and in vivo performance of the microparticle product is the molecular weight of the polymer or polymeric matrix material in the final microparticle product.
  • Molecular weight affects drug release characteristics.
  • the molecular weight of a polymer influences the biodegradation rate of the polymer.
  • the polymer should remain intact until all of the active agent is released from the microparticles, and then degrade.
  • the active agent can also be released from the microparticles as the polymeric matrix material bioerodes.
  • a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in affording multiphasic release patterns.
  • the results reported in the Maulding article reveal that the degradation rate of DL-PL in ketotifen free base microcapsules was greater when the encapsulation process was carried out at 4° C. than it was when the encapsulation process was carried out at 25° C.
  • the degradation rate of DL-PL in thioridazine free base microcapsules was greater when the encapsulation process was carried out at 23° C. than it was when the encapsulation process is carried out at 4° C. Based on these results, the Maulding article suggests circumventing the polymer degradation by carrying out the preparation of microcapsules at 4° C. in the case of thioridazine base.
  • the Maulding article does not provide a method by which the molecular weight of the polymer in the finished microparticle can be conveniently controlled. Nor does the Maulding article provide a method for preparing microparticles that have a selected polymer molecular weight in the finished microparticle product.
  • the present invention relates to a method for preparing microparticles.
  • the present invention allows microparticle products of varying polymer molecular weights to be produced using the same molecular weight starting material.
  • the present invention also allows microparticle products with substantially the same polymer molecular weight to be produced from starting materials of varying molecular weight.
  • a method of preparing microparticles having a selected microparticle polymer molecular weight is provided. The method comprises:
  • step (d) maintaining the first phase as a hold temperature for a hold period prior to step (b), the hold period of sufficient duration to allow the starting molecular weight of the polymer to reduce so that the selected microparticle polymer molecular weight is achieved.
  • microparticle in a further aspect of the present invention, another method for preparing microparticle is provided.
  • the method comprises:
  • step (e) maintaining the first phase at a hold temperature for a hold period prior to step (c), wherein the hold period is selected so that the starting molecular weight reduces so that a selected microparticle polymer molecular weight is achieved.
  • the foregoing methods comprise adding an active agent to the first phase. In yet further aspects of the present invention, the foregoing methods comprise adding an inactive agent to the first phase.
  • the hold temperature is increased, thereby increasing the molecular weight decay of the polymer to reduce the duration or the hold period.
  • the hold temperature can be decreased, thereby decreasing the molecular weight decay of the polymer to increase the duration of the hold period.
  • microencapsulated active agent and microparticles prepared by the methods of the present invention.
  • microparticles including microparticles containing an active agent.
  • An advantage of the present invention is that a selected polymer molecular weight can be achieved in the microparticle product by using a variety of polymers, having varying starting molecular weights, by varying the hold time of the nucleophilic compound/polymer solution.
  • a further advantage of the present invention is that microparticle products of varying polymer molecular weights can be produced using the same starting polymer, or using a polymer having the same starting molecular weight.
  • FIG. 1 depicts a graph of molecular weight loss percentage as a function or solution hold time (hours) at a 1 kg scale
  • FIG. 2 depicts a graph of molecular weight loss percentage as a function of solution hold time (hours) at a 20 kg scale
  • FIG. 3 depicts a graph of molecular weight (kD) as a function of solution hold time (hours) at 15° C., 25° C., and 35° C.;
  • FIG. 4 shows one embodiment of an equipment configuration suitable for preparing microparticles in accordance with the present invention.
  • the present invention provides an improved method for preparing microparticles.
  • the methods of the present invention control the hold time and temperature of a polymer solution in order to control the molecular weight of the polymer in the finished microparticle product.
  • the methods of the present invention advantageously allow a selected polymer molecular weight to be achieved from a variety of starting material molecular weights.
  • microparticle products of varying polymer molecular weights can be produced using the same molecular weight starting material.
  • a range of products can be made from the same starting materials, thereby eliminating the need to reformulate the finished product to achieve the desired molecular weight of the polymer in the finished product.
  • the polymer solution used in the present invention comprises a nucleophilic compound.
  • nucleophilic compound refers to a compound that promotes by nucleophilic catalysis the ester hydrolysis, such as the polymer scission, that occurs in the biodegradion of biodegradable polymers, such as polymers comprising varying lacotide:glycolide ratio.
  • a nucleophilic compound is a more effective nucleophilic toward an ester group of the polymer than hydroxide ion or water.
  • Nucleophilic compound that catalyze the polymer hydrolysis include, but are not limited to, amines and carboxylate anions, and can be “active agents” (defined below or “inactive agents” that are not active agents.
  • nucleophilic compounds that are active agents include, but are not limited to, risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing, naltrexone, and oxybutynin.
  • nucleophilic compounds that are inactive agents include, but are not limited to, protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine. It should be readily apparent to be one skilled in the art that the present invention is not limited to any particular nucleophilic compound, and that the present invention encompasses other nucleophilic active agents and nucleophilic inactive agents.
  • microparticles or “microspheres” is meant particles that comprise a polymer that serves as a matrix or binder of the particle.
  • the microparticle may contain an active agent or other substance dispersed or dissolved within the polymeric matrix.
  • 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 refer 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 total weight of microparticle.
  • 10 wt. % active agent would mean 10 parts active agent by weight and 90 parts polymer 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.
  • active agent is meant an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically and pharmacologically active substance that produces a localized or systemic effect in a patient.
  • Such active agents include antibiotics, antiviral agents, anepileptics, analgesics, anti-asthmatics, anti-inflammatory agents and bronchodilator, and may be inorganic and organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system.
  • Suitable agents may be selected from, for example, polysaccharides, steroids, hypnotics and sedatives, tranquilizers, anticonvulsants, muscle relaxants, antiParkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympatomimetics, polypeptides and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, leukotriene antagonists, antiparasites, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, ophthalmics, antienteritis agents, electrolytes and diagnostic agents.
  • a 16.7 wt. % polymer solution was prepared by dissolving 600 grams of MEDISORB® 7525 DL polymer (Alkermes Inc., Blue Ash, Ohio) in ethyl acetate.
  • a 24 wt. % drug solution was prepared by dissolving 400 grams of risperidone (basic nucleophilic active agent) (Janssen Pharmaceutica, Beerse, Belgium) in benzyl alcohol.
  • a nucleophilic 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 active agent/polymer solution is held for a hold time of sufficient duration to achieve the selected or desired polymer molecular weight in the finished microparticle product, based on the starting molecular weight or the polymer.
  • the results of the experiments, showing the effect of hold time on molecular weight loss, are discussed in more detail below with respect to Table 1 and FIG. 1.
  • the second, continuous phase was prepared by preparing a 30 liter solution of 1% polyvinyl alcohol (PVA), the PVA acting as an emulsifier. To this was added 2086 grams of ethyl acetate to form a 6.5 wt. % solution of ethyl acetate.
  • PVA polyvinyl alcohol
  • the two phases were combined using a static mixer, such as a 1 ⁇ 2′′ Kenics static mixer available from Chemineer, Inc., North Andover, Mass.
  • a total flow rate of 3 L/min generally provides microparticle size distributions with a mass median diameter (MMD) in the range of about 80-90 ⁇ .
  • MMD mass median diameter
  • the ratio of continuous phase to discontinuous phase was 5:1 (v/v).
  • the quench liquid was 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10° C.
  • the volume of the quench liquid is 0.25L per gram of batch size.
  • the quenchstep was carried out for a time period greater than about 4 hours, with stirring of the microparticles in the quench tank.
  • 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 quench tank for washing for a time period of at least 6 hours 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. Drying continued for a time period greater than about 16 hours.
  • FIG. 1 shows an initial loss in molecular weight of approximately 17%, with an additional loss of approximately 5.7% per hour of hold time of the active agent/polymer solution.
  • a 16.7 wt. % polymer solution was prepared by dissolving 12 kg or 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.
  • a nucleophilic 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 active agent/polymer solution is held for a hold time of sufficient duration to achieve the selected or desired polymer molecular weight in the finished microparticle product, based on the starting molecular weight of the polymer.
  • the results of the experiments, showing the effect of hold time on molecular weight loss, are discussed in more detail below with respect to Table 2 and FIG. 2.
  • the second, continuous phase was prepared by preparing a 600 liter solution or 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 quench liquid was 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10° C.
  • the volume of the quench liquid is 0.25L per gram of batch size.
  • the quench step was carried out for a time period greater than about 4 hours, with stirring of the microparticles in the quench tank.
  • 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 quench tank for washing for a time period of at least 6 hours 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. Drying continued for a time period greater than about 16 hours.
  • the starting molecular weight of the polymer (kD) and the final molecular weight of the polymer in a finished microparticle product (kD) was determined for microparticles containing the nucleophilic compound naltrexone.
  • the starting polymer lactide:glycolide ratio was 75:25, 85:15, and 65:35.
  • the polymers used were MEDISORB® 7525 DL polymer, MEDISORB® 8515 DL polymer and MEDISORB® 6535 DL polymer, all available from Alkermes, Inc., Blue Ash, Ohio.
  • the naltrexone base microparticles were produced using a co-solvent extraction process.
  • the theoretical batch size was 15 to 20 grams.
  • the polymer was dissolved in ethyl acetate to produce a 16.7% w/w polymer solution.
  • the naltrexone base anhydrous was dissolved in benzyl alcohol to produce a 30.0% w/w solution.
  • the amount of drug and polymer used was varied to produce microparticles with different theoretical drug loading ranging from 30% to 71%.
  • the ambient polymer and drug solutions were mixed together until a single homogeneous solution (organic phase) was produced.
  • the aqueous phase was at ambient conditions and contained 1% w/w polyvinyl alcohol and a saturating amount of ethyl acetate. These two solutions were pumped via positive displacement pumps at a ratio of 3:1 (aqueous:organic) through a 1 ⁇ 4′′ in-line mixer to form an emulsion.
  • the emulsion was transferred to a stirring solvent extraction solution consisting of 2.5% w/w of ethyl acetate dissolved in distilled water at 5-10° C. and at a volume of 0.5L of extraction solution per theoretical gram of microparticles. Both the polymer and drug solvents were extracted into the extraction solution from the emulsion droplet to produce microparticles.
  • the initial extraction process ranged from two to four hours.
  • microparticles were collected on a 25 ⁇ m sieve and rinsed with a cold ( ⁇ 5° C.) 25% w/w ethanol solution.
  • the microparticles were dried cold overnight (approximately 17 hours) using nitrogen.
  • the microparticles were then transferred to the reslurry solution, which consisted of a vigorously stirring 25% w/w ethanol solution at 5-10° C. After a short mixing time (five to fifteen minutes), the reslurry solution and the microparticles were transferred to a stirring 25% w/w ethanol secondary extraction solution (approximately 25° C. at a volume of 0.2 L of secondary extraction solution per theoretical gram of microparticles).
  • microparticles stirred for six hours enabling additional solvent removal from the microparticles to take place.
