WO2017111292A1 - Composition pharmaceutique à administrer par voie orale et son procédé de préparation - Google Patents

Composition pharmaceutique à administrer par voie orale et son procédé de préparation Download PDF

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WO2017111292A1
WO2017111292A1 PCT/KR2016/012619 KR2016012619W WO2017111292A1 WO 2017111292 A1 WO2017111292 A1 WO 2017111292A1 KR 2016012619 W KR2016012619 W KR 2016012619W WO 2017111292 A1 WO2017111292 A1 WO 2017111292A1
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pharmaceutical composition
oral pharmaceutical
api
cellulose
water
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PCT/KR2016/012619
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English (en)
Korean (ko)
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신광일
이상엽
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롯데정밀화학 주식회사
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Publication of WO2017111292A1 publication Critical patent/WO2017111292A1/fr

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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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to an oral pharmaceutical composition and a method for preparing the same, and more particularly, oral pharmaceutical composition having excellent bioavailability by including a solid dispersion containing an amorphous active pharmaceutical ingredient (API) and It relates to a manufacturing method.
  • API amorphous active pharmaceutical ingredient
  • the drug is not administered to the human body as a chemical state, but is prepared in a dosage form that is convenient for the patient to take or use, or in a dosage form that can express the pharmacological effect efficiently and effectively, and is administered through various routes.
  • the administered drug is lost from the human body by being absorbed at the site of administration or moving to an appropriate location, absorbed into the bloodstream, distributed to each organ, metabolized through urine, and sometimes through the respiratory tract. In order to effectively treat drugs, high bioavailability must be ensured.
  • Bioavailability refers to the degree of drug used in the target area after administration.As a result of oral administration of a poorly water soluble drug, the bioavailability adversely affects bioavailability. It is pointed out.
  • an oral pharmaceutical composition containing an active pharmaceutical ingredient (API) having low solubility in water is difficult to develop a formulation when it is to be prepared in a liquid form, and is prepared in a tablet or capsule form. When it is absorbed into the living body, the solubility and dissolution rate in the digestive fluid is low, so it is difficult to remove and excrete in the gastrointestinal tract before transition to systemic circulation to express an appropriate therapeutic effect.
  • API active pharmaceutical ingredient
  • Patent Document 1 a technique for producing fine particles using wet grinding is disclosed in Patent Document 1 (US 5,145,684).
  • the chemicals are added to a liquid medium that hardly dissolves and the surface modifier is added to form a premix, which then uses mechanical means such as ball mills, atlit mills, vibratory mills, sand mills and bead mills to Reduce the average particle size of the drug substance to less than 400nm.
  • This dispersion is present as a suspension and is then dried to obtain solid fine particles.
  • the milling process time is long and the risk of drug contamination generated from the grinding medium may occur.
  • Patent Document 2 (US 5,858,410).
  • photon correlation spectroscopy is carried out by high pressure homogenization in a piston gap homogeniser of a suspension in which a pure active ingredient or active ingredient mixture suspended in water or an aqueous medium is solid at room temperature and insoluble or poorly soluble in water.
  • particles having an average diameter of 10 nm to 1000 nm are formed.
  • the production method according to the prior documents has a disadvantage in that the production yield is low due to low production yield, there is a limit to improve the solubility as long as it has a crystalline structure even if the size of the particles are small.
  • Patent Document 1 US5145684 B
  • Patent Document 2 US5858410 B
  • the problem to be solved by the present invention is to provide an oral pharmaceutical composition showing a high solubility and improved bioavailability by including a solid dispersion containing an amorphous API.
  • Another problem to be solved by the present invention is to provide a method for producing an oral pharmaceutical composition using a spray drying method does not affect the stability of the drug while having high production efficiency.
  • the present invention provides an oral pharmaceutical composition
  • a water-soluble polymer and a solid dispersion containing an amorphous active pharmaceutical ingredient (API) dispersed in the water-soluble polymer (Amorphous) to provide.
  • API active pharmaceutical ingredient
  • Amorphous API dispersed in the water-soluble polymer may be formed through spray drying.
  • the solid dispersion may further include a surfactant.
  • the API may include any one selected from the group consisting of ezetimibe, simvastatin, and mixtures thereof.
