Classifications

• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • A61K9/10—Dispersions; Emulsions
• • 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
  • A61K9/145—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 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
  • A61K9/141—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to solid preparations containing 6,7-unsaturated-7-carbamoylmorphinan derivatives, especially 17- (cyclopropylmethyl) -6,7-didehydro-4,5 ⁇ -epoxy-3,6,14-trihydroxy-.
• N- [2- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-2-yl] morphinan-7-carboxamide 4-methylbenzenesulfonic acid is related to a solid preparation with improved stability.
• Opioid receptor agonists such as morphine are used as very effective analgesics for cancer pain patients, but they induce strong nausea, vomiting, vomiting, constipation, urinary retention, and itching as side effects. Although various antiemetics and anti-constipation drugs are clinically used, none of them show sufficient effects, and excellent side effect reducing agents are required for improving the QOL of patients.
• Patent Document 1 discloses a 6,7-unsaturated-7-carbamoylmorphinan derivative (hereinafter, may be referred to as "the present derivative"). Of this derivative, 17- (cyclopropyl) is particularly effective as the above-mentioned side effect reducing agent.
• Morphinan-7-carboxamide 4-methylbenzenesulfonic acid (Compound A, hereinafter may be referred to as "this compound") is effective.
• Patent Document 2 discloses a solid preparation containing the present compound.
• a sweet syrup may be taken.
• a syrup is defined as "an orally administered, viscous liquid or solid preparation containing a sugar or a sweetener.”
• the syrup agent includes a dry syrup agent as a "formulation used by dissolving or suspending it at the time of use". Since the dry syrup is solid and can be dissolved in water, suspended and taken, it has higher storage stability and portability than the liquid, but after storage over time, the active ingredient in the dry syrup remains. It may be decomposed, and the active ingredient may be decomposed, especially when the dry syrup is dissolved or suspended in water.
• Cited Documents 3 to 6 disclose a preparation in which the stability of the compound is improved by adding an additive.
• the chemical structures of the compound in the document and the 6,7-unsaturated-7-carbamoylmorphinan derivative are significantly different, and even if an additive is added, the stability, especially the stability in water, is improved. Is not disclosed.
• the present inventors have found the optimum additive as a result of diligent studies in order to improve the stability of the present derivative and the preparation containing the present compound, and have completed the present invention. That is, if one or more selected from the group consisting of ascorbic acids, sulfur-containing amino acids, sulfites, citric acids and apple acids is used as the stabilizer, the stability, particularly the stability in water, is increased. Can be done.
• the present invention has (1) formula (IA): as an active ingredient.
• Solid preparation (2) A group in which the stabilizer consists of ascorbic acid, sodium L-ascorbic acid, erythorbic acid, L-cysteine hydrochloride hydrate, L-methionine, sodium pyrosulfite, sodium sulfite, citric acid anhydride and DL-apple acid.
• the solid preparation according to (1) above which is one or more selected from (3) The solid preparation according to (1) above, wherein the stabilizer is one or more selected from the group consisting of ascorbic acid, sodium L-ascorbic acid, erythorbic acid, L-cysteine hydrochloride hydrate and L-methionine. , (4) The solid preparation according to (1) above, wherein the stabilizer is ascorbic acid and / or L-methionine. (5) The solid preparation according to any one of (1) to (4) above, wherein the amount of the stabilizer is 1 to 2500 parts by weight with respect to 1 part by weight of the compound represented by the formula (IA).
• the 6,7-unsaturated-7-carbamoylmorphinan derivative-containing preparation of the present invention contains one or more selected from the group consisting of ascorbic acids, sulfur-containing amino acids, sulfites, citric acids and malic acids. By containing it, the amount of related substances, particularly the amount of related substances after suspending the present product in water can be reduced.
• the side effect reducing agent of the opioid receptor agonist which is the active ingredient used in the present invention is usually a 6,7-unsaturated-7-carbamoylmorphinan derivative, preferably a compound represented by the above formula (IA) (Compound A). ), Or its pharmaceutically acceptable salt. More preferably, it is a pharmaceutically acceptable salt of the compound represented by the above formula (IA).
• Pharmaceutically acceptable salts of the compound represented by the formula (IA) include, for example, the compound represented by the formula (IA), alkali metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, eg, lithium, sodium, potassium, etc.).
• organic bases eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Salts with picolin, quinoline, etc.
• amino acids or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitrate, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (eg, formic acid, acetic acid, etc.) Propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluen
• salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. It is preferably a salt with an acid.
• These salts can be formed by conventional methods. Particularly preferred is the p-toluenesulfonate, acetate or hydrochloride of the compound represented by the formula (IA), and more preferably the p-toluenesulfonate of the compound represented by the formula (IA). It is a crystal or a crystal of a solvent product of the salt.
• the p-toluenesulfonic acid crystal of the compound (Compound A) represented by the formula (IA) has no hygroscopicity and is excellent in stability, and exists in the crystalline state in the solid preparation.
• the compound, the method for producing the compound crystal, and the like are described in the claims and specification of the international pamphlet of WO2006 / 126637 and the international pamphlet of WO2012 / 0633933.
• the formula (IA) As an active ingredient in the formulation of the present invention, the formula (IA): The compound represented by, or a pharmaceutically acceptable salt thereof is used. Preferably, the p-toluenesulfonate, acetate or hydrochloride of the compound represented by the formula (IA) as the active ingredient, more preferably the p-toluenesulfonate of the compound represented by the formula (IA) as the active ingredient. Is.
