Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B11/00—Preparation of cellulose ethers
  • C08B11/193—Mixed ethers, i.e. ethers with two or more different etherifying groups
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B11/00—Preparation of cellulose ethers
  • C08B11/20—Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B13/00—Preparation of cellulose ether-esters
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J3/00—Processes of treating or compounding macromolecular substances
  • C08J3/20—Compounding polymers with additives, e.g. colouring
  • C08J3/201—Pre-melted polymers
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
  • C08L1/08—Cellulose derivatives
  • C08L1/32—Cellulose ether-esters
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
  • C08J2301/08—Cellulose derivatives
  • C08J2301/32—Cellulose ether-esters

Definitions

• the present invention relates to a composition for hot melt extrusion and a method for producing a hot melt extruded product using the composition.
• a preparation technique in which a mixture of a drug and a polymer is melt-extruded under heating has attracted attention.
• a solid dispersion obtained by solidifying a poorly water-soluble drug and a polymer by a hot melt extrusion method is molecularly dispersed in a polymer carrier with the drug in an amorphous state. Solubility is apparently significantly increased and bioavailability is improved.
• the hot melt extrusion method can avoid the use of a solvent, it can be applied to drugs that are unstable to water, safety and environmental considerations due to the absence of solvent recovery, and energy required for the solvent recovery process. Savings and improved safety for workers.
• continuous production is possible, and attention is paid to the productivity per hour and the energy consumption.
• an ether structure is formed by introducing two substituents of a methoxy group (—OCH 3 ) and a hydroxypropoxy group (—OC 3 H 6 OH) into a cellulose skeleton.
• hypromellose acetate succinate is a polymer that introduces a total of four types of substituents by introducing two substituents, an acetyl group (—COCH 3 ) and a succinyl group (—COC 2 H 4 COOH), into an ester structure.
• an acid ester hereinafter also referred to as “HPMCAS”.
• HPMCAS acid ester
• each substituent content of HPMCAS listed in the 16th revision Japanese Pharmacopoeia is defined as follows (Non-Patent Document 1).
• Solid dispersion containing HPMCAS for example, by adding water of a solid dispersion composition by a hot melt extrusion method containing HPMCAS (commercial product AS-LF; molar substitution degree 0.16 to 0.35), A method of lowering the glass transition temperature and softening temperature of HPMCAS or a poorly water-soluble drug has been proposed (Patent Document 1).
• posaconazole and HPMCAS are formulated by a hot melt extrusion method (Patent Document 2), A method of formulating a soluble drug lipid inhibitor CETP (cholesterol ester transfer protein) inhibitor and HPMCAS (commercially available AS-MF; degree of molar substitution 0.15-0.34) by a hot melt extrusion method has been proposed. (Patent Document 3).
• the molar substitution degree of the poorly water-soluble drug and the hydroxypropoxy group is 0.25
• the molar substitution degree of the succinyl group is 0.02 or more
• the molar substitution degree of the acetyl group is 0.65 or more
• the acetyl group and the succinyl group A method of spray-drying a solid dispersion composition using HPMCAS having a glass transition temperature of 131 to 146 ° C. with 0% RH having a total molar substitution degree of 0.85 or more has been proposed (Patent Document 4).
• the molar substitution degree of the poorly water-soluble drug and the hydroxypropoxy group is 0.21 or less
• the molar substitution degree of the methoxyl group is 1.45 or less
• the total molar substitution degree of the acetyl group and the succinyl group is 1.25 or more.
• the present invention has been made in view of the above circumstances, and by heating and extruding at a lower temperature than before, there is no inactivation of the drug due to heat, etc., preventing a decrease in solubility in the upper small intestine, and a spray drying method Provided is a method for producing a heat-melt extruded product from which a heat-melt extruded product can be obtained by a simpler method.
• the present inventors set the ratio (molar ratio) of acetyl groups to hydroxypropoxy groups and succinyl groups among the four types of substituents of HPMCAS within a specific range.
• Tg glass transition temperature
• the present invention includes at least a hypromellose acetate succinate (HPMCAS) having a hydroxypropoxy group molar substitution degree of 0.40 or more and a ratio of acetyl groups to succinyl groups (molar ratio) of less than 1.6 and a drug.