  • the microparticles were then collected on a 25 ⁇ m sieve and used with a 25% w/w ethanol solution at ambient temperature. These microparticles dried in a hood under ambient conditions overnight (approximately 17 hours), were sieved to remove agglomerated microparticles and then placed into a freezer for storage.
  • Table 3 shows the starting molecular weight of the polymer (kD), and the final molecular weight of the polymer in the finished microparticle products (kD), and the percent loss in molecular weight of the polymer.
  • the molecular weight of the polymer in the finished microparticle product was determined by GPC.
  • the data in Table 3 provides an example of the low in molecular weight of the polymer in a finished microparticle product containing a nucleophilic compound (naltrexone) for polymers having varying lactide:glycolide ratios.
  • Microparticles comprising other polymers having different lactide:glycolide ratios were prepared.
  • Microparticles comprising risperidone using polymers having lactide:glycolide ratios of 65:35, 85:15, and 100:0 were prepared at the 1 Kg scale using the same process described above in Example 1.
  • the polymers used were MEDISORB® 6535 DL polymer, MEDISORB® 8515 DL polymer, and MEDISORB® 100 DL polymer, all available from Alkermes, Inc., Blue Ash, Ohio.
  • Table 4 shows, for each polymer, the starting molecular weight of the polymer (kD), the final molecular weight of the polymer in the finished microparticle product (kD), the percent toss in molecular weight of the polymer, and the hold time (hours) of the active agent/polymer solution.
  • the molecular weight of the polymer in the finished microparticle product was determined by GPC.
  • TABLE 4 Lactide:glycolide Starting Mw Final Mw Hold Time ratio kD kD % Loss hours 65:35 105 79 24.8 0.27 85:15 112 96 14.3 0.23 100 dl 105 98 6.7 0.17
  • microparticle product having about the same molecular weight (96 kD and 98 kD) can be prepared from two different molecular weight polymers (112 kD and 105 kD, respectively) having two different lactide:glycolide ratios (85:15 and 100:0, respectively).
  • the present invention thus advantageously allows microparticle products with the same polymer molecular weight to be produced using two different starting materials.
  • a flask of the combined solution was placed in each of a 15° C., 25° C., and 35° C. chamber.
  • 10 cc of the combined solution was withdrawn from the flask in each chamber via a syringe and needle.
  • the 10 cc sample was then precipitated in a bath containing 200 ml methanol at room temperature (approximately 20° C.).
  • the polymeric precipitate was recovered from the methanol bath, and vacuum dried overnight. The dried samples were tested for their molecular weight by GPC.
  • the results of the experiments are depicted in the graph of FIG. 3.
  • the molecular weight decay increases as temperature increases. Therefore, by increasing the hold temperature of the solution containing the polymer and the nucleophilic compound, the molecular weight decay of the polymer increases, and the duration of the hold period to achieve a particular molecular weight function is reduced.
  • the molecular weight decay of the polymer decreases, and the duration of the hold period to achieve a particular molecular weight reduction is increased.
  • the time required to reduce the molecular weight form 130 kD to 110 kD is the shortest at 35° C. (about 5 hours) and the longest at 15° C. (about 15 hours).
  • FIG. 3 shows an initial increase in polymer molecular weight. This phenomenon is most likely occurring because some portion of the polymer, particularly the lower molecular weight fractions is soluble in the extraction medium. Because the analytical measurement of molecular weight is a representation of all the molecular weight fractions present, removing (dissolving) the low molecular weight material can increase the measured molecular weight.
  • a first phase comprising a nucleophilic compound, a polymer having a starting molecular weight, and a solvent for the polymer is prepared.
  • the first phase is prepared by dissolving a nucleophilic active agent in a first solvent to form an active agent solution.
  • the polymer is dissolved in a second solvent to form a polymer solution.
  • the active agent solution and the polymer solution are blended to form the first phase.
  • the active agent is selected from the group consisting of risperidone, 9-hydroxyrispridone, and pharmaceutically acceptable salts thereof.
  • a preferred first solvent is benzyl alcohol
  • a preferred second solvent is ethyl acetate.
  • the first phase is prepared by dissolving the nucleophilic compound and the polymer in a solvent to form a solution.
  • an active agent is added to the first phase.
  • an inactive agent is added to the first phase.
  • a second phase is prepared, and combined with the first phase under the influence of mixing means to form an emulsion.
  • a static mixer is used to combine the two phases to form an emulsion.
  • a process for forming an emulsion using a static mixer is described for example, in U.S. Pat. No. 5,654,008, the entirety of which is incorporated herein by reference.
  • the emulsion is combined with an extraction medium that extracts solvent from the emulsion droplets, thereby hardening them into microparticles.
  • the first phase Prior to combining the first and second phases, the first phase is maintained at a hold temperature for a hold period.
  • the hold period is of sufficient duration to allow the starting molecular weight of the polymer to reduce to the select microparticle polymer molecular weight at the hold temperature.
  • the starting molecular weight of the polymer reduces by about 10% to about 30% to reach the selected polymer molecular weight.
  • the present invention is not limited to such a percentage reduction.
  • the first phase may be mixed, stirred, or otherwise agitated. Alternatively, during the hold period, the first phase may be subjected to no mixing, stirring, or agitation.
  • the hold temperature is preferably in the range of from about 15° C. to about 35° C., more preferably about 25° C.
  • a polymer having a starting molecular weight and a nucleophilic compound are dissolved in a solvent to form a first phase.
  • An active agent and/or an inactive agent can be added to the first phase.
  • the first phase is combined with a second phase under the influence of mixing means to form an emulsion.
  • the emulsion is combined with an extraction medium that extracts solvent, thereby hardening the emulsion droplets into microparticles.
  • the first phase Prior to combining the first and second phases, the first phase is maintained at a hold temperature for a hold period.
  • the hold period is selected so that the starting molecular weight of the polymer reduces to a selected microparticle polymer molecular weight at the hold temperature.
  • the duration of the hold period can be adjusted by changing the hold temperature in a manner as described above.
  • the microparticles prepared by the process of the present invention preferably comprise a polymeric binder.
  • suitable polymeric binder materials include poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and polyphosphazines.
  • Poly (d,l-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,l-lactic-co-glycolic acid) known as MEDISORB® 5050 DL. This product has a mole percent composition of 50% lactide and 50% glycolid.
  • Other suitable commercially available products are MEDISORB® 6535 DL, 7525 DL, 8515 DL and poly(d,l-lactic acid) (100 DL).
  • Poly(lactide-co-glycolides) are also commercially available from Boebringer Ingelheim (Germany) under its Resomer® mark, e.g. PLGA 50:50 (Resomer® RG 502).
  • PLGA 75:25 (Resomer® RG 752) and d,l-PLA (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.
  • microparticle suitable for preparation by the present invention is a sustained-release microparticle that is biodegradable.
  • the present invention is not limited to biodegradable or other types of sustained-release microparticles.
  • the molecular weight of the polymeric binder material for biodegradable microparticles 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. However, since the properties of the film are also partially dependent on the particular polymeric binder 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.
  • 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 binder 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.
  • a satisfactory starting molecular weight of the polymer is in the range of 5-500 kD, preferably in the range of from about 50 kD to about 250 kD.
  • the microparticle polymer molecular weight is preferably in the range of from about 10 kD to about 185 kD.
  • the microparticles prepared in accordance with the present invention may include an active agent or other type of substance that is released from the microparticles into the host.
  • an active agent can be a nucleophilic compound.
  • the active agent is not a nucleophilic compound and is added to the microparticles during the formation process.
  • Such active agents can include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothazoles.
  • the most preferred active agents of this kind 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-fluoro-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-hydroxyrispendone 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.
  • 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-migrain agents; anti-Parkinson agents such as L-dopa; anti-spasmodics; anticholinergic agents (e.g.
  • oxybutynin antitussives
  • bronchodilators cardiovacular agents such as coronary vasodilators and nitroglycerin
  • alkaloids analgesics
  • narcotics such as cocaine 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-caner agents anti-convulsants
  • anti-emetics antihistamines
  • anti-inflammatorty agents such as hormonal agents, hydrocortisone, prednisdone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like
  • 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, anlogs, muteins, and active fragments thereof, such as immoglobulins, 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 factor (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., tumoralpha-1 (IL-2
  • 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 hydrochlonde and codeine phosphate; sedatives such as chlorpromazine hydrochloride, prochlorperazine hydrochloride and atropine sulfate; muscle relaxants such as tubocurarine chloride, antiepilepics such as sodium phenytoin and ethosuximide; antiulcer agents such as metoclopramide; antidepressants such as clomipramine;
  • microparticles can be mixed by size or by type. However, it should be understood that the present invention is not limited to the use of biodegradable or other types of microparticles that contain an active agent.
  • the microparticles are mixed in a manner that provides for the delivery of active agent to the host in a multiphasic manner and/or on a manner that provides different active agents to the host at different times, or a mixture of active agents at the same time.
  • secondary antibiotics, vaccines, or any desired active agent either in microparticle form or in conventional, unencapsulated form can be blended with a primary active agent and provided to the host.
  • FIG. 4 one embodiment is shown of an equipment configuration suitable for use in preparing microparticles in accordance with the present invention.
  • the equipment contained within the dotted line boundary shown generally at 270 is sterilized using a “steam-in-place” (SIP) process.
  • SIP steam-in-place
  • a first phase 201 is provided.
  • First phase 201 is preferably the discontinuous phase, comprising a polymer dissolved in one or more solvents, and an active agent.
  • the active agent can be dissolved or dispersed in the same or a different solvent than the solvent(s) in which the polymer is dissolved.
  • a second phase 202 is preferably the continuous phase, preferably comprising water as the continuous processing medium.
  • an emulsifying agent such as a surfactant or a hydrophilic colloid is added to the continuous phase to prevent the microdroplets from agglomerating and to control the size of the microdroplets in the emulsion.
  • Examples of compounds that can be used as surfactants or hydrophilic colloids include but are not limited to, poly(vinyl alcohol) (PVA), carboxymethyl cellulose, gelatin, poly(vinyl pyrrolidone), Tween 80, Tween 20, and the like.
  • concentration of surfactant or hydrophilic colloid in the continuous phase will be from about 0.% to about 10% by weight based on the continuous processing medium, depending upon the surfactant, hydrophilic colloid, the discontinuous phase, and the continuous processing medium used.
  • a preferred continuous phase is 0.1 to 10 wt. %, more preferably 0.5 to 2 wt %, solution of PVA in water. Although not absolutely necessary, it is preferred to saturate the continuous phase with at least one of the solvents forming the discontinuous phase.
  • First phase 201 and second phase 202 are combined under the influence of mixing means to form an emulsion.
  • a preferred type of mixing means is a static mixer 210 .
  • Other mixing suitable for use with the present invention include, but are not limited to, devices for mechanically agitating the first and second phases, such as homogenizers, propellers, impellers, stirrers, and the like.
  • the discontinuous and continuous phases 201 and 202 are pumped through static mixer 210 to form an emulsion, and into a large volume of quench liquid, to obtain microparticles containing the active agent encapsulated in the polymeric matrix material.
  • a pump 203 pumps first phase 201 into static mixer 210
  • a pump 204 pumps second phase 202 into static mixer 210 .
