WO2014074114A1 - Drying methods for tuning microparticle properties - Google Patents
Drying methods for tuning microparticle properties Download PDFInfo
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- WO2014074114A1 WO2014074114A1 PCT/US2012/064482 US2012064482W WO2014074114A1 WO 2014074114 A1 WO2014074114 A1 WO 2014074114A1 US 2012064482 W US2012064482 W US 2012064482W WO 2014074114 A1 WO2014074114 A1 WO 2014074114A1
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- microparticle
- poly
- bioactive agent
- drying
- lactide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Definitions
- bioactive agent In order for a bioactive agent to work effectively, it must be delivered to a subject in a way that is both safe and effective.
- An ideal pharmacokinetic profile of a bioactive agent is one which allows for therapeutic concentrations of the bioactive agent to be reached in a subject, while not exceeding the maximum tolerable dose. For certain pharmacological applications, concentrations of the bioactive agent should remain at a therapeutic level for an extended period of time until the desired therapeutic result is achieved.
- microparticles and methods for the manufacture thereof that can substantially provide a suitable release profile for a bioactive agent contained in or on the microparticle.
- Described herein are methods for preparing a microparticle having a selected release profile for the release of a bioactive agent contained therein.
- the disclosed methods can, in one aspect, allow for the tuning of one or more microparticle properties, depending on the method parameters, such as the drying parameters.
- a desired release profile of a bioactive agent can be affected or provided by adjusting or tuning the microparticle preparation method parameters disclosed herein.
- a method for preparing a microparticle having a selected release profile for the release of a bioactive agent contained therein comprises: a) providing a slurry comprising a microparticle having a releasable bioactive agent therein; b) selecting a release profile for the bioactive agent; and c) drying the microparticle under a set of drying parameters such that the selected release profile is substantially achieved.
- a method for drying a microparticle comprises: a) providing a slurry comprising a microparticle having a releasable bioactive agent therein; and b) drying the microparticle using an agitated filter dryer or a stirred cell filter dryer under a set of selected drying parameters.
- microparticles made by the disclosed methods.
- FIG. 1 is a plot of particle size distribution of BSA-loaded microparticles dried with 2 LPM nitrogen flow rate (fast drying conditions) (lot 00387-080).
- FIG. 2 is a plot of particle size distribution of BSA-loaded microparticles dried with 0.2 LPM nitrogen flow rate (slow drying conditions) (lot 00387-075)
- FIG. 3 is a plot of drying profiles of BSA-loaded microparticle showing the change in residual moisture over time in the drying apparatus.
- FIG. 4 is a plot of cumulative in vitro release profiles of BSA-loaded microparticles prepared using different rates of drying.
- 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, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
- a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
- biocompatible refers a substance that is substantially non-toxic to a subject.
- Biodegradable is generally referred to herein as a material that will erode to soluble species or that will degrade under physiologic conditions to smaller units or chemical species that are, themselves, non-toxic (biocompatible) to the subject and capable of being metabolized, eliminated, or excreted by the subject.
- microparticle is used herein to refer generally to a variety of structures having sizes from about 10 nm to 2000 microns (2 millimeters) and includes microcapsule, microsphere, nanoparticle, nanocapsule, nanosphere as well as particles, in general, that are less than about 2000 microns (2 millimeters).
- the bioactive agent is encapsulated in the microparticle.
- a “bioactive agent” refers to an agent that has biological activity.
- the biological agent can be used to treat, diagnose, cure, mitigate, prevent (i.e., prophylactically), ameliorate, modulate, or have an otherwise favorable effect on a disease, disorder, infection, and the like.
- a “releasable bioactive agent” is one that can be released from a disclosed microparticle.
- Bioactive agents also include those substances which affect the structure or function of a subject, or a pro-drug, which becomes bioactive or more bioactive after it has been placed in a predetermined physiological environment.
- These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a number of different polymers and agents are disclosed and discussed, each and every combination and permutation of the polymer and agent are specifically contemplated unless specifically indicated to the contrary.
- the sub-group of A-E, B- F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
- This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions.
- steps in methods of making and using the disclosed compositions are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
- a bioactive agent can be desirable when traditional formulations are not desirable for use.