• HPMCAS hypromellose acetate succinate
• a composition for hot melt extrusion is provided.
• the present invention also relates to a heat-melting composition comprising at least a hypromellose acetate succinate having a hydroxypropoxy group molar substitution degree of 0.40 or more and an acetyl group-to-succinyl group ratio (molar ratio) of less than 1.6 and a drug.
• the composition for extrusion is heated and melted at a temperature higher than the melting temperature of hypromellose acetate succinate or higher than the temperature at which the hypromellose acetate succinate and drug are melted together, and extruded.
• a manufacturing method is provided.
• the hypromellose acetate succinate can be used for the production of a composition for hot melt extrusion or a hot melt extruded product.
• the drug is efficiently dissolved by staying in the small intestine for a long time in a dissolved state, or the elution in the upper part of the small intestine in order to increase the bioabsorbability of the drug having high absorbability in the upper part of the small intestine.
• a hot melt extruded product with improved initial elution performance due to rapid drug release in the small intestine can be obtained.
• heat melt extrusion can be performed at a lower temperature than before, and the heat melt extrudate can be obtained by a simpler method than the spray drying method without inactivation of the drug due to heat or the like.
• the molar substitution degree of the hydroxypropoxy group of HPMCAS is 0.40 or more, preferably 0.40 to 1.50, more preferably 0.40 to 1.0, still more preferably 0.40 to 0.90.
• the heat melt extrusion temperature becomes high, hydrolysis occurs due to thermal decomposition of the hypromellose acetate succinate, and some ester groups are released from the cellulose skeleton, Acetic acid and succinic acid are produced to inactivate the drug by interaction with the drug.
• the substituent content of HPMCAS including a hydroxypropoxy group can be measured by the method described in each article “Hypromellose acetate succinate” in the 16th revised Japanese Pharmacopoeia First Supplement.
• the glass transition temperature (Tg) of HPMCAS is preferably 115 ° C. or lower, more preferably 60 to 115 ° C., still more preferably 70 to 100 ° C. When the glass transition temperature is higher than 115 ° C., the heat melt extrusion temperature is also increased, and the above-described thermal decomposition may occur.
• the glass transition temperature (Tg) is usually measured by a differential scanning calorimeter (DSC) as follows. Specifically, 10 mg of HPMCAS was raised from room temperature to 150 ° C. at a rate of temperature increase of 10 ° C./min from a room temperature, further cooled to 25 ° C. at a rate of temperature decrease of 10 ° C./min, and then again 230 ° C. at a rate of 10 ° C./min. The inflection point observed when the temperature is raised to is the glass transition temperature. The reason why the glass transition temperature is measured in such a completely dry state is that the moisture in the sample affects the measured value of Tg.
• the molar substitution degree of the methoxy group which is a substituent other than the hydroxypropoxy group in HPMCAS is not particularly limited, but is preferably 0.70 to 2.90, more preferably 1.00 to 2.40, and still more preferably 1 .4 to 1.9.
• the degree of molar substitution of the acetyl group in HPMCAS is not particularly limited, but is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, still more preferably 0.16 to 0.96.
• the degree of molar substitution of the succinyl group in HPMCAS is not particularly limited, but is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, still more preferably 0.10 to 0.60.
• the ratio of acetyl groups to succinyl groups is less than 1.6, preferably 0.6 to 1.5, more preferably 0.8 to 1.5, particularly preferably 0.8 to 1.3.
• the viscosity of a dilute (0.1 mol / L) aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20 ° C. is preferably 1.1 to 20 mPa ⁇ s, more preferably 1.5 to 3.6 mPa ⁇ s. .
• the melt viscosity is too low at the time of heat-melt extrusion, and shear force is not applied, and it may be difficult to idle the piston or screw or to extrude from the discharge port.
• the viscosity of the composition for hot melt extrusion becomes too high, the torque applied to the piston or screw becomes excessive, the piston or screw does not rotate, or the machine may stop safely. is there.
