JP6184508B2 - Drying method for adjusting fine particle characteristics - Google Patents

Description

Background In order for a bioactive agent to function effectively, the bioactive agent must be delivered to the subject in a safe and effective manner. The ideal pharmacokinetic profile of a bioactive agent is one that allows the therapeutic concentration of the bioactive agent to reach the subject without exceeding the maximum allowable amount. For certain pharmacological applications, the concentration of the bioactive agent should remain at the therapeutic concentration over an extended period until the desired therapeutic result is achieved.

  Unfortunately, conventional routes for administering bioactive agents often provide an ideal pharmacokinetic profile, especially for bioactive agents that exhibit high toxicity and / or narrow therapeutic windows. Absent. It is known in the art that one method of affecting the pharmacokinetic profile of a bioactive agent is to encapsulate the bioactive agent in microparticles. The microparticles degrade over time, thereby releasing the bioactive agent according to the release profile affected by the microparticles. However, microparticles often still do not provide the desired release profile, and in some cases even an undesirable release profile.

  Accordingly, there is a need for microparticles and methods of making the same that can substantially provide a release profile suitable for bioactive agents contained in or on the microparticles. These needs and other needs are met by the present invention.

SUMMARY Described herein are methods for producing microparticles having a release profile selected for release of a bioactive agent contained therein. The disclosed method may, in one aspect, allow for adjustment of one or more particulate properties depending on method parameters such as drying parameters. In one aspect, the desired release profile of the bioactive agent can be implemented or provided by adjusting or adjusting the manufacturing method parameters of the microparticles disclosed in the present invention.

  In one aspect, a method for producing microparticles having a release profile selected for release of a bioactive agent contained therein provides a slurry comprising microparticles having a bioactive agent releasable therein. B) selecting a release profile for the bioactive agent; and c) drying the microparticles under a series of drying parameters such that the selected release profile is substantially achieved.

  In a further aspect, a method of drying particulates comprises: a) providing a slurry comprising particulates having a bioactive agent releasable therein; and b) a stirred filter dryer under a series of selected drying parameters. Or the process of drying microparticles | fine-particles using a stirring type cell filter dryer is included.

  Also disclosed are microparticles made by the disclosed method.

  The advantages of the present invention are set forth in part in the following detailed description, is in part apparent from the detailed description, or may be obtained by practice of the aspects set forth below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory and are not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a plot of the particle size distribution of BSA-filled microparticles dried at 2 LPM nitrogen flow (rapid drying conditions) (lot00387-080).
FIG. 2 is a plot of the particle size distribution of BSA filled microparticles dried at 0.2 LPM nitrogen flow (slow drying conditions) (lot00387-075).
FIG. 3 is a plot of the drying profile of the BSA-filled microparticles showing the change in residual moisture over time in the drying apparatus.
FIG. 4 is a plot of the cumulative in vitro release profile of BSA loaded microparticles produced using different drying rates.

DETAILED DESCRIPTION OF THE INVENTION Before a compound, composition, composite, article, device, method, or use of the present invention is disclosed and described, the embodiments described below are specific compounds, compositions, composites. It is to be understood that the invention is not limited to articles, devices, methods or uses, and thus can of course vary. It should be understood that the meanings used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

  In this specification and in the claims that follow, reference will be made to a number of terms that are defined to have the following meanings:

  Throughout this application, unless the context dictates otherwise, the term “comprise” or variations such as “comprises” or “comprising” are expressed in integers or stages thereof Or it is understood to imply the inclusion of a group of integers or stages thereof, but to suggest the exclusion of other integers or stages or groups of integers or stages thereof.

  As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural unless the content clearly dictates otherwise. Must be noted. Thus, for example, reference to “bioactive agent” includes a mixture of two or more such agents and the like.

  “Any” or “optionally” means that the event or situation described below occurs or cannot occur, and the explanation includes when the event or situation occurs and when it does not occur Means that.

  Ranges may be expressed herein as from “about” one particular value and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations using the antecedent “about,” it is understood that the particular value forms another aspect. Furthermore, it is understood that the end points of each range are important in relation to and independent of the other end points.

  Ingredient weight percentages are based on the total weight of the formulation or composition in which the ingredient is included, unless stated to the contrary.

  The term “biocompatible” means a substance that is substantially non-toxic to a subject.

  “Biodegradable” generally refers herein to materials that corrode to soluble species or to materials that degrade to smaller units or chemical species under physiological conditions, which are themselves to the subject. Non-toxic (biocompatible) and can be metabolized, removed or excreted by the subject.

  The term “microparticle” is used herein to mean a variety of structures having a size generally between about 10 nm and 2000 microns (2 millimeters), and microcapsules, microspheres, Nanoparticles, nanocapsules, nanospheres as well as particles that are generally less than about 2000 microns (2 millimeters). In another aspect, the bioactive agent is encapsulated in microparticles.

  “Bioactive agent” means an agent having biological activity. The bioactive agent can be used to treat, diagnose, treat, alleviate, prevent (ie preventatively), ameliorate, modulate, or otherwise favorably affect a disease, disorder, infection, etc. A “releasable bioactive agent” is one that can be released from the disclosed microparticles. Bioactive agents also include those substances that affect the structure or function of a subject, or prodrugs that become bioactive or become more bioactive after being placed in a predetermined physiological environment.