- some therapies may desire the slow release of a bioactive agent, the fast release of a bioactive agent, delivery of the bioactive agent to specific tissues or fluids of a subject, or delivery of two or more agents, among many other delivery modes.
- the release profile can be any desired release profile, depending on the therapy for which the bioactive agent will be used.
- the release profile is one or more of controlled-release, extended-release, modified-release, sustained- release, pulsatile-release, delayed-release, or programmed-release, including cyclical-release.
- a release profile for a bioactive agent is selected.
- the selection of the release profile can occur at any time.
- the selection of the release profile can be made prior to, at, during, or after, the manufacture of the microparticle comprising the bioactive agent.
- a release profile can be selected prior to the manufacture of the microparticle, and the microparticle constituents can be selected so as to affect the selected release profile.
- a release profile can be selected after the manufacture of the microparticle, and the final microparticle processing parameters can be selected and/or adjusted to provide the selected release profile.
- a release profile can be selected, and the microparticle manufacturing parameters can be iteratively adjusted so as to approach or achieve the selected release profile.
- the release profile can be achieved or substantially achieved.
- a microparticle can be made that provides a release profile that approaches a selected release profile, but that might not necessarily achieve the selected profile.
- the selected release profile can be achieved.
- Microparticles can be made by any emulsion method known in the art.
- a polymer, a releasable agent, e.g., a bioactive agent, and an organic solvent for the polymer are mixed.
- An emulsion of this mixture can be formed through the addition of water, which is typically used as the continouous process medium.
- the emulsion will usually comprise organic droplets having the polymer, the organic solvent, and the releasable agent therein.
- the organic solvent is then removed by various means, such as liquid extraction, solvent evaporation, etc., which leaves behind a slurry comprising the microparticles having the releasable agent therein.
- the slurry can also comprise residual water and/or residual organic solvent.
- the disclosed methods relate to processing a slurry comprising the microparticle so as to affect the release profile of a bioactive agent contained in or on the microparticle.
- the slurry can comprise any other suitable material in addition to the microparticle and the bioactive agent, depending on the selected processing conditions.
- the slurry comprises a liquid or solvent.
- the slurry comprises water.
- the slurry comprises at least one organic solvent.
- the slurry can comprise both aqueous and organic solvents.
- the microparticle is typically dispersed or suspended in the slurry.
- the slurry comprising the microparticle can be dried under a set of drying parameters such that the selected release profile is substantially achieved.
- the way in which a microparticle is dried can affect the release profile of the bioactive agent contained in the microparticle. Without wishing to be bound by theory, it is believed that the way in which a microparticle is dried may affect the morphology of the microparticle, which thereby affects the release profile of the bioactive agent contained therein.
- the drying parameters which enable the selected release profile to be achieved can be known or unknown prior to drying the microparticle to achieve the selected release profile.
- multiple microparticle drying runs can be useful. For example, a microparticle can be formulated and dried under a set of drying parameters, and the release profile of the bioactive agent contained in the microparticle can be recorded. If the release profile is not substantially close to the selected or desired release profile, the drying parameters can be adjusted, iteratively, until the selected or desired release profile is substantially achieved. By contrast, it may be possible to predict which set of drying parameters will provide the selected release profile.
- the drying parameters can be any drying parameter.
- the drying parameters can be one or more of temperature, pressure, humidity, or drying time.
- the drying parameters can be one or more of temparature, pressure, humidity, drying time, stirring speed, agitation speed, or gas-flow on, in, or through the slurry.
- the gas flow-rate can range, for example, from 0.2 to abou 2.0 L/min.
- the drying gas can be any inert gas, such as air, nitrogen, argon, and the like.
- microparticles can be dried under a set of drying using any suitable method.
- the dryer can be any dryer which substantially achieves the results intended herein.
- the microparticle can be dried using an agitated filter dryer.
- a disclosed method comprises drying a microparticle having a bioactive agent therein in an agitated filter dryer.
- An agitated filter dryer is a drying device known in the art.
- an agitated filter dryer comprises a vessel with a filter plate at the bottom of the vessel.
- a slurry can be loaded into the vessel, and dried optionally under reduced pressure (e.g., vacuum) and/or under a stream of gas, such as air or an inert gas, such as nitrogen or argon, with mechanical agitation of the slurry by scraping blades, which are driven by an agitator shaft.
