WO2020080875A1 - Oral composition containing aprepitant - Google Patents

Oral composition containing aprepitant Download PDF

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Publication number
WO2020080875A1
WO2020080875A1 PCT/KR2019/013736 KR2019013736W WO2020080875A1 WO 2020080875 A1 WO2020080875 A1 WO 2020080875A1 KR 2019013736 W KR2019013736 W KR 2019013736W WO 2020080875 A1 WO2020080875 A1 WO 2020080875A1
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Prior art keywords
aprepitant
coating
solid dispersion
weight
polymer
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PCT/KR2019/013736
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French (fr)
Korean (ko)
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박상엽
이사원
이재영
임혜정
서민효
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주식회사 삼양바이오팜
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Publication of WO2020080875A1 publication Critical patent/WO2020080875A1/en

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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
    • A61K9/167—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
    • A61K9/1676—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 having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • 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
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to an oral composition having improved water solubility and bioavailability obtained by forming a poorly water-soluble drug Aprepitant together with a solubilizing polymer as a solid dispersion, and a method for manufacturing the same.
  • the bioavailability is 60-80% and is not affected by absorption by food, so it can be taken regardless of meal. Less than 5% of the unchanged body is excreted in the urine and metabolized extensively in the liver. Aprepitant is a substrate and an inducer of CYP450, and since it is an inducer of CYP2C9, the effect of drugs metabolized by these enzymes can be reduced. Side effects include asthenia, fatigue, loss of appetite, constipation, and diarrhea.
  • Mendeu ® capsule is a typical formulation is Nanocrystal TM technology to increase the bioavailability applied for increasing the dissolution rate and solubility of the drug through the nano particles using a wet mill method.
  • the first object of the present invention is to provide a solid dispersion comprising a poorly water-soluble drug Aprepitant (Aprepitant) and a solubilizing polymer.
  • the second object of the present invention is to provide an oral composition having improved water solubility and bioavailability by forming a poorly water-soluble drug, Aprepitant, together with a solubilizing polymer as a solid dispersion.
  • a third object of the present invention is to provide a method for preparing an oral composition having improved water solubility and bioavailability by forming a poorly water-soluble drug, Aprepitant, together with a solubilizing polymer as a solid dispersion.
  • One aspect of the present invention is to provide a solid dispersion formed by coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material together with one or more solubilizing polymers.
  • the solid dispersion comprises an inert core material and two or more different coating layers that coat the same, and at least one of the two or more different coating layers comprises an aprepitant and a hydrophilic polymer, and the other At least one of the coating layers includes aprepitant and a gastric-soluble polymer.
  • the coating layer coats the surface of the inert core material, a first coating layer comprising an aprepitant and a hydrophilic polymer, and a coating of the first coating layer, an aprepitant and It includes a second coating layer containing a gastric-soluble polymer.
  • At least one of the coating layers comprises D- ⁇ -tocopheryl polyethylene glycol succinate.
  • the hydrophilic polymer is at least one selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose.
  • the gastric-soluble polymer is a cationic polymer having dimethylaminoethyl methacrylate as a polymethacrylate copolymer.
  • the polymethacrylate copolymer is poly (butylmethacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methylmethacrylate).
  • the polymethacrylate copolymer has a weight average molecular weight of 3,000 to 200,000 g / mole.
  • the solid dispersion comprises 0.1 to 10 parts by weight of a hydrophilic polymer relative to 1 part by weight of aprepitant.
  • the solid dispersion comprises 0.1 to 10 parts by weight of a gastric-soluble polymer with respect to 1 part by weight of aprepitant.
  • the solid dispersion comprises 0.001 to 1 part by weight of D- ⁇ -tocopheryl polyethylene glycol succinate with respect to 1 part by weight of aprepitant.
  • Another aspect of the present invention is an oral composition having improved water solubility and bioavailability by forming a solid dispersion while spraying and coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material with one or more solubilizing polymers.
  • Another aspect of the present invention is to provide an oral composition having improved water solubility and bioavailability by forming a solid dispersion layer of an aprepitant and a solubilizing polymer having two or more different compositions on the surface of an inert core material. .
  • the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer.
  • the present invention relates to an oral composition having improved water solubility and bioavailability including coating by dissolving or dispersing a polymer in an appropriate solvent.
  • the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer.
  • a prepitant is dissolved with a hydrophilic polymer to prepare a primary coating solution; Coating the inactivation core with a primary coating solution; Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And coating the primary coated particles with a secondary coating solution, the method of preparing an oral composition having improved water solubility and bioavailability.
  • an oral composition in which aprepitant is formed of a solid dispersion together with a solubilizing polymer exhibits high bioavailability because water solubility and bioavailability are improved, and is not affected by diet, so it can be taken regardless of food. It can be a useful agent for patients.
  • Aprepitant includes aprepitant free base, isomers thereof, or mixtures thereof, salts and prodrugs of pharmaceutically acceptable aprepitants. In each case, it may be to form various hydrates or various crystal forms.
  • the coating layer of the first layer contained a hydrophilic polymer and aprepitant
  • the coating layer of the second layer had no solid dispersion comprising a gastric-soluble polymer and aprepitant and an oral composition using the same.
  • the present inventors made a great effort to evaluate the effect of various substances on the water solubility of aprepitant, and then used a solid dispersion having an excellent effect on improving the water solubility and bioavailability of aprepitant and an oral composition using the same Was discovered.
  • One aspect of the present invention is to provide a solid dispersion formed by coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material together with one or more solubilizing polymers.
  • Another aspect of the present invention is an oral composition having improved water solubility and bioavailability by forming a solid dispersion while spraying and coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material with one or more solubilizing polymers.
  • Another aspect of the present invention is to provide an oral composition having improved water solubility and bioavailability by forming a solid dispersion layer of an aprepitant and a solubilizing polymer having two or more different compositions on the surface of an inert core material. .
  • the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer.
  • the present invention relates to an oral composition having improved water solubility and bioavailability including coating by dissolving or dispersing a polymer in an appropriate solvent.
  • the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer.
  • a prepitant is dissolved with a hydrophilic polymer to prepare a primary coating solution; Coating the inactivation core with a primary coating solution; Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And coating the primary coated particles with a secondary coating solution.
  • the oral composition of the present invention may be, for example, in the form of a solid oral preparation, particularly a tablet or capsule.
  • the inert core material may be particles comprising or consisting of microcrystalline cellulose, white sugar, lactose, starch, or a combination thereof.
  • the inert core material may be particles comprising or consisting of microcrystalline cellulose, white sugar, or a combination thereof.
  • the shape of the inert core material may be various, for example, a spherical shape or a spherical shape, but is not limited thereto. In terms of circularity, the sphericity may be 0.2 or more, or 0.4 or more, or 0.5 or more, or 0.7 or more.
  • the average diameter of the inert core material may be 20 to 2000 ⁇ m, or 50 to 1500 ⁇ m, or 100 to 1200 ⁇ m, or 200 to 800 ⁇ m.
  • the hydrophilic polymer is, for example, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example Soluplus ® ), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), Polyvinyl acetate (PVA), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low substitution) HPC), polymers of polyvinyl alcohol, acrylic acid and salts thereof, vinylpyrrolidone-vinyl acetate copolymers (e.g.
  • the hydrophilic polymer may be polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (eg Soluplus ® ), hydroxypropylmethylcellulose (HPMC), or mixtures thereof.
  • the gastric-soluble polymer is, for example, a polymethacrylate copolymer, or a cationic polymer having dimethylaminoethyl methacrylate (cationic polymer with dimethyl-aminoethyl methacrylate), or poly (butyl methacrylate-co- ( 2-dimethylaminoethyl) methacrylate-co-methylmethacrylate).
  • the gastric-soluble polymer may be Eudragit® E PO (Evonik, Germany) or Eudragit® E 100 (Evonik, Germany).
  • Eudragit® E polymer is usually a coating agent, and when it is necessary to protect the drug from moisture or when patient compliance is poor, encapsulate sensitive drugs or mask the taste and odor of the drug to alleviate the patient's refusal to take And, it is used for the purpose of providing a smooth and shiny surface so that the drug can be swallowed easily, but in the present invention, it is used as a solubilizing polymer to improve the water solubility and bioavailability of aprepitant.
  • the weight average molecular weight of the polymethacrylate copolymer in the hydrophilic polymer and / or gastric soluble polymer may be 3,000 to 200,000, or 5,000 to 150,000, or 10,000 to 100,000, or 20,000 to 80,000, or 37,000 to 57,000 g / mole . If the weight average molecular weight is less than 3,000 g / mole, the water solubility improvement effect may be low, and if the weight average molecular weight exceeds 200,000 g / mole, disintegration may be delayed.
  • the hydrophilic polymer and / or gastric soluble polymer is based on 1 part by weight of aprepitant, for example, 0.1 to 10 parts by weight, or 0.5 to 5 parts by weight, or 0.8 to 2 parts by weight, or 0.8 to 1.2 parts by weight Can be used as If the polymethacrylate copolymer is less than the above-mentioned lower limit, the water solubility of aprepitant and the degree of improvement in bioavailability may be insignificant, and the effect may be deteriorated. Or tablets), which can cause discomfort when the patient is taking it.
  • hydrophilic polymer and / or gastric soluble polymer there are no particular restrictions on the state of the hydrophilic polymer and / or gastric soluble polymer, but may be in the form of granules or powder.
  • the primary coating layer and / or the secondary coating layer is D- ⁇ -tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) has an excellent effect on improving the solubility and dissolution rate of aprepitant.
  • the TPGS may be used in an amount of 0.001 to 2 parts by weight, or 0.01 to 0.2 parts by weight, or 0.05 to 0.15 parts by weight based on 1 part by weight of aprepitant. If the TPGS is less than the above-mentioned lower limit, the water solubility of aprepitant is improved and the degree of improvement in bioavailability is insignificant, and the effect may be deteriorated. Storage may cause difficulties.