  Disclosed are compounds, compositions, and components that can be used in the disclosed methods and compositions, can be used in combination, can be used in their manufacture, or products thereof. While these and other materials are disclosed herein, combinations, subsets, interactions, groups, etc. of these materials are disclosed, while various solid and collective of each of these compounds. Where specific descriptions of such combinations and their order are not specifically disclosed, each is specifically considered and understood as being described herein. For example, when many different polymers and agents are disclosed and described, each and every combination of polymers and reagents and their order are specifically considered unless indicated to the contrary. Yes. Thus, even though the classes of molecules A, B and C and the classes of molecules D, E and F and the examples of combination molecules AD are disclosed, And collectively considered. Therefore, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically considered, And A, B and C; D, E and F; and the combination of examples AD should be considered disclosed. Similarly, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the subgroups A to E, B to F, and C to E are specifically considered, and the disclosure of A, B and C; D, E and F; Should be regarded as disclosed. This concept applies to all aspects of this disclosure, including, but not limited to, steps in the method of making the disclosed composition and use of the disclosed composition. Thus, if there are various additional steps that can be performed, each of these additional steps can be performed by a particular embodiment or combination of embodiments of the disclosed method, each such combination being specific. It is understood that this should be considered and disclosed.

  As noted above, it may be desirable to provide control over the delivery of the bioactive agent if conventional formulations are not desirable for use. For example, some therapies include, among many other delivery forms, sustained release of the bioactive agent, immediate release of the bioactive agent, delivery of the bioactive agent to a particular tissue or fluid of the subject, or Delivery of more than one drug may be required.

  In one aspect, a method for treating microparticles containing a bioactive agent therein is provided to affect the release profile of the bioactive agent as described herein. In general, the release profile may be any desired release profile, depending on the treatment for which the bioactive agent is used. In further embodiments, the release profile is one or more of controlled release, extended release, controlled release, sustained release, pulsed release, delayed release, or programmed release, eg, periodic release.

  In one aspect, a bioactive agent release profile is selected. The selection of the release profile can occur at any time. In various aspects, the release profile can be selected before, during, or after production of the microparticles comprising the bioactive agent. In one aspect, the release profile can be selected prior to production of the microparticle, and the components of the microparticle can be selected to affect the selected release profile. In a further aspect, the release profile can be selected after production of the microparticles and the final microparticle processing parameters can be selected and / or adjusted to provide a selected release profile.

  In yet another aspect, a release profile is selected and the manufacturing parameters of the microparticles can be repeatedly adjusted to approach or achieve the selected release profile. The release profile can be achieved or substantially achieved. To that end, microparticles can be made that provide a release profile close to the selected release profile, but do not necessarily achieve the selected profile. In a further aspect, a selected release profile can be achieved.

  The microparticles can be made by any emulsification method known in the art. First, the polymer, releasable agent, eg, bioactive agent, and organic polymer solvent are mixed. This mixture of emulsions is formed by the addition of water, which is typically used as the medium for a continuous process. Emulsions usually contain organic droplets with polymers, organic solvents, and releasable agents in them. The organic solvent is then removed by various means, such as liquid extraction, solvent evaporation, etc., which leaves a slurry containing microparticles with releasable drug in it. The slurry may contain residual water and / or residual organic solvent.

  In one aspect, the disclosed method relates to the treatment of slurries containing microparticles that affect the release profile of bioactive agents contained in or on the microparticles. In general, the slurry may contain other suitable materials in addition to the microparticles and bioactive agent, depending on the processing conditions selected. In one aspect, the slurry comprises a liquid or solvent. In a further aspect, the slurry includes water. In yet another aspect, the slurry includes at least one organic solvent. In one aspect, the slurry can include both aqueous and organic solvents. The microparticles are typically dispersed or suspended in a slurry.

  In a further aspect, the slurry comprising the microparticles can be dried under a series of drying parameters such that the selected release profile is substantially achieved. Thus, in one aspect, the manner in which the microparticles are dried can affect the release profile of the bioactive agent contained in the microparticles. While not wishing to be bound by any theory, the way in which the microparticles are dried can affect the morphology of the microparticles, thereby affecting the release profile of the bioactive agent contained therein. It is thought that it exerts.

  In one aspect, the drying parameters with which the selected release profile can be achieved are known or not known prior to drying the microparticles to achieve the selected release profile. Thus, in one aspect, multiple particulate drying operations can be useful to substantially achieve the selected release profile. For example, the microparticles can be formulated and dried under a series of drying parameters and the release profile of the bioactive agent contained in the microparticles can be recorded. If the release profile is not substantially close to the selected or desired release profile, the drying parameters can be iteratively adjusted until the selected or desired release profile is substantially achieved. In contrast, it is possible to predict that a series of drying parameters will provide a selected release profile.

  In general, the drying parameter may be any drying parameter. In the case of air drying using non-mechanical means, for example, the drying parameter may be one or more of temperature, pressure, humidity, or drying time. In a further aspect, in the case of mechanical drying, the drying parameters are one or more of temperature, pressure, humidity, drying time, agitation speed, agitation speed, or a gas flow on, in or through the slurry. It's okay. The gas flow rate may be, for example, in the range of 0.2 to about 2.0 L / min. The drying gas may be any inert gas, such as air, nitrogen, argon or the like.