• the measuring method of a viscosity can be measured by the method as described in the 16th revision Japanese Pharmacopoeia HPMCAS general test method.
• HPMCAS can be produced, for example, using the method described in JP-A No. 54-61282.
• Hypromellose also known as hydroxypropylmethylcellulose, hereinafter referred to as “HPMC”
• HPMC hydroxypropylmethylcellulose
• HPMC hydroxypropylmethylcellulose
• the drug is not particularly limited as long as it is a drug that can be administered orally.
• Such drugs include, for example, central nervous system drugs, circulatory drugs, respiratory drugs, digestive drugs, antibiotics, antitussives, antihistamines, antipyretic analgesics, diuretics, autonomic nervous agents, Antimalarial agents, antistatic agents, psychotropic agents, vitamins and their derivatives, and the like.
• central nervous system drugs examples include diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, etenzamide, ketoprofen and chlordiazepoxide.
• circulatory drugs examples include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedibin, atenolol, spironolactone, metoprolol, vindolol, captopril, izorbitol nitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, Examples include ethylephrine hydrochloride, digitoxin, propranolol hydrochloride, and alprenolol hydrochloride.
• Examples of respiratory drugs include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol and guaifenesin.
• Examples of digestive drugs include 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl] benzimidazole and 5-methoxy-2-[(4 -Methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl] benzimidazole drugs having anti-ulcer activity such as cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl and 5-aminosalicylic acid .
• antibiotics examples include tarampicillin hydrochloride, bacampicillin hydrochloride, cefaclor and erythromycin.
• antitussive and expectorant examples include noscapine hydrochloride, carbetapentane citrate, dextromethorphan hydrobromide, isoaminyl citrate, and dimemorphan phosphate.
• antihistamine examples include chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride and the like.
• antipyretic analgesic / anti-inflammatory agent examples include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin and ketoprofen.
• diuretic examples include caffeine.
• Examples of the autonomic nervous agent include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, propranolol hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine and the like.
• Examples of antimalarial agents include quinine hydrochloride.
• Examples of the diastatic agent include loperamide hydrochloride and the like.
• Examples of the psychotropic agent include chlorpromazine.
• vitamins and derivatives thereof include vitamin A, vitamin B1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate and tranexamic acid. It is done.
• the solubility of a poorly water-soluble drug can be improved by using the HPMCAS of the present invention as a carrier for a solid dispersion of a poorly water-soluble drug.
• the poorly water-soluble drug refers to a drug described in the 16th revised Japanese Pharmacopoeia as “not easily soluble”, “extremely insoluble”, or “almost insoluble”. “Slightly soluble” refers to the degree to which 100 g or more and less than 1000 mL dissolve within 30 minutes when 1 g or 1 mL of solid drug is placed in a beaker and water is added and shaken vigorously for 30 seconds at 20 ⁇ 5 ° C. every 5 minutes. .
• Extremely difficult to dissolve refers to the degree of dissolution within 30 minutes at 1000 mL or more and less than 10000 mL.
• the term “almost insoluble” refers to a material that requires 10,000 mL or more to dissolve within 30 minutes.
• dissolution of a poorly water-soluble drug means that the drug is dissolved or mixed in a solvent, and it means that even if fibers or the like are not recognized or not, they are very slight.
• poorly water-soluble drugs include azole compounds such as itraconazole, ketoconazole, fluconazole, mitoconazole, nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, felodipine, efonidipine and other dihydropyridine compounds, ibuprofen, ketoprofen, naproxen and the like.
• indoleacetic acid-based compounds such as propionic acid compounds, indomethacin, and acemetacin, griseofulvin, phenytoin, carbamazepine, dipyridamole, and the like can be given.
• the mass ratio of HPMCAS and drug is not particularly limited, but preferably from 1: 0.01 to 1: 100, more preferably from 1: 0.1 to 1:10, from the viewpoint of storage stability in an amorphous state. Preferably it is 1: 0.2 to 1: 5.
• composition of the present invention may be added with additives such as plasticizers and surfactants in order to improve moldability during hot melt extrusion.
