WO2018072709A1 - 医药微丸的干粉包衣组合物 - Google Patents

医药微丸的干粉包衣组合物 Download PDF

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WO2018072709A1
WO2018072709A1 PCT/CN2017/106691 CN2017106691W WO2018072709A1 WO 2018072709 A1 WO2018072709 A1 WO 2018072709A1 CN 2017106691 W CN2017106691 W CN 2017106691W WO 2018072709 A1 WO2018072709 A1 WO 2018072709A1
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coating
pellets
drug
composition according
composition
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PCT/CN2017/106691
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English (en)
French (fr)
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祝京旭
马颖亮
周国裔
杨庆良
张蕴涵
林振贤
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宁波西敦医药包衣科技有限公司
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Priority to CN201780003275.2A priority Critical patent/CN108367078A/zh
Publication of WO2018072709A1 publication Critical patent/WO2018072709A1/zh

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • 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
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
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    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Definitions

  • the present invention provides a dry powder coating composition for pharmaceutical pellets.
  • Oral pharmaceutical preparations such as tablets, typically require one or more functions such as moisture barrier, enteric release of the drug, targeted release, and slow controlled release, masking or mediating the taste of the formulation or increasing the aesthetics of the formulation.
  • Coated pans are commonly used to achieve coating of tablets.
  • the coating of the powder or liquid or powder liquid mixture is sprayed onto the core surface of the tablet to complete the coating.
  • Electrostatic dry powder coating is a relatively new coating technology that can be used to achieve tablet coating to achieve drug release rate, moisture resistance, aesthetics and taste.
  • Electrostatic dry powder coating technology is a new coating technology that is environmentally friendly, energy efficient and has the potential to replace existing aqueous coatings and solvent coatings.
  • U.S. Patent No. 2007/0128274 describes an electrostatic dry powder coating technique using a coating pan as a coating device.
  • pellet preparation In addition to tablets, another oral pharmaceutical preparation is a pellet preparation (hereinafter referred to as "pellets") which is much smaller than a tablet. These small pellets can be administered orally by being filled into hard capsules, or can be compressed into tablets together with other excipients. In general, oral pellets can have significant therapeutic effects, such as consistent drug availability in sustained release drugs and patient safety benefits not available in single tablets, such as sustained release of sustained release pellets. It would be advantageous to be able to coat individual pellets, but to make the coated pellets viable, the coating must be uniform and envelop the entire pellet surface.
  • the coating composition used for dry powder coated tablets is not suitable for use in granular preparations (pellets).
  • the pellets are more susceptible to agglomeration (agglomeration) during the coating process due to their greater specific surface area and smaller bulk density than tablets.
  • the larger specific surface area of the pellets provides a more favorable environment for the pellets to be attached together, while the lower bulk density prevents the agglomerated pellets from separating, resulting in uneven coating of the pellets. .
  • coatings for oral pharmaceutical formulations typically employ a wet coating process in which the coated film is formed by simultaneous deposition and drying of the polymeric coating material.
  • the film coating is dry and the product temperature is not too high The film coating is tack free.
  • the coating surface may become tacky if the solvent does not evaporate rapidly or the coating temperature is very high relative to the glass transition temperature.
  • the formulation is too moist due to insufficient movement in the coating pan, and/or the coating material is sprayed at a high rate and high coating temperature, this will cause the product to agglomerate.
  • the dry powder coating in order to promote film formation, it is also necessary to lower the glass transition temperature of the film-forming polymer material. An extreme reduction in the glass transition temperature increases the viscosity of the film coat, resulting in agglomeration. Since the inertia of the pellets from each other is much smaller than that of the tablets, the agglomeration problem existing in the pellets is more prominent than the tablets.
  • agglomeration In order to achieve high quality pellet coating, agglomeration must be avoided. Agglomeration can cause problems such as coating surface defects, drug dissolution failure, and affecting the efficacy of the drug in the body.
  • the agglomeration of tablets and pellets during the coating process is a common cause of failure in formulation preparation and differences in product performance, such as bioavailability and drug absorption characteristics, between batches and batches.
  • the coating composition required for the dry powder coated pellets must include not only the functional ingredients capable of imparting the final coating to the desired pharmaceutical properties, but also the ability to promote the uniformity of the pellet coating film during the dry powder coating process. Ingredients.
  • the present invention provides a dry powder coating composition for coating pharmaceutical pellets comprising one or more powdered film-forming polymeric materials ranging from about 1 to about 95% w/w; comprising one or more a powdery or liquid plasticizer for reducing the glass transition temperature of the coating composition material to 30-100 ° C; comprising one or more powdery or liquid antistatic additives ranging from about 0.1 to about 95% w/w; comprising one or more powdered or liquid glidants ranging from about 0.1 to about 25% w/w.
  • One or more powdered or liquid film-forming polymeric materials ranging from about 10 to about 70% w/w.
  • One or more powdered or liquid glidants ranging from about 0.25 to about 20% w/w.
  • One or more powdered or liquid glidants ranging from 0.5 to about 3.0% w/w.
  • One or more powdered or liquid antistatic additives in the range of from about 1 to about 50% w/w.
  • One or more plasticizers include, but are not limited to, glycerin, propylene glycol, PEG 200-8000, glycerin acetate, diethyl phthalate (DEP), dibutyl phthalate (DBP), citric acid three Butyl ester (TBC), triethyl citrate (TEC), castor oil, fractionated coconut oil, acetylated monoglyceride, glyceryl monostearate, oligomers, copolymers, oils, small molecular organics, low molecular weight Alcoholic hydroxyl-containing sugar alcohols, ester plasticizers, glycol ethers, poly(propylene glycol), monoblock copolymers, multi-block copolymers, low molecular weight poly(ethylene glycol) and citric acid plasticization a mixture of one or more of the agents.
  • DEP diethyl phthalate
  • DBP dibutyl phthalate
  • THC citric acid three Butyl ester
  • TEC
  • One or more plasticizers include, but are not limited to, ethylene glycol, 1,2-butanediol, 2,3-butanediol, phenylethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, and others Polyethylene glycol compound, monoethylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol sorbitol, ethyl lactate, butyl lactate, ethyl glycolate, A mixture of one or more of dibutyl sebacate, acetyl tributyl citrate, acetyl triethyl citrate, allyl glycolic acid, and the like.
  • One or more antistatic agents include, but are not limited to, conventional salts, carbon black, magnesium stearate, vapor phase silicates, magnesium trisilicate, glyceryl monostearate, kaolin, talc, and liquid plasticizers. a mixture of one or more of the agents.
  • Liquid plasticizers include, but are not limited to, a mixture of one or more of PEG 200-600, propylene glycol, glycerol, glycerol acetate, and the like.
  • Conventional salts include, but are not limited to, sodium chloride, calcium chloride, magnesium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium phosphate, sodium citrate, sodium acetate, potassium acetate, potassium citrate, potassium chloride, magnesium sulfate, and the like. a mixture of one or more.
  • One or more antistatic agents include, but are not limited to, calcium stearate, colloidal silica, hydrogenated castor oil, microcrystalline cellulose, fumaric acid, glyceryl behenate, glyceryl monostearate, palm Glyceryl stearate, leucine, magnesium stearate, medium chain triglyceride, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, lauryl sulfate A mixture of one or more of sodium, stearyl fumarate, starch, stearic acid, talc, hydrogenated vegetable oil, and zinc stearate.
  • the one or more film-forming polymer materials have one or more functions of moisture-proof, immediate release, masking or changing taste, including but not limited to methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, polyethylene glycol, propylene glycol, poloxamer, polyvinylpyridone, polyvinyl alcohol based coating composition such as A mixture of one or more of AMB, aminoalkyl methacrylate, and the like.
  • the one or more film-forming polymeric materials have a slow release function of the drug, including but not limited to cellulose-based derivatives, acrylic (resin) resins, acrylic acid and methyl methacrylate copolymers comprising quaternary ammonium groups, acrylic acid and A mixture of one or more of a copolymer of methyl methacrylate, ethyl cellulose, and a poly(meth)acrylate polymer insoluble in a digestive liquid.
  • cellulose-based derivatives acrylic (resin) resins
  • acrylic acid and methyl methacrylate copolymers comprising quaternary ammonium groups acrylic acid and A mixture of one or more of a copolymer of methyl methacrylate, ethyl cellulose, and a poly(meth)acrylate polymer insoluble in a digestive liquid.
  • One or more film-forming polymeric materials have a slow release (delayed release) function, including but not limited to polyethylene oxide (PEO), ethylene oxide-propylene oxide copolymer, polyoxyethylene polyoxypropylene Ether block copolymers (such as poloxamer), carbomers, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC), hydroxypropyl Methylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, polyacrylic resins such as carbomer, polyacrylamide, alginic acid and derivatives thereof a mixture of one or more of a substance, a starch and a derivative thereof, a water-soluble gelatin, and the like.
  • PEO polyethylene oxide
  • ethylene oxide-propylene oxide copolymer polyoxyethylene polyoxypropylene Ether block copolymers (such as polox
  • Poly(meth)acrylate polymers that are insoluble in the digestive juice include, but are not limited to, RS, RL and A mixture of one or more of NE polymers.
  • One or more film-forming polymer materials have a drug delayed release function, including but not limited to cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate Dicarboxylate, acrylic polymer, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose vinyl acetate, cellulose acetate trimellitate, shellac, methacrylic acid copolymer, carboxylic acid group a mixture of one or more of a base acrylic copolymer.
  • a methacrylic acid copolymer having a carboxylic acid group includes, but is not limited to, L30D, L100, FS30D, S100 and One or more mixtures.
  • Figure 1 is a drug dissolution profile of taste-masked coated pellets
  • Figure 2 is a drug dissolution profile of the sustained release coated pellets
  • Figure 3 is a drug dissolution profile of enteric coated pellets
  • FIGS 4-A through 4-D are schematic illustrations of multi-layer dry powder coating of pellets using different coating materials.
  • the term “about”, “approximately” refers to covering all values between the maximum and minimum values, such as performance, parameters, and dimensions. For example, the term “about” and “approximately” mean 10% or less above and below.