  The microparticles can be dried under a series of dryings using any suitable method. If a dryer is used in the methods disclosed herein, the dryer may be any dryer that achieves substantially the results intended herein. In one aspect, the microparticles can be dried using a stirred filter dryer. In a further aspect, the disclosed method includes drying the microparticles with the bioactive agent therein in a stirred filter dryer. A stirring filter dryer is a drying device known in the art. Typically, a stirred filter dryer includes a container having a filter plate at the bottom of the container. The slurry is loaded into a container and optionally driven by a stirring shaft under reduced pressure (eg vacuum) and / or under a gas stream, eg air or inert gas, eg nitrogen or argon. It is dried with mechanical stirring of the slurry by the take-off blade. By having the entire container with a jacketed container and / or other jacketed components through which the heat transfer medium can pass, the desired temperature can be maintained. The drying parameters of the agitating filter dryer are not limited to temperature, pressure, humidity, drying time, agitation speed, amount of cleaning medium, in particular, for example, number of cleanings, scraping blade speed, ventilation rate, discharge mechanism There may be mentioned an inert gas in the stream. In general, any type of agitated filter dryer can be used. In a further aspect, a Nutsche filter may be used. The Nutsche filter is a kind of agitation filter dryer. In yet another embodiment, a commercially available stirred cell dryer may be used, for example, a stirred cell dryer such as a MILLIPORE stirred cell dryer.

  In one aspect, it is understood that the use of an agitated filter dryer can be beneficial to overcome the challenges encountered in conventional bulk material drying methods in the particulate field, such as the use of Sweco dryers. Should. Sco dryers are typically composed of a vessel that is shaken to agitate the bulk material. In many cases, large agglomerates that must be separated from the final powder can be formed during use of the eco-dryer. This is partly due to the fact that conventional scale dryers are not equipped with mechanical agitation or scraping means and are merely shaking the bulk material container while drying. In one aspect, it should be understood that the use of an agitated filter dryer provides good particle distribution with less agglomerates and also allows for control of drying parameters as described above. However, in a further embodiment, the microparticles can be dried using a eco dryer.

  In one aspect, microparticles produced by the disclosed method are disclosed. In general, the microparticles disclosed herein may be any suitable microparticle. In one aspect, the bioactive agent is encapsulated within the microparticles. In another aspect, the bioactive agent is associated with the microparticle. In one aspect, the microparticles comprise a suitable biocompatible and biodegradable or non-biodegradable polymer. The polymer may be a homopolymer or copolymer, such as, but not limited to, a block or block copolymer or terpolymer, a random copolymer or terpolymer, a star polymer, or a dendrimer. Depending on the desired properties of the microparticles, any desired molecular weight polymer can be used. In certain embodiments, where high strength particulates are desired, high molecular weight polymers can be used, for example, to meet strength requirements. In other embodiments, low or medium molecular weight polymers may be used, for example, where polymer resorption time is desired rather than material strength.

  If a biodegradable polymer is used, the microparticles can be formulated to degrade within a desired time interval when present in the subject. In some aspects, the time interval may be from less than about 1 day to about 1 month. Longer time intervals can be extended to 6 months, including, for example, a polymer matrix that degrades from about 0 months to about 6 months, or from about 1 month to about 6 months. In other embodiments, the polymer may degrade over long time intervals of up to 2 years or longer, for example, from about 0 to about 2 years, or from about 1 month to about 2 years.

  In one aspect, the desired release profile can affect the choice of polymer. The biocompatible polymer can be selected, for example, to release or allow release of the bioactive agent therefrom at a desired elapsed time after the microparticles are administered to the subject. For example, the polymer may be at least 25%, for example, at least 25% when the bioactive agent partially reduces its activity when the bioactive agent begins to decrease its activity before the activity of the bioactive agent begins to decrease. Release bioactive agent when it is reduced by 50%, or at least 75%, when the bioactive agent substantially reduces its activity, or when the bioactive agent is completely or no longer active Or can be selected to allow its release.

  In one embodiment, the polymer is a polyester, polyhydroxyalkanoate, polyhydroxybutyrate, polydioxanone, polyhydroxyvalerate, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyphosphoester, polydioxanone, polyphosphoester , Polyphosphate, polyphosphonate, polyphosphate, polyhydroxyalkanoate, polycarbonate, polyalkyl carbonate, polyorthocarbonate, polyesteramide, polyamide, polyamine, polypeptide, polyurethane, polyalkylene alkylate, polyalkylene oxalate, Polyalkylene succinic acid, polyhydroxy fatty acid, polyacetal, polycyanoacrylate, polyketal, polyether ester, polyether Polyalkylene glycols, polyalkylene oxides, polyethylene glycols, polyethylene oxide, polypeptide, polysaccharide, or may be one or more of polyvinylpyrrolidone. Other non-biodegradable but durable polymers include, without limitation, ethylene-vinyl acetate copolymers, polytetrafluoroethylene, polypropylene, polyethylene, and the like. Similarly, other suitable non-biodegradable polymers include, without limitation, silicones and polyurethanes.