• the p-toluenesulfonate of the compound represented by the above formula (IA), which is the present compound, is 17- (cyclopropylmethyl) -6,7-didehydro-4,5 ⁇ -epoxy-3,6,14-trihydroxy-N. -[2- (3-phenyl-1,2,4-oxadiazol-5-yl) propan-2-yl] morphinan-7-carboxamide 4-methylbenzenesulfonic acid can be mentioned.
• the content of the compound represented by the formula (IA), the p-toluenesulfonate, acetate or hydrochloride of the compound represented by the formula (IA), which is the derivative of the present invention, is not particularly limited.
• the amount may be such that it produces a medicinal effect.
• 0.001 to 10% by weight, preferably 0.001 to 5% by weight, more preferably 0.001 to 2.5% by weight, and particularly preferably 0.001 to 2% by weight, based on the total amount of the preparation. is there. If it is larger than these amounts, the dose may increase, and if it is smaller than these amounts, the amount of decomposition of the active ingredient may increase.
• a stabilizer is added in the formulation of the present invention. It may be contained.
• the derivative and the compound can be stabilized, preferably the Japanese Pharmacopoeia, the Japanese Pharmacopoeia non-Japanese Pharmacopoeia, the drug additive standard, the Food Additives Official, the United States Pharmacopeia (USP) and the European Pharmacopoeia. Anything listed in (Ph. Eur.) Will suffice, and it is even better if it can be used as an antioxidant.
• ascorbic acids such as ascorbic acid, sodium L-ascorbic acid, erythorbic acid which is a steric isomer of ascorbic acid, L-ascorbic acid stearate ester, L-ascorbic acid palmitate, L-cysteine, L-cysteine hydrochloride Salts, L-cysteine hydrochloride hydrate, sulfur-containing amino acids such as L-methionine and DL-methionine, sulfites such as sodium pyrosulfate and sodium sulfite, citric acid anhydride, citric acid hydrate, calcium citrate, Sodium citrate hydrate, citric acids such as sodium dihydrogen citrate and disodium citrate, citric acids such as DL-apple acid and DL-sodium malate, sodium etedate, sodium etedate hydrate, etedic acid
• ethedic acids such as disodium calcium, tetrasodium etedate
• ascorbic acid sodium L-ascorbic acid, ascorbic acids such as erythorbic acid which is a stereoisomer of ascorbic acid, L-cysteine hydrochloride hydrate, amino acids containing sulfur such as L-methionine, sodium pyrosulfite,
• examples thereof include sulfites such as sodium sulfite, citric acids such as anhydrous citric acid, and ascorbic acids such as DL-aric acid.
• they are ascorbic acids such as ascorbic acid, sodium L-ascorbic acid, and erythorbic acid which is a stereoisomer of ascorbic acid, and amino acids containing sulfur such as L-cysteine hydrochloride hydrate and L-methionine. More preferably, ascorbic acid and L-methionine are preferable, and ascorbic acid is particularly preferable.
• these stabilizers may be used alone or in combination of two or more. In addition to being used as a stabilizer, the additives described above may be used for other purposes.
• the content of the stabilizer of the preparation of the present invention is not particularly limited, but it may be any amount as long as the amount of related substances of the present compound is small and the present compound can be stabilized.
• 1 to 2500 weights of stabilizer is added to 1 part by weight of the present compound, particularly the compound represented by the formula (IA), the p-toluenesulfonate, the acetate or the hydrochloride of the compound represented by the formula (IA).
• Parts preferably 2 to 1250 parts by weight, more preferably 3 to 1000 parts by weight. It is usually 0.005 to 30% by weight, preferably 0.01 to 25% by weight, more preferably 0.1 to 20% by weight, based on the total amount of the preparation. If it is higher than these contents, the dose may be increased, and if it is lower than these contents, the active ingredient in the preparation may not be stabilized.
• the related substances of this compound in the pharmaceutical product of the present invention are greatly affected by the stabilizer.
• the main related substances of this compound include hydroxides of the compounds represented by the formula (IA) and carboxylic acids of the compounds represented by the formula (IA).
• the amount of related substances of the present compound in the preparation of the present invention is 4.0% of the total of all related substances of the compound represented by the formula (IA) (hereinafter, may be referred to as “total related substances”) in the initials. It is as follows. Here, the initial is before the start of the stability test over time. If the amount of the related substance is larger than the amount of the related substance, toxicity may occur.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0% or less. If the amount of the related substance is larger than the amount of the related substance, toxicity may occur.
• the amount of the hydroxide of the compound represented by the formula (IA) or the carboxylic acid body of the compound represented by the formula (IA) is 1. It is 0% or less. This amount meets the safety confirmation threshold of the ICH (International Council for Harmonization of Pharmaceutical Regulations) Q3B guidelines. If the amount of the related substance is larger than the amount of the related substance, toxicity may occur.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0% or less, and the formula (IA).
• the amount of the hydroxide of the compound represented by) or the carboxylic acid compound of the compound represented by the formula (IA) is 1.0% or less.
• the formulations of the present invention may contain excipients and may contain the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Japanese Pharmacopoeia, the Pharmaceutical Additives Standard, the Food Additives Official, the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Excipients listed in Eur.) Can be used.
• excipients sugar derivatives, starch derivatives, cellulose derivatives, inorganic excipients, ⁇ -cyclodextrin, magnesium stearate, crospovidone, calcium stearate, sucrose fatty acid ester, tragant powder, gum arabic, dextran, Pullulan and the like can be mentioned.