  • First and second phases 201 and 202 are mixed in static mixer 210 to form an emulsion.
  • the emulsion formed comprises microparticles containing active agent encapsulated in the polymeric matrix material.
  • the microparticles are then preferably stirred in a quench or extraction tank 220 containing a quench liquid in order to remove most of the solvent from the microparticles, resulting in the formation of hardened microparticles.
  • the continuous processing medium is diluted, and much of the solvent in the microparticles is removed by extraction.
  • the microparticles can be suspended in the same continuous phase (second phase 202 ) used during emulsification, with or without hydrophilic colloid or surfactant, or in another quench liquid.
  • the quench liquid removes a significant portion of the solvent from the microparticles, but does not dissolve them.
  • the quench liquid containing dissolved solvent can, optionally, be removed and replaced with fresh quench liquid.
  • the microparticles are transferred by a pump 224 to a device 230 that functions as a microparticle collecting device, de-watering device, and drying device.
  • Device 230 comprises a vibrating sieve or screen.
  • the vibration causes smaller particles and liquid to drop through the screen, while larger particles are retained.
  • the smaller particles and liquid that drop through the screen are removed as waste 235 .
  • Device 230 also functions as a vacuum dryer, through the use of a vacuum line 237 .
  • the microparticles are are fluidized by the vibrational energy, and by a small amount of a dry gas bleed, preferably a dry nitrogen (N 2 ) bleed 236 .
  • the dried microparticles are transferred to another extraction medium to carry out a wash step.
  • the wash step is preferably carried out in quench tank 220 , using an extraction medium 222 having a temperature higher than the glass transition temperature (T g ) of the microparticles.
  • T g glass transition temperature
  • the microparticles are first introduced into a re-slurry tank or other type of vessel 240 , as shown by path 231 .
  • the temperature of the extraction medium 242 that is used in vessel 240 is lower than the T g of the microparticles.
  • the microparticles are again transferred via pump 224 into device 230 for de-watering and final drying.
  • the microparticles are discharged from device 230 in the manner described above into a sifter 250 , as shown by path 232 .
  • Sifter 250 is used to fractionate the microparticles by size for filling into vials and for bulk in-process testing (e.g, aspect, active agent content, residual solvents, in vitro release, and particle size distribution.

Abstract

A method for preparing microparticles having a selected polymer molecular weight. The hold time and temperature of a solution containing a nucleophilic compound and a polymer having a starting molecular weight are controlled in order to control the molecular weight of the polymer in the finished microparticle product. In this manner, a selected polymer molecular weight in the finished microparticle product can be achieved from a variety of starting material molecular weights.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • The present invention relates to preparation of microparticles. More particularly, the present invention relates to a method and an apparatus for preparing microparticles having a selected polymer molecular weight. [0002]
  • 2. Related Art [0003]
  • A variety of methods is 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, using stirrers, agitators, or other dynamic mixing techniques, in one or more solvents containing the wall forming material. Solvent is then removed from the microparticles and thereafter the microparticle product is obtained. [0004]
  • One variable that affects the in vitro and in vivo performance of the microparticle product is the molecular weight of the polymer or polymeric matrix material in the final microparticle product. Molecular weight affects drug release characteristics. The molecular weight of a polymer influences the biodegradation rate of the polymer. For a diffusional mechanism of active agent release, the polymer should remain intact until all of the active agent is released from the microparticles, and then degrade. The active agent can also be released from the microparticles as the polymeric matrix material 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 affording multiphasic release patterns. [0005]
  • It has been reported that the molecular weight of the poly(D,L-lactide) (“DL-PL”) component of microcapsules containing up to 50% thioridazine free base decreased during fabrication, and in dissolution rate studies of the microcapsule (see Maulding, H. V. et al., Biodegradable Microcapsules: “Acceleration of Polymeric Excipient Hydrolytic Rate by Incorporation of a Basic Medicament”, Journal of Controlled Release, [0006] Volume 3, 1986, pages 103-117; hereinafter “the Maulding article”). The results reported in the Maulding article reveal that the degradation rate of DL-PL in ketotifen free base microcapsules was greater when the encapsulation process was carried out at 4° C. than it was when the encapsulation process was carried out at 25° C. In contrast, the degradation rate of DL-PL in thioridazine free base microcapsules was greater when the encapsulation process was carried out at 23° C. than it was when the encapsulation process is carried out at 4° C. Based on these results, the Maulding article suggests circumventing the polymer degradation by carrying out the preparation of microcapsules at 4° C. in the case of thioridazine base. The Maulding article does not provide a method by which the molecular weight of the polymer in the finished microparticle can be conveniently controlled. Nor does the Maulding article provide a method for preparing microparticles that have a selected polymer molecular weight in the finished microparticle product.
  • Thus, there is a need in the art for an improved method for preparing microparticles that controls the molecular weight of the polymer or polymeric matrix material in the finished microparticle product. There is a particular need in the art for an improved process that provides a method for preparing microparticles that have a selected polymer molecular weight. The present invention, the description of which is fully set forth below, solves the need in the art for such an improved method. [0007]
  • SUMMARY OF THE INVENTION
  • The present invention relates to a method for preparing microparticles. The present invention allows microparticle products of varying polymer molecular weights to be produced using the same molecular weight starting material. The present invention also allows microparticle products with substantially the same polymer molecular weight to be produced from starting materials of varying molecular weight. In one aspect of the invention, a method of preparing microparticles having a selected microparticle polymer molecular weight is provided. The method comprises: [0008]
  • (a) preparing a first phase, the first phase comprising a nucleophilic compound, a polymer having a starting molecular weight, and a solvent for the polymer; [0009]
  • (b) combining the first phase with a second phase under the influence of mixing means to form an emulsion; [0010]
  • (c) combining the emulsion and an extraction medium, thereby forming microparticles; and [0011]
  • (d) maintaining the first phase as a hold temperature for a hold period prior to step (b), the hold period of sufficient duration to allow the starting molecular weight of the polymer to reduce so that the selected microparticle polymer molecular weight is achieved. [0012]
  • In a further aspect of the present invention, another method for preparing microparticle is provided. The method comprises: [0013]
  • (a) providing a polymer having a starting molecular weight; [0014]
  • (b) dissolving the polymer and a nucleophilic compound in a solvent to form a first phase; [0015]
  • (c) combining the first phase with a second phase under the influence of mixing means to form an emulsion; [0016]
  • (d) combining the emulsion and an extraction medium, thereby forming microparticles; and [0017]
  • (e) maintaining the first phase at a hold temperature for a hold period prior to step (c), wherein the hold period is selected so that the starting molecular weight reduces so that a selected microparticle polymer molecular weight is achieved. [0018]
  • In other aspects of the present invention, the foregoing methods comprise adding an active agent to the first phase. In yet further aspects of the present invention, the foregoing methods comprise adding an inactive agent to the first phase. [0019]
  • In further aspects of the invention, the hold temperature is increased, thereby increasing the molecular weight decay of the polymer to reduce the duration or the hold period. The hold temperature can be decreased, thereby decreasing the molecular weight decay of the polymer to increase the duration of the hold period. [0020]
  • Other aspects of the present invention include a microencapsulated active agent and microparticles prepared by the methods of the present invention. [0021]
  • Features and Advantages [0022]
  • It is a feature of the present invention that it can be used to prepare microparticles, including microparticles containing an active agent. [0023]
  • It is a further feature of the present invention that it allows the hold time and temperature of a nucleophilic compound/polymer solution to be modified to achieve a selected polymer molecular weight in the microparticle product. [0024]
  • An advantage of the present invention is that a selected polymer molecular weight can be achieved in the microparticle product by using a variety of polymers, having varying starting molecular weights, by varying the hold time of the nucleophilic compound/polymer solution. [0025]
  • A further advantage of the present invention is that microparticle products of varying polymer molecular weights can be produced using the same starting polymer, or using a polymer having the same starting molecular weight.[0026]
  • 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. [0027]
  • FIG. 1 depicts a graph of molecular weight loss percentage as a function or solution hold time (hours) at a 1 kg scale; [0028]
  • FIG. 2 depicts a graph of molecular weight loss percentage as a function of solution hold time (hours) at a 20 kg scale; [0029]
  • FIG. 3 depicts a graph of molecular weight (kD) as a function of solution hold time (hours) at 15° C., 25° C., and 35° C.; and [0030]
  • FIG. 4 shows one embodiment of an equipment configuration suitable for preparing microparticles in accordance with the present invention.[0031]
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • Overview [0032]
  • The present invention provides an improved method for preparing microparticles. The methods of the present invention control the hold time and temperature of a polymer solution in order to control the molecular weight of the polymer in the finished microparticle product. In this manner, the methods of the present invention advantageously allow a selected polymer molecular weight to be achieved from a variety of starting material molecular weights. Alternatively, microparticle products of varying polymer molecular weights can be produced using the same molecular weight starting material. Thus, a range of products can be made from the same starting materials, thereby eliminating the need to reformulate the finished product to achieve the desired molecular weight of the polymer in the finished product. [0033]
  • The polymer solution used in the present invention comprises a nucleophilic compound. As used herein, “nucleophilic compound” refers to a compound that promotes by nucleophilic catalysis the ester hydrolysis, such as the polymer scission, that occurs in the biodegradion of biodegradable polymers, such as polymers comprising varying lacotide:glycolide ratio. A nucleophilic compound is a more effective nucleophilic toward an ester group of the polymer than hydroxide ion or water. Nucleophilic compound that catalyze the polymer hydrolysis include, but are not limited to, amines and carboxylate anions, and can be “active agents” (defined below or “inactive agents” that are not active agents. Examples of nucleophilic compounds that are active agents include, but are not limited to, risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing, naltrexone, and oxybutynin. Examples of nucleophilic compounds that are inactive agents include, but are not limited to, protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine. It should be readily apparent to be one skilled in the art that the present invention is not limited to any particular nucleophilic compound, and that the present invention encompasses other nucleophilic active agents and nucleophilic inactive agents. [0034]
  • To ensure clarity of the description that follows, the following definitions are provided. By “microparticles” or “microspheres” is meant particles that comprise a polymer that serves as a matrix or binder of the particle. The microparticle may contain an active agent or other substance dispersed or dissolved within the polymeric matrix. 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 refer 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 total weight of microparticle. For example, 10 wt. % active agent would mean 10 parts active agent by weight and 90 parts polymer 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. [0035]