  In a further aspect, the polymer is poly (lactide), poly (glycolide), poly (lactide-co-glycolide), poly (caprolactone), poly (orthoester), poly (phosphazene), poly (hydroxybutyrate) or Copolymers comprising poly (hydroxybutyrate), poly (lactide-co-caprolactone), polycarbonate, polyesteramide, polyanhydrides, poly (dioxanone), poly (alkylene alkylates), copolymers of polyethylene glycol and polyorthoesters, Biodegradable polyurethane, poly (amino acid), polyamide, polyesteramide, polyetherester, polyacetal, polycyanoacrylate, poly (oxyethylene) / poly (oxypropylene) copolymer, polyacetal, polyketer , Polyphosphoesters, polyhydroxyvalerates or polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, copolymers containing poly (maleic acid), and copolymers, terpolymers, combinations or blends thereof. It's okay.

  In yet another aspect, useful biocompatible polymers are lactic acid, glycolic acid, lactide, glycolide, caprolactone, hydroxybutyrate, hydroxyvalerate, dioxanone, polyethylene glycol (PEG), polyethylene oxide, or combinations thereof It contains one or more residues. In yet another aspect, useful biocompatible polymers are those that include one or more residues of lactide, glycolide, caprolactone, or combinations thereof.

  In one aspect, useful biodegradable polymers include those comprising one or more blocks of hydrophilic or water soluble polymers, such as, but not limited to, polyethylene glycol (PEG) in combination with one or more blocks. Or polyvinylpyrrolidone (PVP); another biocompatible or biodegradable polymer comprising lactide, glycolide, caprolactone, or combinations thereof.

  In certain aspects, the biodegradable polymer can include one or more lactide residues. To that end, the polymer may be any lactide residue including all racemic and stereospecific forms of lactide, such as, but not limited to, L-lactide, D-lactide, and D, L-lactide, or their Mixtures can be included. Useful polymers including lactide include, but are not limited to, poly (L-lactide), poly (D-lactide), and poly (DL-lactide); and poly (lactide-co-glycolide), such as poly ( L-lactide-co-glycolide), poly (D-lactide-co-glycolide), and poly (DL-lactide-co-glycolide); or copolymers, terpolymers, combinations, or blends thereof. Lactide / glycolide polymers can be conveniently prepared by melt polymerization via ring opening of lactide and glycolide monomers. In addition, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available. L-polymers are more crystalline and resorb more slowly than DL-polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Lactide or glycolide homopolymers are also commercially available.

  When the biodegradable polymer is poly (lactide-co-glycolide), poly (lactide), or poly (glycolide), the amount of lactide and glycolide in the polymer can vary. In further embodiments, the biodegradable polymer comprises 0-100 mol%, 40-100 mol%, 50-100 mol%, 60-100 mol%, 70-100 mol%, or 80-100 mol% lactide. Containing, 0 to 100 mol%, 0 to 60 mol%, 10 to 40 mol%, 20 to 40 mol%, or 30 to 40 mol% of glycolide, wherein the amount of lactide and glycolide is 100 mol %. In a further aspect, the biodegradable polymer is 95: 5 poly (lactide-co-glycolide), 85:15 poly (lactide-co-glycolide), 75:25 poly (lactide-co-glycolide), It may be 65:35 poly (lactide-co-glycolide), or 50:50 poly (lactide-co-glycolide), where the ratio is a molar ratio.

  In a further aspect, the polymer may be poly (caprolactone) or poly (lactide-co-caprolactone). In one aspect, the polymer may be poly (lactide-caprolactone), which in various aspects is 95: 5 poly (lactide-co-caprolactone), 85:15 poly (lactide-co-caprolactone). 75:25 poly (lactide-co-caprolactone), 65:35 poly (lactide-co-caprolactone), or 50:50 poly (lactide-co-caprolactone), where the ratio is Molar ratio.

  It is understood that any combination of the aforementioned biodegradable polymers can be used, including, but not limited to, copolymers thereof, mixtures thereof, or blends thereof. Similarly, when a residue of a biodegradable polymer is disclosed, it is understood that any suitable polymer, copolymer, mixture or blend containing the disclosed residue is also considered disclosed. To that end, it is understood that where multiple residues are disclosed individually (ie, not in combination with another), any combination of individual residues can be used.

  In general, the microparticles can be any microparticle made from a suitable starting material. In one aspect, as described above, the microparticles can be made from a suitable polymer. The microparticles contain the bioactive agent contained therein and can affect its release. The microparticles can be composed of any of those polymers described above or any polymer used in the microparticle field. In general, the polymers described above can be crosslinked to a certain level, as is known in the art, thereby forming polymer microparticles.

  In one aspect, the disclosed microparticles can have an average particle size of about 20 microns to about 125 microns. In one embodiment, the average particle size range is from about 40 microns to about 90 microns. In another aspect, the average particle size range is from about 50 microns to about 80 microns. The particle size distribution is measured by laser diffraction methods known to those skilled in the art.

  In further embodiments, the bioactive agent can be encapsulated, microencapsulated, or contained within microparticles. The microparticles can modulate the release of the bioactive agent. The microparticles can include any desired amount of bioactive agent. For example, the microparticles include any range between the disclosed percentages relative to the mass of the microparticles, including 1%, 5%, 10%, 20%, 30%, 40%, 50% %, 60%, 70%, 80%, 90%, 95% bioactive agent may be included.