  • pellets are replaceable, meaning pellets or near pellets.
  • the pellets may be spheroidal or any other shape including, but not limited to, cylinders, cuboids or cubes.
  • the pellets may be after coating or uncoated, depending on their end use.
  • Commercially available uncoated pharmaceutical pellets typically range in size from about 100 to about 2000 microns.
  • the pellets of the present invention have a size of from about 50 to about 3000 microns, more preferably from about 100 to about 2000 microns.
  • methods for preparing uncoated pellets including but not limited to wet granulation, extrusion spheronization, hot melt extrusion, fluidized bed isolation (layering) or dry powder stratification.
  • Quantitative coated pellets or uncoated pellets are filled into capsules together with pharmaceutically acceptable excipients or The tablets were compressed into tablets and prepared into oral preparations.
  • the pellets can also be dispersed directly in a liquid to form an oral suspension.
  • the pellets can be prepared not only as an oral preparation, but also as a topical suspension in combination with a semi-solid ingredient.
  • pharmaceutical pellets for humans range in size from about 5 to 25 millimeters and can be round, rectangular, elliptical or any other shape.
  • film-forming polymer as used in the present invention means a polymer in a dry powder coating material which can form a physical continuous coating film by solidification on the surface of a solid preparation.
  • the continuous coating film contains or does not contain a plasticizer.
  • the film-forming polymer together with other pharmaceutical excipients, acts as a coating material to achieve a pharmaceutical formulation coating film of one or more functions such as functionality, aesthetics, and the like.
  • the one or more film-forming polymers may provide one or more functions including, but not limited to: 1) moisture barrier, such as moisture-proof coated pellets or pellets; 2) delayed release function, such as enteric coating to prevent micro The pellet or pellet drug is released before reaching the small intestine (such as in the stomach); 3) targeted drug delivery, such as a pH-sensitive coating film, allowing the pellet or pellet drug to be released at a fixed point in the cecum (lower gastrointestinal tract); 4) Slow or controlled release functions, such as a sustained release coating, which allows the pellets or pellets to be released at a fixed rate of drug release over an extended period of time, in which case the patient only needs to take the drug once or twice a day instead of one day.
  • moisture barrier such as moisture-proof coated pellets or pellets
  • delayed release function such as enteric coating to prevent micro The pellet or pellet drug is released before reaching the small intestine (such as in the stomach)
  • targeted drug delivery such as a pH-sensitive coating film, allowing the pellet or pellet drug to be released at
  • the present invention provides improved low dose A composition of product composition uniformity.
  • plasticizer refers to an auxiliary agent which can soften a polymer by lowering the glass transition temperature or crystallinity or melting point.
  • a suitable amount of plasticizer allows the polymer and plasticizer materials to combine into a continuous polymer film at a temperature and time.
  • Plasticizers can also refer to the preparation of suitable coating films by imparting the desired viscosity, elasticity, plasticity and any other physical properties of the polymer to withstand mechanical forces during the coating process, product packaging, transfer and transportation. .
  • antistatic auxiliary means an auxiliary agent capable of eliminating static electricity generated on the surface of pellets or pellets.
  • the mechanism for eliminating static electricity is to use an antistatic agent with conductivity to improve the surface conductivity to eliminate static electricity; the other is to make the surface of the pellet or pellet by using a hygroscopic antistatic agent.
  • the static electricity is dispersed to achieve the purpose of eliminating static electricity.
  • the antistatic agent prevents agglomeration or adhesion between the powder particles and between the powder particles and the weak conductor or insulator surface.
  • glidant refers to an auxiliary agent which can improve the fluidity of a powder.
  • Appropriate anti-static additives can effectively improve the transfer efficiency of the coating powder from the whole powder to the electrostatic spray gun during the dry powder coating process.
  • composition of the present invention provides for uniformity and non-caking film formation for pellet preparations A composition that requires processing properties.
  • the inventors have unexpectedly discovered that a composite coating composition of several functional ingredients can achieve a good coating of the pellets by an electrostatic coating process.
  • These functional ingredients include polymers that achieve the desired release of the drug, plasticizers that optimize the film formation temperature, antistatic auxiliaries that affect the electrostatic distribution, and flow aids that improve the transport of the coated powder.
  • the pellets can be dry powder coated in a coating machine. Since the coating of the pellets is much more difficult than the coating of the tablets, the wet coating of the pellets is usually carried out in a fluidized bed embedded with a Wurster inner bed, as described in U.S. Patent No. 3,241,520 (Wruster 1966). Bottom spray fluidized bed coating equipment with Wurster embedded.
  • Film-forming polymers that provide immediate release, flavor, taste, or moisture resistance include, but are not limited to, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hypromellose (HPMC) , polyethylene glycol, propylene glycol, poloxamer and povidone, based on Polyvinyl alcohol composed of AMB, such as A mixture of one or more of E, such as aminoalkyl methacrylate copolymers.
  • Coating polymers that can achieve sustained drug release functions include, but are not limited to, cellulose ether derivatives, acrylic resins, copolymers of acrylic and acrylate quaternary ammonium groups, acrylic and acrylate copolymers or any of them a combination, or it may contain ethyl cellulose, cellulose acetate and poly(meth)acrylate polymers insoluble in the digestive juice, such as RS/RL polymer with a basic group and NE has a neutral group polymer and the like.
  • the coating polymer capable of achieving a sustained release function comprises a water soluble polymer such as, but not limited to, ethylene oxide (PEO), ethylene oxide-propylene oxide copolymer, polyethylene polypropylene glycol (eg, mooring) Losham), Carbomer, Polycarbophil, Chitosan, Polyvinylpyrrolidone (PVP), Polyvinyl Alcohol (PVA), Hydroxyalkyl Cellulose such as Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose, hydroxymethylcellulose and hypromellose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylmethylcellulose, hypromellose, polyacrylates such as carbomer, poly Acrylamide, polymethacrylamide, polyphosphazene, polyoxazolidinone, polyhydroxyalkyl carboxylic acid, alginic acid and derivatives thereof such as carrageenan alginate, ammonium alginate and sodium alginate, starch and Starch
  • Coating polymers that can achieve delayed release include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, acrylic acid polymerization. , polyethylene acetal diethylaminoacetate, hypromellose acetate succinate, trimellitic acid triacetate, shellac, methacrylic acid copolymer, carboxylic acid methyl propionate Copolymer (such as L30D, L100, FS30D, SI00 and And a mixture of one or more.
  • the multi-coated pellet formulation with the pre-set coating composition provides additional advantages in that it can achieve multiple drug release such as immediate release, sustained release/controlled release, and enteric release with moisture and drug protection functions.
  • a multifunctional drug particle carrier system refers not only to the coating of the drug-containing pellets by multiple predetermined coating compositions, but also to the one or more drugs in the drug-free pellets (such as sucrose micro). The surface of the pellet or microcrystalline cellulose pellets is deposited and then multi-coated to achieve versatility.
  • Figure 4 is a schematic representation of some multi-coated pellet formulations.
  • Figure 4-A describes the coating of a protective layer of the drug pellets, followed by enteric coating or controlled release coating to achieve enteric release or controlled release of the drug
  • B describes the coating of a protective layer of the drug pellets, followed by a controlled release coating, and finally an enteric coating to simultaneously achieve enteric release and controlled release of the drug
  • Figure 4-C depicts First, a drug is deposited on the surface of a pellet (such as sucrose or microcrystalline cellulose pellets), and then coated with a protective layer, and an enteric coating or a controlled release coating to achieve deposition on the surface of the pellet.
  • a pellet such as sucrose or microcrystalline cellulose pellets
  • Figure 4-D depicts the first deposition of a drug on the surface of a pellet (such as sucrose or microcrystalline cellulose pellets), followed by a protective coating, followed by a slowing
  • the controlled release coating is finally subjected to enteric coating to simultaneously achieve enteric release and controlled release of the drug deposited on the surface of the pellet.
  • liquid and solid plasticizers can be used to achieve the desired glass transition temperature required for dry powder coating, and can be used in coating compositions to reduce the glass transition temperature of the coating polymer to about 30-100 ° C, more preferably to 45. -70 ° C.
  • liquid plasticizers have multiple functions during the dry powder coating of the pellets. Including: 1) reducing the glass transition temperature of the film-forming polymer (ie, enhancing the movement of the molecule) to prepare an oral pharmaceutical preparation coating film that meets functional and aesthetic requirements; 2) enhancing the adhesion of the film-forming powder to the surface of the pellet; as well as 3) Improve the conductivity of the surface of the pellet.
  • the surface plasticizer therefore acts as an antistatic additive before it enters the coated polymer matrix to produce a polymer coating film.
  • the plasticizer can be combined with the molecular chain of the film-forming polymer to increase the free volume between the polymer molecular chains and thereby greatly reduce the glass transition temperature of the polymer powder. If the plasticizer consists of a liquid polymer or a polymer solution, spraying it on the surface of the pellet can also greatly reduce the resistivity of the surface of the pellet to improve the adhesion of the coated powder and the uniformity of the coating. Coating efficiency. In addition, a certain amount of plasticizer or plasticizer solution can create a strong capillary force between the particles to enable polymer sintering and film formation.
  • Plasticizers used in the coating composition of the present invention include, but are not limited to, glycerin, propylene glycol, polyethylene glycol of 200-600 grade, triacetin, diethyl ester (DEP), dibutyl phthalate (DBP). And tributyl citrate (TBC), triethyl citrate (TEC), castor oil, fractionated coconut oil, acetylated glycerol and glyceryl monostearate.
  • Plasticizers used in the coating composition of the present invention include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, aliphatic hydroxy low molecular weight polyols, and ester type additions. Plasticizers, glycol ethers, polypropylene glycols, multi-block copolymers, monoblock copolymers, and citrate-type plasticizers.
  • plasticizers may also include ethylene glycol, 1,2-butanediol, 2,3-butanediol, phenylethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, and other poly(ethylene) Alcohol) compound, monopropanol monoisopropyl ether, propylene glycol ethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl Tributyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolic acid.