  • the content of the water-soluble polymer is preferably 50 to 300 parts by weight based on 100 parts by weight of the API.
  • the amount of the surfactant is preferably 10 to 100 parts by weight based on 100 parts by weight of the API.
  • the solid dispersion may further include 1 to 10 parts by weight of a stabilizer based on 100 parts by weight of the API.
  • the oral pharmaceutical composition according to the present invention may further include any one or two or more additives selected from the group consisting of excipients, disintegrants and lubricants, wherein the oral pharmaceutical composition is the solid dispersion 15 to 50 It is preferable to include 50% by weight and 50% by weight of the additive.
  • the present invention comprises the steps of dissolving an active pharmaceutical ingredient (API) in an organic solvent; Preparing a mixed solution by adding a water-soluble polymer to the solution in which the API is dissolved; And spray-drying the mixed solution to prepare a solid dispersion in which an amorphous API is dispersed in the water-soluble polymer.
  • API active pharmaceutical ingredient
  • a surfactant may be further added.
  • the organic solvent may be any one or two or more selected from the group consisting of ethanol, methanol, acetone and dichloromethane, and the concentration of the mixed solution is preferably 2 to 10% (w / w).
  • the spray drying may be performed by using any one or a combination of a disk type spray dryer and a nozzle type spray dryer, and may be performed under conditions of an air inlet temperature of 85 to 100 ° C and a chamber temperature of 70 to 75 ° C. It is preferable to be.
  • the present invention also provides an oral medicament comprising the oral pharmaceutical composition described above.
  • the oral medicine may be tableted by direct tableting.
  • the solubility of the API may be improved by dispersing the crystalline API having low solubility in water in an organic solvent and then dispersing the solid in an amorphous manner through spray drying. Therefore, the oral pharmaceutical composition comprising the solid dispersion containing the amorphous API according to the present invention exhibits high bioavailability and can be usefully used for disease prevention or treatment.
  • the oral pharmaceutical composition according to the present invention is manufactured using a spray drying method, not only the production efficiency is high, but also due to the crushing or homogenizing machine in the conventional method for increasing the solubility of the API by reducing the size of the particles It is possible to solve the problem of contamination of the drug that has been generated can ensure the stability of the drug.
  • FIG. 1 schematically shows a solid dispersion in which an amorphous API is dispersed between water-soluble polymers according to an embodiment of the present invention.
  • Figure 2 is a schematic diagram of the spray dryer used in Example 1 and a photograph taken a portion to be spray dried.
  • Figure 3 is a graph showing the solubility of the ezetimibe in the solid dispersion prepared according to Examples 1 to 3 and the pH solubility of the ezetimibe in the mixed powder according to the comparative example.
  • Figure 4 is a graph showing the comparison of the solubility of the simvastatin in the solid dispersion prepared according to Examples 1 to 3 and the simvastatin in the mixed powder according to the comparative example for each pH.
  • Figure 5 shows a SEM photograph of the solid dispersion prepared according to Example 1.
  • Figure 6 shows a comparison of the XRD analysis results of the solid dispersion prepared according to Examples 1 and 2, the mixed powder according to the comparative example and hydroxypropylmethyl cellulose (trade name: AnyCoat AN6).
  • the present invention relates to an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising a water-soluble polymer and a solid dispersion containing an amorphous active pharmaceutical ingredient (API) dispersed in the water-soluble polymer and a method for preparing the same.
  • API active pharmaceutical ingredient
  • Amorphous API dispersed in the water-soluble polymer may be formed through spray drying.
  • the API refers to the drug substance just prior to producing an easy-to-administer formulation, where approximately 40% of existing APIs and much higher proportions of all newly developed drugs are poorly soluble or insoluble in water. Is reported. This is to find one cause in the crystalline structure of the API, oral administration of a drug prepared from a pharmaceutical composition containing a crystalline API, poor dissolution properties of the drug may lower the bioavailability.
  • Examples of poorly soluble APIs with low solubility in water include xanthine, tadalafil, fenofibrate, cholecalciferol (vitamin D), simvastatin, ezetimibe, ketoprofen, celecoxib, candesartan, atova NSAIDs such as statins, sirolimus, naproxen and ibuprofen, megestrol acetate, ritnabil (HIV protease inhibitor) or cyclosporin, and the like.