- the entire vessel can be kept at desired temperature by having a jacketed vessel, and/or other jacketed components through which heat transfer medium can be passed.
- Drying parameters for an agitated filter dryer can include without limitation, temperature, pressure, humidity, drying time, agitation speed, amount of washing medium, including the number of washings, speed of scraping blades, amount of venting, discharge mechanism, inert gas in- flow, among others.
- any type of agitated filter dryer can be used.
- a Nutsche filter can be used.
- a Nutsche filter is a type of agitated filter dryer.
- a stirred cell dryer can be used, such as a commercially available stirred cell dryer, e.g., a MILLIPORE stirred cell dryer.
- an agitated filter dryer can be beneficial to overcome challenges encountered with traditional bulk material drying methods in the microparticle art, including, for example, the use of Sweco dryers.
- a Sweco dryer is typically comprised of a vessel which shakes to agitate the bulk material. Oftentimes with the use of a Sweco dryer, large agglomerates can form, which have to be separated from the final powder. This is partly due to the fact that traditional Sweco dryers are not equipped with a mechanical stirring or scraping means, but rather simply shake a vessel of bulk material while drying.
- an agitated filter dryer can provide for good particle distrubution with fewer agglomerates, and also allow for the control of the drying parameters, as discussed above.
- a microparticle can be dried using a Sweco dryer.
- microparticles are disclosed that are produced by the disclosed methods.
- the microparticles disclosed herein can be any suitable microparticle.
- a bioactive agent is encapsulated within the microparticle.
- the bioactive agent is associated with the microparticle.
- the microparticle comprises a suitable biocompatible and biodegradable or non-biodegradable polymer.
- the polymers can be homopolymers or copolymers, including without limitation block or blocky co- or ter- polymers, random co- or ter- polymers, star polymers, or dendrimers. Any desired molecular weight polymer can be used, depending on the desired properties of the microparticle.
- high molecular weight polymers can be used, for example, to meet strength requirements.
- low or medium molecular weight polymers can be used when, for example, when resorption time of the polymer, rather than material strength is desired.
- the microparticle can be formulated so as to degrade within a desired time interval, once present in a subject.
- the time interval can be from about less than one day to about 1 month. Longer time intervals can extend to 6 months, including for example, polymer matrices that degrade from about > 0 to about 6 months, or from about 1 to about 6 months.
- the polymer can degrade in longer time intervals, up to 2 years or longer, including, for example, from about > 0 to about 2 years, or from about 1 month to about 2 years.
- the desired release profile can influence the selection of the polymer.
- a biocompatible polymer for example, can be selected so as to release or allow the release of a bioactive agent therefrom at a desired lapsed time after the microparticle has been
- the polymer can be selected to release or allow the release of the bioactive agent prior to the bioactive agent beginning to diminish its activity, as the bioactive agent begins to diminish in activity, when the bioactive agent is partially diminished in activity, for example at least 25%, at least 50% or at least 75% diminished, when the bioactive agent is substantially diminished in activity, or when the bioactive agent is completely gone or no longer has activity.
- the polymer can be one or more of polyesters, polyhydroxyalkanoates, polyhydroxybutyrates, polydioxanones, polyhydroxyvalerates, polyanhydrides,
- polyorthoesters polyphosphazenes, polyphosphates, polyphosphoesters, polydioxanones, polyphosphoesters, polyphosphates, polyphosphonates, polyphosphates,
- polyhydroxyalkanoates polycarbonates, polyalkylcarbonates, polyorthocarbonates, polyesteramides, polyamides, polyamines, polypeptides, polyurethanes, polyalkylene alkylates, polyalkylene oxalates, polyalkylene succinates, polyhydroxy fatty acids, polyacetals, polycyanoacrylates, polyketals, polyetheresters, polyethers, polyalkylene glycols, polyalkylene oxides, polyethylene glycols, polyethylene oxides, polypeptides,
- non-biodegradable but durable polymers include without limitation ethylene-vinyl acetate co-polymer, polytetrafluoroethylene, polypropylene, polyethylene, and the like.
- suitable non-biodegradable polymers include without limitation silicones and polyurethanes.