  The microparticles are disclosed in methods known in the art, for example, US Patent Publication No. 2007/0190154 by Zeigerson, published August 16, 2007, and US Patent No. 5,407,609 by Tice et al. (Both of which are incorporated herein by reference in their entirety for the purpose of teaching how to produce microparticles). As will be apparent, depending on the processing conditions, the polymer used as starting material in the mixing step may or may not be the same polymer that is ultimately present in the implantable composite. For example, the polymer during processing undergoes a polymerization or depolymerization reaction, which can ultimately produce various polymers that are used prior to processing. Thus, the term “polymer” as used herein covers the polymer used as the starting material as well as the final polymer present in the device manufactured by the methods described herein. The manufacturing method of microparticles | fine-particles can be used combining said drying method and a drying parameter.

  As described above, the microparticles include a bioactive agent. The bioactive agent may be a releasable bioactive agent, ie, a bioactive agent that can be released from the microparticles into the adjacent tissue or fluid of the subject. In certain embodiments, the bioactive agent can be in or on the microparticle.

  Various forms of bioactive agents can be used that can be released from the microparticles into adjacent tissues or body fluids. To that end, liquid or solid bioactive agents can be introduced into the implantable composites described herein. The bioactive agent is at least very slightly water soluble, preferably moderately water soluble. Bioactive agents can include salts of the active ingredients. Thus, the bioactive agent can be an acidic, basic, or amphoteric salt. They may be non-ionic molecules capable of hydrogen bonding, polar molecules, or molecular complexes. A bioactive agent is, for example, an uncharged molecule, molecular complex, salt, ether, ester, amide, polymeric drug complex, or other form to provide effective biological or physiological activity. Can be included in the composition.

  Examples of bioactive agents introduced into the systems herein include, but are not limited to, peptides, proteins such as hormones, enzymes, antibodies, etc., nucleic acids such as aptamers, iRNA, DNA, RNA, antisense nucleic acids. Or an analog, an antisense nucleic acid analog or analog, a low molecular weight compound, or a high molecular weight compound. Bioactive agents intended for use in the disclosed implantable composites include anabolic agents, antacids, anti-asthma agents, anti-cholesterolemia and anti-lipid agents, anti-coagulants, anti-convulsants, anti- Diarrhea, antiemetics, anti-infectives, for example, antibacterial and antibacterial agents, anti-inflammatory agents, anti-manic drugs, antimetabolites, antiemetics, anti-neoplastic agents, anti-obesity agents, antipyretics and analgesics, anticonvulsants , Antithrombotic, antitussive, antiuricemia, antianginal, antihistamine, appetite suppressant, biologic, brain dilator, coronary dilator, bronchiodilators, cytotoxicity Drugs, decongestants, diuretics, diagnostic agents, erythropoietin preparations, expectorants, gastrointestinal sedatives, hyperglycemic drugs, hypnotics, hypoglycemic drugs, immunomodulators, ion exchange resins, laxatives, mineral supplements, mucolytic agents, nerves Muscle drugs, peripheral vasodilators, psychotropic drugs, sedatives, stimulants, Thyroid and antithyroid drugs, tissue growth drugs, uterine relaxants, vitamins, or antigenic substances.

  Other bioactive agents include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenic factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentan enoic acid, clofedianol hydrochloride, Chlorpheniramine maleate, phenindamine tartaric acid, pyriramine maleic acid, doxylamine succinate, phenyltolamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine morphine sulfate, mineral supplement, cholestyramine N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenylpropanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide, Magnesium oxide, peptides, polypeptides, proteins, amino acids, hormones, interferons, cytokines, and vaccines and the like.

  Representative agents that can be used as bioactive agents in microparticles include, but are not limited to, peptide drugs, protein drugs, desensitizers, antigens, anti-infective agents such as antibiotics, antibacterial agents, antivirals Agent, antibacterial agent, antiparasitic, antifungal substance and combinations thereof, antiallergy, androgenic steroid, decongestant, hypnotic, steroidal anti-inflammatory, anticholinergic, sympathetic, sedative, miotic, Psychoactive, tranquilizer, vaccine, estrogen, progesterone, liquid, prostaglandin, analgesic, antispasmodic, antimalarial, antihistamine, cardioactive, nonsteroidal anti-inflammatory, antiparkinsonian Antihypertensives, beta-adrenergic blockers, nutrients, and benzophenanthridine alkaloids. The drug may further be a substance that can act as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like.