• sugar derivatives include sugars and sugar alcohols
• examples of sugars include lactose, sucrose, glucose, fructose, sucrose, and maltose
• sugar alcohols include D-mannitol and D-sorbitol.
• examples of other sugar derivatives include fructooligosaccharide, palatinose, maltose, reduced maltose, powdered syrup, starch syrup, lactitol, reduced lactitol, and honey sugar.
• Starch derivatives include starch, potato starch, corn starch (corn starch), rice starch, partially pregelatinized starch, pregelatinized starch, perforated starch, wheat starch, carboxystarch sodium, hydroxypropyl starch, low substitution carboxymethyl starch, Examples thereof include carboxymethyl starch.
• the cellulose derivative include crystalline cellulose, powdered cellulose, sodium carmellose, carmellose, sodium croscarmellose, carmellose calcium, carboxymethyl ethyl cellulose, low-degree-of-substitution hydroxypropyl cellulose and the like.
• Inorganic excipients include silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dry aluminum hydroxide, magnesium oxide, bentonite. And so on.
• Examples of the silicate derivative include hydrous silicon dioxide, silicon dioxide such as light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate and the like.
• Phosphates include anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and phosphate.
• the excipient of the present invention preferably includes D-mannitol. These excipients may be used alone or in combination of two or more. In addition to being used as an excipient, the additives described above may be used for other purposes.
• the particle size of the excipient of the pharmaceutical product of the present invention may be any particle size that can produce the pharmaceutical product.
• the particle size of the excipient has a volume average particle size of 1 to 1000 ⁇ m, preferably 10 to 750 ⁇ m, more preferably 50 to 500 ⁇ m, and particularly preferably 75 to 250 ⁇ m. If the particle size is larger than this, it may be difficult to produce a formulation as a granule or powder, and if the particle size is small, the powder may scatter during production and affect the content of the active ingredient. There is.
• the content of the excipient of the present invention is not particularly limited, but is usually 50 to 99.9% by weight, preferably 60 to 99.5% by weight, more preferably 70 to 99.0% by weight based on the total amount of the preparation. %. If it is less than these contents, it may be difficult for the present product to form a product. When two or more kinds of excipients are used, the total amount of the excipients may be within the above-mentioned content range.
• the formulation of the present invention may contain a disintegrant and may contain the Japanese Pharmacopoeia, the Japanese Pharmacopoeia non-Japanese Pharmacopoeia, the Pharmaceutical Additives Standard, the Food Additives Official, the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur).
• the disintegrants listed in.) Can be used.
• examples of the disintegrant include a cellulosic disintegrant, a starch-based disintegrant, a vinyl-based disintegrant, and magnesium aluminate metasilicate.
• cellulosic disintegrants include croscarmellose sodium (Ac-Di-Sol), carmellose sodium, carmellose calcium, carmellose, crystalline cellulose, crystalline cellulose / carmellose sodium, low-substituted hydroxypropyl cellulose, and hydroxyethyl methyl cellulose. , Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, powdered cellulose and the like.
• starch-based disintegrants examples include sodium carboxymethyl starch, hydroxypropyl starch, corn starch, wheat starch, potato starch, pregelatinized starch, partially pregelatinized starch, corn starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, and the like.
• starch examples include starch.
• vinyl-based disintegrant examples include polyvinylpyrrolidone, crospovidone, polyvinyl alcohol and the like.
• Cellulose-based disintegrants and vinyl-based disintegrants are preferable, and in the case of cellulosic disintegrants, sodium salts such as croscarmellose sodium, carmellose sodium, crystalline cellulose / carmellose sodium, and carboxymethyl starch sodium are more preferable. is there. More preferably, croscarmellose sodium and crospovidone are preferable, and croscarmellose sodium is particularly preferable.
• These disintegrants may be used alone or in combination of two or more.
• the additive described above may be used for other purposes besides being used as a disintegrant.
• the content of the disintegrant in the formulation of the present invention is not particularly limited, but is usually 0.01 to 10.0% by weight, preferably 0.05 to 7.5% by weight, more preferably, based on the total amount of the formulation. Is 0.1 to 5.0% by weight.
• the disintegrant is 1 to 100 parts by weight, preferably 5 to 80 parts by weight, and more preferably 10 to 60 parts by weight with respect to 1 part by weight of the compound used in the pharmaceutical product of the present invention. If it is higher than these contents, the dose may be increased, and if it is lower than these contents, the disintegration and dissolution property of the preparation may not be sufficiently obtained. When two or more kinds of disintegrants are used, the total amount of the disintegrant may be within the above content range.
• the formulation of the present invention may contain a suspending agent that suspends the drug in water, and may contain the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Japanese Pharmacopoeia, the Pharmaceutical Additives Standard, the Food Additives Official, the United States Pharmacopeia (USP). ) And the agents listed in the United States Pharmacopeia (Ph. Eur.) Can be used.
• the suspending agent may also be referred to as a suspending agent.
• suspending agents gum arabic, sodium alginate, kaolin, carrageenan, carboxyvinyl polymer, carmellose, carmellose calcium, carmellose sodium, xanthan gum, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose carme Sodium loin, sucrose fatty acid ester, sorbitan fatty acid ester, hypromellose, hydroxypropyl cellulose, propylene glycol, propylene glycol fatty acid ester, polyvinylpyrrolidone (povidone), polyoxyethylene hydrogenated castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 4000, macrogol 6000, methyl cellulose, ethylene glycol monolaurate, sorbitan monolaurate, polyoxyethylene sorbit monolaurate and the like.