- the polymer can be a poly(lactide), a poly(glycolide), a poly(lactide-co-glycolide), a poly(caprolactone), a poly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate) or a copolymer containing a poly(hydroxybutarate), a poly(lactide-co- caprolactone), a polycarbonate, a polyesteramide, a polyanhydride, a poly(dioxanone), a poly(alkylene alkylate), a copolymer of polyethylene glycol and a polyorthoester, a biodegradable polyurethane, a poly(amino acid), a polyamide, a polyesteramide, a polyetherester, a polyacetal, a polycyanoacrylate, a poly(oxyethylene)/poly(oxypropylene) copolymer, polyacetals, polyketals
- useful biocompatible polymers are those that comprise one or more residues of lactic acid, glycolic acid, lactide, glycolide, caprolactone, hydroxybutyrate, hydroxy valerates, dioxanones, polyethylene glycol (PEG), polyethylene oxide, or a combination thereof.
- useful biocompatible polymers are those that comprise one or more residues of lactide, glycolide, caprolactone, or a combination thereof.
- useful biodegradable polymers are those that comprise one or more blocks of hydrophilic or water soluble polymers, including, but not limited to, polyethylene glycol, (PEG), or polyvinyl pyrrolidone (PVP), in combination with one or more blocks another biocompabible or biodegradable polymer that comprises lactide, glycolide, caprolactone, or a combination thereof.
- PEG polyethylene glycol
- PVP polyvinyl pyrrolidone
- the biodegradable polymer can comprise one or more lactide residues.
- the polymer can comprise any lactide residue, including all racemic and stereospecific forms of lactide, including, but not limited to, L-lactide, D-lactide, and D,L- lactide, or a mixture thereof.
- Useful polymers comprising lactide include, but are not limited to poly(L-lactide), poly(D-lactide), and poly(DL-lactide); and poly(lactide-co-glycolide), including 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 made by melt polymerization through ring opening of lactide and glycolide monomers. Additionally, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available.
- the L-polymers are more crystalline and resorb slower than DL- polymers.
- copolymers comprising glycolide and DL-lactide or L- lactide
- copolymers of L-lactide and DL-lactide are commercially available.
- homopolymers of lactide or glycolide are also commercially available.
- the amount of lactide and glycolide in the polymer can vary.
- the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole % glycolide, wherein the amount of lactide and glycolide is 100 mole %.
- the biodegradable polymer can be poly(lactide), 95:5 poly(lactide-co-glycolide) 85: 15 poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), 65:35 poly(lactide-co- glycolide), or 50:50 poly(lactide-co-glycolide), where the ratios are mole ratios.
- the polymer can be a poly(caprolactone) or a poly(lactide-co- caprolactone).
- the polymer can be a poly(lactide-caprolactone), which, in various aspects, can be 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 ratios are mole ratios.
- any combination of the aforementioned biodegradable polymers can be used, including, but not limited to, copolymers thereof, mixtures thereof, or blends thereof.
- any suitable polymer, copolymer, mixture, or blend, that comprises the disclosed residue is also considered disclosed.
- any combination of the individual residues can be used.
- the microparticle can be any microparticle made from a suitable starting material.
- the microparticle can be made out of a suitable polymer.
- the microparticle can contain and effect the release of the bioactive agent contained therein.
- the microparticle can be comprised of any of those polymers mentioned above or any polymer used in the microparticle art.
- the above mentioned polymers can be cross-linked to a certain level, which thereby can form a microparticle of the polymer, as is known in the art.
- the disclosed microparticles can have an average or mean particle size of from about 20 microns to about 125 microns. In one embodiment the range of mean particle size is from about 40 microns to about 90 microns. In another embodiment the range of mean particle sizes is from about 50 microns to about 80 microns. Particle size
- the bioactive agent can be encapsulated, microencapsulated, or otherwise contained within a microparticle.
- the microparticle can modulate the release of the bioactive agent.
- the microparticle can comprise any desired amount of the bioactive agent.
- the microparticle can comprise 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% by weight bioactive agent, relative to the weight of the microparticle, including any range between the disclosed percentages.
- microparticles can be made using methods known in the art, including, for example, those methods disclosed in U.S. Patent Publication No. 2007/0190154 to Zeigerson, published August 16, 2007, and U.S. Patent No. 5,407,609 to Tice et ah, both of which are incorporated herein in their entirety by this reference for teachings of microparticle preparation methods.