  • By “active agent” is meant an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically and pharmacologically active substance that produces a localized or systemic effect in a patient. Such active agents include antibiotics, antiviral agents, anepileptics, analgesics, anti-asthmatics, anti-inflammatory agents and bronchodilator, and may be inorganic and organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, polysaccharides, steroids, hypnotics and sedatives, tranquilizers, anticonvulsants, muscle relaxants, antiParkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympatomimetics, polypeptides and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, leukotriene antagonists, antiparasites, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, ophthalmics, antienteritis agents, electrolytes and diagnostic agents. [0036]
  • Methods and Examples [0037]
  • The following exanples are provided to explain the invention, and to describe the materials and methods used in carrying out the invention. The examples are not intended to limit the invention in any manner. [0038]
  • Molecular Weight Experiments with Nucleophilic Compounds [0039]
  • EXAMPLE 1
  • A series of experiments were conducted at the 1 kg scale that demonstrate the relationship between molecular weight of the finished microparticle product, and the duration of a hold period of a nucleophilic compound/polymer solution. Microparticles comprising risperidone were prepared at the one-kilogram scale. The 1 Kg process (400 grams of active agent and 600 grams of polymer) provides a theoretical drug loading of the microparticles of 40% (400 grams/1000 grams×100%). [0040]
  • A 16.7 wt. % polymer solution was prepared by dissolving 600 grams of MEDISORB® 7525 DL polymer (Alkermes Inc., Blue Ash, Ohio) in ethyl acetate. A 24 wt. % drug solution was prepared by dissolving 400 grams of risperidone (basic nucleophilic active agent) (Janssen Pharmaceutica, Beerse, Belgium) in benzyl alcohol. A nucleophilic 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 active agent/polymer solution is held for a hold time of sufficient duration to achieve the selected or desired polymer molecular weight in the finished microparticle product, based on the starting molecular weight or the polymer. The results of the experiments, showing the effect of hold time on molecular weight loss, are discussed in more detail below with respect to Table 1 and FIG. 1. [0041]
  • The second, continuous phase was prepared by preparing a 30 liter solution of 1% polyvinyl alcohol (PVA), the PVA acting as an emulsifier. To this was added 2086 grams of ethyl acetate to form a 6.5 wt. % solution of ethyl acetate. [0042]
  • The two phases were combined using a static mixer, such as a ½″ Kenics static mixer available from Chemineer, Inc., North Andover, Mass. A total flow rate of 3 L/min generally provides microparticle size distributions with a mass median diameter (MMD) in the range of about 80-90μ. The ratio of continuous phase to discontinuous phase was 5:1 (v/v). [0043]
  • The quench liquid was 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10° C. The volume of the quench liquid is 0.25L per gram of batch size. The quenchstep was carried out for a time period greater than about 4 hours, with stirring of the microparticles in the quench tank. [0044]
  • After completion of the quench step, the microparticles were collected, de-watered, and dried. The temperature was maintained at less than about 15° C. [0045]
  • 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 quench tank for washing for a time period of at least 6 hours with another extraction medium (25% ethanol solution) that was maintained at preferably 25±1° C. [0046]
  • The microparticles were collected, de-watered and dried. The temperature was warmed to greater than about 20° C. but below 40° C. Drying continued for a time period greater than about 16 hours. [0047]
  • Twenty-four batches of risperidone microparticles at the 1 kg scale were prepared using the process described above. Table 1 below shows, for each batch, the starting molecular weight of the polymer (kD), the final molecular weight of the polymer in the finished microparticle product (kD), the percent loss in molecular weight of the polymer, and the hold time (hours) of the active agent/polymer solution. The molecular weight of the polymer in the finished microparticle product was determined by GPC. [0048]
    TABLE 1
    Starting Mw Final Mw Hold time
    Batch# kD kD % Loss Hours
    825 230 182 21.0 0.10
    708 161 110 32.0 2.08
    714 161 133 17.3 0.33
    812 161 100 37.9 2.40
    819 161 102 36.7 2.47
    319 131 110 16.2 0.10
    331 131 115 12.2 0.07
    423 131 78 40.7 2.85
    506 129 112 13.6 0.02
    512 129 86 33.7 3.10
    520 129 92 29.1 3.07
    527 129 95 26.8 2.22
    603 129 65 49.4 6.10
    610 129 101 22.0 1.13
    617 128 95 26.1 2.20
    902 128 85 33.8 1.90
    908 128 91 29.0 1.18
    921 128 99 23.2 0.08
    930 128 103 19.4 0.03
    915 92 69 24.8 1.82
    1021 135 104 23.0 0.03
    1028 138 119 13.7 0.45
    1110 138 115 16.8 1.28
    1215 138 111 19.4 1.50
  • The data reported in Table 1 is depicted in the graph shown in FIG. 1. FIG. 1 shows an initial loss in molecular weight of approximately 17%, with an additional loss of approximately 5.7% per hour of hold time of the active agent/polymer solution. [0049]
  • EXAMPLE 2
  • Additional experiments were conducted at the 20 kg scale that also demonstrate the relationship between molecular weight of the finished microparticle product, and the duration of a hold period of a nucleophilic compound/polymer solution. Microparticles comprising risperidone were prepared at the twenty-kilogram scale. 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%). [0050]
  • A 16.7 wt. % polymer solution was prepared by dissolving 12 kg or 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. A nucleophilic 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 active agent/polymer solution is held for a hold time of sufficient duration to achieve the selected or desired polymer molecular weight in the finished microparticle product, based on the starting molecular weight of the polymer. The results of the experiments, showing the effect of hold time on molecular weight loss, are discussed in more detail below with respect to Table 2 and FIG. 2. [0051]
  • The second, continuous phase was prepared by preparing a 600 liter solution or 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. [0052]
  • The quench liquid was 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10° C. The volume of the quench liquid is 0.25L per gram of batch size. The quench step was carried out for a time period greater than about 4 hours, with stirring of the microparticles in the quench tank. [0053]
  • After completion of the quench step, the microparticles were collected, de-watered, and dried. The temperature was maintained at less than about 15° C. [0054]
  • 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 quench tank for washing for a time period of at least 6 hours with another extraction medium (25% ethanol solution) that was maintained at preferably 25±1° C. [0055]
  • The microparticles were collected, de-watered and dried. The temperature was warmed to greater than about 20° C. but below 40° C. Drying continued for a time period greater than about 16 hours. [0056]
  • Four batches of risperidone microparticles at the 20 kg scale were prepared using the process described above. Table 2 below shows, for each batch, the starting molecular weight of the polymer (kD), the final molecular weight of the polymer in the finished microparticle product (kD), the percent loss in molecular weight of the polymer, and the hold time (hours) of the active agent/polymer solution. The molecular weight of the polymer in the finished microparticle product was determined by GPC. [0057]
    TABLE 2
    Starting Mw Final Mw Hold time
    Batch# kD kD % Loss Hours
    3308 146 117 20 0.5
    4068 145 103 29 1.75
    4138 143 111 22 1.0
    4208 143 110 23 1.0
  • The data reported in Table 2 show that from a relatively constant molecular weight starting material (143 kD, 145 kD, and 146 kD), a variable finished microparticle product molecular weight was achieved by varying the hold time of the active agent/polymer solution hold time. The data reported in Table 2 is depicted in the graph shown in FIG. 2. FIG. 2 shows an initial loss in molecular weight of approximately 16%, with an additional loss of approximately 7.3% per hour of hold time of the active agent/polymer solution. [0058]
  • EXAMPLE 3
  • The starting molecular weight of the polymer (kD) and the final molecular weight of the polymer in a finished microparticle product (kD) was determined for microparticles containing the nucleophilic compound naltrexone. The starting polymer lactide:glycolide ratio was 75:25, 85:15, and 65:35. The polymers used were MEDISORB® 7525 DL polymer, MEDISORB® 8515 DL polymer and MEDISORB® 6535 DL polymer, all available from Alkermes, Inc., Blue Ash, Ohio. [0059]
  • The naltrexone base microparticles were produced using a co-solvent extraction process. The theoretical batch size was 15 to 20 grams. The polymer was dissolved in ethyl acetate to produce a 16.7% w/w polymer solution. The naltrexone base anhydrous was dissolved in benzyl alcohol to produce a 30.0% w/w solution. In various batches, the amount of drug and polymer used was varied to produce microparticles with different theoretical drug loading ranging from 30% to 71%. The ambient polymer and drug solutions were mixed together until a single homogeneous solution (organic phase) was produced. The aqueous phase was at ambient conditions and contained 1% w/w polyvinyl alcohol and a saturating amount of ethyl acetate. These two solutions were pumped via positive displacement pumps at a ratio of 3:1 (aqueous:organic) through a ¼″ in-line mixer to form an emulsion. The emulsion was transferred to a stirring solvent extraction solution consisting of 2.5% w/w of ethyl acetate dissolved in distilled water at 5-10° C. and at a volume of 0.5L of extraction solution per theoretical gram of microparticles. Both the polymer and drug solvents were extracted into the extraction solution from the emulsion droplet to produce microparticles. The initial extraction process ranged from two to four hours. The microparticles were collected on a 25 μm sieve and rinsed with a cold (<5° C.) 25% w/w ethanol solution. The microparticles were dried cold overnight (approximately 17 hours) using nitrogen. The microparticles were then transferred to the reslurry solution, which consisted of a vigorously stirring 25% w/w ethanol solution at 5-10° C. After a short mixing time (five to fifteen minutes), the reslurry solution and the microparticles were transferred to a stirring 25% w/w ethanol secondary extraction solution (approximately 25° C. at a volume of 0.2 L of secondary extraction solution per theoretical gram of microparticles). The microparticles stirred for six hours enabling additional solvent removal from the microparticles to take place. The microparticles were then collected on a 25 μm sieve and used with a 25% w/w ethanol solution at ambient temperature. These microparticles dried in a hood under ambient conditions overnight (approximately 17 hours), were sieved to remove agglomerated microparticles and then placed into a freezer for storage. [0060]
  • As shown below in Table 3, three batches of microparticles were prepared using the 75:25 polymer, two batches for the 85:15 polymer, and four batches for the 65:35 polymer. For each batch, Table 3 shows the starting molecular weight of the polymer (kD), and the final molecular weight of the polymer in the finished microparticle products (kD), and the percent loss in molecular weight of the polymer. The molecular weight of the polymer in the finished microparticle product was determined by GPC. The data in Table 3 provides an example of the low in molecular weight of the polymer in a finished microparticle product containing a nucleophilic compound (naltrexone) for polymers having varying lactide:glycolide ratios. [0061]
    TABLE 3
    Starting Polymer Starting Mw Final Mw
    Lactide:glycolide ratio Batch kD kD % Loss
    75:25 99-123-004 116.2 76.0 34.6
    99-123-009 116.2 74.0 36.3
    99-123-012 116.2 74.3 36.1
    85:15 99-123-016 109.7 83.7 23.7
    99-123-024 109.7 74.9 31.7
    65:35 99-123-021 102.3 56.3 4.50
    99-123-028 102.3 63.4 38.0
    99-123-037 102.3 69.6 32.0
    99-123-034 102.3 79.6 22.2
  • EXAMPLE 14
  • Additional experiments were conducted with other polymers that also demonstrate the relationship between molecular weight of the finished microparticle product, and the duration of a hold period of a nucleophilic compound/polymer solution. Microparticles comprising other polymers having different lactide:glycolide ratios were prepared. Microparticles comprising risperidone using polymers having lactide:glycolide ratios of 65:35, 85:15, and 100:0 were prepared at the 1 Kg scale using the same process described above in Example 1. The polymers used were MEDISORB® 6535 DL polymer, MEDISORB® 8515 DL polymer, and [0062] MEDISORB® 100 DL polymer, all available from Alkermes, Inc., Blue Ash, Ohio.