  • One or more antistatic agents include, but are not limited to, conventional salts, carbon black, magnesium stearate, fumed silicates, magnesium trisilicate, glyceryl monostearate, kaolin, talc, and liquid plasticization.
  • Agent. The liquid plasticizer may include a mixture of one or more of polyethylene glycol 200 to 600, propylene glycol, glycerin, and glycerin acetate.
  • Salts may include, but are not limited to, sodium chloride, calcium chloride, magnesium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium phosphate, sodium citrate, sodium acetate, potassium acetate, potassium citrate, potassium chloride, and magnesium sulfate. Medium or a mixture of one or more.
  • the antistatic additive may be present in the composition in a range from about 0.1 to about 95% w/w, more preferably from about 1 to about 50% w/w.
  • One or more glidants may include calcium stearate, colloidal silica, hydrogenated castor oil and microcrystalline cellulose, fumaric acid, glyceryl behenate, glyceryl monostearate, palm Glyceryl stearate, leucine, magnesium stearate, medium chain triglyceride, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate A mixture of one or more of sodium, sodium stearyl fumarate, starch, stearic acid, talc, hydrogenated vegetable oil, and zinc stearate.
  • the powdered one or more glidants may be present in the composition in the range of from about 0.1 to about 25% w/w, more preferably from about 0.25 to about 20% w/w. In an example, one or more glidants are present in the composition in a range from about 0.5 to about 3% w/w.
  • piroxicam pellets as a model pellet formulation in the examples of the present invention is effective to demonstrate the effectiveness of the dry powder coating composition of the electrostatic dry powder coated pellets.
  • Three different functions are contained separately EPO, RS/RL and The coating composition of the equal polymer achieves the functions of taste masking, slow release, and enteric release, respectively.
  • Example 1 Dry powder coated piroxicam pellets to achieve taste masking function (coating material contained EPO)
  • This example describes the process of dry coating of piroxicam pellets using a dry powder coating technique, the coating composition comprising EPO (a cationic polymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate), a class of pH-sensitive polymers dissolved in gastric juice (pH below 5.0), swollen And has permeability (pH above 5.0); and a liquid plasticizer used to improve the adhesion of coated powder and piroxicam pellets, polyethylene glycol 400 (PEG 400, EMD Chemicals Inc. Ontario, Canada ); talc is used as an antistatic agent, and colloidal silica is used as a flow aid.
  • EPO a cationic polymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate
  • a class of pH-sensitive polymers dissolved in gastric juice pH below 5.0
  • swollen And has permeability pH above
  • Table 1 Each component in Table 1 was prepared as a coating powder using a leaf mill (about 25 seconds). EPO and colloidal silica (AEROSIL Pharma) donation from Evonik Degussa Corporation (Germany). Talc was purchased from Mallinckrodt Baker Inc. (Canada).
  • piroxicam pellets 40 g were placed in a rotating dry powder coating apparatus and preheated to 40 ° C with a rotation speed of 20 rpm. The speed was then increased to 70 rpm and the temperature was maintained at 40 °C.
  • the liquid plasticizer polyethylene glycol 400 (PEG 400) was sprayed on the surface of the pellets (0.25 g/min for 35 seconds) using a liquid spray gun, and then 1.5 g of the coating powder was sprayed onto the surface of the pellets using an electrostatic spray gun. .
  • the spraying of the plasticizer and the coating powder can be repeated 3 times after 15 minutes to achieve the preset coating weight gain.
  • the coated powder is then cured at 40 ° C to 2 hours to form a film on the surface of the pellet.
  • Example 2 Dry powder coated piroxicam pellets to achieve slow drug release function (coating material contained RS/RL)
  • This example describes the process of dry coating of piroxicam pellets using a dry powder coating technique, the coating composition comprising RS (a low permeability copolymer based on ethyl acrylate, methyl methacrylate and a small amount of quaternary ammonium group methacrylate) and RL (a highly permeable copolymer based on ethyl acrylate, methyl methacrylate and a small amount of quaternary ammonium group methacrylate), two pH independent polymers commonly used in sustained release coating materials, and a Used to improve the adhesion of coated powder and piroxicam pellets RS/RL liquid plasticizer with a glass transition temperature from 63-65 to 35 ° C, triethyl citrate (TEC, Caledon Laboratories Ltd. Ontario, Canada); talc used as an antistatic agent, colloidal dioxide Silicon is used as a flow aid.
  • RS low permeability copolymer based on ethyl acrylate, methyl
  • Table 2 Each component in Table 2 was prepared into a coating powder using a leaf mill (about 25 seconds).
  • Talc was purchased from Mallinckrodt Baker Inc. (Canada).
  • Coated powder RS The particle diameter (volume average diameter) D [4, 3] of the RL and talc powder were 47.7 micrometers, 40.8 micrometers, and 28.9 micrometers, respectively.
  • piroxicam pellets 40 g were placed in a rotating dry powder coating apparatus and preheated to 50 ° C with a rotation speed of 20 rpm. The speed was then increased to 70 rpm and the temperature was maintained at 50 °C.
  • a liquid plasticizer, triethyl citrate (TEC) was sprayed onto the surface of the pellets (0.25 g/min for 35 seconds) using a liquid spray gun, and then 1.5 g of the coating powder was sprayed onto the surface of the pellets using an electrostatic spray gun.
  • the spraying of the plasticizer and the coating powder can be repeated 6 times after 15 minutes to achieve the preset coating weight gain.
  • the coated powder is then cured on the surface of the pellets to form a film at 50 ° C to 2 hours.
  • the dissolution test of the dry powder coated piroxicam pellets in a phosphate buffer solution was carried out in accordance with the requirements of the United States Pharmacopoeia using a USP dissolution apparatus (Appartus 2) at 37 ° C, 50 rpm.
  • the eluted sample of the drug was analyzed at 354 nm using an ultraviolet-visible spectrophotometer.
  • the dissolution test of the drug in the phosphate buffer solution showed that the piroxicam pellet after the dry powder coating had the expected slow release of the drug.
  • Example 3 Dry powder coated piroxicam pellets to achieve drug enteric release function (coating material contained )
  • the coating composition (Table 3) contains the product supplied by Colorcon, USA. (contain L100-55, an anionic copolymer based on methacrylic acid and ethyl acrylate), a pH-sensitive polymer (soluble in water at pH greater than 5.5), and a modified powder and piroxicam Pill adhesion and film forming material A liquid plasticizer having a glass transition temperature lowered from 133 ° C to 50-55 ° C, polyethylene glycol 400 (PEG 400, EMD Chemicals Inc. Ontario, Canada), which is also used as an antistatic additive.
  • PEG 400 polyethylene glycol 400
  • Each component in Table 2 was prepared into a coating powder using a leaf mill (about 25 seconds).
  • piroxicam pellets 40 g were placed in a rotating dry powder coating apparatus and preheated to 50 ° C with a rotation speed of 20 rpm. The speed was then increased to 70 rpm and the temperature was maintained at 50 °C.
  • the liquid plasticizer polyethylene glycol 400 (PEG 400) was sprayed on the surface of the pellets (0.25 g/min for 35 seconds) using a liquid spray gun, and then 1.5 g of the coating powder was sprayed onto the surface of the pellets using an electrostatic spray gun. . Spraying of plasticizer and coating powder can be repeated after 15 minutes (repeated 4 times to obtain 13.25% coating weight gain; repeat 7 times to obtain 21.93% coating weight gain) to achieve the preset coating Weight gain.
  • the coated powder is then cured on the surface of the pellets to form a film at 50 ° C to 2 hours.
  • the operation was carried out at 100 rpm, and the eluted sample of the drug was analyzed at 353 nm using an ultraviolet-visible spectrophotometer.
  • Example 4 Dry powder coated pellets sucrose to achieve multi-layer coating of esomeprazole drug deposition, coating protective layer and enteric coating layer
  • This illustration describes the use of a dry powder coating technique to apply a three-coating composition (Table 4) to a pellet formulation to achieve a multi-layer coating of esomeprazole pellets.
  • Table 4 a three-coating composition
  • the first, second and third layers of coating respectively achieve immediate release, chemical decomposition protection and immediate release, enteric release.
  • the first coating composition comprises esomeprazole (pharmaceutical ingredient), hydroxypropyl cellulose (a pH independent and water soluble polymer), crosslinked polyvinylpyrrolidone (PVP-XL), hydrogen Magnesium oxide (two stabilizers), talc (an antistatic agent) and polyethylene glycol 400 (a plasticizer and an additive to increase the powdering rate of the coated powder on the surface of the pellet).
  • esomeprazole pharmaceutical ingredient
  • hydroxypropyl cellulose a pH independent and water soluble polymer
  • PVP-XL crosslinked polyvinylpyrrolidone
  • hydrogen Magnesium oxide two stabilizers
  • talc an antistatic agent
  • polyethylene glycol 400 a plasticizer and an additive to increase the powdering rate of the coated powder on the surface of the pellet.
  • the second coating composition comprises hydroxypropyl cellulose (a pH-independent and water-soluble polymer), cross-linked polyvinylpyrrolidone (PVP-XL), magnesium hydroxide (two stabilizers), Talc (an antistatic agent) and polyethylene glycol 400 (a plasticizer and an additive that increases the powder rate of the coated powder on the surface of the pellet).
  • hydroxypropyl cellulose a pH-independent and water-soluble polymer
  • PVP-XL cross-linked polyvinylpyrrolidone
  • magnesium hydroxide two stabilizers
  • Talc an antistatic agent
  • polyethylene glycol 400 a plasticizer and an additive that increases the powder rate of the coated powder on the surface of the pellet.
  • the third layer coating composition comprises L100-55 (an anionic copolymer based on methacrylic acid and ethyl acrylate, a pH-sensitive polymer, soluble in water at pH greater than 5.5), talc (an antistatic agent) and polyethylene glycol 400 (a plasticizer and an additive to increase the powder rate of the coated powder on the surface of the pellet).