• Hypromellose, hydroxypropyl cellulose and methyl cellulose are preferable, hypromellose and hydroxypropyl cellulose are more preferable, and hypromellose is particularly preferable.
• These suspending agents may be used alone or in combination of two or more.
• the additive described above may be used for other purposes besides being used as a suspending agent.
• the content of the suspending agent in the formulation of the present invention is not particularly limited, but is usually 0.01 to 10.0% by weight, preferably 0.05 to 5.0% by weight, based on the total amount of the preparation. It is preferably 0.1 to 2.5% by weight.
• the disintegrant is 1 to 100 parts by weight, preferably 2.5 to 50 parts by weight, and more preferably 5 to 25 parts by weight with respect to 1 part by weight of the compound used in the pharmaceutical product of the present invention. If it is higher than these contents, the dose may be increased, and if it is lower than these contents, the drug may not be sufficiently suspended in water. When two or more kinds of suspending agents are used, the total amount of the suspending agents may be within the above content range.
• the formulation of the present invention may contain a binder and may contain a Japanese Pharmacopoeia, a non-Japanese Pharmacopoeia drug standard, a drug additive standard, a food additive official standard, the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur).
• the binders listed in.) Can be used.
• a binder a cellulosic binder, a starch binder, a vinyl binder, a polyol, arabic rubber, arabic rubber powder, arabic rubber powder, alginic acid, sodium alginate, sucrose, gelatin, dextrin, purulan, tragant, etc.
• Examples thereof include tragant powder, xanthan gum, starch, sodium polyacrylate, agar, powdered aubergine, guar gum, light anhydrous silicic acid, and hardened oil.
• examples of the cellulose-based binder include carboxymethyl cellulose (carmellose, CMC), sodium carboxymethyl cellulose (sodium carmellose), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hypromellose (hydroxypropyl methyl cellulose) (HPMC), and methyl cellulose (MC).
• starch-based binders include starch, pregelatinized starch, partially pregelatinized starch, potato starch, wheat starch, rice starch, perforated starch, corn starch, hydroxypropyl starch, sodium starch glycolate (sodium carboxymethyl starch) and the like. Can be mentioned.
• vinyl binder examples include polyvinyl alcohol (PVA), polyvinylpyrrolidone (povidone) (PVP), carboxyvinyl polymer, copolyvidone and the like (subordinate concept).
• PVA polyvinyl alcohol
• PVP polyvinylpyrrolidone
• carboxyvinyl polymer copolyvidone and the like (subordinate concept).
• macrogol polyethylene glycol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000, glycerin
• examples thereof include polyoxyethylene [105] polyoxypropylene [5] glycol and propylene glycol.
• a cellulosic binder more preferably sodium carboxymethyl cellulose (sodium carmellose), hydroxypropyl cellulose (HPC), hypromellose (hydroxypropyl methyl cellulose), and particularly preferably hypromellose.
• binders may be used alone or in combination of two or more.
• the additives described above may be used for other purposes.
• the content of the binder in the formulation of the present invention is not particularly limited, but is 0.01 to 10.0% by weight, preferably 0.05 to 5.0% by weight, more preferably 0, based on the total amount of the preparation. .1 to 2.5% by weight.
• the binder is 1 to 30 parts by weight, preferably 2.5 to 25 parts by weight, and more preferably 5 to 20 parts by weight with respect to 1 part by weight of the compound used in the pharmaceutical product of the present invention. If the amount is out of this range, it may be difficult to manufacture the product. When two or more kinds of binders are used, the total amount of the binders may be within the above content range.
• the formulation of the present invention may contain a lubricant and may contain the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Japanese Pharmacopoeia, the Pharmaceutical Additives Standard, the Food Additives Official, the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph.
• the lubricants listed in Eur.) Can be used.
• the lubricant include stearic acid and metal stearic acid salts, inorganic lubricants, hydrophobic lubricants, hydrophilic lubricants, stearyl sodium fumarate and the like.
• Examples of stearic acid and metal stearic acid salt include magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, and polyoxyl 40 stearate.
• examples of inorganic lubricants include talc, light anhydrous silicic acid, hydrous silicon dioxide, magnesium carbonate, precipitated calcium carbonate, dry aluminum hydroxide gel, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, Examples include magnesium sulfate.
• hydrophobic lubricant examples include cacao butter, carnauba wax, glycerin fatty acid ester, hydrogenated oil, hydrogenated oil, beeswax, hardened soybean oil, beeswax, cetanol, sodium laurate, sodium fumarate and the like.
• hydrophilic lubricant examples include sucrose fatty acid ester and polyethylene glycol (macrogol).
• it is a metal stearate salt, an inorganic lubricant, and more preferably magnesium stearate, calcium stearate, talc, light silicic acid anhydride, hydrous silicon dioxide, magnesium carbonate, precipitated calcium carbonate, and dry aluminum hydroxide gel.
• These lubricants may be used alone or in combination of two or more. In addition to being used as a lubricant, the additives described above may be used for other purposes.
• the content of the lubricant in the formulation of the present invention is not particularly limited, but is 0.01 to 5.0% by weight, preferably 0.02 to 2.5% by weight, more preferably 0.02 to 2.5% by weight, based on the total amount of the formulation. It is 0.05 to 2.0% by weight. Further, the amount of the lubricant is 0.1 to 50 parts by weight, preferably 0.5 to 40 parts by weight, and more preferably 1 to 30 parts by weight with respect to 1 part by weight of the compound used in the formulation of the present invention. is there. If the amount is out of this range, the product may not flow sufficiently. When two or more kinds of lubricants are used, the total amount of the lubricants may be within the above content range.