- the polymer used as a starting material in the admixing step may or may not be the same polymer present in the final implantable composite.
- the polymer during processing may undergo polymerization or depolymerization reactions, which ultimately can produce a different polymer that was used prior to processing.
- polymer as used herein covers the polymers used as starting materials as well as the final polymer present in the device produced by the methods described herein. Methods for making microparticles can be used in combination with the drying methods and dyring parameters described above.
- the microparticle comprises a bioactive agent.
- the bioactive agent can be a releasable bioactive agent, i.e., a bioactive agent that can be released from the microparticle into adjacent tissues or fluids of a subject.
- the bioactive agent can be in or on the microparticle.
- bioactive agent can be used, which are capable of being released from the microparticle into adjacent tissues or fluids.
- a liquid or solid bioactive agent can be incorporated into the implantable composites described herein.
- the bioactive agents are at least very slightly water soluble, and preferably moderately water soluble.
- the bioactive agents can include salts of the active ingredient.
- the bioactive agents can be acidic, basic, or amphoteric salts. They can be nonionic molecules, polar molecules, or molecular complexes capable of hydrogen bonding.
- the bioactive agent can be included in the compositions in the form of, for example, an uncharged molecule, a molecular complex, a salt, an ether, an ester, an amide, polymer drug conjugate, or other form to provide the effective biological or physiological activity.
- bioactive agents examples include, but are not limited to, peptides, proteins such as hormones, enzymes, antibodies and the like, nucleic acids such as aptamers, iRNA, DNA , RNA, antisense nucleic acid or the like, antisense nucleic acid analogs or the like, low-molecular weight compounds, or high-molecular-weight compounds.
- Bioactive agents contemplated for use in the disclosed implantable composites include anabolic agents, antacids, anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics, anti-infective agents including antibacterial and antimicrobial agents, anti-inflammatory agents, anti-manic agents, antimetabolite agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-tussive agents, anti- uricemic agents, anti-anginal agents, antihistamines, appetite suppressants, biologicals, cerebral dilators, coronary dilators, bronchiodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic
- bioactive agents include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenesis factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlophedianol hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral
- cholestyramine N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenyl propanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones, interferons, cytokines, and vaccines.
- drugs that can be used as bioactive agents in the microparticles include, but are not limited to, peptide drugs, protein drugs, desensitizing materials, antigens, anti- infective agents such as antibiotics, antimicrobial agents, antiviral, antibacterial, antiparasitic, antifungal substances and combination thereof, antiallergenics, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anti-cholinergics, sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, nonsteroidal anti-inflammatory agents, antiparkinsonian agents, antihypertensive agents, ⁇ -adrenergic blocking agents, nutritional agents, and the benzophenanthridine alkaloids.
- the agent can further be a substance capable of
- the microparticle can comprise a large number of bioactive agents either singly or in combination.
- 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; anorexics such as dexadrine, phendimetrazine tartrate, and the like; antiarthritics such as methylprednisolone, ibuprofen, and the like; antiasthmatics such as terbutaline sulfate, theophylline, ephedrine, and the like; antibiotics such as sulfisoxazole, penicillin G, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, and the like; antifung
- amphotericin B, nystatin, ketoconazole, and the like antivirals 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 phenytoin sodium, diazepam, and the like; antidepressants such as isocarboxazid, amoxapine, and the like; antihistamines such as diphenhydramine HC1, chlorpheniramine maleate, and the like; hormones such as insulin, progestins, estrogens, corticoids, glucocorticoids, androgens, and the like; tranquilizers such as thorazine, diazepam, chlorpromazine HC1, reserpine, chlordiazepoxide HC1, and the like; antispasmodics such
- narcotics such as morphine, codeine, and the like, psychotherapeutics; anti-malarials, L-dopa, diuretics such as furosemide, spironolactone, and the like; antiulcer drugs such as rantidine HC1, cimetidine HC1, and the like.
- the bioactive agent can also be an immunomodulator, including, for example, cytokines, interleukins, interferon, colony stimulating factor, tumor necrosis factor, and the like; allergens such as cat dander, birch pollen, house dust mite, grass pollen, and the like; antigens of bacterial organisms such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphteriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens. Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus mutans.