• plasticizers include higher alcohols such as acetone, methanol, ethanol, isopropanol, cetyl alcohol, and stearyl alcohol, polyhydric alcohols such as mannitol, sorbitol, and glycerin, bees wax, triethyl citrate, polyethylene glycol, and propylene glycol.
• Plasticizers such as alkylene glycol, triacetin, dibutyl sebacate, glycerol monostearate, monoglycerol acetate and the like can be mentioned.
• the surfactant examples include anionic surfactants such as sodium lauryl sulfate, diglycerides, poloxamers, polyoxyethylene sorbitan fatty acid esters (twin 20, 60, 80), glycerin fatty acid esters, propylene glycol fatty acid esters, and the like.
• anionic surfactants such as sodium lauryl sulfate, diglycerides, poloxamers, polyoxyethylene sorbitan fatty acid esters (twin 20, 60, 80), glycerin fatty acid esters, propylene glycol fatty acid esters, and the like.
• examples thereof include ionic surfactants, natural surfactants such as lecithin and sodium taurocholate.
• the blending amount is preferably 30% by mass or less for the plasticizer and 10% by mass or less for the surfactant with respect to HPMCAS.
• the hot melt extruded product is blended with various additives that can be commonly used in this field, such as excipients, binders, disintegrants, lubricants, anti-aggregation agents, etc.
• additives such as excipients, binders, disintegrants, lubricants, anti-aggregation agents, etc.
• Oral solid preparations such as fine granules and capsules, and oral film preparations can be used.
• excipient examples include sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose and the like.
• binder examples include polyvinyl alcohol, polyacrylic acid, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, macrogols, gum arabic, gelatin, starch and the like.
• disintegrant include low-substituted hydroxypropylcellulose, carmellose or a salt thereof, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, crystalline cellulose, crystalline cellulose / carmellose sodium, and the like.
• lubricant and the aggregation inhibitor examples include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oil, polyethylene glycols, sodium benzoate and the like.
• the resulting oral solid preparation is coated with a water-soluble coating agent such as methylcellulose or hypromellose, or with an enteric coating agent such as hypromellose acetate succinate, hypromellose phthalate, or methacrylic acid acrylate copolymer. May be.
• a water-soluble coating agent such as methylcellulose or hypromellose
• an enteric coating agent such as hypromellose acetate succinate, hypromellose phthalate, or methacrylic acid acrylate copolymer. May be.
• an HPMCAS having a hydroxypropoxy group molar substitution degree of 0.40 or more and a drug are mixed with other components as necessary to prepare a composition for hot melt extrusion.
• the prepared composition for hot melt extrusion can be extruded by a hot melt extruder into a desired shape such as a columnar shape or a film shape in addition to a shape such as a circle or a quadrangle to obtain a molded body.
• the heating melt extruder is not particularly limited as long as it is an extruder having a structure of extruding from a die after melting and kneading by applying a shearing force with a piston or screw while heating in a system such as HPMCAS and a drug.
• a biaxial extruder is preferred. Specifically, Toyo Seiki Capillograph (uniaxial piston type extruder), Leistritz (Nano-16) (Twin screw type extruder), Thermo Fisher Scientific (Thermo Fisher Scientific) MiniLab (a twin screw extruder) and PharmaLab (a twin screw extruder) may be mentioned.
• the heating and melting temperature is not particularly limited, but it is preferably performed in a temperature range in which the composition for heating and melting extrusion can be melted and extrusion can be performed without difficulty, and decomposition of the drug or polymer by heat can be avoided as much as possible. That is, when a solid dispersion is not manufactured, a temperature equal to or higher than the melting temperature of HPMCAS is preferable, and when a solid dispersion is manufactured, a temperature equal to or higher than a temperature at which both HPMCAS and the drug are melted is preferable. In addition, even when the melting point of HPMCAS is lowered by the addition of a drug, a temperature equal to or higher than the temperature at which both are melted is preferable.
• the specific heating and melting temperature is preferably 50 to 250 ° C, more preferably 60 to 200 ° C, and still more preferably 90 to 190 ° C. If it is lower than 50 ° C, melting may be incomplete and extrusion may be difficult. If it exceeds 250 ° C, molecular weight may be reduced due to HPMCAS or drug decomposition, and substitution may be caused by hydrolysis.