• the formulation of the present invention may contain an anti-solidification agent in order to prevent solidification of the formulation and facilitate packaging, transportation and consumption.
• Additives listed in the Food Additives Protocol, United States Pharmacopeia (USP) and European Pharmacopoeia (Ph. Eur.) Can be used as anti-solidification agents.
• an anticaking agent powdered cellulose, sodium stearate, talc, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium silicate, magnesium trisilicate, tricalcium phosphate, tricalcium phosphate, magnesium oxide and the like can be used.
• These anticaking agents may be used alone or in combination of two or more. In addition to being used as an anticaking agent, the additives described above may be used for other purposes.
• the content of the anticaking agent in the formulation of the present invention is not particularly limited, but is 0.1 to 5.0% by weight, preferably 0.2 to 2.5% by weight, more preferably 0.2 to 2.5% by weight, based on the total amount of the formulation. It is 0.25 to 2.0% by weight.
• the anticaking agent is 0.1 to 50 parts by weight, preferably 0.5 to 40 parts by weight, more preferably 1 to 30 parts by weight, based on 1 part by weight of the compound used in the formulation of the present invention. is there. If the amount is out of this range, the product may not flow sufficiently. When two or more kinds of anticaking agents are used, the total amount of the anticaking agents may be within the above content range.
• This product may contain a pigment or a colorant, and the dye or colorant listed in the Japanese Pharmacopoeia, the non-Japanese Pharmacopoeia drug standard, the drug additive standard, and the food additive official standard may be used. it can.
• iron oxide, tar pigments, natural pigments and the like can be mentioned.
• iron oxide include iron sesquioxide, iron yellow oxide, iron yellow sesquioxide, and iron black iron oxide.
• tar pigments edible yellow No. 4 aluminum lake, edible blue No. 1 aluminum lake, edible red No. 3 aluminum lake, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible red No. 102 , Edible Red No. 2, Edible Red No. 3, etc.
• natural pigments include turmeric extract, ⁇ -carotene, carotene solution, sodium copper chlorophyllin, copper chlorophyll, green leaf extract powder of hadakamugi, dried powder of green leaf green juice of bare wheat, and green leaf extract of bare wheat.
• the present formulation may further contain additives other than those mentioned above, and the additives listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Non-Pharmaceutical Standards, the Pharmaceutical Additives Standards and the Food Additives Official Standards. Can be used. Moreover, the content of these additives may be any ratio. Examples of additives other than the above include fragrances, fluidizing agents, and flavoring agents. As fragrances, for example, orange essence, orange oil, caramel, camphor, kehi oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, tow oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence. , Mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil and the like.
• the fluidizing agent examples include hydrous silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, talc and the like.
• a flavoring agent for example, aspartame, scullose, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salt, citric acid anhydride, L-glutamic acid and its salt, succinic acid and its salt, acetic acid, tartrate and its salt.
• examples thereof include salts, sodium hydrogen carbonate, fumaric acid and its salts, citric acid and its salts, glacial acetic acid, disodium inosinate, honey and the like.
• any amount can be usually used alone or in combination as long as the stability of the active ingredient is not reduced.
• solid formulations containing stabilizers For example, a group consisting of a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, a stabilizer, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and ascorbic acids For example, from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, ascorbic acids, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid preparations containing the salts to be prepared and amino acids containing sulfur comprises a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, amino acids containing sulfur, and an excipient, a disintegrant, a suspending agent, a binder lubricant and an anticaking agent.
• solid formulations containing one or more selected from the group are solid formulations containing one or more selected from the group.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and sulfites Selected from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, sulfites, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and citric acid For example, from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, citric acids, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and the excipients For example, from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, apple acids, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and ascorbic acid For example, from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, ascorbic acid, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and sodium L-ascorbate For example, from the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, sodium L-ascorbate, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• a solid preparation containing 1 or more selected from the group There is a solid preparation containing 1 or more selected from the group.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and erythorbic acid For example, from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, erythorbic acid, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and L-cysteine hydrochloride hydrate there is a solid preparation containing the salt to be added and L-cysteine hydrochloride hydrate.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and L-methionine for example, a group consisting of a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, L-methionine, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected from are solid formulations containing one or more selected from.
• a solid preparation containing the salt to be added and sodium pyrosulfite For example, a group consisting of a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, sodium pyrosulfite, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected from are solid formulations containing one or more selected from.
• the solid preparation containing the active ingredient the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof
• the additive the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt to be added and sodium sulfite For example, from the group consisting of the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, sodium sulfite, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• a solid preparation containing the salt or the compound or a solvate of the salt, and citric acid anhydride for example, a group consisting of a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, citric acid anhydride, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and an additive is pharmaceutically acceptable.
• the compound represented by the formula (IA) is pharmaceutically acceptable.
• solid preparations containing a salt or the compound or a solvent mixture of the salt, and DL-malic acid for example, it comprises a compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof, DL-malic acid, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected from the group are solid formulations containing one or more selected from the group.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added stabilizers, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts, ascorbic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added sodium L-ascorbate, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added erythorbic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salt to be added L-cysteine hydrochloride hydrate, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added L-methionine, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added sodium pyrosulfite, D-mannitol, croscarmellose sodium, hypromerose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added sodium sulfite, D-mannitol, croscarmellose sodium, hypromerose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added citric acid anhydride, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc.
• solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• solid formulations containing the salts to be added DL-malic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0. % Or less solid product.
• the solid preparation containing the salt and amino acids containing sulfur When there is a solid preparation containing the salt and amino acids containing sulfur, and the solid preparation is suspended in water at room temperature for 3 hours, the total amount of related substances of the compound represented by the formula (IA) is increased. It is a solid preparation of 4.0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0. % Or less solid product.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0. % Or less solid product.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• a solid preparation containing the salt and the apple acid to be prepared and the solid preparation is used. When suspended in water for 3 hours at room temperature, it is a solid preparation in which the total amount of related substances of the compound represented by the formula (IA) is 4.0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0. % Or less solid product.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0.0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0%.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the solid preparation containing the salt and L-cysteine hydrochloride hydrate, and the solid preparation is suspended in water for 3 hours at room temperature, it is a general relative of the compound represented by the formula (IA). It is a solid preparation having an amount of 4.0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0. % Or less solid product.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0% or less.
• the solid preparation containing the active ingredient, the compound represented by the formula (IA), or a pharmaceutically acceptable salt thereof, and the additive, the compound represented by the formula (IA), or the pharmaceutically acceptable salt thereof.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0.0% or less.
• a solid preparation containing and sulfite When there is a solid preparation containing and sulfite, and the solid preparation is suspended in water for 3 hours at room temperature, among the related substances of the compound represented by the formula (IA), the compound represented by the formula (IA) It is a solid preparation having an amount of hydroxide and / or carboxylic acid compound of 1.0% or less.
• a solid preparation containing and malic acids When there is a solid preparation containing and malic acids, and the solid preparation is suspended in water for 3 hours at room temperature, among the related substances of the compound represented by the formula (IA), the compound represented by the formula (IA). It is a solid preparation having an amount of hydroxide and / or carboxylic acid compound of 1.0% or less.
• a solid preparation containing DL-apple acid When there is a solid preparation containing DL-apple acid and the solid preparation is suspended in water at room temperature for 3 hours, it is represented by the formula (IA) among the related substances of the compound represented by the formula (IA). It is a solid preparation in which the amount of hydroxide and / or carboxylic acid compound of the compound is 1.0% or less.
• solid formulations containing stabilizers For example, select from the group consisting of p-toluenesulfonate, stabilizer, and excipient, disintegrant, suspending agent, binder, lubricant and anticaking agent of the compound represented by the formula (IA).
• the p-toluene of the compound represented by the formula (IA) which is the active ingredient As another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive, the p-toluene of the compound represented by the formula (IA) which is the active ingredient.
• the p-toluene of the compound represented by the formula (IA) which is the active ingredient there are solid formulations containing sulfonates and ascorbic acids.
• the compound represented by the formula (IA) is selected from the group consisting of p-toluenesulfonates, ascorbic acids, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive the p-toluene of the compound represented by the formula (IA) which is the active ingredient.
• solid formulations containing sulfonates and amino acids containing sulfur For example, a group consisting of the compound represented by the formula (IA), p-toluenesulfonate, amino acids containing sulfur, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• solid formulations containing one or more selected from are solid formulations containing one or more selected from.
• the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive the p-toluene of the compound represented by the formula (IA) which is the active ingredient.
• solid formulations containing sulfonates and sulfites Selected from the group consisting of p-toluenesulfonates, sulfites, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents of the compounds represented by the formula (IA).
• solid preparation containing the above.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid preparations containing citric acids are solid preparations containing citric acids.
• the compound represented by the formula (IA) is selected from the group consisting of p-toluenesulfonates, citric acids, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid preparations containing sulphonic acids are selected from the group consisting of p-toluenesulfonates, malic acids, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing ascorbic acid are solid formulations containing ascorbic acid.
• the compound represented by the formula (IA) is selected from the group consisting of p-toluenesulfonate, ascorbic acid, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing sodium L-ascorbate For example, a group consisting of the compound represented by the formula (IA), p-toluenesulfonate, sodium L-ascorbate, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected from are solid formulations containing one or more selected from.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing erysorbic acid are solid formulations containing erysorbic acid.
• the compound represented by the formula (IA) is selected from the group consisting of p-toluenesulfonate, erythorbic acid, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing L-Cysteine Hydrochloride Hydrate For example, select from the group consisting of the compound represented by the formula (IA), p-toluenesulfonate, L-methionine, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more of the following are solid formulations containing one or more of the following.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing L-methionine For example, select from the group consisting of the compound represented by the formula (IA), p-toluenesulfonate, L-methionine, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more of the following are solid formulations containing one or more of the following.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing sodium pyrosulfite For example, select from the group consisting of the compound represented by the formula (IA), p-toluenesulfonate, sodium pyrosulfite, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more of the following are solid formulations containing one or more of the following.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing sodium sulfite are solid formulations containing sodium sulfite.
• the compound represented by the formula (IA) is selected from the group consisting of p-toluenesulfonate, sodium sulfite, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing anhydrous citric acid are selected from the group consisting of p-toluenesulfonate, citric acid anhydride, and excipients, disintegrants, suspending agents, binders, lubricants and anticaking agents.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing DL-malic acid For example, from the group consisting of the compound represented by the formula (IA), p-toluenesulfonate, DL-malic acid, and an excipient, a disintegrant, a suspending agent, a binder, a lubricant and an anticaking agent.
