JP5222917B2 - Sustained release composition and method for producing the same - Google Patents

Description

  The present invention relates to sustained release systems. In particular, it relates to a sustained release composition containing a release rate determining agent.

  It is well known to coat medical devices such as surgical implants, sutures and wound dressings with pharmaceutical agents. Such a coated device provides a means for local delivery of a pharmaceutical or therapeutic agent to a medical intervention site for treating various diseases. For example, antibiotic-coated surgical implants or sutures may provide direct local delivery of antibiotics to the site of implantation or suture, thereby causing the development of infection after surgical intervention Can be reduced.

  Accordingly, there is increasing interest in developing drug delivery systems that are safe and provide high drug bioavailability, i.e., to maximize the pharmaceutical activity of known drugs and minimize their side effects. Yes. Biodegradable polymers have been extensively studied as drug carriers due to their uniform release rate in a given time frame and the non-toxic nature of degradation products. Biodegradable polymeric drug carriers are particularly useful for the delivery of drugs that require continuous and sustained release in a single dose, such as peptide or protein drugs that must be administered daily due to their rapid loss of activity in the body. Useful.

  However, conventional drug release curves include three phases: an initial release phase, a delayed phase and a secondary release phase, where the drug is released only in the initial and secondary release phases. Thus, in the lag phase, it is necessary to combine oral administration with topical administration to achieve the desired therapeutic purpose, but additional oral administration increases costs and causes inconvenience. In order to solve the above problems, a novel sustained-release composition and a method for producing the same are required.

  The present invention includes a polymer, a bioactive agent and a release rate determining agent, wherein the bioactive agent and the release rate determining agent are dispersed in the sustained release composition, and the bioactivity is determined by the release rate determining agent. A sustained release composition is provided in which the release rate of the agent is controlled.

  Furthermore, the present invention provides an oil phase comprising a bioactive agent, a polymer and a release rate determining agent; providing an aqueous phase comprising a surfactant; mixing the oil phase with the aqueous phase to provide a controlled release effect. A method for producing a sustained release composition comprising forming a sustained release composition is provided.

  Furthermore, the present invention provides a method of treating an animal comprising administering a pharmaceutically effective amount of the sustained release composition of the present invention.

  A detailed description is given in the following embodiments with reference to the accompanying drawings.

  The invention may be more fully understood by reading the following detailed description and examples with reference to the accompanying drawings.

2 shows a drug release curve of a sustained release composition.

  The following description is the best mode for carrying out the invention. This description is made for the purpose of illustrating the general principles of the invention and should not be construed in a limiting sense. The scope of the invention is best determined by reference to the appended claims.

  The present invention includes a polymer, a bioactive agent and a release rate determining agent, wherein the bioactive agent and the release rate determining agent are dispersed in the sustained release composition, and the bioactivity is determined by the release rate determining agent. A sustained release composition is provided in which the release rate of the agent is controlled.

  Sustained release compositions may include one or more bioactive agents including, for example, nucleic acids, carbohydrates, peptides, proteins, small molecule drug substances, immunogens, antitumor agents or hormones. Examples of nucleic acids include, but are not limited to, DNA, RNA, chemically modified DNA and chemically modified RNA, aptamers, antisense oligonucleotides, RNA interference, and small interfering RNA. Examples of carbohydrates include but are not limited to heparin, low molecular weight heparin and the like. Examples of peptides include, but are not limited to, LHRH agonists and synthetic analogs, leuprolide, somatostatin analogs, hormones, octreotide, glucagon-like peptides, oxytocin and the like. Examples of proteins include, but are not limited to, antibodies, therapeutic proteins, human growth hormone (eg, bone morphogenetic protein, TGF-β1, fibroblast growth factor, platelet derived growth factor or insulin-like growth factor), oxytocin, Examples include octreotide, gonadotropin releasing hormone, leuprolide, interferon, insulin, calcitonin, and interleukin. Examples of small molecule drug substances include, but are not limited to, anti-infective agents (eg, amphotericin B), cytotoxic agents, antihypertensive agents, antifungal agents (eg, fluconazole, itraconazole, ketoconazole), antipsychotic agents (eg, Clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone or quetiapine), antidiabetics, immunostimulants (eg, β-1,3 / 1,6-glucan), immunosuppressants (eg, cyclosporine or prednisone) , Antibiotics (eg penicillin, cephalosporin, vancomycin or lincomycin), antivirals, anticonvulsants, antihistamines, cardiovascular drugs, anticoagulants, hormones, antimalarials, analgesics, Anesthetics, steroids, non-steroidal anti-inflammatory drugs And antiemetics, and the like. Examples of hormones include, but are not limited to, growth factors, melatonin, serotonin, thyroxine, triiodothyronine, epinephrine, norepinephrine, dopamine, adiponectin, angiotensinogen, cholecystokinin, erythropoietin, gastrin, glucagon, inhibin, secretin Thrombopoietin or aldosterone. The bioactive agent may be present in the oil phase at a concentration of 0.1 to 10% by weight, preferably 2% by weight.