• the hot melt extrusion conditions are not particularly limited as long as the composition for hot melt extrusion having a viscosity at the time of hot melt extrusion of preferably 1 to 100,000 Pa ⁇ s can be extruded, but in the case of a single-screw piston extruder, the extrusion speed is The speed is preferably 1 to 1000 mm / min, more preferably 10 to 500 mm / min, and in the case of a twin screw type extruder, the screw speed is preferably 1 to 1000 rpm, more preferably 1 to 500 rpm.
• the residence time in the system may become long and may be thermally decomposed, while the extrusion speed exceeds 10,000 mm / min or the clew speed is 1000 rpm. In the case where it exceeds 1, the heat-melting process in the kneading part becomes insufficient, and the molten state of the drug and the polymer in the heat-melt extruded product may become uneven.
• the hot melt extruded product is cooled by natural cooling or cold air blowing at room temperature (1-30 ° C) from the die discharge port, but in order to minimize the thermal decomposition of the drug and in the case of an amorphous drug In order to suppress recrystallization, it is preferable to rapidly cool to 50 ° C. or lower, more preferably to room temperature or lower (30 ° C. or lower).
• the heated melt-extruded product after cooling may be pelletized to 0.1 to 5 mm or less by a cutting machine, or may be further pulverized to adjust the particle size until it becomes granular and powdery.
• an impact pulverizer such as a jet mill, a knife mill, or a pin mill is preferred because of the structure of the equipment.
• HPMCAS is softened by heat and particles are fixed, it is preferable to grind under cold air.
• the ratio (molar ratio) of the acetyl group to the succinyl group is preferably 1.6 to 4.0, more preferably 1.8 to 3.8 from the viewpoint of maintaining the supersaturated state of the drug for a longer time.
• Tg glass transition temperature of HPMCAS-1 to 7
• DSC3200SA differential scanning calorimeter manufactured by Bruker. That is, 10 mg of each HPMCAS was raised from room temperature to 150 ° C. at a rate of temperature increase of 10 ° C./min from a room temperature, further cooled to 25 ° C. at a rate of temperature decrease of 10 ° C./min, and again 230 ° C. at a rate of 10 ° C./min.
• the temperature at the inflection point in the absorption / exotherm curve seen when the temperature was raised to 0 ° C., that is, the temperature at the inflection point measured at the second temperature rise was taken as the glass transition temperature.
• Examples 1 to 5 and Comparative Examples 1 and 2> A dry HPMCAS-1-7 was dried in advance using a vacuum extruder (uniaxial piston type melting) under conditions of a die diameter of 1 mm, a height of 10 mm, and an extrusion speed of 50 mm / min so that the moisture in the measurement sample was less than 1% by mass.
• the minimum extrusion temperature of HPMCAS-1 to 7 when extruded from the die of the discharge port was measured using an extrusion apparatus (Capillograph manufactured by Toyo Seiki Co., Ltd.). The results are shown in Table 3.
• Examples 1 to 5 and Comparative Example 1 using HPMCAS having a hydroxypropoxy group molar substitution degree of 0.40 or more had a lower glass transition temperature and lower minimum extrusion temperature than Comparative Example 2 of less than 0.4. It was. From the above results, since the composition for hot melt extrusion can be extruded at a lower temperature, an extrudate can be obtained without the drug being deactivated by thermal decomposition.
• a composition for hot melt extrusion was prepared using ascorbic acid, a water-soluble drug.
• Ascorbic acid has a thermal decomposition temperature of 176 ° C., and is a model drug that is feared to be deactivated by thermal decomposition during hot melt extrusion.