  • L100-55 an anionic copolymer based on methacrylic acid and ethyl acrylate, a pH-sensitive polymer, soluble in water at pH greater than 5.5
  • talc an antistatic agent
  • polyethylene glycol 400 a plasticizer and an additive to increase the powder rate of the coated powder on the surface of the pellet.
  • HPC hydroxypropyl cellulose
  • the particle size (volume average diameter) of L100-55 was reduced to 30 microns and 23 microns.
  • the various coating ingredients (except polyethylene glycol) used were uniformly mixed before the coating was carried out.
  • the sucrose pellets were placed in a rotating dry powder coating apparatus and preheated to 45 ° C with a rotational speed of 20 rpm. The speed was then increased to 70 rpm and the temperature was maintained at 45 °C.
  • the liquid plasticizer polyethylene glycol 400 (PEG 400) was sprayed on the surface of the pellets (0.25 g/min for 35 seconds) using a liquid spray gun, and then 1.5 g of the coating powder was sprayed onto the surface of the pellets using an electrostatic spray gun. . Spraying of the plasticizer and coating powder can be repeated after 15 minutes to meet the requirements of the multilayer coating and achieve a preset coating weight gain. The coated powder is then cured on the surface of the pellets to form a film at 45 ° C to 72 hours.
  • the sample was processed at 100 rpm and the dissolved sample of the drug was analyzed at 280 nm using an ultraviolet-visible spectrophotometer.
  • the dissolution test results show that the enteric coating film meets the requirements of the USP.
  • the dry powder coated esomeprazole pellets were placed in a sealed container and stored at 50 ° C for 6 weeks. No change in color was observed. The results indicate that the stabilizer acts to prevent or reduce the decomposition of dwarcome. And the protective layer coating acts to prevent the incompatible ingredients of the coated pellets from dwarsh meprazole and The role of chemical reaction (chemical decomposition) between L100-55.

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Abstract

一种用于包衣医药微丸的干粉包衣组合物，其包含以下重量百分含量的组分：1.0-95%的一种或多种粉状成膜高分子材料，用于降低包衣组合物材料的玻璃化转变温度至30-100℃的一种或多种粉状或液体增塑剂，0.1-95%的一种或多种粉状或液体防静电剂，以及0.1-25%的一种或多种粉状或液体助流剂。

Description

医药微丸的干粉包衣组合物 技术领域
本发明提供了用于医药微丸的干粉包衣组合物。
背景技术
口服药物制剂(如片剂)通常需要通过包衣来实现防潮、药物的肠溶释放、靶向释放以及缓慢控制释放、掩盖或调解制剂味道或增加制剂美观等一种或多种功能。
包衣锅通常用来实现对片剂的包衣。将粉体或液体或粉体液体混合物的包衣材料喷涂于片剂的片芯表面完成包衣。静电干粉包衣是一项相对较新的包衣技术，该技术可以用来实现片剂的包衣从而达到调解药物释放速率、防潮、改善美观及掩盖味道等功能。静电干粉包衣技术是一种环保、节能且有潜力取代现有水性包衣及溶剂包衣的新型包衣技术。美国专利US 2007/0128274介绍了使用包衣锅作为包衣设备的静电干粉包衣技术。
除了片剂，另外一种口服药物制剂是微丸制剂(以下称“微丸”)，这种制剂比片剂小很多。这些小的微丸可以通过装进硬胶囊实现口服给药，也可以与其他赋型剂一起被压制成片剂给药。通常而言，口服微丸可带来显著的疗效，例如缓释药物持续一致的药物利用度以及单一片剂所不具备的患者安全效益，例如缓释微丸药物的突释。能够对单个微丸进行包衣将非常有利，但为使包衣微丸可行，包衣必须均匀并且包住整个微丸表面。
发明人注意到干粉包衣片剂所使用的包衣组合物不适用于颗粒制剂(微丸)。由于比片剂拥有更大的比表面积及更小的容积密度，微丸在包衣过程中会更易结块(团聚)。微丸所具有的较大比表面积能够为微丸附着在一起提供更为有利的环境，而其较低的容积密度能够阻止结块的微丸分离开来，从而导致微丸的包衣不均。
包衣过程中结块的其中一个原因是与聚合物包衣膜的粘性有关。例如，口服药物制剂的包衣通常使用湿法包衣工艺，其中包衣薄膜是通过聚合物包衣材料同时进行的沉积和干燥而形成。通常在薄膜包衣干燥并且产品温度不太高的情况 下，薄膜包衣无粘性。然而，由于在增塑剂和溶剂的作用下包衣材料的玻璃化转变温度下降，倘若溶剂未迅速蒸发或者包衣温度相对玻璃化转变温度非常高，包衣表面可以变得有粘性。倘若制剂由于在包衣锅内运动不充足，及/或包衣材料喷涂速率过高以及高包衣温度而过于潮湿，这将导致产品结块。在干粉包衣中，为促进薄膜成型，也需降低成膜聚合物材料的玻璃化转变温度。玻璃化转变温度的极度降低增加了薄膜衣的粘性，从而导致结块。由于微丸脱离彼此的惯性比片剂小得多，因此相比片剂，微丸中存在的结块问题更加突出。
固体口服制剂在包衣过程中结块的另一种原因在于静电的存在。由于带电荷装置的静电力比不带电荷装置的非特异范德华力更强，因此带静电表面的吸引力比不带静电的表面大。这对于较小的微丸更是个问题，静电能使较轻的微丸与带相反电荷的微丸结合，从而导致比拥有较低表面积体积之比的片剂相连更强的结合力。
如上所述，为实现高质量的微丸包衣，必须避免结块。结块会导致包衣表面缺陷、药物溶出失败以及影响体内药效等问题。片剂和微丸在包衣过程中的结块是制剂制备失败以及诸如生物利用度和药物吸收特性等产品效能在批间和批内存在差异的常见原因。
因此，干粉包衣微丸所需的包衣组合物必须不仅包括能够赋予最终的包衣以预期药学特性的功能性成分，而且必须包括能够在干粉包衣过程中促进微丸包衣膜均一性的成分。
因此，为静电干粉包衣微丸制剂提供能够避免上述局限性的包衣组合物将有巨大的优势。
发明内容
本发明提供了用于包衣医药微丸的干粉包衣组合物，包含一种或多种粉状成膜高分子材料，其范围为约1-约95％w/w；包含一种或多种粉状或液体增塑剂，用于降低包衣组合物材料的玻璃化转变温度至30-100℃；包含一种或多种粉状或液体防静电助剂，其范围为约0.1-约95％w/w；包含一种或多种粉状或液体助流剂，其范围为约0.1-约25％w/w。
一种或多种粉状或液体成膜高分子材料，其范围为约10-约70％w/w。
一种或多种粉状或液体助流剂，其范围为约0.25-约20％w/w。
一种或多种粉状或液体助流剂，其范围为0.5-约3.0％w/w。
一种或多种粉状或液体防静电助剂，其范围为约1-约50％w/w。
一种或多种增塑剂包括但不限于甘油、丙二醇、PEG 200-8000、甘油醋酸酯、邻苯二甲酸二乙酯(DEP)、邻苯二甲酸二丁酯(DBP)、柠檬酸三丁酯(TBC)、柠檬酸三乙酯(TEC)、蓖麻油、分馏椰子油、乙酰化单甘酯、单硬脂酸甘油酯、低聚物、共聚物、油、小分子有机物、低分子量的具有脂肪族羟基的糖醇、酯类增塑剂、乙二醇醚、聚(丙二醇)、单嵌段共聚物、多嵌段共聚物、低分子量聚(乙二醇)和柠檬酸增塑剂中的一种或多种的混合物。
一种或多种增塑剂包括但不限于乙二醇、1，2-丁二醇、2，3-丁二醇、苯代乙二醇、二甘醇、三甘醇、四甘醇和其他聚乙二醇化合物、一乙二醇单异丙醚、丙二醇单乙醚、乙二醇单乙醚、二乙二醇单乙醚、乳酸山梨糖醇、乳酸乙酯、乳酸丁酯、乙醇酸乙酯、癸二酸二丁酯、乙酰柠檬酸三丁酯、乙酰基柠檬酸三乙酯、烯丙基乙醇酸等一种或多种的混合物。
一种或多种防静电助剂包括但不限于常规盐类、炭黑、硬脂酸镁、气相硅酸盐、三硅酸镁、单硬脂酸甘油酯、高岭土、滑石粉和液体增塑剂等一种或多种的混合物。液体增塑剂包括但不限于PEG 200-600、丙二醇、丙三醇、甘油醋酸酯等一种或多种的混合物。常规盐类包括但不限于氯化钠、氯化钙、氢氧化镁、碳酸钠、碳酸氢钠、磷酸钠、柠檬酸钠、乙酸钠、乙酸钾、柠檬酸钾、氯化钾、硫酸镁等一种或多种的混合物。
一种或多种增塑剂，用于降低包衣组合物材料的玻璃化转变温度至45-70℃.