  • the primary coating layer and / or secondary coating layer may further include a surfactant.
  • the surfactant may be, for example, an anionic surfactant.
  • Anionic surfactants include sodium dodecyl sulfate, sodium lauryl sulfate, sodium N-lauroyl salicylate, N-long chain acyl glutamate, sucrose fatty acid ester, polyoxyethylene cured castor oil, sorbitan fatty acid ester, polyoxyethylene and It may be a copolymer of polyoxypropylene or a combination thereof, or sodium dodecyl sulfate.
  • the surfactant is based on 1 part by weight of aprepitant, for example, 0.0001 to 1 part by weight, or 0.0005 to 0.5 part by weight, or 0.001 to 0.1 part by weight, or 0.001 to 0.01 part by weight, or 0.001 to 0.005 part by weight It can be used in quantity.
  • the primary coating solution and / or the solvent used for the secondary coating solution may be a water-miscible organic solvent, water or a mixture thereof.
  • Water-miscible organic solvents for example, alcohols, acetone, tetrahydrofuran, acetic acid, acetonitrile, dioxane, and combinations thereof may be used, but are not limited thereto.
  • the water-miscible organic solvent may be, for example, low-cost alcohol having 1 to 5 carbon atoms, acetone or a mixture thereof, or ethanol, acetone or a mixture thereof, or ethanol.
  • the thickness of the coating layer can be measured using a scanning electron microscope (SEM) method. At this time, it is possible to check the average thickness by measuring 5 or more.
  • the average thickness of the primary coating layer is 10 ⁇ m or more and 200 ⁇ m or less, or 20 ⁇ m or more and 180 ⁇ m or less, or 50 ⁇ m or more and 150 ⁇ m or less, or It may be 90 ⁇ m or more and 120 ⁇ m or less.
  • the average thickness of the secondary coating layer is 5 ⁇ m or more and 100 ⁇ m or less, or 10 ⁇ m or more and 90 ⁇ m or less, or 15 ⁇ m or more and 80 ⁇ m or less, or It may be 20 ⁇ m or more and 70 ⁇ m or less.
  • the average thickness of the coating layer is thinner than the above-mentioned range, the content of the drug in the particles is lowered, so that a large amount of inert core is required, and thus the formulation may be enlarged. The desired purpose cannot be achieved due to delays, excessive processing time, etc.
  • various biologically inert ingredients may be additionally used for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, bonding, performance improvement, and manufacturing process improvement. .
  • the biologically inert component that may be further included in the coating layer is a plasticizer, a lubricant, a colorant, a flavoring agent, a surfactant, a stabilizer, an antioxidant, a foaming agent, an antifoaming agent, and a desiccant (for example, paraffin, wax ) May be one or more selected from the group consisting of.
  • the plasticizer is 100% by weight or less (eg, 0.1 to 100% by weight), or 50% by weight or less (eg, 0.1 to 50% by weight), or 30% by weight, based on the dry weight of the total polymer used in each coating layer. It may be included below (eg, 0.1 to 30% by weight).
  • the plasticizer is triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl citrate, propylene glycol, triacetin ,
  • Polyethylene glycol, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol may be one or more selected from the group consisting of, but is not limited thereto.
  • the lubricant may be included in 100% by weight or less (eg, 0.1 to 100% by weight), or 50% by weight or less, based on the dry weight of the entire polymer used in each coating layer.
  • the lubricant is, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloid) Type) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono stearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof. It is not.
  • various additives may be mixed to improve physical properties, manufacturability, compressibility, appearance, taste, and drug stability of the tablet or capsule.
  • the additives include, for example, stabilizers, solubilizers, sweeteners, mating agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, mating agents, binders, suspending agents , Curing agent, antioxidant, brightener, flavoring agent, flavoring agent, pigment, coating agent, wetting agent, wetting control agent, filler, antifoaming agent, refreshing agent, chewing agent, antistatic agent, coloring agent, dragee, isotonic agent, emollient, emulsifier, adhesive, Thickeners, foaming agents, pH adjusting agents, excipients, dispersing agents, disintegrating agents, waterproofing agents, preservatives, preservatives, dissolving aids, solvents, fluidizing agents,
  • another aspect of the present invention comprises: dissolving aprepitant together with a hydrophilic polymer to prepare a primary coating solution; Coating the inactivation core with a primary coating solution; Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And coating the primary coated particles with a secondary coating solution.
  • the manufacturing method may further include a step of coating with a secondary coating solution, and then preparing an oral preparation.
  • the oral preparation may be in the form of a tablet, capsule, granule, or powder, but is not limited thereto.
  • the coating may be performed using a fluidized bed coater.
  • the coating step may be to use a bottom spray coating method, a tangential spray coating method, a top spray coating method.
  • the coating step may be a bottom spray coating method, a tangential spray coating method.
  • the coating step can be produced regardless of the size and batch size of the coating equipment, and can be manufactured in mini-glatt (Glatt, Germany), which is a small unit on a lab scale, or smoothly on large equipment of the GPCG series including GPCG 1. can do. It can also be produced in Soild Lab 2 (Bosch, Germany) in a tangential spray method.
  • microparticles prepared in Examples 1 and 2 were treated with aerosil 0.4% (w / w%), and filled in No. 1 capsules to be 125 mg as aprepitant, thereby obtaining an oral composition having improved bioavailability.
  • Example 2 For the sample obtained in Example 2, as an experimental animal, Sprague-Dawley male rats of about 180-220 g (6-8 weeks old) were supplied from Charles River Laboratories (Orient, Korea) and randomly distributed 5 specimens per group. The sample was suspended in a buffer solution and orally administered (po).
  • Each drug was administered once (5 mg / kg), and blood samples for analysis were heparin-treated syringes from tail vein 0.5, 1, 2, 4, 6, 8, 24 hours after drug administration. Blood was collected and centrifuged (3,000 rpm, Han-il, Korea). Plasma was stored in -70 ° C deep freezer (Sanyo, Japan) until the time of analysis. The concentration analysis of the drug in plasma was analyzed by LC / MS / MS (HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK) after pretreatment.
  • Each drug was administered once (125 mg / head), and blood samples for analysis were treated with heparin immediately before drug administration and 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after drug administration.
  • Blood was collected from the left lateral veins with a syringe and centrifuged (12,000 rpm) to separate plasma. The separated plasma was stored in a deep freezer (Sanyo, Japan) at -70 ° C until analysis.
  • the concentration analysis of the drug in plasma was analyzed by LC / MS / MS (HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK) after pretreatment.

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Abstract

Disclosed are: an oral composition having improved water solubility and bioavailability, and obtained by forming a solid dispersion of Aprepitant, which is a poorly water-soluble drug, with a solubilizing polymer; and a method for preparing same.

Description

아프레피탄트의 경구용 조성물Oral composition of aprepitant
본 발명은 수난용성 약물인 아프레피탄트(Aprepitant)를 가용화 고분자와 함께 고체분산체로 형성하여 얻어지는 수용해도 및 생체이용율이 개선된 경구용 조성물 및 이의 제조 방법에 관한 것이다.The present invention relates to an oral composition having improved water solubility and bioavailability obtained by forming a poorly water-soluble drug Aprepitant together with a solubilizing polymer as a solid dispersion, and a method for manufacturing the same.
아프레피탄트(Aprepitant)는 2003년 3월에 FDA 승인을 받은 후 2007년에 국내에 도입된 항구토제(상품명: 에멘드® 캡슐(한국엠에스디(유))로 구역, 우울, 염증, 면역반응에 관여하는 Substance P의 작용을 길항하는 Substance P NK-1 수용체 길항제이다. NK-1 receptor에 선택적이며, 5-HT3 수용체와 dopamine 수용체에는 거의 활성을 나타내지 않는다. Cisplatin을 포함한 심한 구토를 유발하는 항암화학요법제 투여 시 aprepitant 추가 투여로 급성 구토와 지연형 구토에 5HT3 antagonist와 dexamethasone의 효과를 증가시킨다고 알려져 있다.Oh Preppy tanteu (Aprepitant) after receiving FDA approval in March 2003, the antiemetic (trade name introduced in Korea in 2007: in a mendeu ® Capsules (Korea MSD (u)) in the area, depression, inflammation, immune response It is a Substance P NK-1 receptor antagonist that antagonizes the action of the involved Substance P. It is selective for the NK-1 receptor and has little activity on the 5-HT3 and dopamine receptors Anti-cancer chemistry causing severe vomiting including Cisplatin It is known that the addition of aprepitant increases the effects of 5HT3 antagonist and dexamethasone on acute and delayed vomiting by administration of a therapeutic agent.
급성 구토의 예방을 위해서 화학요법 1시간 전 corticosteroid 및 5-HT3 길항제와 병용하여 125mg을 복용하고 지연형 구토의 예방을 위해서는 화학 요법 투여 다음날부터 2일간 corticosteroid와 병용하여 80mg을 하루에 한번 복용한다.To prevent acute vomiting, take 125mg 1 hour before chemotherapy in combination with corticosteroid and 5-HT3 antagonist. To prevent delayed vomiting, take 80mg once a day in combination with corticosteroid for 2 days from the day following chemotherapy.
경구투여 시 생체이용률은 60~80%이며 음식에 의해 흡수에 영향을 받지 않으므로 식사와 관계없이 복용이 가능하다. 간에서 광범위하게 대사되어 제거되며 뇨로 배설되는 미변화체는 5% 미만이다. Aprepitant는 CYP450의 기질이면서 유도제이며, CYP2C9의 유도제이므로 이들 효소에 의해 대사되는 약물의 효과를 감소시킬 수 있다. 부작용은 무력증, 피로감, 식욕부진, 변비, 설사 등이 있다. When used orally, the bioavailability is 60-80% and is not affected by absorption by food, so it can be taken regardless of meal. Less than 5% of the unchanged body is excreted in the urine and metabolized extensively in the liver. Aprepitant is a substrate and an inducer of CYP450, and since it is an inducer of CYP2C9, the effect of drugs metabolized by these enzymes can be reduced. Side effects include asthenia, fatigue, loss of appetite, constipation, and diarrhea.