  • Table 4 below shows, for each polymer, the starting molecular weight of the polymer (kD), the final molecular weight of the polymer in the finished microparticle product (kD), the percent toss in molecular weight of the polymer, and the hold time (hours) of the active agent/polymer solution. The molecular weight of the polymer in the finished microparticle product was determined by GPC. [0063]
    TABLE 4
    Lactide:glycolide Starting Mw Final Mw Hold Time
    ratio kD kD % Loss hours
    65:35 105 79 24.8 0.27
    85:15 112 96 14.3 0.23
    100 dl 105 98  6.7 0.17
  • The data reported in Table 4 show that a microparticle product having about the same molecular weight (96 kD and 98 kD) can be prepared from two different molecular weight polymers (112 kD and 105 kD, respectively) having two different lactide:glycolide ratios (85:15 and 100:0, respectively). The present invention thus advantageously allows microparticle products with the same polymer molecular weight to be produced using two different starting materials. [0064]
  • EXAMPLE 5
  • Additional experiments were conducted that demonstrate the molecular weight loss of polymers in the presence of a nucleophilic compound (oxybutynin) as a function of time. Tests were conducted using a 100:0 lactide:glycolide polymer and two 75:25 lactide:glycolide polymers with differing inherent viscosity. For each test, the following protocol was carried out. Weigh about 6 g polymer into an Erlenmeyer flask. Add to the polymer 44 g ethyl acetate, sonicate and shake to dissolve the polymer. Weigh 1.5 g oxybutynin base. Stir the polymer solution, and add the drug to the polymer solution. Start the timer as the drug is added. Sample the drug/polymer solution at 1, 5 and 15 minutes taking about ⅓ of the original volume for each aliquot as the solution stirs. Dispense the aliquot into 250 mL 50:30 H[0065] 2O:MeOH, and stir. This mix precipitates the polymer and removes the drug from the precipitate. Allow precipitated polymer to settle and decant the supernatant. Wash polymer residue with 100 mL MeOH, stir approximately one minute, add up to 250 mL H2O. Allow polymer to settle again, and repeat. Residue is then removed from the beaker and placed in a scintillation vial and frozen. Once all samples are collected and frozen, all samples are placed in a lyophilizer, cooled to −10° C. The lyophilizer is activated, and once a stable vacuum is achieved, the shelf temperature is raised to 15° C. and held overnight (˜18 hours) to remove residual solvents.
  • The results of these experiments are shown in Table 5. For each experiment, the starting molecular weight of the polymer is shown, along with the polymer molecular weight at 1, 5, and 15 minutes of exposure of the polymer to the nucleophilic compound in the drug/polymer solution. As can be seen in Table 5, the longer the exposure or hold time of the drug/polymer solution, the lower the molecular weight of the polymer. [0066]
    TABLE 5
    Starting
    Polymer
    Lacide:
    glycolide Starting Time = 1 min Time = 5 min Time = 15 min
    ratio Mw, kD Mw, kD Mw, kD Mw, kD
    100:0  77.1 67.2 63 60.8
    75:25 82.8 56.2 55.1 48.8
    75:25 54.1 44.1 42.9 38.4
  • Molecular Weight Temperature Experiments [0067]
  • EXAMPLE 6
  • Additional experiments were conducted to determine the effect of temperature on the relationship between molecular weight of the finished microparticle product, and the duration of a hold period of a nucleophilic compound/polymer solution. Fifty grams of risperidone (Janssen Pharmaceutica Beerse, Belgium) were dissolved in 275 g of benzyl alcohol to form a drug solution. A polymer solution was formed by dissolving 75 g of MEDISORB® 7525 DL polymer (Alkermes, Inc., Blue Ash, Ohio) in ethyl acetate. The starting molecular weight of the polymer was 146 kD. The drug solution and the polymer solution were mixed to form a combined solution. A flask of the combined solution was placed in each of a 15° C., 25° C., and 35° C. chamber. At periodic time intervals, 10 cc of the combined solution was withdrawn from the flask in each chamber via a syringe and needle. The 10 cc sample was then precipitated in a bath containing 200 ml methanol at room temperature (approximately 20° C.). The polymeric precipitate was recovered from the methanol bath, and vacuum dried overnight. The dried samples were tested for their molecular weight by GPC. [0068]
  • The results of the experiments are depicted in the graph of FIG. 3. As shown in FIG. 3, the molecular weight decay increases as temperature increases. Therefore, by increasing the hold temperature of the solution containing the polymer and the nucleophilic compound, the molecular weight decay of the polymer increases, and the duration of the hold period to achieve a particular molecular weight function is reduced. Similarly, by decreasing the hold temperature of the solution containing the polymer and the nucleophilic compound, the molecular weight decay of the polymer decreases, and the duration of the hold period to achieve a particular molecular weight reduction is increased. For example, the time required to reduce the molecular weight form 130 kD to 110 kD is the shortest at 35° C. (about 5 hours) and the longest at 15° C. (about 15 hours). [0069]
  • FIG. 3 shows an initial increase in polymer molecular weight. This phenomenon is most likely occurring because some portion of the polymer, particularly the lower molecular weight fractions is soluble in the extraction medium. Because the analytical measurement of molecular weight is a representation of all the molecular weight fractions present, removing (dissolving) the low molecular weight material can increase the measured molecular weight. [0070]
  • Methods of Preparing Microparticles [0071]
  • EXAMPLE 7
  • As exemplified by the examples discussed above, methods for preparing microparticles having a selected microparticle polymer molecular weight in accordance with the present invention will now be described in more detail. In one embodiment of the present invention, a first phase comprising a nucleophilic compound, a polymer having a starting molecular weight, and a solvent for the polymer is prepared. In one embodiment of the present invention, the first phase is prepared by dissolving a nucleophilic active agent in a first solvent to form an active agent solution. The polymer is dissolved in a second solvent to form a polymer solution. The active agent solution and the polymer solution are blended to form the first phase. In a particularly preferred embodiment, the active agent is selected from the group consisting of risperidone, 9-hydroxyrispridone, and pharmaceutically acceptable salts thereof. In such an embodiment, a preferred first solvent is benzyl alcohol, and a preferred second solvent is ethyl acetate. [0072]
  • In another embodiment of the present invention, the first phase is prepared by dissolving the nucleophilic compound and the polymer in a solvent to form a solution. In yet a further embodiment, an active agent is added to the first phase. In a further embodiment, an inactive agent is added to the first phase. It should be understood that the present invention is not limited to any particular method or process by which the first phase is prepared, and other suitable processes would be readily apparent to one skilled in the art. [0073]
  • A second phase is prepared, and combined with the first phase under the influence of mixing means to form an emulsion. In a preferred embodiment, a static mixer is used to combine the two phases to form an emulsion. A process for forming an emulsion using a static mixer is described for example, in U.S. Pat. No. 5,654,008, the entirety of which is incorporated herein by reference. The emulsion is combined with an extraction medium that extracts solvent from the emulsion droplets, thereby hardening them into microparticles. [0074]
  • Prior to combining the first and second phases, the first phase is maintained at a hold temperature for a hold period. The hold period is of sufficient duration to allow the starting molecular weight of the polymer to reduce to the select microparticle polymer molecular weight at the hold temperature. Based on the teachings and examples provided herein, and the knowledge of skilled artisans, the determination of suitable hold temperatures and hold periods is within the outline skill of skilled artisans and would not require undue experimentation, in a preferred embodiment of the present invention, the starting molecular weight of the polymer reduces by about 10% to about 30% to reach the selected polymer molecular weight. However, it should be understood by one skilled in the art that the present invention is not limited to such a percentage reduction. [0075]
  • During the hold period the first phase may be mixed, stirred, or otherwise agitated. Alternatively, during the hold period, the first phase may be subjected to no mixing, stirring, or agitation. The hold temperature is preferably in the range of from about 15° C. to about 35° C., more preferably about 25° C. [0076]
  • An alternate method for preparing microparticles in accordance with the present invention will now be described. A polymer having a starting molecular weight and a nucleophilic compound are dissolved in a solvent to form a first phase. An active agent and/or an inactive agent can be added to the first phase. The first phase is combined with a second phase under the influence of mixing means to form an emulsion. The emulsion is combined with an extraction medium that extracts solvent, thereby hardening the emulsion droplets into microparticles. Prior to combining the first and second phases, the first phase is maintained at a hold temperature for a hold period. The hold period is selected so that the starting molecular weight of the polymer reduces to a selected microparticle polymer molecular weight at the hold temperature. The duration of the hold period can be adjusted by changing the hold temperature in a manner as described above. [0077]
  • Microparticles of the Present Invention [0078]
  • The microparticles prepared by the process of the present invention preferably comprise a polymeric binder. Suitable polymeric binder materials include poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and polyphosphazines. Poly (d,l-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,l-lactic-co-glycolic acid) known as MEDISORB® 5050 DL. This product has a mole percent composition of 50% lactide and 50% glycolid. Other suitable commercially available products are MEDISORB® 6535 DL, 7525 DL, 8515 DL and poly(d,l-lactic acid) (100 DL). Poly(lactide-co-glycolides) are also commercially available from Boebringer Ingelheim (Germany) under its Resomer® mark, e.g. PLGA 50:50 (Resomer® RG 502). PLGA 75:25 (Resomer® RG 752) and d,l-PLA (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. [0079]
  • One type of microparticle suitable for preparation by the present invention is a sustained-release microparticle that is biodegradable. However, it should be understood by one skilled in the art that the present invention is not limited to biodegradable or other types of sustained-release microparticles. As would be apparent to one skilled in the art, the molecular weight of the polymeric binder material for biodegradable microparticles 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. However, since the properties of the film are also partially dependent on the particular polymeric binder 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 binder 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. A satisfactory starting molecular weight of the polymer is in the range of 5-500 kD, preferably in the range of from about 50 kD to about 250 kD. The microparticle polymer molecular weight is preferably in the range of from about 10 kD to about 185 kD. [0080]
  • The microparticles prepared in accordance with the present invention may include an active agent or other type of substance that is released from the microparticles into the host. However, it should be understood that the present invention is not limited to preparation of microparticles that contain an active agent. The active agent can be a nucleophilic compound. Alternatively, the active agent is not a nucleophilic compound and is added to the microparticles during the formation process. Such active agents can include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothazoles. The most preferred active agents of this kind 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-fluoro-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-hydroxyrispendone 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. [0081]
  • 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-migrain agents; anti-Parkinson agents such as L-dopa; anti-spasmodics; anticholinergic agents (e.g. oxybutynin); antitussives; bronchodilators; cardiovacular agents such as coronary vasodilators and nitroglycerin; alkaloids; analgesics; narcotics such as cocaine 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-caner agents; anti-convulsants; anti-emetics; antihistamines; anti-inflammatorty agents such as hormonal agents, hydrocortisone, prednisdone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like; prostaglandins and cytotoxic drugs. [0082]
  • Still other suitable active agents include estrogens, antibacterials; antifungals; antivirals; anticoagulants; anticonvulsants; antidepressants; antihistamines; and immunological agents. [0083]
  • Other examples of suitable biologically active agents include peptides and proteins, anlogs, muteins, and active fragments thereof, such as immoglobulins, 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 factor (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 vital 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 hydrochlonde and codeine phosphate; sedatives such as chlorpromazine hydrochloride, prochlorperazine hydrochloride and atropine sulfate; muscle relaxants such as tubocurarine chloride, antiepilepics such as sodium phenytoin and ethosuximide; antiulcer agents such as metoclopramide; antidepressants such as clomipramine; antiallergc agents such as diphenhydramine; cardiotonics such as theophilol; antiarrhythmic agents such as propranolol hydrochloride; vasodilators such as diltiazem hydrochloride and bamethan sulfate; hypotensive diureics 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. [0084]
  • The microparticles can be mixed by size or by type. However, it should be understood that the present invention is not limited to the use of biodegradable or other types of microparticles that contain an active agent. In one embodiment, the microparticles are mixed in a manner that provides for the delivery of active agent to the host in a multiphasic manner and/or on a manner that provides different active agents to the host at different times, or a mixture of active agents at the same time. For example, secondary antibiotics, vaccines, or any desired active agent, either in microparticle form or in conventional, unencapsulated form can be blended with a primary active agent and provided to the host. [0085]
  • Apparatus [0086]
  • With reference now to FIG. 4, one embodiment is shown of an equipment configuration suitable for use in preparing microparticles in accordance with the present invention. In a preferred embodiment of the present invention, the equipment contained within the dotted line boundary shown generally at [0087] 270 is sterilized using a “steam-in-place” (SIP) process.