一种或多种防静电助剂包括但不限于硬脂酸钙、胶体二氧化硅、氢化蓖麻油、微晶纤维素、富马酸、山嵛酸甘油酯、单硬脂酸甘油酯、棕榈酸硬脂酸甘油酯、白氨酸、硬脂酸镁、中链甘油三酯、豆蔻酸、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、十二烷基硫酸钠、硬脂富马酸钠、淀粉、硬脂酸、滑石粉、氢化植物油和硬脂酸锌一种或多种的混合物。
一种或多种成膜高分子材料具有防潮、速释、掩盖或改变味道等功能的一种 或多种，包括但不限于甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇、丙二醇、泊洛沙姆、聚乙烯吡啶酮、聚乙烯醇基包衣组合物如
Figure PCTCN2017106691-appb-000001
AMB、氨基烷基甲基丙烯酸酯等一种或多种的混合物。
一种或多种成膜高分子材料具有实现药物缓慢释放功能，包括但不限于纤维素基衍生物、丙烯酸(类)树脂、丙烯酸和甲基丙烯酸甲酯且包含季铵基团的共聚物、丙烯酸和甲基丙烯酸甲酯的共聚物、乙基纤维素及不溶于消化液的聚(甲基)丙烯酸酯类聚合物等一种或多种的混合物。
一种或多种成膜高分子材料具有实现药物缓慢释放(延迟释放)功能，包括但不限于聚环氧乙烷(PEO)、环氧乙烷-氧化丙烯共聚物、聚氧乙烯聚氧丙烯醚嵌段共聚物(如泊洛沙姆)、卡波姆、聚乙烯吡咯酮(PVP)、聚乙烯醇(PVA)、羟烷基纤维素如羟丙基纤维素(HPC)、羟丙基甲基纤维素、羧甲基纤维素钠、甲基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、聚丙烯酸树脂如卡波姆、聚丙烯酰胺、藻酸及其衍生物、淀粉及其衍生物、水溶性明胶等一种或多种的混合物。
不溶于消化液的聚(甲基)丙烯酸酯类聚合物包括但不限于
Figure PCTCN2017106691-appb-000002
RS、
Figure PCTCN2017106691-appb-000003
RL及
Figure PCTCN2017106691-appb-000004
NE聚合物等一种或多种的混合物。
一种或多种成膜高分子材料具有实现药物延迟释放功能，包括但不限于邻苯二甲酸乙酸纤维素、乙酸纤维素trimaletate、苯二甲酸羟丙基甲基纤维素、聚醋酸乙烯邻苯二甲酸酯、丙烯酸类聚合物、polyvinyl acetaldiethylamino acetate、羟丙基甲基纤维素醋酸乙烯酯、乙酸纤维素偏苯三酸酯、虫漆、甲基丙烯酸共聚物、具有羧酸基团的甲基丙烯酸共聚物等一种或多种的混合物。
具有羧酸基团的甲基丙烯酸共聚物包括但不限于
Figure PCTCN2017106691-appb-000005
L30D、
Figure PCTCN2017106691-appb-000006
L100、
Figure PCTCN2017106691-appb-000007
FS30D、
Figure PCTCN2017106691-appb-000008
S100和
Figure PCTCN2017106691-appb-000009
等一种或多种的混合物。
通过参考下文的详细描述和附图能够实现对本发明的功能和优点方面的进一步理解。
附图说明
从下文的本发明详细描述与附图结合可更充分地理解本发明。附图是本发明 的一部分，并且其中：
图1是掩味包衣微丸的药物溶出曲线；
图2是缓释包衣微丸的药物溶出曲线；
图3是肠溶包衣微丸的药物溶出曲线；
图4-A至图4-D是利用不同包衣材料对微丸进行多层干粉包衣的示意图。
具体实施方式
下面将进行各种具体的细节描述，但以下描述和附图用于描述本发明而不应被理解为限制，本文将描述更多的细节以便理解本发明。但在一些实例中，众所周知的或常规的细节将不进行描述以便对本发明进行简明的讨论。
本发明所用的术语“包含(comprises)”，“包含(comprising)”，“包括(including)”和“包括(includes)”应被解释为开放性的包括，而不是排除。尤其是当使用在本说明书包括权利中时，“包含(comprises)”、“包含(comprising)”、“包括(including)”和“包括(includes)”及其各种变化形式均指包括特定的特征、步骤或组分。这些术语不应被解释为排除其它特征、步骤或组分的存在。
本发明所用的术语“示例(exemplary)”应被解释为“作为例证、实例、情况、说明”，不应被认为比其他情况更有优势或者优于其他示例。
本发明所用的术语“大约(about)”，“近似地(approximately)”是指覆盖介于最大值与最小值之间的所有值，如性能、参数和尺寸。例如，术语“大约(about)”，“近似地(approximately)”是指上下10％或更少。
本发明所用的术语“微丸(pellets)”，“小珠(beads)”，“球状体(spheroids)”(下文称为微丸)是可替换的、意为微丸或者接近微丸形状的单一颗粒或者多个药物活性成分颗粒或微粉的团聚物。需要注意的是微丸可能是球状体，也可能是其他任何形状，包括但不限于圆柱体、长方体或者正方体等。微丸可以是包衣之后的或者是未经过包衣的，取决于其最终用途。商业上存在的未经过包衣的医药微丸尺寸一般在约100-约2000微米。本发明中微丸的尺寸为约50-约3000微米，更可取的是约100-约2000微米。未经过包衣微丸的制备方法很多，包括但不限于湿法造粒、挤出滚圆、热熔挤出、流化床离析(成层)或干粉成层。
定量的包衣微丸或未包衣微丸连同药学上可接受的赋形剂填充到胶囊内或 者压制成片，制备成口服制剂。微丸也可以直接分散于一种液体之中形成口服悬浮剂。微丸不仅仅可以是口服制剂，例如与半固体成分结合制备成局部滴悬剂。
相比之下，用于人的药物微丸的尺寸范围大约5-25毫米，可以是圆形、长方形、椭圆形或任何其他形状。
本发明所用的术语“成膜聚合物”是指干粉包衣材料中可以在固体制剂表面通过固化形成物理连续包衣膜的聚合物。连续包衣膜包含或不包含增塑剂。成膜聚合物连同其他药物辅料一起作为包衣材料去实现功能性、美观性等一种或多种功能的药物制剂包衣膜。一种或多种成膜聚合物可以提供一种或多种功能，包括但不限于：1)防潮，如防潮包衣微丸或微丸；2)延迟释放功能，如肠溶包衣防止微丸或者微丸药物在到达小肠之前(如在胃部)释放；3)靶向药物传递，如一种pH敏感型包衣膜使微丸或者微丸药物在盲肠(胃肠道下端)定点释放；4)缓慢或控制释放功能，如缓释包衣使微丸或者微丸药物在延长的时间段内按固定的药物释放速率释放，该情况下患者只需每天吃一次或两次药物而不是一天多次用药；5)掩盖味道以阻止口腔内的药物释放，或包衣内的味道调解剂；6)低剂量包衣，如少量的药物成分嵌入聚合物包衣，本发明提供可以改善低剂量产品成分均一性的组合物。
本发明所用的术语“增塑剂”是指可以通过降低玻璃化转变温度或结晶度或熔点而软化聚合物的助剂。对于干粉包衣，适当用量的增塑剂允许聚合物和增塑剂材料在一定的温度和时间内合并而成连续的聚合物膜。增塑剂也可以是指通过给予聚合物理想的粘度、弹性、塑性和任意其他物理性能而制备出适合的包衣膜，从而经受包衣过程中、产品包装、转移以及运输过程中的机械力。
本发明所用的术语“防静电助剂”是指能够消除在微丸或微丸表面产生的静电的助剂。其消除静电的机理一种是使用具有导电性的防静电助剂，提高表面导电性从而达到消除静电的目的；另一种是通过使用吸湿性的防静电助剂，使微丸或微丸表面的静电分散从而达到消除静电的目的。防静电助剂防止粉体颗粒之间以及粉体颗粒和弱导体或绝缘体表面的结块或粘合。
本发明所用的术语“助流剂“是指可以改善粉体流动性的助剂。适当的防静电助剂可以有效地提高干粉包衣过程中包衣粉由整装粉体到静电喷枪的传递效率。
本发明所述的组合物是为微丸制剂提供的具有满足均一性和非结块成膜和 加工性能要求的组合物。发明人意外地发现如下几种功能性成分的复合包衣组合物通过静电包衣过程可以实现对微丸的良好包衣。这些功能性成分包括实现药物预期释放的聚合物、优化成膜温度的增塑剂、影响静电分布的防静电助剂和改善包衣粉体传输的助流剂等。
对于干粉包衣，一个出人意料的发现是微丸可在包衣机中进行干粉包衣。由于微丸的包衣比片剂的包衣难很多，微丸的湿法包衣通常是在嵌有Wurster内床的流化床中进行的，见美国专利第3,241,520号(Wruster 1966)所描述的带有Wurster内嵌的底喷流化床包衣设备。
成膜聚合物
可实现速释、增味/掩味或防潮功能的成膜聚合物包括但不限于甲基纤维素、羟乙基纤维素、羟丙基纤维素(HPC)、羟丙甲纤维素(HPMC)、聚乙二醇、丙二醇、泊洛沙姆和聚维酮、基于诸如
Figure PCTCN2017106691-appb-000010
AMB构成的聚乙烯醇、诸如
Figure PCTCN2017106691-appb-000011
E等氨烷基甲基丙烯酸酯类共聚物中等一种或多种的混合物。
可实现药物缓释功能的包衣聚合物包括，但不限于纤维素醚衍生物、丙烯酸树脂、丙烯酸和丙烯酸酯类季带铵基基团的共聚物、丙烯酸和丙烯酸酯类共聚物或其中任何之组合，亦或其可含有不溶于消化液的乙基纤维素、醋酸纤维素和聚(甲基)丙烯酸酯聚合物如
Figure PCTCN2017106691-appb-000012
RS/RL带有碱性基团的聚合物以及
Figure PCTCN2017106691-appb-000013
NE带有中性基团聚合物等。