- immunomodulator including, for example, cytokines, interleukins, interferon, colony stimulating factor, tumor necrosis factor, and the like; aller
- the bioactive agent comprises an antibiotic.
- the antibiotic can be, for example, one or more of Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromomycin, Ansamycins, Geldanamycin, Herbimycin, Carbacephem, Loracarbef, Carbapenems, Ertapenem, Doripenem,
- Imipenem/Cilastatin Meropenem, Cephalosporins (First generation), Cefadroxil, Cefazolin, Cefalotin or Cefalothin, Cefalexin, Cephalosporins (Second generation), Cefaclor,
- Cefamandole Cefoxitin, Cefprozil, Cefuroxime, Cephalosporins (Third generation), Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cephalosporins (Fourth generation), Cefepime, Cephalosporins (Fifth generation), Ceftobiprole, Glycopeptides, Teicoplanin, Vancomycin, Macrolides, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Monobactams, Aztreonam, Penicillins, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocill
- Minocycline Oxytetracycline, Tetracycline, and others; Arsphenamine, Chloramphenicol, Clindamycin, Lincomycin, Ethambutol, Fosfomycin, Fusidic acid, Furazolidone, Isoniazid, Linezolid, Metronidazole, Mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide, Quinupristin/Dalfopristin, Rifampicin (Rifampin in U.S.), Tinidazole, or a combination thereof.
- the bioactive agent can be a combination of Rifampicin (Rifampin in U.S.) and Minocycline.
- the bioactive agent can be present as a component in a
- compositions can be conveniently prepared in a desired dosage form, including, for example, a unit dosage form or controlled release dosage form, and prepared by any of the methods well known in the art of pharmacy.
- pharmaceutical compositions are prepared by uniformly and intimately bringing the bioactive agent into association with a liquid carrier or a finely divided solid carrier, or both.
- the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- Other pharmaceutically acceptable carriers or components that can be mixed with the bioactive agent can include, for example, a fatty acid, a sugar, a salt, a water-soluble polymer such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose, a surfactant, a plasticizer, a high- or low-molecular-weight porosigen such as polymer or a salt or sugar, or a hydrophobic low-molecular-weight compound such as cholesterol or a wax.
- the microparticle can be administered to any desired subject.
- the subject can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
- the subject of the herein disclosed methods 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 denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
- Disclosed herein in one aspect are methods for preparing a microparticle having a selected release profile for the release of a bioactive agent contained therein, the method comprising: a) providing a slurry comprising a microparticle having a releasable bioactive agent therein; b) selecting a release profile for the bioactive agent; and c) drying the microparticle under a set of drying parameters such that the selected release profile is substantially achieved. Also disclosed herein in one aspect are methods for drying a microparticle, comprising: a) providing a slurry comprising a microparticle having a releasable bioactive agent therein; and b) drying the microparticle using an agitated filter dryer under a set of selected drying parameters.
- microparticle is dried using an agitated filter dryer or a Nutsche filter dryer.
- any preceding apect wherein the slurry comprises at least one organic. Also disclosed are methods of any preceding apect, wherein the slurry comprises ethyl acetate.
- the microparticle comprises poly(lactide), poly(glycolide), poly(caprolactone), or a combination thereof.
- microparticle comprises poly(lactide-co-glycolide).
- a microparticle made by the method of any preceding aspect made by the method of any preceding aspect.
- Bovine serum albumin, BSA (Fraction V, Sigma Chemical Co., St. Louis, MO) was added to a 20% solution of 5050 PLG 4.5E polymer (Lakeshore Biomaterials brand polymer from SurModics Pharmaceuticals, Birmingham, AL) in ethyl acetate at a level of 10% based on the combined weight of polymer and BSA.
- BSA was suspended in the polymer solution using an IKA Ultraturrax at 13,500 rpm for 30 seconds.
- the drug/polymer suspension (15 ml) was then emulsified at a rate of 15 mL/min into an aqueous solution containing 2 wt% poly(vinyl alcohol) (PVA) that was fed at a rate of 150 mL/min by using a Silverson L4RT-A homogenizer at 860 rpm.
- PVA poly(vinyl alcohol)
- the resulting o/w emulsion was then extracted into deionized water which was fed at a rate of 1450 mL/min and stirred an additional 60 minutes to extract the organic solvent and form polymer microparticles.