  • A [0088] first phase 201 is provided. First phase 201 is preferably the discontinuous phase, comprising a polymer dissolved in one or more solvents, and an active agent. The active agent can be dissolved or dispersed in the same or a different solvent than the solvent(s) in which the polymer is dissolved. A second phase 202 is preferably the continuous phase, preferably comprising water as the continuous processing medium. Preferably, an emulsifying agent such as a surfactant or a hydrophilic colloid is added to the continuous phase to prevent the microdroplets from agglomerating and to control the size of the microdroplets in the emulsion. Examples of compounds that can be used as surfactants or hydrophilic colloids include but are not limited to, poly(vinyl alcohol) (PVA), carboxymethyl cellulose, gelatin, poly(vinyl pyrrolidone), Tween 80, Tween 20, and the like. The concentration of surfactant or hydrophilic colloid in the continuous phase will be from about 0.% to about 10% by weight based on the continuous processing medium, depending upon the surfactant, hydrophilic colloid, the discontinuous phase, and the continuous processing medium used. A preferred continuous phase is 0.1 to 10 wt. %, more preferably 0.5 to 2 wt %, solution of PVA in water. Although not absolutely necessary, it is preferred to saturate the continuous phase with at least one of the solvents forming the discontinuous phase.
  • [0089] First phase 201 and second phase 202 are combined under the influence of mixing means to form an emulsion. A preferred type of mixing means is a static mixer 210. Other mixing suitable for use with the present invention include, but are not limited to, devices for mechanically agitating the first and second phases, such as homogenizers, propellers, impellers, stirrers, and the like.
  • Preferably, the discontinuous and [0090] continuous phases 201 and 202 are pumped through static mixer 210 to form an emulsion, and into a large volume of quench liquid, to obtain microparticles containing the active agent encapsulated in the polymeric matrix material. A pump 203 pumps first phase 201 into static mixer 210, and a pump 204 pumps second phase 202 into static mixer 210. An especially preferred method of mixing with a static mixer in the process of the present invention is disclosed in U.S. Pat. No. 5,654,008, the entirety of which is incorporated herein by reference.
  • First and [0091] second phases 201 and 202 are mixed in static mixer 210 to form an emulsion. The emulsion formed comprises microparticles containing active agent encapsulated in the polymeric matrix material. The microparticles are then preferably stirred in a quench or extraction tank 220 containing a quench liquid in order to remove most of the solvent from the microparticles, resulting in the formation of hardened microparticles. Following the movement of the microparticles from static mixer 210 and entrance into quench tank 220, the continuous processing medium is diluted, and much of the solvent in the microparticles is removed by extraction. In this extraction quench step, the microparticles can be suspended in the same continuous phase (second phase 202) used during emulsification, with or without hydrophilic colloid or surfactant, or in another quench liquid. The quench liquid removes a significant portion of the solvent from the microparticles, but does not dissolve them. During the extractive quench step, the quench liquid containing dissolved solvent can, optionally, be removed and replaced with fresh quench liquid.
  • Upon completion of the quench step in quench [0092] tank 220, the microparticles are transferred by a pump 224 to a device 230 that functions as a microparticle collecting device, de-watering device, and drying device.
  • [0093] Device 230 comprises a vibrating sieve or screen. The vibration causes smaller particles and liquid to drop through the screen, while larger particles are retained. The smaller particles and liquid that drop through the screen are removed as waste 235. Device 230 also functions as a vacuum dryer, through the use of a vacuum line 237. The microparticles are are fluidized by the vibrational energy, and by a small amount of a dry gas bleed, preferably a dry nitrogen (N2) bleed 236.
  • The dried microparticles are transferred to another extraction medium to carry out a wash step. The wash step is preferably carried out in quench [0094] tank 220, using an extraction medium 222 having a temperature higher than the glass transition temperature (Tg) of the microparticles. To carry out the wash step, the microparticles are first introduced into a re-slurry tank or other type of vessel 240, as shown by path 231. The temperature of the extraction medium 242 that is used in vessel 240 is lower than the Tg of the microparticles.
  • After the wash stop is completed in quench [0095] tank 220, the microparticles are again transferred via pump 224 into device 230 for de-watering and final drying. At the completion of final drying, the microparticles are discharged from device 230 in the manner described above into a sifter 250, as shown by path 232. Sifter 250 is used to fractionate the microparticles by size for filling into vials and for bulk in-process testing (e.g, aspect, active agent content, residual solvents, in vitro release, and particle size distribution.
  • Conclusion [0096]
  • 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 the preparation of controlled release microparticles or microparticles containing an active agent, nor is it 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 claim and their equivalents. [0097]

Claims (30)

What is claimed is:
1. Microparticles prepared by a method, comprising:
preparing a first phase, the first phase comprising naltrexone, a polymer having a starting molecular weight, and a solvent;
combining the first phase with a second phase to form an emulsion;
extracting the solvent from the emulsion to thereby form microparticles; and
wherein the starting molecular weight of the polymer reduces in the first phase so that a finished microparticle polymer molecular weight is achieved.
2. The microparticles of claim 1, wherein the solvent comprises ethyl acetate.
3. The microparticles of claim 1, wherein the preparing step comprises:
dissolving naltrexone in benzyl alcohol to form a first solution;
dissolving the polymer in ethyl acetate to form a second solution; and
combining the first solution and the second solution to form the first phase.
4. The microparticles of claim 3, wherein the naltrexone is naltrexone base anhydrous.
5. The microparticles of claim 1, wherein a theoretical drug loading is in the range of from about 30% to 75%.
6. The microparticles of claim 1, wherein the starting molecular weight is in the range of from about 50 kD to about 250 kD.
7. The microparticles of claim 1, wherein the finished microparticle polymer molecular weight is in the range of from about 10 kD to about 185 kD.
8. The microparticles of claim 1, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, and copolymers of lactide and glycolide.
9. The microparticles of claim 8, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.
10. The microparticles of claim 2, wherein the solvent further comprises benzyl alcohol.
11. The microparticles of claim 1, wherein the extracting step is carried out using an extraction solution.
12. The microparticles of claim 11, wherein the extraction solution is aqueous.
13. The microparticles of claim 11, wherein the extraction solution comprises a quantity of the solvent.
14. The microparticles of claim 1, wherein the combining step is carried out using a static mixer.
15. The microparticles of claim 1, wherein the method further comprises:
cold drying the microparticles.
16. The microparticles of claim 15, wherein the method further comprises prior to the cold drying step:
rinsing the microparticles with an ethanol solution.
17. The microparticles of claim 15, wherein the method further comprises after the cold drying step:
transferring the microparticles to an ethanol solution.
18. The microparticles of claim 17, wherein the method further comprises after the transferring step:
final drying the microparticles.
19. The microparticles of claim 2, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide of about 75:25 and the naltrexone is naltrexone base anhydrous.
20. Microparticles prepared by a method, comprising:
dissolving naltrexone and a polymer having a starting molecular weight in a solvent to form a first phase;
combining the first phase and an aqueous second phase under the influence of mixing means to form an emulsion;
extracting the solvent from the emulsion to thereby form microparticles; and
wherein the starting molecular weight of the polymer reduces in the first phase so that a finished microparticle polymer molecular weight is achieved.
21. The microparticles of claim 20, wherein a theoretical drug loading is in the range of from about 30% to 75%.
22. The microparticles of claim 20, wherein the starting molecular weight is in the range of from about 50 kD to about 250 kD.
23. The microparticles of claim 20, wherein the finished microparticle polymer molecular weight is in the range of from about 10 kD to about 185 kD.
24. The microparticles of claim 20, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, and copolymers of lactide and glycolide.