可实现缓释功能的包衣聚合物包含水溶性聚合物，例如但不限于环氧乙烷(PEO)、环氧乙烷-环氧丙烷共聚物、聚乙烯聚丙烯乙二醇(如，泊洛沙姆)、卡波姆、聚卡波非、壳聚糖、聚乙烯吡咯烷酮(PVP)、聚乙烯醇(PVA)、羟烷基纤维素诸如羟丙基纤维素(HPC)、羟乙基纤维素、羟甲基纤维素和羟丙甲纤维素、羧甲基纤维素钠、甲基纤维素、羟乙基甲基纤维素、羟丙甲纤维素、聚丙烯酸酯诸如卡波姆、聚丙烯酰胺、聚甲基丙烯酰胺、聚膦嗪、聚噁唑烷酮、聚羟基烷基羧酸、藻酸及其衍生物诸如鹿角菜胶海藻酸盐、藻酸铵和海藻酸钠、淀粉及淀粉衍生物、多糖、聚羧乙烯、聚乙二醇、天然树胶诸如瓜尔豆胶、阿拉伯树胶、黄蓍胶、刺梧桐树胶和黄原胶、聚维酮、明胶等等。可实现迟释的包衣聚合物包括，但不限于邻苯二甲酸乙酸纤维素、醋酸纤维素trimaletate、羟丙基甲基纤维素邻 苯二甲酸酯、聚醋酸乙烯酞酸酯、丙烯酸聚合物、聚乙烯乙缩醛二乙氨基乙酸盐、醋酸羟丙甲纤维素琥珀酸酯、偏苯三酸三醋酸纤维素、虫胶、甲基丙烯酸共聚物、带羧酸甲基丙酸烯共聚物(诸如
Figure PCTCN2017106691-appb-000014
L30D、
Figure PCTCN2017106691-appb-000015
L100、
Figure PCTCN2017106691-appb-000016
FS30D、
Figure PCTCN2017106691-appb-000017
SI00和
Figure PCTCN2017106691-appb-000018
)等一种或多种的混合物。
本领域技术人员应该理解可在微丸中应用多重包衣，且根据上方关于成膜聚合物所述为各层包衣选定预设功能。
以预设包衣组合物进行多层包衣的微丸制剂可以提供额外的优势，制备成可实现多种药物释放如具有防潮和保护药物功能的速释、缓释/控制释放以及肠溶释放等的多功能药物颗粒载体系统。这种多功能药物颗粒载体系统不仅指含有药物的微丸被多重预设的包衣组合物所包衣，也可指将一种或多种药物先在不含药物的微丸(如蔗糖微丸或微晶纤维素微丸)表面进行沉积，然后再对其进行多重包衣，以实现其多功能性。
图4是一些多重包衣微丸制剂的示意图。其中，图4-A描述的是对药物微丸先包一层保护层包衣，然后进行肠溶包衣或者缓控释包衣，以实现药物的肠溶释放或者缓控释放；图4-B描述的是对药物微丸先包一层保护层包衣，然后进行缓控释包衣，最后进行肠溶包衣，以同时实现药物的肠溶释放和缓控释放；图4-C描述的是首先将一种药物沉积在微丸(如蔗糖或者微晶纤维素微丸)的表面，然后进行保护层包衣，和肠溶包衣或者缓控释包衣，以实现沉积在微丸表面药物的肠溶释放或者缓控释放；图4-D描述的是首先将一种药物沉积在微丸(如蔗糖或者微晶纤维素微丸)的表面，然后进行保护层包衣，接着进行缓控释包衣，最后进行肠溶包衣，以同时实现沉积在微丸表面药物的肠溶释放和缓控释放。
增塑剂
液体和固体增塑剂均可用于达到干粉包衣所需的目标玻璃化温度，且可用于包衣组合物中来降低包衣聚合物的玻璃化温度至大约30-100℃，更适宜至45-70℃。令人惊讶的是，在微丸干粉包衣过程中，液体增塑剂具备多种功能。包括：1)降低成膜聚合物的玻璃化温度(即，增强分子的运动)制备符合功能和美观要求的口服药物制剂包衣膜；2)增强成膜粉末与微丸表面的粘附性；以及 3)提高微丸表面的导电率。因此表面增塑剂在其进入包衣聚合物基体产生聚合物包衣膜之前还充当着防静电助剂的角色。
增塑剂可同成膜聚合物分子链相结合，从而增加聚合物分子链之间的自由体积继而大大降低聚合粉的玻璃化温度。若增塑剂由液体聚合物或者聚合物溶液所组成，将其喷涂于微丸表面之后上也可大幅降低微丸表面的电阻率从而提高带电包衣粉末的粘附性以及包衣均匀性和包衣效率。此外，一定量的增塑剂或增塑剂溶液可在颗粒之间产生强大的毛细管力从而能够产生聚合物烧结和成膜。
本发明所述包衣组合物所使用的增塑剂包括但不限于甘油、丙二醇、200-600级聚乙二醇、三醋精、酸二乙酯(DEP)、酞酸二丁酯(DBP)和柠檬酸三丁酯(TBC)、柠檬酸三乙酯(TEC)、蓖麻油、分馏椰子油、乙酰化甘油和单硬脂酸甘油酯。
本发明所述包衣组合物所使用的增塑剂还包括但不限于低分子量聚合物、低聚物、共聚物、油类、有机小分子、带脂肪族羟基低分子量多元醇、酯型增塑剂、乙二醇醚、聚丙二醇、多嵌段共聚物、单嵌段共聚物，以及柠檬酸酯型增塑剂。此类增塑剂还可包括乙二醇、1，2-丁二醇、2，3-丁二醇、苯乙二醇、二甘醇、三甘醇、四甘醇以及其他聚(乙二醇)化合物、一丙醇单异丙醚、丙二醇乙醚、乙二醇一乙醚、二甘醇一乙醚、山梨醇乳酸盐、乳酸丁酯、乙醇酸乙酯、癸二酸二丁酯、乙酰柠檬酸三丁酯、乙酰柠檬酸三乙酯、柠檬酸三丁酯和烯丙基甘醇酸。
防静电助剂
一种或多种防静电助剂包括但不限于常规盐类、炭黑、硬脂酸镁、煅制硅酸盐、三硅酸镁、单硬脂酸甘油酯、高岭土、滑石以及液态增塑剂。液态增塑剂可包括聚乙二醇200至600、丙二醇、甘油和甘油醋酸酯中等一种或多种的混合物。食盐可包括，但不限于，氯化钠、氯化钙、氢氧化镁、碳酸钠、碳酸氢钠、磷酸钠、柠檬酸钠、乙酸钠、乙酸钾、柠檬酸钾、氯化钾和硫酸镁中等一种或多种的混合物。防静电助剂可以在约0.1-约95％w/w，更优选在约1-约50％w/w的范围存在于组合物中。
助流剂
一种或多种助流剂可包括硬脂酸钙、胶态二氧化硅、氢化蓖麻油和微晶纤维素、反丁烯二酸、山嵛酸甘油酯、单硬脂酸甘油酯、棕榈酰硬脂酸甘油酯、亮氨酸、硬脂酸镁、中链甘油三酯、肉豆蔻酸、棕榈酸、泊咯沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、十二醇硫酸钠、硬脂酰醇富马酸钠、淀粉、硬脂酸、滑石、氢化植物油和硬脂酸锌中等一种或多种的混合物。
粉状的一种或多种助流剂可以在约0.1至约25％w/w的范围，更优选在约0.25-约20％w/w的范围存在于组合物中。在实例中，一种或多种助流剂以约0.5至约3％w/w的范围存在于组合物中。
下面给出几个非限定性实施例。
实施例
在本发明的实施例使用吡罗昔康微丸作为模型微丸制剂来有效地说明静电干粉包衣微丸的干粉包衣组合物的有效性。三种不同功能的分别含有
Figure PCTCN2017106691-appb-000019
EPO，
Figure PCTCN2017106691-appb-000020
RS/RL和
Figure PCTCN2017106691-appb-000021
等聚合物的包衣组合物分别实现掩味、缓慢释放以及肠溶释放的功能。
实施例1：干粉包衣吡罗昔康微丸实现掩味功能(包衣材料含有
Figure PCTCN2017106691-appb-000022
EPO)
此实施例描述了利用干粉包衣技术实现吡罗昔康微丸干法包衣的过程，包衣组合物包含
Figure PCTCN2017106691-appb-000023
EPO(一种基于甲基丙烯酸二甲胺乙酯，甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子聚合物)，一类pH敏感型聚合物，溶解于胃液(pH低于5.0)，溶胀且具有渗透性(pH高于5.0)；和一种用来改善包衣粉和吡罗昔康微丸粘附性的液体增塑剂，聚乙二醇400(PEG 400，EMD Chemicals Inc.Ontario，Canada)；滑石粉用来作为防静电助剂，胶体二氧化硅用来作为助流剂。
1)包衣粉的制备：
利用叶片磨机(25秒左右)将表1中的各成分制备成包衣粉。
Figure PCTCN2017106691-appb-000024
EPO和胶体二氧化硅(AEROSIL
Figure PCTCN2017106691-appb-000025
Pharma)来自Evonik Degussa Corporation(Germany)公司的捐赠。滑石粉从Mallinckrodt Baker Inc.(Canada)公司购得。
表1.掩味包衣粉的组合物*
Figure PCTCN2017106691-appb-000026
＊增塑剂，包衣组合物中的聚乙二醇400在包衣过程中直接喷涂于微丸的表面。包衣粉中
Figure PCTCN2017106691-appb-000027
EPO和滑石粉的粒径(体积平均直径)D[4，3]分别为13.3微米和28.9微米。
2)包衣过程
将40g吡罗昔康微丸放置于旋转的干粉包衣设备中，预热使其达到40℃，期间转速为20rpm。然后提高转速至70rpm，保持温度为40℃。利用液体喷枪将液体增塑剂聚乙二醇400(PEG 400)喷涂于微丸的表面(0.25g/min喷涂35秒)，然后立刻利用静电喷枪将1.5g包衣粉喷涂于微丸的表面。增塑剂和包衣粉的喷涂可以在15分钟以后继续重复3次以达到预设的包衣增重。然后保持40℃到2个小时使包衣粉在微丸表面固化成膜。
3)溶出实验
将干粉包衣之后的吡罗昔康微丸在磷酸缓冲溶液中检测药物的溶出(pH＝6.8)。前10分钟没有药物的溶出且包衣膜完好。干粉包衣后的吡罗昔康微丸在0.1N HCl溶液(pH＝1.2)中的溶出实验按照美国药典的要求利用USP溶出装置(Apparatus 2)在37℃，100rpm下进行操作。在334纳米处利用紫外可见光分光光度计分析药物的溶出样品。如图1所示，磷酸缓冲溶液和0.1N HCl溶液的 溶出实验结果显示干粉包衣后的吡罗昔康微丸具备掩味的功能，即在药物到达胃部之前很小或者没有药物溶出。
实施例2：干粉包衣吡罗昔康微丸实现药物缓慢释放功能(包衣材料含有
Figure PCTCN2017106691-appb-000028
Figure PCTCN2017106691-appb-000029
RS/RL)
此实施例描述了利用干粉包衣技术实现吡罗昔康微丸干法包衣的过程，包衣组合物包含
Figure PCTCN2017106691-appb-000030
RS(一种基于丙烯酸乙酯，甲基丙烯酸甲酯和含有少量季铵基团甲基丙烯酸酯的低渗透性共聚物)和
Figure PCTCN2017106691-appb-000031
RL(一种基于丙烯酸乙酯，甲基丙烯酸甲酯和含有少量季铵基团甲基丙烯酸酯的高渗透性共聚物)，两种pH独立的常用于缓释包衣材料的聚合物，和一种用来改善包衣粉和吡罗昔康微丸粘附性且降低尤
Figure PCTCN2017106691-appb-000032