The microparticles can contain many bioactive agents, alone or in combination. Other bioactive agents include, but are not limited to, analgesics such as acetaminophen, acetylsalicylic acid, and the like; anesthetics such as lidocaine, xylocaine, and the like; anorectic agents such as dexadrine, Phendimetrazine tartrate, and the like; anti-arthritic drugs such as methylprednisolone, ibuprofen, and the like; anti-asthmatic drugs such as terbutaline sulfate, theophylline, ephedrine, and the like; antibiotics such as sulfiso Xazole, penicillin G, ampicillin, cephalosporin, amikacin, gentamicin, tetracycline, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, and the like; antifungal agents such as amphotericin B, nystatin, ketocona Antiviral agents such as acyclovir, amantadine, and the like; anticancer agents such as cyclophosphamide, methotrexate, etretinate, and the like; anticoagulants such as heparin, warfarin, and the like Anticonvulsants such as sodium phenytoin, diazepam, and the like; antidepressants such as isocarboxazide, amoxapine, and the like; antihistamines such as diphenhydramine HCl, chlorpheniramine maleate, and the like Hormones such as insulin, progestins, estrogens, corticoids, glucocorticoids, androgens, and the like; tranquilizers such as sorazine, diazepam, chlorpromazine HCl, reserpine, chlordiazepoxide HCl And the like; antispasmodics, e.g., belladonna alkaloids, dicyclomine hydrochloride, and the like; vitamins and minerals, for example, essential amino acids, calcium, iron, potassium, zinc, vitamin B _12, and the like; cardiovascular agents, for example, Prazosin HCl, nitroglycerin, propranolol HCl, hydralazine HCl, pancrelipase, succinate dehydrogenase, and the like; peptides and proteins such as LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptide, growth release factor, angiotensin , FSH, EGF, bone morphogenetic protein (BMP), erythropoeitin (EPO), interferon, interleukin, collagen, fibrinogen, insulin, factor VIII, factor IX Child, Enbrel (R), Rituxam (R), Herceptin (R), alpha-glucosidase, Cerazyme / Ceredose (R), vasopressin, ACTH, human serum albumin, gamma globulin, structural protein, blood product protein, complex Proteins, enzymes, antibodies, monoclonal antibodies, and the like; prostaglandins; nucleic acids; carbohydrates; fats; anesthetics such as morphine, codeine, and the like, psychotherapeutics; antimalarials, L-dopa, diuretics For example, furosemide, spironolactone, and the like; anti-ulcer drugs such as rantidine HCl, cimetidine HCl, and the like.

  Bioactive agents are also immunomodulators such as cytokines, interleukins, interferons, colony stimulating factors, tumor necrosis factors, and the like; allergens such as cat dander, birch pollen, house dust mite, pollen, and the like Antigens of bacterial organisms, such as pneumococci, influenza, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphteriae, Listeria, anthrax, tetanus, Clostridium botulinum, Clostridium perfringens, marrow Neisseria gonorrhoeae, Neisseria gonorrhoeae, Mutans, Pseudomonas aeruginosa, Salmonella typhi, Hemophilus parainfluenza, Bordetella pertussis, Strains, Plague, Cholera, Legionella pneumophila, Mycobacterium tuberculosis, Leprosy, Syphilis treponema, Leptospire telogenans (Leptspirosis interrogans), Lyme disease bacteria (Borrelia burgddorferi) , Campylobacter jejuni, and the like; smallpox, influenza A and B, RS (respiratory synctial) virus, parainfluenza, measles, HIV, SARS, varicella zoster, herpes simplex 1 and 2, cytomegalovirus, Epstein -Bar virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella, coxsackie virus, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocytic choriomeningitis, B Antigens of viruses such as hepatitis B and the like; such fungi, protozoa, and parasites such as Cryptococcuc neoformans, histoplasma capslatum, candida albicans, candida tropicalis, nocardia asterloy (Nocardia asteroids), Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Parrot disease Chlamyda psittaci, Chlamydia trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba atoba histo ), Toxoplasma, vaginal Trichomonas, Schistosoma mansoni, and the like. These antigens may be in the form of whole dead organisms, peptides, proteins, glycoproteins, carbohydrates, or combinations thereof.

  In a more particular embodiment, the bioactive agent includes an antibiotic. Antibiotics are, for example, amikacin, gentamicin, kanamycin, neomycin, netilmycin, streptomycin, tobramycin, paromomycin, ansamycin, geldanamycin, herbimycin, carbacephem, loracarbef, carbapenems, ertapenem, dripenem, imipenem / silastatin, meropenem, Cephalosporin (first generation), cefadroxyl, cephazoline, cephalothin, cephalexin, cephalosporin (second generation), cefaclor, cephamandol, cefoxitin, cefprozil, cefuroxime, cephalosporin (third generation), Cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, ceftizoxy , Ceftriaxone, cephalosporins (4th generation), cefepime, cephalosporins (5th generation), ceftbiprole, glycopeptide, teicoplanin, vancomycin, macrolide, azithromycin, clarithromycin, dirithromycin , Erythromycin, roxithromycin, troleandomycin, tethromycin, spectinomycin, monobactam, aztreonam, penicillin, amoxicillin, ampicillin, azulocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, citricillin Penicillin, piperacillin, ticarcillin, polypeptide, bacitracin, colistin, polymyxin B, quinolone, ciprofloxacin, eno Sasin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, sulfonamide, maphenide, prontodil (prototype), sulfacetamide, sulfamethizol, sulfanilimide (prototype), sulfasalazine, su Rufisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole) (TMP-SMX), tetracycline such as demeclocyclone, doxycycline, minocycline, oxytetracycline, tetracycline and the like; Ramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid , Linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampicin (rifapine in the United States), tinidazole, or combinations thereof. In one aspect, the bioactive agent may be a combination of rifampicin (Rifampin in the United States) and minocycline.

  In certain embodiments, the bioactive agent can be present as an ingredient in a pharmaceutical composition. The pharmaceutical composition is conveniently manufactured in the desired dosage form, eg, in unit dosage form or controlled release dosage form, and may be manufactured by any method well known in the pharmaceutical arts. In general, pharmaceutical compositions are prepared by uniformly and intimately associating a bioactive agent with a liquid carrier, a finely divided solid carrier, or both. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gas carriers include carbon dioxide and nitrogen. Other pharmaceutically acceptable carriers or ingredients that can be mixed with the bioactive agent include, for example, fatty acids, sugars, salts, water soluble polymers such as polyethylene glycol, proteins, polysaccharides, or carboxymethylcellulose, surfactants , Plasticizers, high molecular weight or low molecular weight porosigens such as polymers or salts or sugars, or hydrophobic low molecular weight compounds such as cholesterol or waxes.