에멘드®캡슐은 wet mill 방식을 이용한 약물입자의 나노화를 통해서 용해 속도와 용해도를 향상시켜 생체이용율을 높이는 NanocrystalTM 기술이 적용된 대표적인 제제이다. Mendeu ® capsule is a typical formulation is Nanocrystal TM technology to increase the bioavailability applied for increasing the dissolution rate and solubility of the drug through the nano particles using a wet mill method.
그러나, 이러한 방식의 기술은 특수한 설비와 오랜 제조 시간, 높은 생산 단가가 소요될 수 있어서 보다 개선된 방식으로 용해도를 향상시켜 동등한 효과를 낼 수 있는 기술이 요구되고 있다.However, this type of technology may require special equipment, long manufacturing time, and high production cost, and thus, there is a need for a technology capable of improving solubility in a more improved manner to achieve equivalent effects.
본 발명의 제1 목적은 수난용성 약물인 아프레피탄트(Aprepitant) 및 가용화 고분자를 포함하는 고체분산체를 제공하는 것이다. The first object of the present invention is to provide a solid dispersion comprising a poorly water-soluble drug Aprepitant (Aprepitant) and a solubilizing polymer.
본 발명의 제2 목적은 수난용성 약물인 아프레피탄트(Aprepitant)를 가용화 고분자와 함께 고체분산체로 형성하여 수용해도 및 생체이용율이 개선된 경구용 조성물을 제공하는 것이다. The second object of the present invention is to provide an oral composition having improved water solubility and bioavailability by forming a poorly water-soluble drug, Aprepitant, together with a solubilizing polymer as a solid dispersion.
본 발명의 제3 목적은 수난용성 약물인 아프레피탄트(Aprepitant)를 가용화 고분자와 함께 고체분산체로 형성하여 수용해도 및 생체이용율이 개선된 경구용 조성물을 제조하는 방법을 제공하는 것이다.A third object of the present invention is to provide a method for preparing an oral composition having improved water solubility and bioavailability by forming a poorly water-soluble drug, Aprepitant, together with a solubilizing polymer as a solid dispersion.
본 발명의 일 측면은, 불활성 코어물질 표면에 적절한 용매에 녹이거나 분산시킨 아프레피탄트를 1종 이상의 가용화 고분자와 함께 코팅하여 형성된 고체분산체를 제공하는 것이다.One aspect of the present invention is to provide a solid dispersion formed by coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material together with one or more solubilizing polymers.
일 구체예에서, 상기 고체분산체는, 불활성 코어 물질 및 이를 코팅하는 서로 다른 2 개 이상의 코팅층을 포함하고, 상기 서로 다른 2 개 이상의 코팅층 중 하나 이상은 아프레피탄트 및 친수성 고분자를 포함하고, 다른 코팅층 중 하나 이상은 아프레피탄트 및 위용성 고분자를 포함한다.In one embodiment, the solid dispersion comprises an inert core material and two or more different coating layers that coat the same, and at least one of the two or more different coating layers comprises an aprepitant and a hydrophilic polymer, and the other At least one of the coating layers includes aprepitant and a gastric-soluble polymer.
상기 고체분산체의 일 구체예에서, 상기 코팅층은, 상기 불활성 코어물질을 표면을 코팅하고, 아프레피탄트 및 친수성 고분자를 포함하는 제1 코팅층, 및 상기 제1 코팅층을 코팅하고, 아프레피탄트 및 위용성 고분자를 포함하는 제2 코팅층을 포함한다. In one embodiment of the solid dispersion, the coating layer coats the surface of the inert core material, a first coating layer comprising an aprepitant and a hydrophilic polymer, and a coating of the first coating layer, an aprepitant and It includes a second coating layer containing a gastric-soluble polymer.
상기 고체분산체의 일 구체예에서, 상기 코팅층 중 하나 이상은 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트를 포함한다.In one embodiment of the solid dispersion, at least one of the coating layers comprises D-α-tocopheryl polyethylene glycol succinate.
상기 고체분산체의 일 구체예에서, 상기 친수성 고분자는 폴리비닐카프로락탐-폴리비닐 아세테이트-폴리에틸렌글리콜 그라프트 공중합체, 히드록시프로필메틸셀룰로스 중에서 선택되는 1종 이상이다.In one embodiment of the solid dispersion, the hydrophilic polymer is at least one selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose.
상기 고체분산체의 일 구체예에서, 상기 위용성 고분자는 폴리메타크릴레이트 공중합체로서 디메틸아미노에틸메타크릴레이트를 갖는 양이온성 고분자이다.In one embodiment of the solid dispersion, the gastric-soluble polymer is a cationic polymer having dimethylaminoethyl methacrylate as a polymethacrylate copolymer.
상기 고체분산체의 일 구체예에서, 상기 폴리메타크릴레이트 공중합체는 폴리(부틸메타크릴레이트-co-(2-디메틸아미노에틸)메타크릴레이트-co-메틸메타크릴레이트)이다.In one embodiment of the solid dispersion, the polymethacrylate copolymer is poly (butylmethacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methylmethacrylate).
상기 고체분산체의 일 구체예에서, 상기 폴리메타크릴레이트 공중합체는 3,000 내지 200,000 g/mole의 중량 평균분자량을 갖는 것이다.In one embodiment of the solid dispersion, the polymethacrylate copolymer has a weight average molecular weight of 3,000 to 200,000 g / mole.
일 구체예에서, 상기 고체분산체는 아프레피탄트 1 중량부에 대하여 친수성 고분자를 0.1 내지 10 중량부로 포함한다.In one embodiment, the solid dispersion comprises 0.1 to 10 parts by weight of a hydrophilic polymer relative to 1 part by weight of aprepitant.
일 구체예에서, 상기 고체분산체는 아프레피탄트 1 중량부에 대하여 위용성 고분자를 0.1 내지 10 중량부로 포함한다.In one embodiment, the solid dispersion comprises 0.1 to 10 parts by weight of a gastric-soluble polymer with respect to 1 part by weight of aprepitant.
일 구체예에서, 상기 고체분산체는 아프레피탄트 1 중량부에 대하여 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트를 0.001 내지 1 중량부로 포함한다.In one embodiment, the solid dispersion comprises 0.001 to 1 part by weight of D-α-tocopheryl polyethylene glycol succinate with respect to 1 part by weight of aprepitant.
본 발명의 다른 측면은, 불활성 코어물질 표면에 적절한 용매에 녹이거나 분산시킨 아프레피탄트를 1종 이상의 가용화 고분자와 함께 스프레이하여 코팅하면서 고체분산체로 형성시킴으로써 수용해도 및 생체이용율이 개선된 경구용 조성물을 제공하는 것이다.Another aspect of the present invention is an oral composition having improved water solubility and bioavailability by forming a solid dispersion while spraying and coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material with one or more solubilizing polymers. Is to provide
본 발명의 또 다른 측면은, 불활성 코어물질 표면에 2개의 층 이상의 서로 다른 조성의 아프레피탄트와 가용화 고분자의 고체분산체 층을 형성하여 수용해도 및 생체이용율이 개선된 경구용 조성물을 제공하는 것이다.Another aspect of the present invention is to provide an oral composition having improved water solubility and bioavailability by forming a solid dispersion layer of an aprepitant and a solubilizing polymer having two or more different compositions on the surface of an inert core material. .
본 발명의 또 다른 측면은, 불활성 코어물질 표면에 1차 코팅층은 아프레피탄트와 가용화 고분자로서 친수성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하고, 2차 코팅층은 아프레피탄트와 가용화 고분자로서 위용성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하는 것을 포함하는 수용해도와 생체이용율이 개선된 경구용 조성물에 관한 것이다.Another aspect of the present invention, the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer. The present invention relates to an oral composition having improved water solubility and bioavailability including coating by dissolving or dispersing a polymer in an appropriate solvent.
본 발명의 또 다른 측면은, 불활성 코어물질 표면에 1차 코팅층은 아프레피탄트와 가용화 고분자로서 친수성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하고, 2차 코팅층은 아프레피탄트와 가용화 고분자로서 위용성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하되 각 코팅층 혹은 일부의 코팅층에 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트(Vitamin E TPGS or TPGS)를 포함하는 수용해도와 생체이용율이 개선된 경구용 조성물에 관한 것이다.Another aspect of the present invention, the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer. Dissolve or disperse the polymer in a suitable solvent to coat it, but in the oral composition with improved water solubility and bioavailability comprising D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) on each coating layer or a portion of the coating layer It is about.
본 발명의 또 다른 측면은, 아프레피탄트를 친수성 고분자와 함께 용해하여 1차 코팅액을 제조하는 단계; 불활성화 코어를 1차 코팅액으로 코팅하는 단계; 아프레피탄트를 위용성 고분자와 함께 용해하여 2차 코팅액을 제조하는 단계; 및 상기 1차 코팅된 입자를 2차 코팅액으로 코팅하는 단계를 포함하는, 수용해도와 생체이용율이 개선된 경구용 조성물의 제조 방법에 관한 것이다.Another aspect of the present invention, a prepitant is dissolved with a hydrophilic polymer to prepare a primary coating solution; Coating the inactivation core with a primary coating solution; Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And coating the primary coated particles with a secondary coating solution, the method of preparing an oral composition having improved water solubility and bioavailability.