RS/RL玻璃化转变温度从63-65到35℃的液体增塑剂，柠檬酸三乙酯(TEC，Caledon Laboratories Ltd.Ontario，Canada)；滑石粉用来作为防静电助剂，胶体二氧化硅用来作为助流剂。
1)包衣粉的制备
利用叶片磨机(25秒左右)将表2中的各成分制备成包衣粉。
Figure PCTCN2017106691-appb-000033
RS/RL和胶体二氧化硅(AEROSIL
Figure PCTCN2017106691-appb-000034
Pharma)来自Evonik Degussa Corporation(Germany)公司的捐赠。滑石粉从Mallinckrodt Baker Inc.(Canada)公司购得。
表2.缓慢释放包衣粉的组合物*
Figure PCTCN2017106691-appb-000035
＊增塑剂，包衣组合物中的柠檬酸三乙酯(TEC)在包衣过程中直接喷涂于微丸的表面。包衣粉中
Figure PCTCN2017106691-appb-000036
RS、
Figure PCTCN2017106691-appb-000037
RL和滑石粉的粒径(体积平均直径)D[4，3]分别为47.7微米、40.8微米和28.9微米。
2)包衣过程
将40g吡罗昔康微丸放置于旋转的干粉包衣设备中，预热使其达到50℃，期间转速为20rpm。然后提高转速至70rpm，保持温度为50℃。利用液体喷枪将液体增塑剂柠檬酸三乙酯(TEC)喷涂于微丸的表面(0.25g/min喷涂35秒)，然后立刻利用静电喷枪将1.5g包衣粉喷涂于微丸的表面。增塑剂和包衣粉的喷涂可以在15分钟以后继续重复6次以达到预设的包衣增重。然后保持50℃到2个小时使包衣粉在微丸表面固化成膜。
3)溶出实验
干粉包衣后的吡罗昔康微丸在磷酸缓冲溶液(pH＝7.0)中的溶出实验按照美国药典的要求利用USP溶出装置(Apparatus 2)在37℃，50rpm下进行操作。在354纳米处利用紫外可见光分光光度计分析药物的溶出样品。如图2所示，药物在磷酸缓冲溶液中的溶出实验结果显示干粉包衣后的吡罗昔康微丸具备了预期的药物缓慢释放的功能。
实施例3：干粉包衣吡罗昔康微丸实现药物肠溶释放功能(包衣材料含有
Figure PCTCN2017106691-appb-000038
Figure PCTCN2017106691-appb-000039
)
此例证描述了利用干粉包衣技术实现吡罗昔康微丸干法包衣的过程，包衣组合物(表3)包含美国卡乐康公司提供的
Figure PCTCN2017106691-appb-000040
(含有
Figure PCTCN2017106691-appb-000041
L100-55，一种基于甲基丙烯酸和丙烯酸乙酯的阴离子共聚物)，一种pH敏感型聚合物(pH大于5.5时溶于水)，和一种用来改善包衣粉和吡罗昔康微丸粘附性且可以将成膜材料
Figure PCTCN2017106691-appb-000042
的玻璃化转变温度从133℃降低到50-55℃的液体增塑剂，聚乙二醇400(PEG 400，EMD Chemicals Inc.Ontario，Canada)，此液体也用来作为防静电助剂。
1)包衣粉的制备
利用叶片磨机(25秒左右)将表2中的各成分制备成包衣粉。
表3.肠溶包衣粉的组合物*
Figure PCTCN2017106691-appb-000043
＊增塑剂，包衣组合物中的聚乙二醇400在包衣过程中直接喷涂于微丸的表面。包衣粉中
Figure PCTCN2017106691-appb-000044
的粒径(体积平均直径)D[4，3]分别为20.5微米。
2)包衣过程
将40g吡罗昔康微丸放置于旋转的干粉包衣设备中，预热使其达到50℃，期间转速为20rpm。然后提高转速至70rpm，保持温度为50℃。利用液体喷枪将液体增塑剂聚乙二醇400(PEG 400)喷涂于微丸的表面(0.25g/min喷涂35秒)，然后立刻利用静电喷枪将1.5g包衣粉喷涂于微丸的表面。增塑剂和包衣粉的喷涂可以在15分钟以后继续重复(重复4次以获取13.25％的包衣增重；重复7次以获取21.93％的包衣增重)以达到预设的包衣增重。然后保持50℃到2个小时使包衣粉在微丸表面固化成膜。
3)溶出实验
干粉包衣后的吡罗昔康微丸，前两个小时在0.1N HCl溶液(pH＝1.2)中的溶出实验按照美国药典的要求利用USP溶出装置(Apparatus 2)在37℃，100rpm下进行操作，在334纳米处利用紫外可见光分光光度计分析药物的溶出样品；两个小时之后的溶出实验在磷酸缓冲溶液(pH＝6.8)中实验按照美国药典的要求利用USP溶出装置(Apparatus 2)在37℃，100rpm下进行操作，在353纳米处利用紫外可见光分光光度计分析药物的溶出样品。
干粉包衣吡罗昔康肠溶微丸(包衣增重13.25％和21.93％)的药物溶出曲线 如图3所示，两种包衣增重条件下药物前两个小时在0.1N HCl溶液(pH＝1.2)中的溶出均不超过美国药典要求的10％，说明干粉包衣后的吡罗昔康微丸具备了预期药物肠溶释放的功能。
实施例4：干粉包衣微丸蔗糖实现埃索美拉唑药物沉积、包衣保护层以及肠溶包衣层的多层包衣
此例证描述了利用干粉包衣技术使用三种包衣组合物(表4)应用于微丸制剂从而实现埃索美拉唑微丸的多层包衣。第一、第二和第三层包衣分别实现速释、化学分解保护及速释、肠溶释放。
第一层包衣组合物包含有埃索美拉唑(药物成分)、羟丙基纤维素(一种pH独立且溶于水的聚合物)、交联聚乙烯吡咯烷酮(PVP-XL)，氢氧化镁(两种稳定剂)、滑石粉(一种抗静电剂)和聚乙二醇400(一种增塑剂和提高包衣粉在微丸表面上粉率的添加剂)。
第二层包衣组合物包含有羟丙基纤维素(一种非pH依赖且溶于水的聚合物)、交联聚乙烯吡咯烷酮(PVP-XL)，氢氧化镁(两种稳定剂)、滑石粉(一种抗静电剂)和聚乙二醇400(一种增塑剂和提高包衣粉在微丸表面上粉率的添加剂)。
第三层包衣组合物包含
Figure PCTCN2017106691-appb-000045
L100-55(一种基于甲基丙烯酸和丙烯酸乙酯的阴离子共聚物，一种pH敏感型聚合物，pH大于5.5时溶于水)，滑石粉(一种抗静电剂)和聚乙二醇400(一种增塑剂和提高包衣粉在微丸表面上粉率的添加剂)。
表4.药物沉积层、保护层以及肠溶释放层的组合物*
Figure PCTCN2017106691-appb-000046
Figure PCTCN2017106691-appb-000047
＊一种液体增塑剂，包衣组合物中的聚乙二醇400在包衣过程中直接喷涂于微丸的表面。
1)包衣粉的制备
利用气流粉碎机将包衣粉中羟丙基纤维素(HPC)和
Figure PCTCN2017106691-appb-000048
L100-55的粒径(体积平均直径)缩减为30微米和23微米。包衣进行之前将所用各种包衣成分(聚乙二醇除外)混合均匀。
2)包衣过程
将蔗糖微丸放置于旋转的干粉包衣设备中，预热使其达到45℃，期间转速为20rpm。然后提高转速至70rpm，保持温度为45℃。利用液体喷枪将液体增塑剂聚乙二醇400(PEG 400)喷涂于微丸的表面(0.25g/min喷涂35秒)，然后立刻利用静电喷枪将1.5g包衣粉喷涂于微丸的表面。增塑剂和包衣粉的喷涂可以在15分钟以后继续重复以满足多层包衣的要求且达到预设的包衣增重。然后保持45℃到72个小时使包衣粉在微丸表面固化成膜。
3)溶出实验
干粉包衣后的埃索美拉唑微丸，前两个小时在pH＝1的缓冲溶液进行溶出实验，按照美国药典的要求利用USP溶出装置(Apparatus 2)在37℃，100rpm下进行操作，在305纳米处利用紫外可见光分光光度计分析药物的溶出样品；两个小时之后的溶出实验在缓冲溶液(pH＝6.8)中实验按照美国药典的要求利用USP溶出装置(Apparatus 2)在37℃，100rpm下进行操作，在280纳米处利用紫外可见光分光光度计分析药物的溶出样品。溶出实验结果显示肠溶包衣膜满足了USP的要求。
将干粉包衣后的埃索美拉唑微丸放置于密封容器中，然后在50℃条件下储存 6个周。没有观察到颜色的变化。结果说明稳定剂起到了阻止或降低矮索美拉唑分解的作用。且保护层包衣起到了阻止包衣微丸中不相容成分矮索美拉唑和
Figure PCTCN2017106691-appb-000049
Figure PCTCN2017106691-appb-000050
L100-55之间化学反应(化学分解)的作用。

Claims (23)

  1. 一种医药微丸的干粉包衣组合物，包含：
    a)一种或多种粉状成膜高分子材料，其范围为约1-约95％w/w；
    b)一种或多种粉状或液体增塑剂，用于降低包衣组合物的玻璃化转变温度至30-100℃；
    c)一种或多种粉状或液体防静电助剂，其范围为约0.1-约95％w/w；
    d)一种或多种粉状或液体防静电助剂，其范围为约0.1-约25％w/w。
  2. 如权利要求1所述的组合物，其中所述一种或多种成膜高分子材料以约10-约70％w/w的范围存在。
  3. 如权利要求1所述的组合物，其中所述一种或多种防静电助剂以约0.25-约20％w/w的范围存在。
  4. 如权利要求1所述的组合物，其中所述一种或多种防静电助剂以约0.5-约3.0％w/w的范围存在。
  5. 如权利要求1-4中任一权利要求所述的组合物，其中所述一种或多种防静电助剂以约1-约50％w/w的范围存在。
  6. 如权利要求1-5中任一权利要求所述的组合物，其中所述一种或多种增塑剂包括甘油、丙二醇、PEG 200-8000、甘油醋酸酯、邻苯二甲酸二乙酯(DEP)、邻苯二甲酸二丁酯(DBP)、柠檬酸三丁酯(TBC)、柠檬酸三乙酯(TEC)、蓖麻油、分馏椰子油、乙酰化单甘酯、单硬脂酸甘油酯、低聚物、共聚物、油、小分子有机物、低分子量的具有脂肪族羟基的多元醇、酯类增塑剂、乙二醇醚、聚(丙二醇)、单嵌段共聚物、多嵌段共聚物、低分子量聚(乙二醇)和柠檬酸增塑剂中的一种或多种的混合物。