  • poorly soluble APIs preferably used in the present invention are ezetimimi, simvastatin, fenofibrate, sirolimus, ketoprofen, celecoxib (celecoxib), candesartan and atorvastatin, any one or two or more selected from the group consisting of, more preferably, the API is selected from the group consisting of ezetimibe, simvastatin and mixtures thereof It may include any one.
  • the ezetimibe is an azetidinone-based drug, and its chemical name is [1- (4-fluorophenyl)-(3R)-[3- (4-fluorophenyl)-(3S) -hydroxypropyl] -(4S)-(4-hydroxyphenyl) -2-azetidinone)].
  • Ezetimibe is a lipid that acts on the Niemann-Pick C1 Like 1 protein in the apical membrane of small intestinal epithelial cells to block the absorption of cholesterol in food or bile.
  • simvastatin can greatly improve the effect of low density lipoprotein cholesterol (LDL-C) reduction.
  • the ezetimibe and simvastatin are expected to have a complementary effect when used in combination with different mechanisms of action.
  • the ezetimibe and simvastatin are BCS (Biopharmaceutical Classification System) Class II drugs, and have low solubility, so that the dissolution rate in the digestive fluid is lowered, and as a result, they are excreted before being absorbed into the living body, and thus it is difficult to express an appropriate therapeutic effect. Therefore, as an example of the method for improving the absorption rate of the drug in the body by improving the solubility of the ezetimibe and simvastatin, the present invention proposes a method of dissolving them in an organic solvent and then dispersed in a water-soluble polymer to convert to an amorphous structure. have.
  • BCS Biopharmaceutical Classification System
  • the solubility of ezetimibe and simvastatin When converted to the amorphous structure as described above, the solubility of ezetimibe and simvastatin is further increased may exhibit excellent drug absorption. These ezetimibe and simvastein can improve the bioavailability in the body, and as a result can express an excellent effect on the prevention and treatment of hyperlipidemia.
  • the water-soluble polymer serves as a base for dispersing the API in the solid dispersion
  • Figure 1 schematically shows a solid dispersion comprising an amorphous API uniformly dispersed between the water-soluble polymer.
  • the water-soluble polymer also affects the solubility of the API, for example, referring to FIGS. 3 and 4 showing the solubility of ezetimibe and simvastatin corresponding to the API in the solid dispersion prepared according to Examples 1 to 3 of the present invention. It can be seen that as the content of the water-soluble polymer increases, solubility of the API is also improved.
  • the content of the water-soluble polymer is excessive, there is a fear that the therapeutic effect is lowered because the API content is relatively low, so in consideration of these points, the content of the water-soluble polymer is 50 to 300 parts by weight based on 100 parts by weight of the API. desirable.
  • the water-soluble polymer is hydroxypropylmethyl cellulose, hydroxypropylbutyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose , Hydroxybutyl cellulose, hydroxypentyl cellulose, hydroxypentyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and any one or two selected from the group consisting of polyvinyl alcohol may be included. More preferably hydroxypropylmethyl cellulose.
  • the solid dispersion may further include a surfactant.
  • the surfactant serves to effectively solubilize the API and the water-soluble polymer during the preparation of the oral pharmaceutical composition according to the present invention, and helps the API to be uniformly dispersed in the water-soluble polymer.
  • the amount of the surfactant may be 10 to 100 parts by weight based on 100 parts by weight of the API, and when the content is less than 10 parts by weight, it is difficult to effectively solubilize the API, whereas when the content exceeds 100 parts by weight of the drug Care must be taken as it may adversely affect the situation.
  • the surfactant can be used without limitation so long as it does not affect the drug efficacy of the oral pharmaceutical composition, for example, polyoxyethylene (POE) -20-sorbitan monooleate, Tween 80, Crillet 4 (Crillet) 4), Polyoxyethylene (POE) -20-sorbitan monolaurate, Tween 60, Tween 40, Tween 20, Crillet 1, Poloxamer 188 (Poloxamer 188), Pluronic / Lutrol F 68, polyoxyethylene (POE) alkyl ethers, polyoxyethylene (POE) -10-oleyl ether and oleyl ether or breeze 96V (Brij 96 V) and the like can be used.