  The microparticles can be administered to a desired subject. The subject may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. The subject of the methods disclosed herein can be, for example, a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not imply a particular age or gender. Thus, adult and neonatal subjects, as well as fetuses, are intended to be covered, whether male or female.

  In this application, in one aspect, a method of producing microparticles having a release profile selected for release of a bioactive agent contained therein comprising: a) a bioactive agent releasable therein. Providing a slurry comprising microparticles having; b) selecting a release profile of the bioactive agent; and c) drying the microparticles under a series of drying parameters such that the selected release profile is substantially achieved. The said manufacturing method including the process to perform is disclosed. Also herein, in one aspect, a) providing a slurry comprising microparticles having a bioactive agent releasable therein; and b) a stirred filter under a series of selected drying parameters. There is also disclosed a method for drying fine particles, which includes a step of drying fine particles using a dryer.

  Also disclosed is any of the methods disclosed herein wherein the particulates are dried using a stirred filter dryer or Nutsche filter dryer.

  Also disclosed is the method of any of the above embodiments, wherein the slurry comprises water.

  Also disclosed are methods of any of the above embodiments, wherein the slurry comprises at least one organic material.

  Also disclosed is the method of any of the above embodiments, wherein the slurry comprises ethyl acetate.

  Also disclosed is the method of any of the above embodiments, wherein the microparticles comprise poly (lactide), poly (glycolide), poly (caprolactone), or combinations thereof.

  Also disclosed is the method of any of the above embodiments, wherein the microparticles comprise poly (lactide-co-glycolide).

  Also disclosed is the method of any of the above embodiments, wherein the microparticles are dried using a stirred cell filter dryer.

  Also disclosed is the process of any of the above embodiments, wherein the microparticles are dried under nitrogen at a nitrogen flow rate in the range of 0.2 to 2 liters per minute.

  The microparticles are produced by the method of any of the above aspects.

FIG. 1 shows the particle size distribution of BSA-filled microparticles dried at a 2 LPM nitrogen flow rate (rapid drying condition). FIG. 2 shows the particle size distribution of BSA-filled microparticles dried at 0.2 LPM nitrogen flow rate (slow drying conditions). FIG. 3 shows a drying profile of BSA-filled microparticles showing changes in residual moisture over time in the drying apparatus. FIG. 4 shows the cumulative in vitro release profile of BSA filled microparticles produced using different drying rates.

Examples The following examples provide those skilled in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated. And is intended to be merely exemplary of the invention and is not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (amount, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Celsius or ambient temperature, and pressure is at or near atmospheric.

Example 1 Production / Drying of Microspheres Bovine serum albumin, BSA (Fraction V, Sigma Chemical Co., St. Louis, MO), 20% 5050PLG4. At a concentration of 10% based on the combined mass of polymer and BSA. 5E polymer (Lakeshoe Biomaterials brand polymer from SurModics Pharmaceuticals (Birmingham, Alab.)) Was added to an ethyl acetate solution. BSA was suspended in the polymer solution for 30 seconds at 13500 rpm using an IKA Ultraturrax. The drug / polymer suspension (15 mL) is then emulsified in an aqueous solution containing 2% by weight poly (vinyl alcohol) (PVA) at a rate of 15 ml / min and this is subjected to a Silverson L4RT-A homogenizer at 860 rpm. Used and fed at a rate of 150 ml / min. The resulting o / w emulsion is then extracted into deionized water, which is fed at a rate of 1450 ml / min and stirred for an additional 60 minutes to extract the organic solvent and form polymer particulates. The resulting microsphere suspension was passed through 150 and 25 micron test sieves (Retsch GmbH) to isolate a fine particle fraction between 25 and 250 microns in size. The product collected on a 25 micron sieve was washed with deionized water (1 liter) and then transferred to a dryer.

  The drying apparatus was a modified MILLIPORE stirred cell (MILLIPORE stirred cell 8200, Fisher Scientific), and a 25 μm sieve mesh material (Retsch GmbH) was used as the bottom filtration membrane. This dryer was then connected to a nitrogen source. Nitrogen flow is initiated to remove excess water from the system to form a solid microsphere cake at the bottom of the cell. Nitrogen flow is then controlled through the cell using a regulator so that the drying conditions allow either fast or slow drying conditions based on the rate of nitrogen flow through the drying device. Selected. The high speed drying conditions used a nitrogen flow rate of 2 LPM, while the low speed drying conditions used a flow rate of 0.2 LPM. Aliquots of microspheres were taken throughout the drying process and the microsphere cake was stirred at each time point to facilitate further drying across the sample. As soon as the product was dried, it was recovered and saved for further analysis.

Particle Size Analysis Particle size analysis was performed by laser diffraction using a Beckman Coulter LSI 3,320 particle size analyzer. The size distribution was calculated based on volume average statistics using the Fraunhofer model. Particle size was performed on a portion of the bulk particulate product taken just prior to collection on the test sieve. Reported particle size results are in microns, including average size (average), and particle size with 10% and 90% particle size distributions (D10 and D90, respectively).