  Polymers dissolved in the solvent are biomolecules (biodegradable polymers) such as phospholipids, lecithin, poly (lactide), poly (glycolide), polylactide-co-glycolide (PLGA), polyglutamic acid, polycaprolactone (PCL). , Polyanhydride, polyamino acid, polydioxanone, polyhydroxybutyrate, polyphosphazene, polyester urethane, polycarboxyphenoxypropane-co-sebacic acid, polycarbonate, polyesteramide, polyacetyl, polycyanoacrylate, polyetherester, poly (alkylene Alkylate) or a copolymer thereof. Hydrophobic polymers can be degraded without impact in living subjects.

  TPGS (d-α-tocopheryl polyethylene glycol succinate) is commercially available as “Vitamin E-TPGS” from Eastman Chemical Company. Vitamin E-TPGS is a water-soluble derivative of the natural source vitamin E and is similar to amphiphiles. In the present invention, various chemical derivatives of vitamin E-TPGS, for example, ester and ether conjugates of various chemical moieties are included in the definition of vitamin E-TPGS. Correctly this is dispersed in the oil phase to control the release of the bioactive agent. According to an important feature of the present invention, the drug release curve of the sustained release composition of the present invention has no lag phase. Thus, the bioactive agent can be released continuously, thereby eliminating the need for additional oral administration. In the present invention, TPGS is present in an amount of about 1-50% by weight, preferably 4-15% by weight of the total weight of the sustained release composition.

  In one embodiment, the sustained release composition is in the form of microparticles, microspheres or microcapsules. The microspheres are typically nearly homogeneous in the composition, and the microcapsules contain a core with a composition that differs from the surrounding shell. For purposes of this disclosure, the terms microsphere, microparticle, and microcapsule are used interchangeably. In another embodiment, the sustained release composition of the present invention has a drug encapsulation of greater than 70%, preferably 70% to 99.9%, greater than 5 μm, preferably 5 μm to 200 μm, most preferably 30 μm. It has a diameter of ˜100 μm and can release bioactive agent continuously in vivo without lag phase.

  The sustained release composition of the present invention can be applied systemically or locally. For example, the composition can be administered by intramuscular, intraperitoneal, intravenous or subcutaneous injection. Furthermore, the composition can be in virtually any form, such as lotions, ointments, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be incorporated.

  Furthermore, the present invention provides a method for producing a sustained release composition. The method provides an oil phase containing a bioactive agent, a polymer and a release rate determining agent; providing an aqueous phase comprising a surfactant; and mixing the oil phase with the aqueous phase to provide a sustained release composition Forming an object.

  As used herein, the term “oil phase” of the present invention refers to a solution of solvent, polymer, bioactive agent and release rate determining agent that, when mixed with the aqueous phase, undergoes an emulsion process through A solution in which a releasable composition is provided. The solvent of the oil phase is not limited, but methylene chloride, ethyl acetate, benzyl alcohol, acetone, acetic acid, propylene carbonate, dichloromethane, chloroform, 1,4-dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene Or tetrahydrofuran (THF) is mentioned.

  The term “release rate determining agent” of the present invention refers to a solution of surfactant that can control the release rate of a bioactive agent.

  Release rate determining agents of the present invention include, but are not limited to, Span® 80, Span® 85, oleic acid, PEG-PCL di-block copolymer, glyceryl tricaprylate, Pluronic® ( F68), Tween® 80 or vitamin E-TPGS.

  The term “aqueous phase” refers to a solution of water and a surfactant that provides the sustained release composition of the present invention via an emulsion process when contacted with an oil phase. The release rate determining agent is present in the oil phase at a concentration of 1 to 50% by weight, for example at a concentration of 4 to 15% by weight.

  Examples of the surfactant of the present invention include, but are not limited to, polyvinyl alcohol (PVA), NP-5, Triton X-100, Tween (registered trademark) 80, PEG 200 to 800, sodium dodecyl sulfate (SDS), alcohol ethoxylate. , Alkylphenol ethoxylates, secondary alcohol ethoxylates, fatty acid esters or alkylpolyglycosides. The surfactant is present in the aqueous phase at a concentration of 0.1 to 10% by weight, for example, at a concentration of 0.1 to 5% by weight.