  • polyoxyethylene (POE) -20-sorbitan monooleate Tween 80, Crillet 4 (Crillet) 4
  • Polyoxyethylene (POE) -20-sorbitan monolaurate Tween 60, Tween 40, Tween 20, Crillet 1, Poloxamer
  • the solid dispersion according to the present invention may further include a stabilizer to ensure the stability of the drug, such as anti-oxidation.
  • the amount of the stabilizer may be 1 to 10 parts by weight based on 100 parts by weight of the API, when the content is less than 1 part by weight is insufficient to ensure the stability of the drug, while if it exceeds 10 parts by weight of the drug Care must be taken as it may adversely affect the situation.
  • the stabilizer can be used without limitation so long as it does not affect the efficacy of the oral pharmaceutical composition, such as butylhydroxyanisole, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol succinic acid or propyl.
  • Antioxidants such as gallate, cyclodextrins, carboxyethyl cyclodextrins, hydroxypropyl cyclodextrins, cyclic compounds of the saccharides such as sulfobutylether or cyclodextrins, phosphoric acid, lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, glycols Acids such as acids, propionic acid, gluconic acid or glucuronic acid may be used.
  • Oral pharmaceutical compositions according to the present invention may further comprise any one or two or more additives selected from the group consisting of excipients, disintegrants and lubricants.
  • excipient serves to improve the ease of tableting and to maintain the shape of the tablet.
  • excipients include starch (eg potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (eg low water microcrystalline cellulose), lactose (eg lactose monohydrate, Anhydrous lactose, spray lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate, anhydrous calcium phosphate or silicon dioxide may be used alone or in combination, but not limited thereto. It doesn't happen.
  • the disintegrant is added to facilitate the collapse or disintegration of the solid formulation after in vivo administration.
  • examples of the disintegrant include starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch; Clay such as bentonite, montmorillonite and veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins, such as sodium alginate or alginic acid, and crosslinked celluloses, such as croscarmellose sodium; Gums such as guar gum and xanthan gum, and crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid and the like may be used alone or in combination, but is not limited thereto.
  • starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch
  • Clay such as bentonit
  • the glidant improves the fluidity of the granules to increase the filling ability to the die, which is the lower part of the tableting machine, and between the granules and the punch-die which is the upper part of the granules and the tableting machine. Reducing friction to facilitate compression and release of the tablet.
  • lubricants include silicon dioxide, talc, stearic acid, metal salts of stearic acid (such as magnesium salts or calcium salts), lauryl sulfate sodium, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl bihenate, glyceryl monostea Elate or polyethylene glycol may be used alone or in combination, but is not limited thereto.
  • the oral pharmaceutical composition may include 15 to 50% by weight of the solid dispersion and 50 to 85% by weight of the additive.
  • the content of the pharmaceutical composition composition is within the above range, the bioavailability of the API is high, it is possible to obtain an oral drug that can provide an excellent therapeutic effect.
  • the present invention provides a method for preparing the oral pharmaceutical composition, the method comprising the steps of dissolving an active pharmaceutical ingredient (active pharmaceutical ingredient, API) in an organic solvent; Preparing a mixed solution by adding a water-soluble polymer to the solution in which the API is dissolved; And spray drying the mixed solution to prepare a solid dispersion in which an amorphous API is dispersed in the water-soluble polymer.
  • APIs that can be used in the manufacturing method are as described above, and particularly preferably the API may include any one selected from the group consisting of ezetimibe, simvastatin and mixtures thereof.
  • the poorly soluble API is a material having a crystalline structure usually, the crystal structure may be converted into an amorphous during the spray drying process according to the production method of the present invention.
  • the API, converted to amorphous form has a higher solubility and faster dissolution rate than the crystalline form.
  • the advantages of amorphous APIs over these crystalline forms are particularly evident for low solubility substances such as ezetimibe and simvastatin, which crystallization contributes significantly to the dissolution properties and bioavailability of the drug.
  • the organic solvent is used to dissolve an API having low solubility in water, and any one or two or more selected from the group consisting of ethanol, methanol, acetone and dichloromethane may be used.