Residual moisture and residual solvent analysis Samples pulled throughout the drying process were analyzed for residual moisture content by a Computrac Vapor Pro moisture analyzer (Arizona Instruments). Analysis of residual solvent against ethyl acetate was performed by gas chromatography (GC).

BSA content The final product was analyzed for BSA content by accurately weighing 10 mg of microspheres into a test tube and adding 3 ml of ethyl acetate. This mixture was vortexed for 30 seconds and then centrifuged at 3500 rpm for 15 minutes. The supernatant was removed, 3 ml of ethyl acetate was added, the mixture was vortexed for 30 seconds and centrifuged at 3500 rpm for 15 minutes. This procedure was repeated once more at the end of a total of three ethyl acetate washes. After the last wash and removal of the supernatant, the remaining BSA pellets were dried under a stream of nitrogen to remove excess ethyl acetate. Next, 3 ml of phosphate buffered saline (PBS, IX) (Fisher Scientific) was added to the dried BSA material and the mixture was vortexed for 30 seconds to completely dissolve the BSA. The mixture was then centrifuged at 3500 rpm for 15 minutes to remove residual polymer precipitates. The supernatant containing water-soluble BSA was then collected and analyzed by HPLC for BSA content.

In vitro release In vitro testing was performed by accurately weighing 30 mg of BSA-filled microspheres into a test tube, adding 3 ml of IX PBS, and placing the sample in a 37 ° C. static incubator. At each time point, microspheres were filtered from the release buffer using a serum separator and the release buffer was collected for analysis. At each time point, the total volume of release buffer was removed and completely replaced with fresh 1X PBS. Each lot of microspheres was evaluated in triplicate for release studies. Samples were analyzed by HPLC.

HPLC Method HPLC analysis was performed on a Perkin Elmer instrument using the following parameters: Shodex Protein KW-803 column, 214 nm detection wavelength, 1 mL / min mobile phase flow rate, 10 μl sample injection volume, and 20 per sample. Running time in minutes. The sample tray and column were maintained at ambient temperature. The mobile phase was 1: 1 100 mM sodium phosphate: 100 mM sodium sulfate premixed at pH 7.

Results The properties of the following samples were evaluated:

The particle sizes of the samples from Table 1 are listed in Table 2 below. The particle size distribution of these samples is shown in FIGS.

The drying profiles of the above two samples are shown in FIG. As can be seen from FIG. 3, fast drying (ie, at a high nitrogen flow rate) reduces moisture faster than slow drying. Table 3 lists the residual solvent for each sample. Table 4 shows the drug filling after drying.

  With respect to FIG. 4, this shows the cumulative release profile of the two samples, demonstrating that different release profiles can be achieved by adjusting the drying characteristics. Specifically, in this case, slow drying results in slow release for microspheres dried under high speed conditions.

  Various modifications and variations can be made to the compounds, composites, kits, articles, devices, compositions, and methods described herein. Other aspects of the compounds, composites, kits, articles, devices, compositions, and methods described herein can be found in the compounds, composites, kits, articles, devices, compositions, and methods disclosed herein. And a discussion of the method and discussion of implementation. It is intended that the specification and examples be considered as exemplary.

Claims (12)

A method of producing microparticles having a release profile selected for release of a bioactive agent contained therein,
a) providing a slurry comprising microparticles having a bioactive agent releasable therein;
b) selecting a release profile for the bioactive agent; and c) selecting a series of drying parameters to achieve a drying rate such that the selected release profile is substantially achieved.
d) drying the microparticles under a selected set of drying parameters, wherein slow drying results in slow bioactive agent release to the microparticles dried under high speed drying conditions, and Wherein the microparticles are dried using a stirred cell filter dryer and the microparticles are dried at a nitrogen flow rate in the range of 0.2 to 2 liters per minute under nitrogen . The slurry comprises water, The method of claim 1. The slurry comprises at least one organic substance, the method according to claim 1 or 2. 4. A method according to any one of claims 1 to 3 , wherein the slurry comprises ethyl acetate. 5. The method of any one of claims 1-4 , wherein the microparticles comprise poly (lactide), poly (glycolide), poly (caprolactone), or combinations thereof. 6. The method according to any one of claims 1 to 5 , wherein the microparticles comprise poly (lactide-co-glycolide). A method for drying fine particles,
a) providing a slurry comprising microparticles with bioactive agent releasable therein; and b) using a stirred filter dryer under a series of drying parameters selected to achieve a drying rate. A step of drying the microparticles, wherein slow drying results in a slow release of bioactive agent to the microparticles dried under high speed drying conditions, wherein the microparticles are mixed with a stirred cell filter dryer. Said method wherein the fine particles are dried at a gas flow rate in the range of 0.2 to 2 liters per minute under gas . The method of claim 7 , wherein the slurry comprises water. The method according to claim 7 or 8 , wherein the slurry contains at least one organic substance. The process according to any one of claims 7 to 9 , wherein the slurry comprises ethyl acetate. 11. A method according to any one of claims 7 to 10 , wherein the microparticles comprise poly (lactide), poly (glycolide), poly (caprolactone), or combinations thereof. 12. A method according to any one of claims 7 to 11 wherein the microparticles comprise poly (lactide-co-glycolide).

Images