  In one embodiment, the oil phase is contacted with the aqueous phase to form an emulsion comprising droplets of the oil phase dispersed in the aqueous phase. Subsequently, when the solvent is removed from the emulsion droplets, hardened microparticles are formed. The solvent can be removed by evaporation, filtration or extraction into an extract. For example, the extract can be water. The cured microparticles can then be recovered from the aqueous phase and dried.

  An emulsion is made by stirring an organic phase and an aqueous phase. In one embodiment, the emulsion is made by use of a mixer such as a static mixer. Alternatively, the emulsion is made by use of turbulent mixing.

  The emulsion process can be performed at any temperature between the boiling point and freezing point of the component. In one embodiment, the temperature ranges from 0 ° C to 100 ° C or from about 5 ° C to 75 ° C or from about 15 ° C to about 60 ° C.

  Further, a cosolvent may be added to the oil phase. A co-solvent is optionally used to improve the solubility of the bioactive agent in the oil phase. In one embodiment, co-solvents include, but are not limited to, dimethyl sulfoxide, dimethylformamide, n-methylpyrrolidinone, PEG 200, PEG 400, methyl alcohol, ethyl alcohol, isopropyl alcohol, and benzyl alcohol. The co-solvent may be present at 0-90% by weight of the oil phase solvent or 0-50% by weight of the oil phase solvent. The bioactive agent was first dissolved in an appropriate volume of co-solvent so that a solution containing all components of the oil phase was formed, which was then optionally dissolved with the biodegradable polymer. Add to oil phase solvent. Note that one skilled in the art can adjust the volume and order of addition to obtain the desired solution of bioactive agent and biodegradable polymer. In one embodiment, the bioactive agent is present in the oil phase at a concentration of 0.1 to 10% by weight. In another embodiment, the biodegradable polymer is present in the oil phase at a concentration of 0.1-20% by weight. For example, the biodegradable polymer is present in the oil phase at a concentration of 1-10% by weight.

  Furthermore, the present invention provides a method of treating an animal comprising administering a pharmaceutically effective amount of the sustained release composition of the present invention. Because the sustained release composition can release bioactive agent continuously, it is not necessary for the animal to combine oral administration with topical administration to improve the treatment effect.

  The sustained release compositions of the invention can be suspended in any aqueous solution or other diluent for injection in human or animal patients in need of treatment. The aqueous dilution solution may further comprise a viscosity improver selected from the group consisting of sodium carboxymethylcellulose, sucrose, mannitol, dextrose, trehalose and other biocompatible viscosity improvers.

  The “animal” of the present invention as used herein refers to any mammal of the class Mammalia. Mammals of the present invention include human or non-human mammals such as dogs, cats, mice, rats, cows, sheep, pigs, goats or primates, experimental mammals, livestock and livestock mammals are Explicitly included. In one embodiment, the mammal can be a human and in other embodiments the mammal can be a rodent such as a mouse or rat.

Example 1: 50/50 PLGA microspheres containing 0, 7, 26, 42% vitamin-E TPGS 80 mg olanzapine, 200 mg PLGA (LA / GA ratio = 50/50, MW = 43000) and Different amounts of vitamin E-TPGS (0, 7, 26, 42 wt%) were co-dissolved in 5 mL of dichloromethane to form an oil phase. The oil phase was dropped into a 1000 mL cooling water phase containing 0.1% polyvinyl alcohol (PVA) and emulsified at 1000 rpm. The obtained o / w emulsion was continuously stirred at room temperature for 3 hours. The microspheres were collected by centrifugation, washed with F68, water and lyophilized. The microspheres were then evaluated for particle size and drug encapsulation efficiency by multisizer and high performance liquid chromatography (HPLC). As a result, the particle sizes were 68.4 ± 28.3, 71.6 ± 27.3, 91.0 ± 35.8, 101.9 ± 42.8 μm, and the encapsulation efficiency was 0, 7, Microspheres containing 26, 42% (w / w) vitamin E-TPGS were shown to be 77.7, 83.5, 85.9 and 85.2%, respectively.