  • the organic solvent may be used in an appropriate range capable of sufficiently dissolving poorly soluble API, preferably the concentration of the mixed solution may be in the range of 2 to 10% (w / w), more preferably 2.5 to 3 It may be% (w / w). In this case, the unit% (w / w) of the concentration represents the number of g of the solute contained in 100 g of the mixed solution.
  • the content of the water-soluble polymer that the API is added to the solution dissolved in the organic solvent may be 50 to 300 parts by weight based on 100 parts by weight of the API as described above, an example of the water-soluble polymer is hydroxypropylmethyl cellulose (hydroxypropylmethyl cellulose, hydroxypropylbutyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxy Hydroxypentyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol. Any one or a mixture of two or more may be mentioned.
  • a surfactant may be further added in the preparation of the mixed solution.
  • the amount of the surfactant added is preferably 10 to 100 parts by weight based on 100 parts by weight of the API, and when the amount of the surfactant is included in the range, it is preferable in terms of effective solubilization and therapeutic effect of the API.
  • the surfactant may be added together with the water-soluble polymer in the step of preparing the mixed solution, or after the water-soluble polymer is dissolved in a solution in which the API is dissolved, it may be added thereto to prepare a mixed solution.
  • the type of surfactant used at this time is as described above.
  • a stabilizer may be further added and mixed, and the stabilizer may be added together with the water-soluble polymer in the step of preparing the mixed solution like the surfactant, or the API After the water-soluble polymer is dissolved in the dissolved solution, it may be added thereto.
  • the amount of the stabilizer added may be 1 to 10 parts by weight based on 100 parts by weight of the API, and when the amount of the stabilizer is included in the range, it is preferable in terms of stability or therapeutic effect of the API in the solid dispersion.
  • the type of stabilizer used at this time is as described above.
  • the spray drying is preferably carried out under the conditions of the air inlet temperature (inlet temperature) 85 ⁇ 100 °C, chamber temperature 70 ⁇ 75 °C, the API of the crystalline form having low solubility in water through this spray drying method It is converted into an amorphous structure and uniformly dispersed in the water-soluble polymer.
  • the spray drying may be carried out using a conventional spray dryer known in the art, preferably may be performed using any one or a combination of a disk type spray dryer and a nozzle type spray dryer. For example, when a disk type spray dryer is used, the spray drying may be carried out under the conditions of the disk rotational speed 7,000 ⁇ 10,000rpm / min, flow rate 16 ⁇ 20kg / h.
  • the amorphous API prepared through this process has excellent solubility in water, and therefore, the solid dispersion formed by dispersing the API in a water-soluble polymer also has high solubility. Therefore, the oral pharmaceutical composition containing the solid dispersion has high bioavailability because it exhibits high dissolution properties.
  • the present invention also provides an oral medicament comprising the oral pharmaceutical composition.
  • the oral medicine may be prepared in one form selected from tablets, capsules and solutions.
  • the method for preparing the oral medicament a conventional method known in the art can be used without limitation, and in the case of a tablet type, it can be compressed using a direct tableting method or a wet tableting method.
  • the present invention provides a method for preparing an oral medicament comprising the step of tableting by a direct compression method.
  • the solid dispersion and the additive may be homogeneously mixed, and then compressed into a tablet molding compressor to prepare an oral medicine.
  • hydroxypropylmethyl cellulose manufactured by Samsung Fine Chemicals, Inc., HPMC 2910
  • a Poloxamer 188 BASF Corp.
  • the mixture was added to prepare a mixed solution having a concentration of 2.46% (w / w). At this time, the viscosity of the hydroxypropyl methyl cellulose is 6cps.
  • a stabilizer was added to the mixed solution to dissolve it.
  • a stabilizer 0.5 g of citric acid (Sigma-Aldrich Co., LLC), an antioxidant, 0.04 g of butylhydroxyanisole (Merck & Co., Inc.) and propyl gallate (Merck & Co., Inc.) 0.01 g was used by mixing.
  • the mixed solution in which the surfactant and the stabilizer were dissolved was added to a disk type spray dryer and spray dried to prepare a solid dispersion in which amorphous simvastatin and ezetimibe were dispersed in hydroxypropylmethyl cellulose.