- the resulting microsphere suspension was passed through 150 and 25 micron test sieves (Retsch GmbH) in order to isolate the microparticle fraction between 25-250 microns in size.
- the product collected on the 25 micron sieve was washed with deionized water (1 liter) and was then transferred to a drying apparatus.
- the drying apparatus was a modified MILLIPORE stirred cell (MILLIPORE Stirred Cell 8200, Fisher Scientific) where a 25 ⁇ sieve mesh material (Retsch GmbH) was used as the bottom filter membrane. This drying apparatus was then connected to a nitrogen source. Nitrogen flow was initiated to remove excess water from the system to form a solid microsphere cake at the bottom of the cell. Nitrogen flow was then controlled through the cell using a regulator Drying conditions were selected that allowed for either fast or slow drying conditions based on the nitrogen flow rate through the drying apparatus. Fast drying conditions used a nitrogen flow rate of 2 LPM while slow drying conditions used a flow rate of 0.2 LPM. Aliquots of microspheres were taken throughout the course of drying and the microsphere cake was stirred at each time point to promote even drying throughout the sample. Once the product was dry, it was collected and reserved for further analysis.
- Particle size analysis was performed by laser diffraction using a Beckman Coulter LSI 3, 320 particle size analyzer. The fraunhoffer model was used to compute size distribution based on volume-averaged statistics. Particles sizes were conducted on portions of the bulk microparticle product taken just prior to collection on the test sieves. Reported particle size results are in microns and include the mean size (mean), and the particle sizes at 10% and 90% of the particle size distribution (D10 and D90, respectively).
- 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, then centrifuged at 3500 rpm for 15 minutes. Supernatant was removed, 3 mL of ethyl acetate added, mixture vortexed for 30 seconds, and centrifuged at 3500 rpm for 15 minutes. This procedure was repeated one last time for a total of three ethyl acetate washes. After the last wash and removal of supernatant, the remaining BSA pellet was dried under nitrogen flow to remove excess ethyl acetate.
- 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 ⁇ ⁇ sample injection volume, and 20 minute run time per sample. Sample tray and column were kept at ambient temperature. Mobile phase was a pre-mixed 1 : 1 lOOmM Sodium Phosphate: lOOmM Sodium Sulfate, pH 7.
- Particle sizes of the samples from Table 1 are listed below in Table 2. Particle size distributions for these samples are shown in FIGs. 1 and 2. Table 2. Particle Size.
- FIG. 4 shows the cumulative release profile for the two samples. demonstrates that by tuning the drying profile, a different release profile can be achieved. Specifically, in this case, slower drying led to a slower rate of release relative to the microspheres dried under fast conditions.
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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CA2890833A CA2890833A1 (en) | 2012-11-09 | 2012-11-09 | Drying methods for tuning microparticle properties |
JP2015541752A JP6184508B2 (en) | 2012-11-09 | 2012-11-09 | Drying method for adjusting fine particle characteristics |
CN201280077831.8A CN104869981B (en) | 2012-11-09 | 2012-11-09 | For coordinating the drying means of particle properties |
EP12791046.1A EP2916825A1 (en) | 2012-11-09 | 2012-11-09 | Drying methods for tuning microparticle properties |
AU2012393962A AU2012393962A1 (en) | 2012-11-09 | 2012-11-09 | Drying methods for tuning microparticle properties |
PCT/US2012/064482 WO2014074114A1 (en) | 2012-11-09 | 2012-11-09 | Drying methods for tuning microparticle properties |
BR112015010434A BR112015010434A2 (en) | 2012-11-09 | 2012-11-09 | drying methods for adjusting microparticle properties |
RU2015121799A RU2015121799A (en) | 2012-11-09 | 2012-11-09 | Drying methods for adjusting the properties of microparticles |
IL238720A IL238720A0 (en) | 2012-11-09 | 2015-05-10 | Drying methods for tuning microparticle properties |