25. The microparticles of claim 24, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.
26. The microparticles of claim 20, wherein the extracting step is carried out using an extraction solution.
27. The microparticles of claim 26, wherein the extraction solution is aqueous.
28. The microparticles of claim 26, wherein the extraction solution comprises a quantity of the solvent.
29. The microparticles of claim 20, wherein the combining step is carried out using a static mixer.
30. The microparticles of claim 20, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide of about 75:25 and the naltrexone is naltrexone base anhydrous.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070292475A1 (en) * 2005-12-02 2007-12-20 Campbell Kathleen M Controlled release microparticles
US20100087337A1 (en) * 2008-09-10 2010-04-08 Bind Biosciences, Inc. High Throughput Fabrication of Nanoparticles
EP4233844A4 (en) * 2020-11-09 2023-10-25 Shenzhen Sciencare Pharmaceutical Co., Ltd. Naltrexone and risperidone combination sustained-release composition

Families Citing this family (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194006B1 (en) * 1998-12-30 2001-02-27 Alkermes Controlled Therapeutics Inc. Ii Preparation of microparticles having a selected release profile
US6264987B1 (en) * 2000-05-19 2001-07-24 Alkermes Controlled Therapeutics Inc. Ii Method for preparing microparticles having a selected polymer molecular weight
US7666445B2 (en) 2000-10-20 2010-02-23 The Trustees Of The University Of Pennsylvania Polymer-based surgically implantable haloperidol delivery systems and methods for their production and use
JP2004534721A (en) * 2000-10-31 2004-11-18 ピーアール ファーマシューティカルズ,インク. Methods and compositions for enhanced delivery of bioactive molecules
US10285910B2 (en) 2001-10-12 2019-05-14 Aquestive Therapeutics, Inc. Sublingual and buccal film compositions
US8603514B2 (en) 2002-04-11 2013-12-10 Monosol Rx, Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
US8765167B2 (en) 2001-10-12 2014-07-01 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US8900498B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for manufacturing a resulting multi-layer pharmaceutical film
US20110033542A1 (en) 2009-08-07 2011-02-10 Monosol Rx, Llc Sublingual and buccal film compositions
US8900497B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for making a film having a substantially uniform distribution of components
US11207805B2 (en) 2001-10-12 2021-12-28 Aquestive Therapeutics, Inc. Process for manufacturing a resulting pharmaceutical film
US7357891B2 (en) 2001-10-12 2008-04-15 Monosol Rx, Llc Process for making an ingestible film
US20190328679A1 (en) 2001-10-12 2019-10-31 Aquestive Therapeutics, Inc. Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US7615227B2 (en) * 2001-12-20 2009-11-10 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Use of CpG oligodeoxynucleotides to induce angiogenesis
US20030176929A1 (en) * 2002-01-28 2003-09-18 Steve Gardner User interface for a bioinformatics system
WO2003082247A2 (en) * 2002-03-26 2003-10-09 Teva Pharmaceutical Industries Ltd. Drug microparticles
AU2003269904A1 (en) * 2002-07-10 2004-01-23 The Ohio State University Research Foundation Antigen-polymer compositions
DE10235556A1 (en) * 2002-08-03 2004-02-19 Hf Arzneimittelforschung Gmbh Medicament for treating substance cravings, especially alcohol and/or tobacco abuse, comprising separate dosage forms for continuous release of nicotinic receptor modulator and rapid delivery of galanthamine
WO2004034888A2 (en) * 2002-10-18 2004-04-29 Ellis Charles N Method for rating severity of psoriasis
US7658998B2 (en) * 2003-01-22 2010-02-09 Alkermes Controlled Therapeutics, Inc. Method of preparing sustained release microparticles
US20070207211A1 (en) * 2003-04-10 2007-09-06 Pr Pharmaceuticals, Inc. Emulsion-based microparticles and methods for the production thereof
WO2005003180A2 (en) * 2003-04-10 2005-01-13 Pr Pharmaceuticals A method for the production of emulsion-based micro particles
AU2004245057B2 (en) * 2003-06-04 2008-07-31 Alkermes Pharma Ireland Limited Polymorphic forms of naltrexone
BRPI0412059A (en) * 2003-07-15 2006-09-05 Pr Pharmaceuticals Inc Method for preparing controlled release formulation
JP2008518881A (en) 2003-07-18 2008-06-05 オークウッド ラボラトリーズ,エル.エル.シー. Prevention of molecular weight reduction, impurity formation and gelation of polymer in polymer composition
EP2444069B1 (en) * 2003-07-23 2019-06-05 Evonik Corporation Controlled release compositions
US6987111B2 (en) 2003-08-06 2006-01-17 Alkermes Controlled Therapeutics, Ii Aripiprazole, olanzapine and haloperidol pamoate salts
EP1663289A2 (en) * 2003-08-29 2006-06-07 Amylin Pharmaceuticals, Inc. Methods for treating or ameliorating ghrelin-associated diseases and disorders
AU2005206143B2 (en) * 2004-01-12 2010-12-16 The Trustees Of The University Of Pennsylvania Long-term delivery formulations and methods of use thereof
US8221778B2 (en) 2005-01-12 2012-07-17 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
US8329203B2 (en) 2004-01-12 2012-12-11 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
BRPI0507623A (en) 2004-02-11 2007-07-03 Amylin Pharmaceuticals Inc amylin family peptides and methods for preparing and employing them
KR20140104986A (en) * 2004-02-17 2014-08-29 트랜스셉트 파마슈티칼스, 인코포레이티드 Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof
US7399744B2 (en) * 2004-03-04 2008-07-15 Amylin Pharmaceuticals, Inc. Methods for affecting body composition
US20050245461A1 (en) * 2004-03-19 2005-11-03 Elliot Ehrich Methods for treating alcoholism
US20050245541A1 (en) * 2004-03-19 2005-11-03 Elliot Ehrich Methods for treating alcoholism
US7919499B2 (en) * 2004-04-22 2011-04-05 Alkermes, Inc. Naltrexone long acting formulations and methods of use
US20050260272A1 (en) * 2004-05-05 2005-11-24 Alkermes Controlled Therapeutics, Inc. Method of forming microparticles that include a bisphosphonate and a polymer
DK1814590T4 (en) 2004-11-01 2014-02-24 Amylin Pharmaceuticals Llc Treatment of obesity and related diseases.
MX2007006830A (en) 2004-12-13 2008-02-07 Amylin Pharmaceuticals Inc Pancreatic polypeptide family motifs, polypeptides and methods comprising the same.
WO2006078841A1 (en) * 2005-01-21 2006-07-27 President And Fellows Of Harvard College Systems and methods for forming fluidic droplets encapsulated in particles such as colloidal particles
NZ561361A (en) 2005-02-11 2010-02-26 Amylin Pharmaceuticals Inc GIP hybrid polypeptides with at least two hormonal activities
EP2135617A3 (en) 2005-03-31 2013-09-18 Amylin Pharmaceuticals, LLC Amylin and amylin agonists for treating psychiatric diseases and disorders
KR20130042041A (en) * 2005-05-25 2013-04-25 트랜스셉트 파마슈티칼스, 인코포레이티드 Solid compositions and methods for treating middle-of-the night insomnia
US20070287740A1 (en) * 2005-05-25 2007-12-13 Transcept Pharmaceuticals, Inc. Compositions and methods of treating middle-of-the night insomnia
US20070225322A1 (en) * 2005-05-25 2007-09-27 Transoral Pharmaceuticals, Inc. Compositions and methods for treating middle-of-the night insomnia
KR101283946B1 (en) * 2005-07-18 2013-07-15 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 Drug-containing implants and methods of use thereof
US20070066514A1 (en) * 2005-08-30 2007-03-22 Acologix, Inc. Regulation of mineral and skeletal metabolism
US8852638B2 (en) 2005-09-30 2014-10-07 Durect Corporation Sustained release small molecule drug formulation
WO2007041190A2 (en) * 2005-09-30 2007-04-12 The University Of Iowa Research Foundation Polymer-based delivery system for immunotherapy of cancer
EP2120985B1 (en) 2007-02-05 2012-06-27 Amylin Pharmaceuticals, Inc. FN-38 peptides for use in the treatment of psychotic and anxiety disorders
US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
JP2012515790A (en) * 2009-01-23 2012-07-12 サーモディクス ファーマシューティカルズ, インコーポレイテッド Continuous double emulsion process for fine particle production
US20100196436A1 (en) * 2009-01-30 2010-08-05 Gooberman Lance L Implants containing disulfiram and an anti-inflammatory agent
US8791093B2 (en) * 2009-05-29 2014-07-29 Lance L. Gooberman Pharmaceutical delivery systems for treatment of substance abuse and other addictions
EP2523657A1 (en) 2010-01-12 2012-11-21 Portola Pharmaceuticals, Inc. Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof
GB2481017B (en) 2010-06-08 2015-01-07 Rb Pharmaceuticals Ltd Microparticle buprenorphine suspension
US9272044B2 (en) 2010-06-08 2016-03-01 Indivior Uk Limited Injectable flowable composition buprenorphine
JP6121330B2 (en) 2010-09-28 2017-04-26 アミリン・ファーマシューティカルズ, リミテッド・ライアビリティ・カンパニーAmylin Pharmaceuticals, Llc Modified polypeptides with increased duration of action
EP3241558B1 (en) 2010-09-28 2021-03-03 Aegerion Pharmaceuticals, Inc. Highly soluble leptins
US9149959B2 (en) 2010-10-22 2015-10-06 Monosol Rx, Llc Manufacturing of small film strips
JP2013544271A (en) 2010-12-03 2013-12-12 ポートラ ファーマシューティカルズ, インコーポレイテッド Pharmaceutical compositions, dosage forms and novel forms of compounds of formula (I) and methods of use thereof
JP6006309B2 (en) 2011-07-08 2016-10-12 アミリン・ファーマシューティカルズ,リミテッド・ライアビリティ・カンパニーAmylin Pharmaceuticals,Llc Engineered polypeptides with increased duration of action and reduced immunogenicity
EP2729160B1 (en) 2011-07-08 2019-03-27 Aegerion Pharmaceuticals, Inc. Engineered polypeptides having enhanced duration of action and reduced immunogenicity
BRPI1106938A2 (en) * 2011-10-17 2015-12-08 Fbm Indústria Farmacêutica Ltda controlled release pharmaceutical composition containing naltrexone and topiramate
RU2471478C1 (en) * 2011-12-08 2013-01-10 Станислав Анатольевич Кедик Pharmaceutical composition for treating alcoholism, drug addiction and chemical abuse with improved naltrexone release profile
AU2014283692B2 (en) 2013-06-20 2017-04-27 Pharmathen S.A. Preparation of polylactide-polyglycolide microparticles having a sigmoidal release profile
EP3010962B2 (en) 2013-06-20 2023-02-08 Pharmathen S.A. Preparation of polylactide-polyglycolide microparticles having a sigmoidal release profile
GB201404139D0 (en) 2014-03-10 2014-04-23 Rb Pharmaceuticals Ltd Sustained release buprenorphine solution formulations
NZ731309A (en) 2014-11-07 2022-02-25 Indivior Uk Ltd Buprenorphine dosing regimens
CN108368502B (en) 2015-06-03 2022-03-18 内布拉斯加大学董事委员会 DNA editing using single-stranded DNA
EP3348268A4 (en) * 2015-09-07 2019-04-10 Nipro Corporation Risperidone-containing microcapsule, method for manufacturing same and release control method
US11273131B2 (en) 2016-05-05 2022-03-15 Aquestive Therapeutics, Inc. Pharmaceutical compositions with enhanced permeation
CN109310646A (en) 2016-05-05 2019-02-05 阿奎斯蒂弗医疗股份有限公司 Enhance the adrenaline composition of delivering
WO2018031771A1 (en) 2016-08-11 2018-02-15 University Of Iowa Research Foundation CATIONIC CaMKII INHIBITING NANOPARTICLES FOR THE TREATMENT OF ALLERGIC ASTHMA
US10646484B2 (en) 2017-06-16 2020-05-12 Indivior Uk Limited Methods to treat opioid use disorder
CN109718212A (en) * 2017-10-30 2019-05-07 浙江圣兆药物科技股份有限公司 A method of reducing low solvent flashing benzyl alcohol in Risperidone microballoon
BR112021012210A2 (en) * 2018-12-27 2021-08-31 Alar Pharmaceuticals Inc. NALTREXONE SUSTAINED RELEASE INJECT FORMULATION
KR102072968B1 (en) * 2019-05-28 2020-02-04 주식회사 울트라브이 The fabrication method of fine particle of biodegradable polymer and a biodegradable material for recovering tissues