  • the spray drying was carried out under the conditions of the air inlet temperature (Inlet temperature) 95 °C, chamber temperature 70 ⁇ 75 °C, disk rotational speed 7,500 rpm / min, flow rate 17kg / h.
  • Figure 2 there is shown a photograph showing a state in which the mixed solution is sprayed through the disk type spray dryer and a schematic diagram of the spray dryer.
  • a solid dispersion was prepared in the same manner as in Example 1, except that 30 g of hydroxypropylmethyl cellulose was added to prepare a mixed solution, and the concentration of the mixed solution was adjusted to 2.75% (w / w). It was.
  • a solid dispersion was prepared in the same manner as in Example 1, except that 60 g of hydroxypropylmethyl cellulose was added to prepare a mixed solution, and the concentration of the mixed solution was adjusted to 3.0% (w / w). .
  • the solubility of the solid dispersion prepared according to Examples 1 to 3 and the mixed powder of the comparative example was measured. Specifically, the simvastatin and ezetimibe mixture was weighed to 1 g in the solid dispersion and the mixed powder, and added to 250 ml of hydrochloric acid buffer solution (pH 1.2) and 250 ml of water (pH 7), respectively, and stirred at 25 ° C. for 2 hours. After that, ultrasonic grinding was performed for 2 hours. Subsequently, the ultrasonic grinding step was performed by filtering the solution with a 0.45 ⁇ m PVDF syringe filter, and then analyzing the filtrate using HPLC (high performance liquid chromatography). 4 is shown.
  • HPLC high performance liquid chromatography
  • the solubility of ezetimibe and simvastatin contained in the solid dispersion prepared according to Examples 1 to 3 is at least three times higher than that of ezetimibe and simvastatin in the pure raw state (comparative example). As much as 10 times more can be confirmed that the increase.
  • the solid-dispersed API provides much better solubility than the pure raw API (comparative example) through the spray drying method, and according to the present invention, it is possible to increase the solubility of poorly soluble API.
  • API can be used to provide an oral pharmaceutical composition with excellent bioavailability.
  • the crystal peaks of simvastatin and ezetimibe which are raw materials, are very high and clear, and thus the crystallinity is very high.
  • the solid dispersion prepared according to Examples 1 to 2 of the present invention can be confirmed that the crystal peaks of simvastatin and ezetimibe appear very low or hardly appear.
  • AnyCoat AN6 is a trade name of hydroxypropylmethyl cellulose (manufactured by Samsung Fine Chemicals Co., Ltd.), and has a amorphous structure that does not show crystal peaks as a result of XRD analysis.
  • FIG. 6 it can be seen that the XRD pattern of the AnyCoat AN6 and the XRD patterns of the solid dispersions of Examples 1 and 2 are similar. From these results, it can be seen that in the case of simvastatin and ezetimibe dispersed in the water-soluble polymer through the spray drying method, the raw material having a crystalline structure was converted into a material having an amorphous form.

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Abstract

La présente invention concerne une composition pharmaceutique à administrer par voie orale comprenant une dispersion solide contenant : un polymère hydrosoluble; et un principe actif pharmaceutique amorphe (API) dispersé dans le polymère hydrosoluble, et son procédé de préparation. La composition pharmaceutique destinée à être administrée par voie orale selon la présente invention comprend une dispersion solide contenant un principe actif pharmaceutique amorphe, et présente ainsi une solubilité élevée, conduisant à une excellente biodisponibilité, et la composition pharmaceutique destinée à être administrée par voie orale est préparée au moyen d'un séchage par pulvérisation, et peut ainsi fournir un procédé de préparation d'une composition pharmaceutique destinée à être administrée par voie orale, ledit procédé n'affectant pas la stabilité des médicaments tout en améliorant l'efficacité de production.
PCT/KR2016/012619 2015-12-22 2016-11-04 Composition pharmaceutique à administrer par voie orale et son procédé de préparation WO2017111292A1 (fr)

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CN111601590A (zh) * 2017-11-23 2020-08-28 浙江海正药业股份有限公司 一种海泽麦布片剂及其制备方法

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