Example 2: 85/15 PLGA microspheres containing 0, 4, 15, 26% vitamin E-TPGS 320 mg olanzapine, 800 mg PLGA (LA / GA ratio = 85/15, MW = 53000) and Different amounts of vitamin E-TPGS (0, 4, 15, 26 wt%) were co-dissolved in 15 mL of dichloromethane to form an oil phase. The oil phase was dropped into a 2000 mL cooling water phase containing 0.1% polyvinyl alcohol (PVA) and emulsified at 1000 rpm. The method of stirring, recovery and analysis is as defined in Example 1 above. As a result, the particle sizes were 40.0 ± 21.3, 58.8 ± 28.4, 47.4 ± 21.4, 62.9 ± 25.9 μm, and the encapsulation efficiency was 0, 4, Microspheres containing 15, 26% (w / w) vitamin E-TPGS were shown to be 77.2, 74.7, 87.6, and 83.7%, respectively.

Example 3: 50/50 PLGA microspheres containing different aqueous phases 80 mg olanzapine, 200 mg PLGA (LA / GA ratio = 50/50, MW = 43000) and 42% (w / w) vitamin E -TPGS was co-dissolved in 5 mL of dichloromethane to form an oil phase. The oil phase was dropped into 1000 mL of cooling water phase and then emulsified at 1000 rpm. At this time, the cooling water phase contained 0.05% PVA or 0.05% PVA containing 0.5% gelatin. The obtained o / w emulsion was continuously stirred at room temperature for 3 hours. The microspheres were collected by centrifugation, washed with F68, water and lyophilized. The analysis method of the particle size and drug encapsulation efficiency is as defined above. As a result, the particle sizes were 108.7 ± 37.3, 85.5 ± 31.4 μm, and the encapsulation efficiency was 0.05% PVA containing no gelatin and 0.05% containing 0.5% gelatin. The PVA-containing microspheres were 74.1% and 73.1%, respectively.

Example 4: 85/15 PLGA microspheres containing different oil phases 320 mg olanzapine, 800 mg PLGA (LA / GA ratio = 85/15, MW = 43000) and 15 w / w% vitamin E-TPGS Co-dissolved in 15 mL dichloromethane to form an oil phase. In this example, in dichloromethane, pure dichloromethane (formulation number 1), ethanol-containing dichloromethane (DCM: ethanol = 2: 1, formulation number 2), and acetone-containing dichloromethane (DCM: acetone = 2: 1, formulation, respectively) Number 3) was included. The oil phase was dropped into a 2000 mL cooling water phase containing 0.1% PVA and emulsified at 1000 rpm. The method of stirring, recovery and analysis is as defined in Example 1 above. As a result, the particle size was 76.2 ± 31.4, 70.6 ± 31.8, 70.6 ± 31.8 μm, and the encapsulation efficiency was 86 for the microspheres of formulation numbers 1, 2, 3 .8, 89.7, 88.5%.

Example 5: 85/15 PLGA microspheres with different LA / GA ratios 320 mg olanzapine, 800 mg PLGA and 15% (w / w) vitamin E-TPGS are co-dissolved in 15 mL dichloromethane to form an oil phase did. At this time, PLGA is 85/15: 50/50 = 3: 1 (formulation number 1), 85/15: 50/50 = 1: 3 (formulation number 2) and 75/20: 50/50 =, respectively. It had different LA / GA ratios including 4: 1 (Formulation No. 3). The oil phase was dropped into a 2000 mL cooling water phase containing 0.1% PVA and emulsified at 1000 rpm. The method of stirring, recovery and analysis is as defined in Example 1 above. As a result, the particle size was 62.2 ± 32.0, 59.1 ± 24.9, 41.1 ± 19.1 μm, and the encapsulation efficiency was 84 microspheres with formulation numbers 1, 2, 3 .9, 84.2, 83.2%.

Example 6: 75/25 PLGA microspheres 320 mg olanzapine, 800 mg PLGA (LA / GA ratio = 75/25) and 4% (w / w) vitamin E-TPGS were co-dissolved in 15 mL dichloromethane and the oil phase Formed. In this example, the molecular weight of PLGA is 30000 Da. And 21000 Da. Met. The oil phase was dropped into a 2000 mL cooling water phase containing 0.1% PVA and emulsified at 1000 rpm. The method of stirring, recovery and analysis is as defined in Example 1 above. As a result, the particle sizes were 43.5 ± 18.8 and 37.4 ± 20.2 μm, and the encapsulation efficiency was 30000, 21000 Da. It was shown that it was 80.8 and 77.6% in the microsphere comprised by PLGA.