EP4045152A1 (en) 2019-10-15 2022-08-24 Cornell University Methods for modulating level of expression from gene therapy expression cassette
KR20220082050A (en) 2019-10-16 2022-06-16 코넬 유니버시티 Gene therapy for Alzheimer's disease
WO2021086973A2 (en) 2019-10-28 2021-05-06 University Of Iowa Research Foundation Formulation for delivery of lubricin gene
EP4065600A1 (en) 2019-11-25 2022-10-05 Cornell University Apoe gene therapy
CN113546060B (en) * 2020-04-08 2023-04-07 江苏长泰药业有限公司 Naltrexone microspheres
KR20230004758A (en) 2020-04-23 2023-01-06 유니버시티 오브 아이오와 리써치 파운데이션 GPER proteolytic targeting chimera
WO2022040564A1 (en) 2020-08-21 2022-02-24 University Of Iowa Research Foundation Cationic nanoparticle adjuvants
WO2022047201A1 (en) 2020-08-27 2022-03-03 University Of Iowa Research Foundation Gene knock-out for treatment of glaucoma
WO2022125963A1 (en) 2020-12-11 2022-06-16 University Of Iowa Research Foundation Compositions comprising molecules for cystic fibrosis treatment
WO2022246280A1 (en) 2021-05-21 2022-11-24 University Of Iowa Research Foundation Anti-oxidant containing particles and methods of use
WO2022271951A1 (en) 2021-06-23 2022-12-29 University Of Iowa Research Foundation Sustained release formulations comprising a selective androgen receptor modulator

Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3523906A (en) * 1962-07-11 1970-08-11 Gevaert Photo Prod Nv Process for encapsulating water and compounds in aqueous phase by evaporation
US3691090A (en) * 1969-01-16 1972-09-12 Fuji Photo Film Co Ltd Encapsulation method
US3737337A (en) * 1970-03-04 1973-06-05 Bayer Ag Process for the production of microgranulates
US3773919A (en) * 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US3891570A (en) * 1972-01-26 1975-06-24 Toyo Jozo Kk Process for preparing microcapsules
US3960757A (en) * 1973-06-27 1976-06-01 Toyo Jozo Co., Ltd. Process for encapsulation of medicaments
US4221862A (en) * 1975-06-27 1980-09-09 Fuji Photo Film Co., Ltd. Method of producing finely divided polymer particles
US4384975A (en) * 1980-06-13 1983-05-24 Sandoz, Inc. Process for preparation of microspheres
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4530840A (en) * 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4818517A (en) * 1986-01-24 1989-04-04 Akzo N.V. Pharmaceutical preparation for obtaining a highly viscose hydrogel or suspension
US4940588A (en) * 1984-10-30 1990-07-10 Elan Corporation Controlled release powder and process for its preparation
US5066436A (en) * 1989-01-04 1991-11-19 Gist-Brocades N.V. Process for microencapsulation
US5407609A (en) * 1989-05-04 1995-04-18 Southern Research Institute Microencapsulation process and products therefrom
US5428024A (en) * 1992-02-28 1995-06-27 Collagen Corporation High concentration homogenized collagen compositions
US5478564A (en) * 1990-02-22 1995-12-26 Teva Pharmaceutical Industries, Ltd. Preparation of microparticles for controlled release of water-soluble substances
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency
US5541172A (en) * 1991-06-28 1996-07-30 Endorecherche, Inc. Controlled release systems and low dose androgens
US5650173A (en) * 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
US5654010A (en) * 1992-12-02 1997-08-05 Alkermes, Inc. Composition for sustained release of human growth hormone
US5654008A (en) * 1993-11-19 1997-08-05 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
US5656299A (en) * 1992-11-17 1997-08-12 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release microsphere preparation containing antipsychotic drug and production process thereof
US5656297A (en) * 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
US5658593A (en) * 1992-01-16 1997-08-19 Coletica Injectable compositions containing collagen microcapsules
US5688801A (en) * 1993-11-19 1997-11-18 Janssen Pharmaceutica Method of inhibiting neurotransmitter activity using microencapsulated 3-piperidiny2-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
US5747058A (en) * 1995-06-07 1998-05-05 Southern Biosystems, Inc. High viscosity liquid controlled delivery system
US5792477A (en) * 1996-05-07 1998-08-11 Alkermes Controlled Therapeutics, Inc. Ii Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent
US5942253A (en) * 1995-10-12 1999-08-24 Immunex Corporation Prolonged release of GM-CSF
US6264987B1 (en) * 2000-05-19 2001-07-24 Alkermes Controlled Therapeutics Inc. Ii Method for preparing microparticles having a selected polymer molecular weight
US6306425B1 (en) * 1999-04-09 2001-10-23 Southern Research Institute Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
WO1989003678A1 (en) 1987-10-30 1989-05-05 Stolle Research & Development Corporation Low residual solvent microspheres and microencapsulation process
US5158952A (en) 1988-11-07 1992-10-27 Janssen Pharmaceutica N.V. 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use
IT1243390B (en) 1990-11-22 1994-06-10 Vectorpharma Int PHARMACEUTICAL COMPOSITIONS IN THE FORM OF PARTICLES SUITABLE FOR THE CONTROLLED RELEASE OF PHARMACOLOGICALLY ACTIVE SUBSTANCES AND PROCEDURE FOR THEIR PREPARATION.
WO1993017668A1 (en) * 1992-03-12 1993-09-16 Alkermes Controlled Therapeutics, Inc. Controlled release acth containing microspheres
FR2692147B1 (en) * 1992-06-15 1995-02-24 Centre Nat Rech Scient Bioresorbable polymer microspheres free of surfactant, their preparation and their use as medicaments.
US5904935A (en) 1995-06-07 1999-05-18 Alza Corporation Peptide/protein suspending formulations
GB9718986D0 (en) 1997-09-09 1997-11-12 Danbiosyst Uk Controlled release microsphere delivery system
US6495166B1 (en) * 1999-11-12 2002-12-17 Alkermes Controlled Therapeutics Inc. Apparatus and method for preparing microparticles using in-line solvent extraction
US6331317B1 (en) * 1999-11-12 2001-12-18 Alkermes Controlled Therapeutics Ii Inc. Apparatus and method for preparing microparticles

Patent Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3523906A (en) * 1962-07-11 1970-08-11 Gevaert Photo Prod Nv Process for encapsulating water and compounds in aqueous phase by evaporation
US3691090A (en) * 1969-01-16 1972-09-12 Fuji Photo Film Co Ltd Encapsulation method
US3773919A (en) * 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US3737337A (en) * 1970-03-04 1973-06-05 Bayer Ag Process for the production of microgranulates
US3891570A (en) * 1972-01-26 1975-06-24 Toyo Jozo Kk Process for preparing microcapsules
US3960757A (en) * 1973-06-27 1976-06-01 Toyo Jozo Co., Ltd. Process for encapsulation of medicaments
US4221862A (en) * 1975-06-27 1980-09-09 Fuji Photo Film Co., Ltd. Method of producing finely divided polymer particles
US4384975A (en) * 1980-06-13 1983-05-24 Sandoz, Inc. Process for preparation of microspheres
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4530840A (en) * 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4940588A (en) * 1984-10-30 1990-07-10 Elan Corporation Controlled release powder and process for its preparation
US4818517A (en) * 1986-01-24 1989-04-04 Akzo N.V. Pharmaceutical preparation for obtaining a highly viscose hydrogel or suspension
US5066436A (en) * 1989-01-04 1991-11-19 Gist-Brocades N.V. Process for microencapsulation
US5407609A (en) * 1989-05-04 1995-04-18 Southern Research Institute Microencapsulation process and products therefrom
US5478564A (en) * 1990-02-22 1995-12-26 Teva Pharmaceutical Industries, Ltd. Preparation of microparticles for controlled release of water-soluble substances
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency
US5541172A (en) * 1991-06-28 1996-07-30 Endorecherche, Inc. Controlled release systems and low dose androgens
US5658593A (en) * 1992-01-16 1997-08-19 Coletica Injectable compositions containing collagen microcapsules
US5428024A (en) * 1992-02-28 1995-06-27 Collagen Corporation High concentration homogenized collagen compositions
US5656297A (en) * 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
US5871778A (en) * 1992-11-17 1999-02-16 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release microsphere preparation containing antipsychotic drug
US5656299A (en) * 1992-11-17 1997-08-12 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release microsphere preparation containing antipsychotic drug and production process thereof
US5667808A (en) * 1992-12-02 1997-09-16 Alkermes, Inc. Composition for sustained release of human growth hormone
US5654010A (en) * 1992-12-02 1997-08-05 Alkermes, Inc. Composition for sustained release of human growth hormone
US5650173A (en) * 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
US5688801A (en) * 1993-11-19 1997-11-18 Janssen Pharmaceutica Method of inhibiting neurotransmitter activity using microencapsulated 3-piperidiny2-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
US5770231A (en) * 1993-11-19 1998-06-23 Alkermes Controlled Therapeutics, Inc. Ii Microencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles 1,2-benzisothiazoles
US5654008A (en) * 1993-11-19 1997-08-05 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
US5965168A (en) * 1993-11-19 1999-10-12 Alkermes Controlled Therapeutics, Inc. Ii Microencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
US5747058A (en) * 1995-06-07 1998-05-05 Southern Biosystems, Inc. High viscosity liquid controlled delivery system
US5942253A (en) * 1995-10-12 1999-08-24 Immunex Corporation Prolonged release of GM-CSF
US5792477A (en) * 1996-05-07 1998-08-11 Alkermes Controlled Therapeutics, Inc. Ii Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent
US5916598A (en) * 1996-05-07 1999-06-29 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable, biocompatible microparticles containing a biologically active agent
US6306425B1 (en) * 1999-04-09 2001-10-23 Southern Research Institute Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol
US6264987B1 (en) * 2000-05-19 2001-07-24 Alkermes Controlled Therapeutics Inc. Ii Method for preparing microparticles having a selected polymer molecular weight
US6379704B2 (en) * 2000-05-19 2002-04-30 Alkermes Controlled Therapeutics Inc. Ii Method for preparing microparticles having a selected polymer molecular weight
US6534092B2 (en) * 2000-05-19 2003-03-18 Alkermes Controlled Therapeutics, Inc. Ii Method for preparing microparticles having a selected polymer molecular weight

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070292475A1 (en) * 2005-12-02 2007-12-20 Campbell Kathleen M Controlled release microparticles
US8877229B2 (en) * 2005-12-02 2014-11-04 Eyetech Inc. Controlled release microparticles
US20150037429A1 (en) * 2005-12-02 2015-02-05 Valeant Pharmaceuticals International Controlled Release Microparticles
US20100087337A1 (en) * 2008-09-10 2010-04-08 Bind Biosciences, Inc. High Throughput Fabrication of Nanoparticles
US8846077B2 (en) 2008-09-10 2014-09-30 Bind Biosciences, Inc. High throughput fabrication of nanoparticles
US9358215B2 (en) 2008-09-10 2016-06-07 Bind Therapeutics, Inc. High throughput fabrication of nanoparticles
US9844509B2 (en) 2008-09-10 2017-12-19 Pfizer Inc. High throughput fabrication of nanoparticles
EP4233844A4 (en) * 2020-11-09 2023-10-25 Shenzhen Sciencare Pharmaceutical Co., Ltd. Naltrexone and risperidone combination sustained-release composition

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