본 발명에 따라 아프레피탄트(Aprepitant)가 가용화 고분자와 함께 고체분산체로 형성된 경구용 조성물은 수용해도 및 생체이용율이 개선되었기 때문에 높은 생체이용율을 보이며, 식이영향을 받지 않아 음식물과 무관하게 복용할 수 있어 환자에게 유용한 제제가 될 수 있다. According to the present invention, an oral composition in which aprepitant is formed of a solid dispersion together with a solubilizing polymer exhibits high bioavailability because water solubility and bioavailability are improved, and is not affected by diet, so it can be taken regardless of food. It can be a useful agent for patients.
도 1은 랫트에서의 대조약과 실시예 2 시료의 경구 투여에 대한 아프레피탄트의 약물동력학 시험 결과인 평균혈중농도-시간 그래프(n=5)이다(▲: 대조약,◆: 실시예 2 시료).1 is an average blood concentration-time graph (n = 5) of the results of pharmacokinetics of aprepitant for oral administration of a control drug and a sample of Example 2 in a rat (n: Control drug, ◆: Example 2 sample ).
도 2는 비글견에서의 대조약과 실시예 2 시료의 경구 투여에 대한 아프레피탄트의 약물동력학 시험 결과인 평균혈중농도-시간 그래프(n=6)이다(▲: 대조약,◆: 실시예 2 시료).FIG. 2 is a mean blood concentration-time graph (n = 6) of pharmacokinetics test results of aprepitant for oral administration of a reference drug and a sample 2 sample in a beagle dog (▲: Reference drug, ◆: Example 2 sample).
용어의 정의Definition of Terms
명시적인 다른 기재가 없는 한, 본 명세서 전체에서 사용되는 몇 가지 용어는 다음과 같이 정의될 수 있다.Unless explicitly stated otherwise, several terms used throughout this specification can be defined as follows.
본 명세서 전체에서 특별한 언급이 없는 한 "포함" 또는 "함유"라 함은 어떤 구성 요소(또는 구성 성분)를 별다른 제한없이 포함함을 지칭하며, 다른 구성 요소(또는 구성 성분)의 부가를 배제하는 것으로 해석되지 않는다."Inclusive" or "containing" unless otherwise specified in this specification refers to the inclusion of any component (or component) without particular limitation, and excludes the addition of another component (or component). It is not interpreted as.
"아프레피탄트"는 아프레피탄트 프리 베이스, 그의 이성질체, 또는 이들의 혼합물, 약제학적으로 허용되는 아프레피탄트의 염 및 프로드럭(prodrug)을 포함한다. 각각의 경우에 다양한 수화물, 또는 다양한 결정형을 형성하는 것일 수 있다. "Aprepitant" includes aprepitant free base, isomers thereof, or mixtures thereof, salts and prodrugs of pharmaceutically acceptable aprepitants. In each case, it may be to form various hydrates or various crystal forms.
해결 수단의 발견Finding solutions
수난용성 약물의 수용해도 개선과 생체이용율을 개선하기 위해 다양한 방식들이 사용되어 왔다. 염이나 결정형, 프로드럭(prodrug) 제조 등 약물 자체의 변형, 마이크로 혹은 나노에멀젼, 고체분산체의 제조, 약물의 입자 크기 감소를 통한 미분화 혹은 나노화, 미셀형성 등의 방식들이 주로 사용되어 왔다. 그런데, 수난용성 약물은 약물마다 용해도, pH, pKa, 녹는점, 분자량, 작용기, 입체구조, 결정화도, 투과도, 흡수부위, 분해도, 유효한 약물의 용량 등 약물의 특성들이 서로 다르기 때문에 하나의 기술이 모든 약물에 공통적으로 적용될 수는 없고, 특정 약물에 잘 맞는 방식을 많은 노력을 통해서 찾아야 한다. 또한 약물 자체의 변형 이외에는 수난용성 약물의 수용해도와 생체이용율 개선을 위해서 필수적인 물질 혹은 물질 조합을 찾는 것은 매우 중요한 일 중의 하나이다. 아울러 보다 효율적이고, 경제적인 방식으로 생산할 수 있는 기술 방식을 선택하는 것도 매우 중요한 일 중의 하나이다. Various methods have been used to improve the water solubility of water-insoluble drugs and to improve bioavailability. Methods such as salt or crystal form, modification of the drug itself such as prodrug production, micro or nanoemulsion, production of solid dispersion, micronization or nanonization through reduction of the particle size of the drug, and micelle formation have been mainly used. However, in poorly water-soluble drugs, each drug has different solubility, pH, pKa, melting point, molecular weight, functional group, steric structure, crystallinity, permeability, absorption site, degradability, and effective drug dosage. It cannot be applied to drugs in common, and a method that works well for a specific drug must be found through a lot of efforts. In addition, it is very important to find a substance or a combination of substances necessary for improving the water solubility and bioavailability of poorly water-soluble drugs other than the modification of the drug itself. It is also very important to choose a technology that can be produced in a more efficient and economical way.
아프레피탄트의 수용해도 개선과 생체이용율을 개선하기 위해서 많은 시도가 있어 왔으나, 이중층의 코팅 방식의 고체분산체 및 이를 이용한 경구용 조성물은 없었다. 아울러 제1층의 코팅층은 친수성 고분자와 아프레피탄트를 포함하고, 제2층의 코팅층은 위용성 고분자와 아프레피탄트를 포함하는 고체분산체 및 이를 이용한 경구용 조성물은 없었다. There have been many attempts to improve the water solubility and bioavailability of aprepitant, but there has been no oral composition using the solid dispersion of the double layer coating method and the same. In addition, the coating layer of the first layer contained a hydrophilic polymer and aprepitant, and the coating layer of the second layer had no solid dispersion comprising a gastric-soluble polymer and aprepitant and an oral composition using the same.
본 발명자들은 다양한 물질들이 아프레피탄트의 수용해도에 미치는 영향을 평가하기 위해서 많은 노력을 기울인 끝에, 아프레피탄트의 수용해도와 생체이용율 개선에 탁월한 효과가 있는 고체분산체 및 이를 이용한 경구용 조성물을 발견하게 되었다. The present inventors made a great effort to evaluate the effect of various substances on the water solubility of aprepitant, and then used a solid dispersion having an excellent effect on improving the water solubility and bioavailability of aprepitant and an oral composition using the same Was discovered.
상세한 설명details
본 발명의 일 측면은, 불활성 코어물질 표면에 적절한 용매에 녹이거나 분산시킨 아프레피탄트를 1종 이상의 가용화 고분자와 함께 코팅하여 형성된 고체분산체를 제공하는 것이다.One aspect of the present invention is to provide a solid dispersion formed by coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material together with one or more solubilizing polymers.
본 발명의 다른 측면은, 불활성 코어물질 표면에 적절한 용매에 녹이거나 분산시킨 아프레피탄트를 1종 이상의 가용화 고분자와 함께 스프레이하여 코팅하면서 고체분산체로 형성시킴으로써 수용해도 및 생체이용율이 개선된 경구용 조성물을 제공하는 것이다.Another aspect of the present invention is an oral composition having improved water solubility and bioavailability by forming a solid dispersion while spraying and coating aprepitant dissolved or dispersed in a suitable solvent on the surface of an inert core material with one or more solubilizing polymers. Is to provide
본 발명의 또 다른 측면은, 불활성 코어물질 표면에 2개의 층 이상의 서로 다른 조성의 아프레피탄트와 가용화 고분자의 고체분산체 층을 형성하여 수용해도 및 생체이용율이 개선된 경구용 조성물을 제공하는 것이다.Another aspect of the present invention is to provide an oral composition having improved water solubility and bioavailability by forming a solid dispersion layer of an aprepitant and a solubilizing polymer having two or more different compositions on the surface of an inert core material. .
본 발명의 또 다른 측면은, 불활성 코어물질 표면에 1차 코팅층은 아프레피탄트와 가용화 고분자로서 친수성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하고, 2차 코팅층은 아프레피탄트와 가용화 고분자로서 위용성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하는 것을 포함하는 수용해도와 생체이용율이 개선된 경구용 조성물에 관한 것이다.Another aspect of the present invention, the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer. The present invention relates to an oral composition having improved water solubility and bioavailability including coating by dissolving or dispersing a polymer in an appropriate solvent.
본 발명의 또 다른 측면은, 불활성 코어물질 표면에 1차 코팅층은 아프레피탄트와 가용화 고분자로서 친수성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하고, 2차 코팅층은 아프레피탄트와 가용화 고분자로서 위용성 고분자를 적절한 용매에 녹이거나 분산시켜 코팅하되 각 코팅층 혹은 일부의 코팅층에 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트(Vitamin E TPGS 혹은 TPGS)를 포함하는 수용해도와 생체이용율이 개선된 경구용 조성물에 관한 것이다.Another aspect of the present invention, the primary coating layer on the surface of the inert core material is coated with an aprepitant and a solubilizing polymer by dissolving or dispersing a hydrophilic polymer in an appropriate solvent, and the secondary coating layer is compatible with the aprepitant and solubilizing polymer. Dissolve or disperse the polymer in a suitable solvent to coat it, but each coating layer or a portion of the coating layer contains D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) in an oral composition with improved water solubility and bioavailability. It is about.
본 발명의 또 다른 측면은, 아프레피탄트를 친수성 고분자와 함께 용해하여 1차 코팅액을 제조하는 단계; 불활성화 코어를 1차 코팅액으로 코팅하는 단계; 아프레피탄트를 위용성 고분자와 함께 용해하여 2차 코팅액을 제조하는 단계; 및 상기 1차 코팅된 입자를 2차 코팅액으로 코팅하는 단계를 포함하는, 경구용 조성물의 제조방법에 관한 것이다.Another aspect of the present invention, a prepitant is dissolved with a hydrophilic polymer to prepare a primary coating solution; Coating the inactivation core with a primary coating solution; Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And coating the primary coated particles with a secondary coating solution.