HK15109283.0A HK1208623A1 (en) | 2012-11-09 | 2015-09-22 | Drying methods for tuning microparticle properties |
AU2018203710A AU2018203710A1 (en) | 2012-11-09 | 2018-05-25 | Drying methods for tuning microparticle properties |
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PCT/US2012/064482 WO2014074114A1 (en) | 2012-11-09 | 2012-11-09 | Drying methods for tuning microparticle properties |
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EP (1) | EP2916825A1 (en) |
JP (1) | JP6184508B2 (en) |
CN (1) | CN104869981B (en) |
AU (2) | AU2012393962A1 (en) |
BR (1) | BR112015010434A2 (en) |
CA (1) | CA2890833A1 (en) |
HK (1) | HK1208623A1 (en) |
IL (1) | IL238720A0 (en) |
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Citations (5)
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US5407609A (en) | 1989-05-04 | 1995-04-18 | Southern Research Institute | Microencapsulation process and products therefrom |
US6596316B2 (en) * | 1998-12-30 | 2003-07-22 | Alkermes Controlled Therapeutics, Inc. Ii | Preparation of microparticles having a selected release profile |
US6913767B1 (en) * | 1993-10-25 | 2005-07-05 | Genentech, Inc. | Compositions for microencapsulation of antigens for use as vaccines |
US20050220887A1 (en) * | 2004-01-20 | 2005-10-06 | Alkermes Controlled Therapeutics, Inc. | Method for milling frozen microparticles |
US20070190154A1 (en) | 2003-04-10 | 2007-08-16 | Pr Phamaceuticals | Method for the production of emulsion-based micro particles |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7980794A (en) * | 1993-10-22 | 1995-05-08 | Genentech Inc. | Methods and compositions for microencapsulation of antigens for use as vaccines |
EP1187602A4 (en) * | 2000-04-18 | 2004-09-15 | Peptron Inc | Injectable sustained release pharmaceutical composition and processes for preparing the same |
WO2008118712A1 (en) * | 2007-03-22 | 2008-10-02 | Alkermes, Inc. | Coacervation process |
-
2012
- 2012-11-09 RU RU2015121799A patent/RU2015121799A/en unknown
- 2012-11-09 EP EP12791046.1A patent/EP2916825A1/en not_active Withdrawn
- 2012-11-09 JP JP2015541752A patent/JP6184508B2/en not_active Expired - Fee Related
- 2012-11-09 AU AU2012393962A patent/AU2012393962A1/en not_active Abandoned
- 2012-11-09 BR BR112015010434A patent/BR112015010434A2/en not_active Application Discontinuation
- 2012-11-09 WO PCT/US2012/064482 patent/WO2014074114A1/en active Application Filing
- 2012-11-09 CA CA2890833A patent/CA2890833A1/en not_active Abandoned
- 2012-11-09 CN CN201280077831.8A patent/CN104869981B/en not_active Expired - Fee Related
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2015
- 2015-05-10 IL IL238720A patent/IL238720A0/en unknown
- 2015-09-22 HK HK15109283.0A patent/HK1208623A1/en unknown
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- 2018-05-25 AU AU2018203710A patent/AU2018203710A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5407609A (en) | 1989-05-04 | 1995-04-18 | Southern Research Institute | Microencapsulation process and products therefrom |
US6913767B1 (en) * | 1993-10-25 | 2005-07-05 | Genentech, Inc. | Compositions for microencapsulation of antigens for use as vaccines |
US6596316B2 (en) * | 1998-12-30 | 2003-07-22 | Alkermes Controlled Therapeutics, Inc. Ii | Preparation of microparticles having a selected release profile |
US20070190154A1 (en) | 2003-04-10 | 2007-08-16 | Pr Phamaceuticals | Method for the production of emulsion-based micro particles |
US20050220887A1 (en) * | 2004-01-20 | 2005-10-06 | Alkermes Controlled Therapeutics, Inc. | Method for milling frozen microparticles |
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AU2018203710A1 (en) | 2018-06-14 |
AU2012393962A1 (en) | 2015-05-28 |
CA2890833A1 (en) | 2014-05-15 |
CN104869981A (en) | 2015-08-26 |
IL238720A0 (en) | 2015-06-30 |
RU2015121799A (en) | 2017-01-10 |
CN104869981B (en) | 2018-05-08 |
JP2015536980A (en) | 2015-12-24 |
BR112015010434A2 (en) | 2017-07-11 |
JP6184508B2 (en) | 2017-08-23 |
HK1208623A1 (en) | 2016-03-11 |
EP2916825A1 (en) | 2015-09-16 |
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