• solid formulations containing one or more selected are solid formulations containing one or more selected.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing stabilizers, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc are solid formulations containing stabilizers, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing ascorbic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc are solid formulations containing ascorbic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing sodium L-ascorbate, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc are solid formulations containing sodium L-ascorbate, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing erythorbic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc are solid formulations containing erythorbic acid, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing L-cysteine hydrochloride hydrate, D-mannitol, croscarmellose sodium, hypromerose, magnesium stearate and talc are solid formulations containing L-cysteine hydrochloride hydrate, D-mannitol, croscarmellose sodium, hypromerose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing L-methionine, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc are solid formulations containing L-methionine, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing sodium pyrosulfite, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc are solid formulations containing sodium pyrosulfite, D-mannitol, croscarmellose sodium, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing sodium sulfite, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc are solid formulations containing sodium sulfite, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc.
• Another embodiment of the p-toluenesulfonate of the compound represented by the formula (IA) which is the active ingredient and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing citric acid anhydride, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc are solid formulations containing citric acid anhydride, D-mannitol, sodium croscarmellose, hypromellose, magnesium stearate and talc.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• solid formulations containing DL-apple acid, D-mannitol, croscarmellose sodium, hypromerose, magnesium stearate and talc are solid formulations containing DL-apple acid, D-mannitol, croscarmellose sodium, hypromerose, magnesium stearate and talc.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0% or less. It is a formulation.
• the solid preparation containing and malic acids there is a solid preparation containing and malic acids, and when the solid preparation is suspended in water for 3 hours at room temperature, the total amount of related substances of the compound represented by the formula (IA) is 4.0% or less. It is a formulation.
• the total amount of related substances of the compound represented by the formula (IA) is 4. It is a solid preparation of 0% or less.
• the total amount of related substances of the compound represented by the formula (IA) is 4.0% or less. It is a solid preparation.
• Another embodiment of the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the solid preparation containing the additive is the p-toluenesulfonate of the compound represented by the formula (IA).
• a solid preparation containing ascorbic acids and when the solid preparation is suspended in water for 3 hours at room temperature, among the related substances of the compound represented by the formula (IA), the compound represented by the formula (IA) It is a solid preparation having an amount of hydroxide and / or carboxylic acid compound of 1.0% or less.
• a solid preparation containing amino acids containing sulfur and when the solid preparation is suspended in water for 3 hours at room temperature, among the related substances of the compound represented by the formula (IA), the formula (IA) is used. It is a solid preparation in which the amount of hydroxide and / or carboxylic acid compound of the indicated compound is 1.0% or less.
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the additive p-toluenesulfonate of the compound represented by the formula (IA) and sulfites are used.
• the solid preparation is suspended in water for 3 hours at room temperature, the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA).
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the additive p-toluenesulfonate of the compound represented by the formula (IA) and citric acids are used.
• the solid preparation is suspended in water for 3 hours at room temperature, the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA).
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA), and an additive, p-toluenesulfonate of the compound represented by the formula (IA), and malic acids are used.
• the solid preparation is suspended in water for 3 hours at room temperature, the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA).
• / or a solid preparation having an amount of carboxylic acid compound of 1.0% or less.
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the additive p-toluenesulfonate of the compound represented by the formula (IA) and ascorbic acid are used.
• the solid preparation is suspended in water for 3 hours at room temperature, the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA).
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the additive p-toluenesulfonate of the compound represented by the formula (IA) and erythorbic acid are used.
• the solid preparation is suspended in water for 3 hours at room temperature, the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA).
• the p-toluenesulfonate of the compound represented by the formula (IA), which is the active ingredient, and the p-toluenesulfonate of the compound represented by the formula (IA), and L-methionine as a solid preparation containing the additive.
• the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA) is prepared. It is a solid preparation having an amount of body and / or carboxylic acid compound of 1.0% or less.
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA), and an additive, p-toluenesulfonate of the compound represented by the formula (IA), and sodium pyrosulfite.
• the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA) is prepared.
• a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the additive p-toluenesulfonate of the compound represented by the formula (IA) and sodium sulfite are used.
• the solid preparation is suspended in water for 3 hours at room temperature, the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA).
• the p-toluenesulfonate of the compound represented by the formula (IA) and the additive As a solid preparation containing the active ingredient p-toluenesulfonate of the compound represented by the formula (IA) and the additive, the p-toluenesulfonate of the compound represented by the formula (IA) and citric acid anhydride
• the hydroxide of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA) is prepared.
• the p-toluenesulfonate of the compound represented by the formula (IA), which is the active ingredient, and the p-toluenesulfonate of the compound represented by the formula (IA), and DL-apple as a solid preparation containing an additive.
• a solid preparation containing an acid When there is a solid preparation containing an acid and the solid preparation is suspended in water for 3 hours at room temperature, the water of the compound represented by the formula (IA) among the related substances of the compound represented by the formula (IA). It is a solid preparation having an amount of an oxidant and / or a carboxylic acid compound of 1.0% or less.
• the dosage form of the preparation of the present invention may be a solid preparation.
• granules, powders, tablets, fine granules, pills and the like may be used, but granules or powders are preferable.
• a granule is a granularly granulated preparation to be orally administered
• a powder is a powdery preparation to be orally administered.
• the method for producing granules or powders among the formulations of the present invention is not particularly limited, but they can be produced by the following methods.
• a method for producing a granule or a powder by mixing an additive such as the present compound, a granular or powdery excipient, a disintegrant, or the like, as another embodiment, the present compound, the excipient, the disintegrant, etc.
• a method of extruding and granulating after kneading the mixed powder mixed with the additives with water or the like, or as another embodiment, water or the like is added to the mixed powder mixed with the additives such as the present compound, excipients and disintegrants.