본 발명의 경구용 조성물은, 예를 들어, 고체 경구 제제, 특히 정제 또는 캡슐제의 형태일 수 있다.The oral composition of the present invention may be, for example, in the form of a solid oral preparation, particularly a tablet or capsule.
상기 불활성 코어물질은 미결정셀룰로오스, 백당, 락토오즈, 전분 또는 이의 조합을 포함하거나 이로 이루어진 입자일 수 있다. 또는, 상기 불활성 코어물질은 미결정셀룰로오스, 백당 또는 이의 조합을 포함하거나 이로 이루어진 입자일 수 있다.The inert core material may be particles comprising or consisting of microcrystalline cellulose, white sugar, lactose, starch, or a combination thereof. Alternatively, the inert core material may be particles comprising or consisting of microcrystalline cellulose, white sugar, or a combination thereof.
상기 불활성 코어 물질의 모양은 다양할 수 있고, 예를 들어 구형이나 구형에 가까운 것일 수 있으나 이에 한정되는 것은 아니다. 구형도(Circularity)의 관점에서는 구형도가 0.2 이상, 또는 0.4 이상, 또는 0.5 이상, 또는 0.7 이상 일 수 있다. 상기 불활성 코어 물질의 평균 직경은 20 내지 2000㎛, 또는 50 내지 1500㎛, 또는 100 내지 1200㎛, 또는 200 내지 800㎛일 수 있다.The shape of the inert core material may be various, for example, a spherical shape or a spherical shape, but is not limited thereto. In terms of circularity, the sphericity may be 0.2 or more, or 0.4 or more, or 0.5 or more, or 0.7 or more. The average diameter of the inert core material may be 20 to 2000 μm, or 50 to 1500 μm, or 100 to 1200 μm, or 200 to 800 μm.
상기 친수성 고분자는, 예를 들어, 폴리비닐카프로락탐-폴리비닐 아세테이트-폴리에틸렌글리콜 그라프트 공중합체(예를 들어 Soluplus®), 히드록시프로필메틸셀룰로스(HPMC), 폴리비닐피롤리돈(PVP), 폴리비닐아세테이트(PVA), 카르복시메틸셀룰로스(나트륨염 및 칼슘염), 에틸셀룰로스, 메틸셀룰로스, 히드록시에틸셀룰로스, 에틸히드록시에틸셀룰로스, 히드록시프로필셀룰로스(HPC), L-HPC(저치환도의 HPC), 폴리비닐알콜, 아크릴산 및 그의 염의 중합체, 비닐피롤리돈-비닐아세테이트 공중합체(예를 들어 콜리돈(Kollidon)®VA64, 바스프(BASF)), 폴리코트 아이알(Polycoat IR), 젤라틴, 구아 고무, 부분적으로 가수분해된 전분, 알기네이트, 잔탄, 및 이들의 혼합물로 구성된 군으로부터 선택된 1종 이상일 수 있으나, 이에 제한되는 것은 아니다. 또는, 상기 친수성 고분자는 폴리비닐카프로락탐-폴리비닐 아세테이트-폴리에틸렌글리콜 그라프트 공중합체 (예를 들어 Soluplus®), 히드록시프로필메틸셀룰로스(HPMC) 또는 이들의 혼합물일 수 있다.The hydrophilic polymer is, for example, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example Soluplus ® ), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), Polyvinyl acetate (PVA), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low substitution) HPC), polymers of polyvinyl alcohol, acrylic acid and salts thereof, vinylpyrrolidone-vinyl acetate copolymers (e.g. Kollidon® VA64, BASF), polycoat IR, gelatin , Guar rubber, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof, but may be one or more selected from the group. Alternatively, the hydrophilic polymer may be polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (eg Soluplus ® ), hydroxypropylmethylcellulose (HPMC), or mixtures thereof.
상기 위용성 고분자는, 예를 들어, 폴리메타크릴레이트 공중합체, 또는 디메틸아미노에틸메타크릴레이트를 갖는 양이온성 고분자(cationic polymer with dimethyl-aminoethyl methacrylate), 또는 폴리(부틸메타크릴레이트-co-(2-디메틸아미노에틸)메타크릴레이트-co-메틸메타크릴레이트)일 수 있다.The gastric-soluble polymer is, for example, a polymethacrylate copolymer, or a cationic polymer having dimethylaminoethyl methacrylate (cationic polymer with dimethyl-aminoethyl methacrylate), or poly (butyl methacrylate-co- ( 2-dimethylaminoethyl) methacrylate-co-methylmethacrylate).
구체적인 예로서, 상기 위용성 고분자는 유드라짓® E PO(에보닉, 독일) 또는 유드라짓® E 100(에보닉, 독일)일 수 있다. 유드라짓® E 고분자는 통상 코팅기제로서 약물을 수분으로부터 보호할 필요가 있거나 환자의 복약순응도가 떨어지는 경우 민감한 약물을 인캡슐레이션하거나 약물의 맛과 냄새를 차폐하여 복용에 대한 환자의 거부감을 완화하고, 부드럽고 윤기 나는 표면을 제공하여 약을 쉽게 삼킬 수 있도록 하는 목적으로 사용되고 있으나, 본 발명에서는 아프레피탄트의 수용해도와 생체이용율을 개선하기 위해 가용화 고분자로 사용되는 것이다.As a specific example, the gastric-soluble polymer may be Eudragit® E PO (Evonik, Germany) or Eudragit® E 100 (Evonik, Germany). Eudragit® E polymer is usually a coating agent, and when it is necessary to protect the drug from moisture or when patient compliance is poor, encapsulate sensitive drugs or mask the taste and odor of the drug to alleviate the patient's refusal to take And, it is used for the purpose of providing a smooth and shiny surface so that the drug can be swallowed easily, but in the present invention, it is used as a solubilizing polymer to improve the water solubility and bioavailability of aprepitant.
상기 친수성 고분자 및/또는 위용성 고분자에서 폴리메타크릴레이트 공중합체의 중량 평균 분자량은 3,000 내지 200,000, 또는 5,000 내지 150,000, 또는 10,000 내지 100,000, 또는 20,000 내지 80,000, 또는 37,000 내지 57,000 g/mole일 수 있다. 중량 평균 분자량이 3,000 g/mole 미만이면 수용해도 개선 효과가 낮을 우려가 있고, 중량 평균 분자량이 200,000 g/mole을 초과하면 붕해가 지연될 우려가 있다.The weight average molecular weight of the polymethacrylate copolymer in the hydrophilic polymer and / or gastric soluble polymer may be 3,000 to 200,000, or 5,000 to 150,000, or 10,000 to 100,000, or 20,000 to 80,000, or 37,000 to 57,000 g / mole . If the weight average molecular weight is less than 3,000 g / mole, the water solubility improvement effect may be low, and if the weight average molecular weight exceeds 200,000 g / mole, disintegration may be delayed.
상기 친수성 고분자 및/또는 위용성 고분자는 아프레피탄트 1 중량부를 기준으로, 예를 들어, 0.1 내지 10 중량부, 또는 0.5 내지 5 중량부, 또는 0.8 내지 2 중량부, 또는 0.8 내지 1.2 중량부의 양으로 사용될 수 있다. 폴리메타크릴레이트 공중합체가 전술한 하한 범위보다 적으면 아프레피탄트의 수용해도 개선 및 생체이용율의 개선 정도가 미미하여 효과가 떨어질 수 있으며, 전술한 상한 범위를 벗어나면 지나치게 제제(예를 들어, 캡슐이나 정제)가 커지게 되어 환자가 복용할 때 불편을 야기할 수 있다.The hydrophilic polymer and / or gastric soluble polymer is based on 1 part by weight of aprepitant, for example, 0.1 to 10 parts by weight, or 0.5 to 5 parts by weight, or 0.8 to 2 parts by weight, or 0.8 to 1.2 parts by weight Can be used as If the polymethacrylate copolymer is less than the above-mentioned lower limit, the water solubility of aprepitant and the degree of improvement in bioavailability may be insignificant, and the effect may be deteriorated. Or tablets), which can cause discomfort when the patient is taking it.
상기 친수성 고분자 및/또는 위용성 고분자의 상태에는 특별한 제한이 없으나, 과립 또는 분말 상태일 수 있다.There are no particular restrictions on the state of the hydrophilic polymer and / or gastric soluble polymer, but may be in the form of granules or powder.
상기 1차 코팅층 및/또는 2차 코팅층은 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트(Vitamin E TPGS or TPGS)은 아프레피탄트의 용해도 및 용해속도 개선에 탁월한 효과가 있다. The primary coating layer and / or the secondary coating layer is D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) has an excellent effect on improving the solubility and dissolution rate of aprepitant.
상기 TPGS는 아프레피탄트 1 중량부를 기준으로, 예를 들어, 0.001 내지 2 중량부, 또는 0.01 내지 0.2 중량부, 또는 0.05 내지 0.15 중량부의 양으로 사용될 수 있다. TPGS가 전술한 하한 범위보다 적으면 아프레피탄트의 수용해도 개선 및 생체이용율의 개선 정도가 미미하여 효과가 떨어질 수 있으며, 전술한 상한 범위를 벗어나면 코팅층이 지나치게 sticky하여 제조시 뿐 아니라, 필름형성, 보관시에 어려움을 야기할 수 있다.The TPGS may be used in an amount of 0.001 to 2 parts by weight, or 0.01 to 0.2 parts by weight, or 0.05 to 0.15 parts by weight based on 1 part by weight of aprepitant. If the TPGS is less than the above-mentioned lower limit, the water solubility of aprepitant is improved and the degree of improvement in bioavailability is insignificant, and the effect may be deteriorated. Storage may cause difficulties.