  7. 如权利要求1-6中任一权利要求所述的组合物，其中所述一种或多种粉状或液体增塑剂包括乙二醇、1，2-丁二醇、2，3-丁二醇、苯代乙二醇、二甘醇、三甘醇、四甘醇和其他聚乙二醇化合物、乙二醇单异丙醚、丙二醇单乙醚、乙二醇单乙醚、二乙二醇单乙醚、乳酸山梨糖醇、乳酸乙酯、乳酸丁酯、乙醇酸乙酯、癸二酸二丁酯、乙酰柠檬酸三丁酯、乙酰基柠檬酸三乙酯、烯丙基乙醇酸中的一种或多种的混合物。
  8. 如权利要求1-7中任一权利要求所述的组合物，其中所述一种或多种防静电助剂包括常规盐类、炭黑、硬脂酸镁、气相硅酸盐、三硅酸镁、单硬脂酸甘油酯、高岭土、滑石粉和液体增塑剂中的一种或多种的混合物。
  9. 如权利要求8所述的组合物，其中所述液体增塑剂包括但不限于PEG200-600、丙二醇、丙三醇、甘油醋酸酯中的一种或多种的混合物。
  10. 如权利要求8所述的组合物，其中所述常规盐类包括但不限于氯化钠、氯化钙、氢氧化镁、碳酸钠、碳酸氢钠、磷酸钠、柠檬酸钠、乙酸钠、乙酸钾、柠檬酸钾、氯化钾、硫酸镁中的一种或多种的混合物。
  11. 如权利要求1所述的组合物，其中所述一种或多种粉状或液体增塑剂，用于降低包衣组合物的玻璃化转变温度至45-70℃。
  12. 如权利要求1-11中任一权利要求所述的组合物，其中所述一种或多种防静电助剂包括但不限于硬脂酸钙、胶体二氧化硅、氢化蓖麻油、微晶纤维素、富马酸、山嵛酸甘油酯、单硬脂酸甘油酯、棕榈酸硬脂酸甘油酯、白氨酸、硬脂酸镁、中链甘油三酯、豆蔻酸、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、十二烷基硫酸钠、硬脂富马酸钠、淀粉、硬脂酸、滑石粉、氢化植物油和硬脂酸锌中的一种或多种的混合物。
  13. 如权利要求1-12中任一权利要求所述的组合物，其中所述一种或多种成膜高分子材料具有防潮、速释、掩盖或改变味道等功能的一种或多种，包括甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇、丙二醇、泊洛沙姆、聚乙烯吡啶酮、聚乙烯醇基包衣组合物如
    Figure PCTCN2017106691-appb-100001
    氨基烷基甲基丙烯酸酯中的一种或多种的混合物。
  14. 如权利要求1-12中任一权利要求所述的组合物，其中所述一种或多种成膜高分子材料具有实现药物缓慢释放功能，包括纤维素基衍生物、丙烯酸(类)树脂、丙烯酸和甲基丙烯酸甲酯且包含季铵基团的共聚物、丙烯酸和甲基丙烯酸甲酯的共聚物、乙基纤维素及不溶于消化液的聚(甲基)丙烯酸酯类聚合物中的一种或多种的混合物。
  15. 如权利要求14所述的的组合物，其中所述不溶于消化液的聚(甲基)丙烯酸酯类聚合物包括
    Figure PCTCN2017106691-appb-100002
    及
    Figure PCTCN2017106691-appb-100003
    聚合物中的一种或多种的混合物。
  16. 如权利要求1-12中任一权利要求所述的组合物，其中所述一种或多种成膜高分子材料具有实现药物延迟释放功能，包括聚环氧乙烷(PEO)、环氧乙烷-氧化丙烯共聚物、聚氧乙烯聚氧丙烯醚嵌段共聚物(如泊洛沙姆)、卡波姆、 聚乙烯吡咯酮(PVP)、聚乙烯醇(PVA)、羟烷基纤维素如羟丙基纤维素(HPC)、羟丙基甲基纤维素、羧甲基纤维素钠、甲基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、聚丙烯酸树脂如卡波姆、聚丙烯酰胺、藻酸及其衍生物、淀粉及其衍生物、水溶性明胶中的一种或多种的混合物。
  17. 如权利要求1-12中任一权利要求所述的组合物，其中所述一种或多种成膜高分子材料具有实现药物延迟释放功能，包括邻苯二甲酸乙酸纤维素、乙酸纤维素trimaletate、苯二甲酸羟丙基甲基纤维素、聚醋酸乙烯邻苯二甲酸酯、丙烯酸类聚合物、polyvinyl acetaldiethylamino acetate、羟丙基甲基纤维素醋酸乙烯酯、乙酸纤维素偏苯三酸酯、虫漆、甲基丙烯酸共聚物、具有羧酸基团的甲基丙烯酸共聚物中的一种或多种的混合物。
  18. 如权利要求17所述的组合物，其中具有羧酸基团的甲基丙烯酸共聚物包括但不限于
    Figure PCTCN2017106691-appb-100004
    和
    Figure PCTCN2017106691-appb-100005
    中的一种或多种的混合物。
  19. 如权利要求1-18中任一权利要求所述的组合物，可以根据预设功能在微丸上多次使用。
  20. 如权利要求1-12中任一权利要求所述的组合物，
    a)对所述微丸进行第一层包衣，以实现保护功能；
    b)对所述微丸进行第二层包衣，以实现预定的药物释放功能如快速释放、缓控释放或者肠溶释放。
  21. 如权利要求1-12中任一权利要求所述的组合物，
    a)对所述微丸进行第一层包衣，以实现保护功能；
    b)对所述微丸进行第二层包衣，以实现药物的缓控释放功能；
    c)对所述微丸进行第三层包衣，以实现药物的肠溶释放功能。
  22. 如权利要求1-12中任一权利要求所述的组合物，
    a)对所述微丸进行第一层一种或多种药物沉积；
    b)对所述微丸进行第一层包衣，以实现保护功能；
    c)对所述微丸进行第二层包衣，以实现预定的药物释放功能如快速释放、缓控释放或者肠溶释放。
  23. 如权利要求1-12中任一权利要求所述的组合物，
    a)对所述微丸进行第一层一种药物沉积；
    b)对所述微丸进行第二层一种药物沉积；
    c)对所述微丸进行第一层包衣，以实现保护功能；
    d)对所述微丸进行第二层包衣，以实现预定的药物释放功能如快速释放、缓控释放或者肠溶释放。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110559270A (zh) * 2019-09-17 2019-12-13 扬子江药业集团广州海瑞药业有限公司 一种磷酸西格列汀药物组合物及其制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110527628B (zh) * 2019-07-30 2022-05-10 南京农业大学 一种啶虫脒降解菌的保护剂及其制备方法和应用
CA3152589C (en) * 2019-09-27 2024-05-07 Hercules Llc Titanium dioxide free white film coating composition, process for preparing the same and method of use thereof
CN113181132A (zh) * 2021-04-27 2021-07-30 宁波西敦医药包衣科技有限公司 一种中草药超细粉组合物及中草药超细粉片剂的制备方法和应用
CN118649150A (zh) * 2024-08-21 2024-09-17 寿光富康制药有限公司 一种艾司奥美拉唑镁肠溶胶囊的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1183715A (zh) * 1995-05-09 1998-06-03 科洛康有限公司 适合药物基质静电包衣的粉末包衣物质

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8216609B2 (en) * 2002-08-05 2012-07-10 Torrent Pharmaceuticals Limited Modified release composition of highly soluble drugs
WO2007033515A1 (fr) * 2005-09-21 2007-03-29 Shenzhen Tys R & D Co., Ltd. Formulation orale contenant de la moxifloxacine et son procédé de préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1183715A (zh) * 1995-05-09 1998-06-03 科洛康有限公司 适合药物基质静电包衣的粉末包衣物质

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAN KE; JIANG SHAO-PING; WU CHUAN-BIN: "Progress and Application of Dry Coating", CHINESE JOURNAL OF MODERN APPLIED PHARMACY, vol. 25, no. 6, 28 December 2008 (2008-12-28), pages 502 - 506, ISSN: 1007-7693 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110559270A (zh) * 2019-09-17 2019-12-13 扬子江药业集团广州海瑞药业有限公司 一种磷酸西格列汀药物组合物及其制备方法
CN110559270B (zh) * 2019-09-17 2020-06-23 扬子江药业集团广州海瑞药业有限公司 一种磷酸西格列汀药物组合物及其制备方法

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