• a hot melt extruder (Thermo Fisher) of a biaxial screw (diameter: 5/14 mm, length: 109.5 mm, screw rotation speed 100 rpm, residence time 5 minutes) in the same direction. Heat-extrusion at 130 ° C. or higher was performed by HAAKE MiniLab), and the minimum extrusion temperature of the obtained heat-melt extruded product was measured in the same manner as in Example 1. Further, the obtained hot-melt extruded product was obtained by pulverizing at 20000 rpm using a pulverizer (Osaka Chemical Co., Ltd. Wonder Blender WB-1 type) and sieving with a 30-mesh (aperture 500 ⁇ m) sieve. The yellowness index (YI) of the powder and the hot melt extruded composition before molding was measured with an SM color computer (SM-T manufactured by Ska Test Instruments Co., Ltd.). The results are shown in Table 4.
• SM color computer SM-T manufactured by Ska Test Instruments Co.,
• the minimum extrusion temperature of Examples 6 to 10 and Comparative Example 3 using HPMCAS having a hydroxypropoxy group molar substitution degree of 0.40 or more is 26 ° C. or more lower than the thermal decomposition temperature (176 ° C.) of ascorbic acid.
• Ascorbic acid was not thermally decomposed by hot melt extrusion and was not deactivated.
• the HPMCAS of Comparative Example 4 has a minimum extrusion temperature of 160 ° C.
• a solution prepared by dissolving 16 g of HPMCAS in 64 g of methylene chloride / ethanol solution (methylene chloride: ethanol 1: 1 mass ratio) was cast on a glass plate and dried at room temperature. The obtained film was dried at 80 ° C. for 2 hours, and then a 100 ⁇ m-thick portion was cut into 1 cm length and 1 cm width to prepare a test piece.
• the test piece measured the dissolution time of the test piece according to the disintegration test method (auxiliary cylinder) described in the 16th revision Japanese Pharmacopoeia.
• test pieces are a United States Pharmacopeia (US Pharmacopia 36) corresponding to the pH of the digestive juice in the upper to middle intestines was added to 1 L of the phosphate buffer solution (pH 6.0) described in 1), and the time until the test piece was dissolved and no undissolved material was observed was measured.
• US Pharmacopia 36 United States Pharmacopeia
• Comparative Example 5 in which the ratio (molar ratio) of the acetyl group to the succinyl group is 1.77 and the molar substitution degree of the hydroxypropoxy group is 0.84 requires a long time for dissolution, and remains undissolved after 120 minutes. The test piece was present. This is because the dissolution pH of HPMCAS was increased due to the high ratio of acetyl group to succinyl group (molar ratio) and the increase in the molar substitution degree of hydroxypropoxy group.
• the time required for dissolution in the phosphate buffer and dissolution of the test piece was less than 53 minutes. From the above results, rapid elution at the upper part of the small intestine is possible by setting the ratio (molar ratio) of acetyl groups to succinyl groups within a specific range. In addition, in the case of HPMAS having a hydroxypropoxy group molar substitution degree of 0.4 or more, rapid elution at the upper part of the small intestine is possible despite an increase in HPMA dissolution pH.
• a heated melt extruder manufactured by Thermo Fisher Co., Ltd.
• a co-directional twin screw (diameter: 5/14 mm, length: 109.5 mm, screw rotation speed 100 rpm, residence time 5 minutes) HAAKE MiniLab) was heated and melt-extruded at 150 ° C.
• the resulting hot-melt extruded product was pulverized at 20000 rpm using a pulverizer (Osaka Chemical Co., Ltd. Wonder Blender WB-1 type), and 30 mesh (mesh)
• the dissolution test described in the 16th revision Japanese Pharmacopoeia was performed on the powder obtained by sieving with a sieve having an opening of 500 ⁇ m.
• the elution rate (mass%) of ketoconazole eluted from 180 mg of this powder was determined by using 900 mL of phosphate buffer (pH 6.0) described in the US Pharmacopoeia (US Pharmacopia 36) and Japanese Pharmacopoeia. Using a dissolution tester (NTR-6100A type manufactured by Toyama Sangyo Co., Ltd.), the measurement was performed at a paddle rotation speed of 100 rpm. Ketoconazole was quantified by measuring the absorbance of UV (wavelength: 225 nm, optical path length: 10 mm) from an absorbance-converted straight line prepared at a known concentration in advance. The results are shown in Table 6.

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