상기 1차 코팅층 및/또는 2차 코팅층은 계면활성제를 더 포함할 수 있다. 상기 계면활성제는 예를 들어 음이온성 계면활성제일 수 있다. 음이온성 계면활성제는 소듐도데실설페이트, 라우릴황산나트륨, N-라우로일살코실산나트륨, N-장쇄아실글루탐산염, 자당지방산에스테르, 폴리옥시에틸렌경화피마자유, 소르비탄지방산에스테르, 폴리옥시에틸렌과 폴리옥시프로필렌의 코폴리머 또는 이들의 조합일 수 있고, 또는 소듐도데실설페이트일 수 있다.The primary coating layer and / or secondary coating layer may further include a surfactant. The surfactant may be, for example, an anionic surfactant. Anionic surfactants include sodium dodecyl sulfate, sodium lauryl sulfate, sodium N-lauroyl salicylate, N-long chain acyl glutamate, sucrose fatty acid ester, polyoxyethylene cured castor oil, sorbitan fatty acid ester, polyoxyethylene and It may be a copolymer of polyoxypropylene or a combination thereof, or sodium dodecyl sulfate.
상기 계면활성제는 아프레피탄트 1 중량부를 기준으로, 예를 들어, 0.0001 내지 1 중량부, 또는 0.0005 내지 0.5 중량부, 또는 0.001 내지 0.1 중량부, 또는 0.001 내지 0.01 중량부, 또는 0.001 내지 0.005 중량부의 양으로 사용될 수 있다.The surfactant is based on 1 part by weight of aprepitant, for example, 0.0001 to 1 part by weight, or 0.0005 to 0.5 part by weight, or 0.001 to 0.1 part by weight, or 0.001 to 0.01 part by weight, or 0.001 to 0.005 part by weight It can be used in quantity.
상기 1차 코팅액 및/또는 2차 코팅액에 사용되는 용매는 수혼화성 유기용매, 물 또는 이의 혼합물일 수 있다. 수혼화성 유기 용매, 예를 들어, 알코올, 아세톤, 테트라하이드로퓨란, 아세트산, 아세토니트릴, 다이옥산 및 이들의 조합으로 이루어진 군에서 선택된 것을 사용할 수 있으나, 이에 한정되지는 않는다. 수혼화성 유기 용매는 예를 들어 탄소수 1 내지 5의 저가알코올, 아세톤 또는 이의 혼합물, 또는 에탄올, 아세톤 또는 이의 혼합물, 또는 에탄올일 수 있다.The primary coating solution and / or the solvent used for the secondary coating solution may be a water-miscible organic solvent, water or a mixture thereof. Water-miscible organic solvents, for example, alcohols, acetone, tetrahydrofuran, acetic acid, acetonitrile, dioxane, and combinations thereof may be used, but are not limited thereto. The water-miscible organic solvent may be, for example, low-cost alcohol having 1 to 5 carbon atoms, acetone or a mixture thereof, or ethanol, acetone or a mixture thereof, or ethanol.
코팅된 입자의 단면을 자른 후 주사전자현미경(SEM) 등의 방식으로 코팅층의 두께를 측정해 볼 수 있다. 이때 5개 이상을 측정하여 평균을 내어 평균 두께를 확인할 수 있다. 상기 1차 코팅이 완료된 입자에 대해 1차 코팅층의 단면을 관찰할 때, 1차 코팅층의 평균 두께는 10㎛ 이상 200㎛ 이하, 또는 20㎛ 이상 180㎛ 이하, 또는 50㎛ 이상 150㎛ 이하, 또는 90㎛ 이상 120㎛ 이하일 수 있다. 상기 2차 코팅이 완료된 입자에 대해 2차 코팅층의 단면을 관찰할 때, 2차 코팅층의 평균 두께는 5㎛ 이상 100㎛ 이하, 또는 10㎛ 이상 90㎛ 이하, 또는 15㎛ 이상 80㎛ 이하, 또는 20㎛ 이상 70㎛ 이하일 수 있다. 코팅층의 평균 두께가 전술한 범위보다 얇은 경우에는 입자 내 약물의 함량이 낮아지게 되어 많은 양의 불활성 코어가 필요하게 되어 제형이 커질 우려가 있으며, 코팅층의 평균 두께가 전술한 범위보다 두꺼운 경우에는 용출 지연, 공정시간 과다 소요 등의 이유로 원하는 목적을 달성할 수 없다.After cutting the cross-section of the coated particles, the thickness of the coating layer can be measured using a scanning electron microscope (SEM) method. At this time, it is possible to check the average thickness by measuring 5 or more. When the cross section of the primary coating layer is observed for the particles having the primary coating, the average thickness of the primary coating layer is 10 μm or more and 200 μm or less, or 20 μm or more and 180 μm or less, or 50 μm or more and 150 μm or less, or It may be 90 μm or more and 120 μm or less. When the cross-section of the secondary coating layer is observed for the particles having the secondary coating completed, the average thickness of the secondary coating layer is 5 μm or more and 100 μm or less, or 10 μm or more and 90 μm or less, or 15 μm or more and 80 μm or less, or It may be 20 μm or more and 70 μm or less. When the average thickness of the coating layer is thinner than the above-mentioned range, the content of the drug in the particles is lowered, so that a large amount of inert core is required, and thus the formulation may be enlarged. The desired purpose cannot be achieved due to delays, excessive processing time, etc.
상기한 바와 같이 코팅하는 과정에서, 코팅의 효율성, 약물의 안정성, 외관, 색상, 보호, 유지, 결합, 성능 개선, 제조 공정 개선 등의 부가적인 목적을 위하여 다양한 생물학적 불활성 성분을 추가로 사용할 수 있다.In the coating process as described above, various biologically inert ingredients may be additionally used for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, bonding, performance improvement, and manufacturing process improvement. .
일 구현예에 따르면, 상기 코팅층에 추가로 포함될 수 있는 생물학적 불활성 성분은 가소제, 활택제, 착색제, 착향제, 계면활성제, 안정화제, 산화방지제, 발포제, 소포제, 방습제(예를 들어, 파라핀, 왁스) 등으로 이루어진 군에서 선택된 1종 이상일 수 있다. 예컨대, 상기 가소제는 각 코팅층에 사용되는 전체 고분자의 건조 중량에 대하여 100 중량% 이하(예컨대, 0.1 내지 100 중량%), 또는 50 중량% 이하(예컨대, 0.1 내지 50 중량%), 또는 30 중량% 이하(예컨대, 0.1 내지 30 중량%)로 포함될 수 있다.According to one embodiment, the biologically inert component that may be further included in the coating layer is a plasticizer, a lubricant, a colorant, a flavoring agent, a surfactant, a stabilizer, an antioxidant, a foaming agent, an antifoaming agent, and a desiccant (for example, paraffin, wax ) May be one or more selected from the group consisting of. For example, the plasticizer is 100% by weight or less (eg, 0.1 to 100% by weight), or 50% by weight or less (eg, 0.1 to 50% by weight), or 30% by weight, based on the dry weight of the total polymer used in each coating layer. It may be included below (eg, 0.1 to 30% by weight).
예컨대, 상기 가소제는 트리에틸 시트레이트, 디부틸 프탈레이트, 디에틸 프탈레이트, 디부틸 세바케이트, 디에틸 세바케이트, 트리부틸 시트레이트, 아세틸 트리에틸 시트레이트, 아세틸 트리에틸 시트레이트, 프로필렌 글리콜, 트리아세틴, 폴리에틸렌 글리콜, 세틸 알코올, 스테아릴 알코올, 및 세토스테아릴 알코올로 이루어진 군에서 선택되는 1종 이상인 것일 수 있으나, 이에 제한되는 것은 아니다. For example, the plasticizer is triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl citrate, propylene glycol, triacetin , Polyethylene glycol, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol may be one or more selected from the group consisting of, but is not limited thereto.
상기 활택제는 각 코팅층에 사용되는 전체 고분자의 건조 중량에 대하여 100 중량% 이하(예컨대, 0.1 내지 100 중량%), 또는 50 중량% 이하로 포함될 수 있다.The lubricant may be included in 100% by weight or less (eg, 0.1 to 100% by weight), or 50% by weight or less, based on the dry weight of the entire polymer used in each coating layer.
구체적으로, 상기 활택제는 예를 들어, 스테아린산 마그네슘, 푸마르산, 스테아르산, 스테아린산 칼슘, 소디움 스테아릴 푸마레이트, 폴리에틸렌 글리콜, 전분(밀, 쌀, 옥수수 또는 감자 전분), 활석, 고도 분산형(콜로이드형) 실리카, 마그네슘 옥시드, 마그네슘 카르보네이트, 글리세릴 베헤네이트, 글리세릴 모노 스테아레이트, 이산화규소, 칼슘 실리케이트, 마그네슘 실리케이트 및 이들의 혼합물로 구성된 군으로부터 선택된 1종 이상일 수 있으나, 이에 제한되는 것은 아니다.Specifically, the lubricant is, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloid) Type) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono stearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof. It is not.