Example 7: 85/15 PLGA microspheres 320 mg olanzapine, 800 mg PLGA (LA / GA ratio = 85/15) and 4% (w / w) vitamin E-TPGS were co-dissolved in 15 mL dichloromethane and the oil phase Formed. In this example, the molecular weight of PLGA is 53000 and 27000 Da. Included. The method of stirring, recovery and analysis is as defined in Example 1 above. As a result, the particle size was 58.8 ± 28.4, 43.9 ± 20.6 μm, and the encapsulation efficiency was 53000, 27000 Da. It was shown to be 74.7% and 77.0% in microspheres composed of PLGA.

Example 8: Formulation of different release rate determining agents 320 mg of olanzapine, 800 mg of PLGA (LA / GA ratio = 85/15, MW = 53000) and different release rate determining agents (Span® 80, Span (Registered trademark) 85, oleic acid, PEG-PCL di-block copolymer, glyceryl tricaprylate, Pluronic (registered trademark), Tween (registered trademark) 80) were co-dissolved in 15 mL of dichloromethane to form an oil phase. The oil phase was dropped into a 2000 mL cooling water phase containing 0.1% polyvinyl alcohol (PVA) and emulsified at 1000 rpm. The method of stirring, recovery and analysis is as defined in Example 1 above. As a result, the particle sizes were 46.7 ± 18.6, 40.3 ± 15.5, 46.3 ± 22.6, 55.7 ± 27.3, 49.5 ± 22.0, 68.1. The encapsulation efficiency is 86.9, 78.2, 79.4, 87.2 with microspheres composed of different release rate determinants, respectively, ± 30.9, 30.1 ± 14.9 μm. 69.5, 85.2, 75.5%.

Example 9: In Vivo Drug Release Sprague-Dawley rats were chosen for evaluation of depot formulations because leg muscle size facilitates dose administration and injection site evaluation.

  The weight of male Sprague-Dawley rats was 250-300 g. The rat biceps femoris was given a single injection with a 20- or 21-gauge needle. The dose administered varied with the concentration of the formulation but did not exceed 1 mL per injection. Rats received 40 mg olanzapine per kg body weight.

  At each time point, a 0.1 mL blood sample was collected from the lateral tail vein into a heparinized collection tube. Blood samples were collected once at various time points before dose administration and after dose administration over a 50 day period. Typical time points are 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 1 day, 2 days, 4 days, 7 days, 10 days, 14 days after dose administration, 17 days, 21 days, 24 days, 28 days, 31 days, 35 days, 38 days, 42 days, 45 days, 50 days. Plasma was collected and the plasma concentration of olanzapine was measured by HPLC / MS-MS.

  The microspheres containing 15% (w / w) vitamin E-TPGS prepared in Example 2 were administered to rats by intramuscular injection. In the control group, TPGS of microspheres was excluded (PLGA only) or replaced with Tween® 80 (PLGA / Tween® 80). Referring to FIG. 1, microspheres containing TPGS continuously released olanzapine in rats, and the microsphere drug release curves had no lag phase.

  Although the invention has been described by way of example and in terms of preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. On the contrary, it is intended to encompass various modifications and similar arrangements (as will be apparent to those skilled in the art). Accordingly, the appended claims should be accorded the widest interpretation so that all such modifications and similar arrangements are encompassed.

Claims (9)

A bioactive agent and a release rate determining agent, wherein the bioactive agent and the release rate determining agent are dispersed in the sustained release composition, and the release rate determining agent releases the bioactive agent Is controlled,
The polymer is polylactide-co-glycolide (PLGA);
The bioactive agent is olanzapine,
The release rate determining agent is d-α-tocopheryl polyethylene glycol succinate (vitamin E-TPGS);
The release rate determining agent has a final concentration of 1 to 50% by weight;
A sustained-release composition without a lag period, which is produced by an emulsification process in which an oil phase containing the polymer, bioactive agent and release rate determining agent is mixed with an aqueous phase containing an emulsifier. The sustained release composition according to claim 1, wherein the sustained release composition continuously releases the bioactive agent. The sustained release composition of claim 1, wherein the sustained release composition has a bioactive agent with an encapsulation rate of greater than 70%. The sustained-release composition according to claim 1, wherein the sustained-release composition is a microsphere, a fine particle, or a microcapsule. The sustained-release composition according to claim 1, wherein the sustained-release composition has a diameter of more than 5 µm. The sustained-release composition according to claim 1, wherein the sustained-release composition is used for intramuscular or subcutaneous injection. The sustained release composition of claim 1 for use in a method of treating an animal comprising administering a pharmaceutically effective amount of the sustained release composition. The sustained-release composition according to claim 7 , wherein the animal is a mammal. The sustained-release composition according to claim 7 , wherein the animal is a human.

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