상기 정제나 캡슐에 있어서 정제나 캡슐의 물리적인 특성, 제조성, 압축성, 외관, 기호, 약물의 안정성 등을 개선하기 위하여 다양한 첨가제를 혼합할 수 있다. 상기 첨가제로는 예를 들어, 안정화제, 가용화제, 감미제, 교미제, 안료, 습윤제, 충전제, 안정화제, 계면활성제, 활택제, 가용화제, 완충제, 감미제, 흡착제, 교미제, 결합제, 현탁화제, 경화제, 항산화제, 광택제, 착향제, 향미제, 안료, 코팅제, 습윤제, 습윤 조정제, 충전제, 소포제, 청량화제, 저작제, 정전 방지제, 착색제, 당의제, 등장화제, 연화제, 유화제, 점착제, 점증제, 발포제, pH조절제, 부형제, 분산제, 붕해제, 방수제, 방부제, 보존제, 용해 보조제, 용제, 유동화제 등을 들 수 있으나, 이에 제한되지 않고 약학적으로 허용가능한 것이면 어떠한 것이든 사용될 수 있다. In the tablet or capsule, various additives may be mixed to improve physical properties, manufacturability, compressibility, appearance, taste, and drug stability of the tablet or capsule. The additives include, for example, stabilizers, solubilizers, sweeteners, mating agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, mating agents, binders, suspending agents , Curing agent, antioxidant, brightener, flavoring agent, flavoring agent, pigment, coating agent, wetting agent, wetting control agent, filler, antifoaming agent, refreshing agent, chewing agent, antistatic agent, coloring agent, dragee, isotonic agent, emollient, emulsifier, adhesive, Thickeners, foaming agents, pH adjusting agents, excipients, dispersing agents, disintegrating agents, waterproofing agents, preservatives, preservatives, dissolving aids, solvents, fluidizing agents, and the like, but are not limited thereto, and any pharmaceutically acceptable one may be used. .
제조 방법Manufacturing method
경구용 조성물의 제조에 있어서 본 발명의 다른 측면은, 아프레피탄트를 친수성 고분자와 함께 용해하여 1차 코팅액을 제조하는 단계; 불활성화 코어를 1차 코팅액으로 코팅하는 단계; 아프레피탄트를 위용성 고분자와 함께 용해하여 2차 코팅액을 제조하는 단계; 및 상기 1차 코팅된 입자를 2차 코팅액으로 코팅하는 단계를 포함하는 경구용 조성물의 제조방법에 관한 것이다.In the preparation of an oral composition, another aspect of the present invention comprises: dissolving aprepitant together with a hydrophilic polymer to prepare a primary coating solution; Coating the inactivation core with a primary coating solution; Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And coating the primary coated particles with a secondary coating solution.
상기 제조방법은 2차 코팅액으로 코팅 후, 경구용 제제로 제조하는 단계를 더 포함할 수 있다. 상기 경구용 제제는 정제, 캡슐제, 과립제, 또는 분말 형태일 수 있으나, 이에 제한되지 않는다.The manufacturing method may further include a step of coating with a secondary coating solution, and then preparing an oral preparation. The oral preparation may be in the form of a tablet, capsule, granule, or powder, but is not limited thereto.
상기 코팅하는 단계는 유동층 코팅기를 이용하여 코팅할 수 있다. 일 구체예에서, 상기 코팅하는 단계는 bottom spray 코팅 방식, tangential spray 코팅 방식, top spray 코팅 방식을 이용하는 것일 수 있다. 또는, 상기 코팅하는 단계는 bottom spray 코팅 방식, tangential spray 코팅 방식일 수 있다.The coating may be performed using a fluidized bed coater. In one embodiment, the coating step may be to use a bottom spray coating method, a tangential spray coating method, a top spray coating method. Alternatively, the coating step may be a bottom spray coating method, a tangential spray coating method.
상기 코팅하는 단계는 코팅 장비의 크기와 batch size에 무관하게 제조할 수 있으며, lab scale에서 작은 단위인 mini-glatt(Glatt, Germany)에서 하거나 GPCG 1을 포함하는 GPCG series의 큰 장비에서도 원활하게 제조할 수 있다. 또한 tangential spray 방식의 Soild Lab 2 (Bosch, Germany)에서도 제조할 수 있다.The coating step can be produced regardless of the size and batch size of the coating equipment, and can be manufactured in mini-glatt (Glatt, Germany), which is a small unit on a lab scale, or smoothly on large equipment of the GPCG series including GPCG 1. can do. It can also be produced in Soild Lab 2 (Bosch, Germany) in a tangential spray method.
이하, 본 발명의 이해를 돕기 위하여 실시예들을 제시한다. 그러나 하기의 실시예들은 본 발명을 예시하기 위한 것일 뿐, 본 발명을 어떤 식으로든 제한하는 것은 아니다.Hereinafter, examples are provided to help understanding of the present invention. However, the following examples are only intended to illustrate the invention, and are not intended to limit the invention in any way.
<실시예 1: 고체분산체의 제조 1><Example 1: Preparation of solid dispersion 1>
제1차 코팅1st coating
아프레피탄트 10 g과 Soluplus 10 g, TPGS 0.1 g, SDS(Sodium dodecyl sulphate) 0.037 g을 84 ㎖의 EtOH과 84 ㎖ 아세톤과 57 ㎖의 증류수에 녹여 약물과 고분자가 혼합된 액을 제조하였다. 유동층 코팅기(Mini-Glatt, Glatt, Germany)에 미결정셀룰로오스 구형 코어 10 g을 넣고 bottom spray coating 방식을 이용하여 제조된 용액을 분사하여 코어 위에 코팅하였다. 10 g of aprepitant, 10 g of Soluplus, 0.1 g of TPGS, and 0.037 g of SDS (Sodium dodecyl sulphate) were dissolved in 84 ml of EtOH, 84 ml of acetone, and 57 ml of distilled water to prepare a mixture of drug and polymer. Into a fluidized bed coating machine (Mini-Glatt, Glatt, Germany), 10 g of microcrystalline cellulose spherical core was added, and a solution prepared using a bottom spray coating method was sprayed to coat the core.
제2차 코팅Second coating
아프레피탄트 10 g과 Eudragit E PO 10 g, TPGS 0.1 g, SDS(Sodium dodecyl sulphate) 0.037 g을 333 ㎖의 EtOH과 113 ㎖의 증류수에 녹여 약물과 고분자가 혼합된 액을 제조하였다. 유동층 코팅기(Mini-Glatt, Glatt, Germany)에 1차 코팅이 완료된 구형 코어를 모두 넣고 bottom spray coating 방식을 이용하여 제조된 용액을 분사하여 코어 위에 코팅이 이루어지게 하였다. 10 g of aprepitant, 10 g of Eudragit E PO, 0.1 g of TPGS, and 0.037 g of SDS (Sodium dodecyl sulphate) were dissolved in 333 ml of EtOH and 113 ml of distilled water to prepare a mixture of drug and polymer. In the fluidized bed coating machine (Mini-Glatt, Glatt, Germany), all the spherical cores having the first coating were put therein, and the solution prepared using the bottom spray coating method was sprayed to coat the cores.
<실시예 2: 고체분산체의 제조 2><Example 2: Preparation of solid dispersion 2>
제1차 코팅1st coating
아프레피탄트 10 g과 HPMC 10 g, TPGS 0.1 g, SDS(Sodium dodecyl sulphate) 0.037 g을 500 ㎖의 EtOH과 162 ㎖의 증류수에 녹여 약물과 고분자가 혼합된 액을 제조하였다. 유동층 코팅기(Mini-Glatt, Glatt, Germany)에 미결정셀룰로오스 구형 코어 10 g을 넣고 bottom spray coating 방식을 이용하여 제조된 용액을 분사하여 코어 위에 코팅하였다. 10 g of aprepitant, 10 g of HPMC, 0.1 g of TPGS, and 0.037 g of SDS (Sodium dodecyl sulphate) were dissolved in 500 ml of EtOH and 162 ml of distilled water to prepare a liquid mixture of drug and polymer. Into a fluidized bed coating machine (Mini-Glatt, Glatt, Germany), 10 g of microcrystalline cellulose spherical core was added, and a solution prepared using a bottom spray coating method was sprayed to coat the core.
제2차 코팅Second coating
아프레피탄트 10 g과 Eudragit E PO 10 g, TPGS 0.1 g, SDS(Sodium dodecyl sulphate) 0.037 g을 333 ㎖의 EtOH과 113 ㎖의 증류수에 녹여 약물과 고분자가 혼합된 액을 제조하였다. 유동층 코팅기(Mini-Glatt, Glatt, Germany)에 1차 코팅이 완료된 구형 코어를 모두 넣고 bottom spray coating 방식을 이용하여 제조된 용액을 분사하여 코어 위에 코팅이 이루어지게 하였다. 10 g of aprepitant, 10 g of Eudragit E PO, 0.1 g of TPGS, and 0.037 g of SDS (Sodium dodecyl sulphate) were dissolved in 333 ml of EtOH and 113 ml of distilled water to prepare a mixture of drug and polymer. In the fluidized bed coating machine (Mini-Glatt, Glatt, Germany), all the spherical cores having the first coating were put therein, and the solution prepared using the bottom spray coating method was sprayed to coat the cores.
<실시예 3: 캡슐의 제조><Example 3: Preparation of capsule>
실시예 1, 2에서 제조된 미립자를 에어로실 0.4%(w/w%) 처리하고, 1호 캡슐에 아프레피탄트로서 125mg이 되도록 충진하여 생체이용율이 개선된 경구용 조성물을 최종 수득하였다. The microparticles prepared in Examples 1 and 2 were treated with aerosil 0.4% (w / w%), and filled in No. 1 capsules to be 125 mg as aprepitant, thereby obtaining an oral composition having improved bioavailability.
<시험예 1: 랫드에서의 약물동력학 시험><Test Example 1: Pharmacokinetic test in rats>
실시예 2에서 얻어진 시료에 대해서 실험동물로는 180~220g(6~8주령) 내외의 Sprague-Dawley계 웅성 흰쥐를 Charles River Laboratories(Orient, Korea)로부터 공급 받아 피시험체를 군당 5마리씩 무작위 분배하고 시료를 완충 용액에 현탁하여 경구투여(p.o.)하였다.For the sample obtained in Example 2, as an experimental animal, Sprague-Dawley male rats of about 180-220 g (6-8 weeks old) were supplied from Charles River Laboratories (Orient, Korea) and randomly distributed 5 specimens per group. The sample was suspended in a buffer solution and orally administered (po).
각 약물은 1회 투여(5 mg/kg) 하였으며, 분석을 위한 혈액 시료는 약물 투여 후 0.5, 1, 2, 4, 6, 8, 24시간에 heparin 처리된 주사기로 미정맥(tail vein)으로부터 채혈, 원심분리(3,000rpm, Han-il, Korea)하였다. 혈장은 분석시점까지 -70℃ deep freezer(Sanyo, Japan)에 보관하였다. 혈장 내 약물의 농도 분석은 전처리를 거쳐 LC/MS/MS(HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK)로 분석하였다. Each drug was administered once (5 mg / kg), and blood samples for analysis were heparin-treated syringes from tail vein 0.5, 1, 2, 4, 6, 8, 24 hours after drug administration. Blood was collected and centrifuged (3,000 rpm, Han-il, Korea). Plasma was stored in -70 ° C deep freezer (Sanyo, Japan) until the time of analysis. The concentration analysis of the drug in plasma was analyzed by LC / MS / MS (HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK) after pretreatment.
얻어진 약물동력학 파라메터를 분석한 결과는 아래 표 1에 나타내었으며, Emend® 대비 실시예 2의 시료의 AUC0 - 24hr 와 Cmax는 각각 103.6%, 104.9%에 해당하여 생물학적으로 동등함을 확인하였다.Analysis of the resulting pharmacokinetic parameters were shown in Table 1 below, AUC 0 of the sample of Example 2 ® compared Emend - to 24hr and C max corresponds to each of 103.6%, 104.9% was confirmed that equivalent biologically.
[표 1][Table 1]
Figure PCTKR2019013736-appb-I000001
Figure PCTKR2019013736-appb-I000001
<시험예 2: 비글견에서의 약물동력학시험><Test Example 2: Pharmacokinetics test in a beagle dog>
실시예 2에서 얻어진 시료에 대해서 실험동물로는 7.5~9.0 kg(7~8개월령) 내외의 비글견(수컷)을 BEIJING MARSHALL BIOTECHNOLOGY로부터 공급받아 피시험체를 군당 6마리씩 무작위 분배하고 시료를 완제 형태 그대로 경구투여(p.o.)하였다.With respect to the sample obtained in Example 2, 7.5 to 9.0 kg (7 to 8 months old) beagle dogs (males) of about 7.5 to 9.0 kg (7 to 8 months old) were supplied from BEIJING MARSHALL BIOTECHNOLOGY, and randomly distributed 6 specimens per group, and samples were intact in the finished form. It was administered orally (po).
각 약물은 1회 투여(125 mg/head) 하였으며, 분석을 위한 혈액 시료는 약물 투여 직전과 약물 투여 후 각 0.5, 1, 2, 4, 6, 8, 12, 24, 48시간째에 heparin 처리된 주사기로 좌측 요측피정맥으로부터 채혈, 원심분리(12,000rpm)하여 혈장을 분리하였다. 분리한 혈장은 분석시점까지 -70℃ deep freezer(Sanyo, Japan)에 보관하였다. 혈장 내 약물의 농도 분석은 전처리를 거쳐 LC/MS/MS(HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK)로 분석하였다.Each drug was administered once (125 mg / head), and blood samples for analysis were treated with heparin immediately before drug administration and 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after drug administration. Blood was collected from the left lateral veins with a syringe and centrifuged (12,000 rpm) to separate plasma. The separated plasma was stored in a deep freezer (Sanyo, Japan) at -70 ° C until analysis. The concentration analysis of the drug in plasma was analyzed by LC / MS / MS (HPLC; HP1100 series, US, MS; Quattro Ultima-Pt, UK) after pretreatment.
얻어진 파라메터를 분석한 결과는 아래 표에 나타내었으며, Emend® 대비 실시예 2의 시료의 AUC0 - 48hr 와 Cmax는 각각 93.8%, 103.1%에 해당하여 생물학적으로 동등함을 확인하였다.Analysis of the resulting parameters are showed in the following table, AUC 0 of the sample of Example 2 compared Emend ® - 48hr and the C max was confirmed that the biologically equivalent to those in each of 93.8%, 103.1%.
[표 2][Table 2]
Figure PCTKR2019013736-appb-I000002
Figure PCTKR2019013736-appb-I000002

Claims (12)

  1. 불활성 코어 물질 및 이를 코팅하는 서로 다른 2 개 이상의 코팅층을 포함하고,An inert core material and two or more different coating layers coating the same,
    상기 서로 다른 2 개 이상의 코팅층 중 하나 이상은 아프레피탄트 및 친수성 고분자를 포함하고, 다른 코팅층 중 하나 이상은 아프레피탄트 및 위용성 고분자를 포함하는 고체분산체.At least one of the two or more different coating layers comprises an aprepitant and a hydrophilic polymer, and at least one of the other coating layers comprises an aprepitant and a gastric-soluble polymer.
  2. 제1항에 있어서, 상기 코팅층은, According to claim 1, The coating layer,
    상기 불활성 코어물질을 표면을 코팅하고, 아프레피탄트 및 친수성 고분자를 포함하는 제1 코팅층, 및A first coating layer coating the surface of the inert core material, and comprising an aprepitant and a hydrophilic polymer, and
    상기 제1 코팅층을 코팅하고, 아프레피탄트 및 위용성 고분자를 포함하는 제2 코팅층을 포함하는 고체분산체.A solid dispersion comprising a first coating layer, and a second coating layer comprising an aprepitant and a gastric-soluble polymer.
  3. 제1항에 있어서, 상기 코팅층 중 하나 이상은 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트를 포함하는 고체분산체.The solid dispersion according to claim 1, wherein at least one of the coating layers comprises D-α-tocopheryl polyethylene glycol succinate.
  4. 제2항에 있어서, 상기 친수성 고분자는 폴리비닐카프로락탐-폴리비닐 아세테이트-폴리에틸렌글리콜 그라프트 공중합체, 히드록시프로필메틸셀룰로스 중에서 선택되는 1종 이상인 고체분산체.The method of claim 2, wherein the hydrophilic polymer is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, a solid dispersion of at least one selected from hydroxypropyl methylcellulose.
  5. 제2항에 있어서, 상기 위용성 고분자는 폴리메타크릴레이트 공중합체로서 디메틸아미노에틸메타크릴레이트를 갖는 양이온성 고분자인 고체분산체.The solid dispersion according to claim 2, wherein the gastric-soluble polymer is a cationic polymer having dimethylaminoethyl methacrylate as a polymethacrylate copolymer.
  6. 제5항에 있어서, 상기 폴리메타크릴레이트 공중합체는 폴리(부틸메타크릴레이트-co-(2-디메틸아미노에틸)메타크릴레이트-co-메틸메타크릴레이트)인 고체분산체.The solid dispersion according to claim 5, wherein the polymethacrylate copolymer is poly (butylmethacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methylmethacrylate).
  7. 제5항에 있어서, 상기 폴리메타크릴레이트 공중합체는 3,000 내지 200,000 g/mole의 중량 평균 분자량을 갖는 것인 고체분산체.The solid dispersion according to claim 5, wherein the polymethacrylate copolymer has a weight average molecular weight of 3,000 to 200,000 g / mole.
  8. 제2항에 있어서, 아프레피탄트 1 중량부에 대하여 친수성 고분자를 0.1 내지 10 중량부로 포함하는 고체분산체.The solid dispersion according to claim 2, comprising 0.1 to 10 parts by weight of a hydrophilic polymer with respect to 1 part by weight of aprepitant.
  9. 제2항에 있어서, 아프레피탄트 1 중량부에 대하여 위용성 고분자를 0.1 내지 10 중량부로 포함하는 고체분산체.The solid dispersion according to claim 2, comprising 0.1 to 10 parts by weight of a gastric-soluble polymer relative to 1 part by weight of aprepitant.
  10. 제3항에 있어서, 아프레피탄트 1 중량부에 대하여 D-α-토코페릴 폴리에틸렌 글리콜 숙시네이트를 0.001 내지 1 중량부로 포함하는 고체분산체.The solid dispersion according to claim 3, comprising 0.001 to 1 part by weight of D-α-tocopheryl polyethylene glycol succinate with respect to 1 part by weight of aprepitant.
  11. 제1항 내지 제10항 중 어느 한 항의 고체분산체를 포함하는 경구용 조성물.Oral composition comprising the solid dispersion of any one of claims 1 to 10.
  12. 아프레피탄트를 친수성 고분자와 함께 용해하여 1차 코팅액을 제조하는 단계;Preparing a primary coating solution by dissolving aprepitant with a hydrophilic polymer;
    불활성화 코어를 1차 코팅액으로 코팅하는 단계;Coating the inactivation core with a primary coating solution;
    아프레피탄트를 위용성 고분자와 함께 용해 하여 2차 코팅액을 제조하는 단계; 및Preparing a secondary coating solution by dissolving aprepitant together with a gastric-soluble polymer; And
    상기 1차 코팅된 입자를 2차 코팅액으로 코팅하는 단계;를 포함하는,Including; coating the primary coated particles with a secondary coating solution;
    경구용 조성물의 제조방법.Method for preparing oral composition.
PCT/KR2019/013736 2018-10-19 2019-10-18 Oral composition containing aprepitant WO2020080875A1 (en)

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US20100151035A1 (en) * 2007-03-13 2010-06-17 Sandoz Ag Pharmaceutical compositions of poorly soluble drugs
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WO2015104047A1 (en) * 2014-01-09 2015-07-16 Sanofi Formulation of aprepitant with enhanced solubility
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US20110009362A1 (en) * 2008-02-27 2011-01-13 Dr. Reddy's Laboratories Ltd. Solubility-enhanced forms of aprepitant and pharmaceutical compositions thereof
KR20150127253A (en) * 2013-03-14 2015-11-16 레드힐 바이오파마 엘티디 Antiemetic extended release solid dosage forms
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