• a method of spraying and granulating a fluid layer as another embodiment, a method of spraying water or the like on a mixed powder in which additives such as the present compound, an excipient, and a disintegrant are mixed, and stirring and granulating, another embodiment.
• a method of spraying water or the like on a mixed powder obtained by mixing additives such as the present compound, an excipient, and a disintegrant, and rolling and granulating as another embodiment, the present compound, an excipient, a disintegrant, etc.
• the granules When the granules are obtained, they may be granulated with any of an organic solvent (ethanol, acetone, ethyl alcohol, propyl alcohol, etc.) and a mixed solvent of water and an organic solvent in addition to water. Further, after producing the granules, the granules can be coated by coating the granules with a coating agent.
• an organic solvent ethanol, acetone, ethyl alcohol, propyl alcohol, etc.
• the average particle size of the preparation of the present invention is not particularly limited, but the volume average particle size is 1 to 1000 ⁇ m, preferably 5 to 500 ⁇ m, more preferably 10 to 250 ⁇ m, and particularly preferably 100 ⁇ m.
• the dose of the compound represented by the formula (IA) in the preparation of the present invention is usually 0.01 to 1.0 mg, preferably 0.2 mg of the compound orally administered once a day for adults. ..
• the product of the present invention may be directly orally administered, or may be suspended in water.
• the pharmaceutical product of the present invention does not visually show agglomerates at the initial stage of production.
• the average value of the compound content represented by the formula (IA) in the pharmaceutical product of the present invention is 95 to 105%.
• the standard deviation of the individual contents is 4.0% or less.
• the dissolution property of the pharmaceutical product of the present invention conforms to the dissolution test method of the Japanese Pharmacopoeia, and as a result of the test with the second solution of the dissolution test, the dissolution rate 15 minutes after the start of the test is 80% or more.
• the suspension of the present invention in water is good.
• 5 mL of water is added to about 500 mg of the pharmaceutical product of the present invention, if the container is shaken, particularly if the container is shaken for about 15 seconds, a visually uniform suspending agent can be obtained.
• D-mannitol Pearlitol 100SD (ROQUETTE)
• croscarmellose sodium AcDiSol, FMC
• hypromellose TC-5, Shin-Etsu Chemical
• magnesium stearate MALLINCKRODT
• talc talc
• D-mannitol used for rinsing was included and premixed in a polyethylene bag.
• the drug substance premixed powder and D-mannitol, croscarmellose sodium and hypromellose were mixed by an 8LV type mixer.
• magnesium stearate and talc were added and mixed by an 8LV type mixer.
• This mixed powder is hereinafter referred to as "drug substance mixed powder”.
• the mixture was sieved through a 30-mesh sieve. Then, a part of the drug substance mixed powder and the stabilizer were mixed in a plastic bag.
• sample solution preparation method 0.5 g of a sample was collected and placed in a centrifuge tube. 10 mL of a solution prepared by dissolving 1.0 g of a stabilizer in 1000 mL of a water / methanol (3: 1) mixed solution was accurately weighed and placed in a centrifuge tube containing a sample. The centrifuge tube was shaken at room temperature for 5 minutes, and then ultrasonically irradiated for 2 minutes with occasional shaking.
• ⁇ Detector Ultraviolet absorptiometer (measurement wavelength: 240 nm)
• Column L-colum ODS (filler 3 ⁇ m, 4.6 ⁇ 100 mm, manufactured by Chemical Substance Evaluation Research Organization)
• -Column temperature constant temperature around 45 ° C.
• -Mobile phase 20 mmol / L phosphate buffer solution at pH 6.1 / acetonitrile for HPLC / methanol mixture for HPLC (13: 6: 1)
• -Transfer of mobile phase 1.0 mL / part
• the amount of related substances was calculated by setting the total peak area of the chromatogram of the HPLC chart as 100% and calculating the ratio (%) to the amount.
• the pharmaceutical product of the present invention was stored at 50 ° C. in a brown glass bottle closed for 2 weeks.
• a predetermined amount of the pharmaceutical product of the present invention (Examples 1, 7, 9 and Comparative Examples 1 to 9, 12) was sampled, and the amount of a related substance of the compound represented by the formula (IA) in the sample was measured.
• Table 7 shows the stabilizer, the blending amount of the stabilizer, the maximum value (%) of the amount of each related substance, the related substance showing the maximum value, and the total amount of related substances.
• the total amount of related substances was 4.0% or more in Comparative Examples 2, 6 and 8, and the maximum value of each related substance amount was 1% or more, but the other Examples 1 and 7 , 9, the total amount of related substances of Comparative Examples 1, 3 to 5, 7, 9 and 12 is 4% or less, and that of Examples 1, 7, 9 and Comparative Examples 1, 3, 5, 7, 9 and 12.
• the maximum value of the amount of individual related substances was 1% or less.
• the D-mannitol used for rinsing was premixed in a polyethylene bag.
• the drug substance premixed powder and D-mannitol, croscarmellose sodium (AcDiSol, manufactured by FMC Corporation), and hypromellose (TC-5, manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed by an 8LV type mixer.
• magnesium stearate (manufactured by MALLINCKRODT) and talc (manufactured by MERCK) were added and mixed by an 8LV type mixer.
• the amounts shown in Tables 2 to 7 were added as the stabilizers in the formulation.
• the pharmaceutical product of the present invention may be suspended in water. Therefore, a stabilizer capable of improving the stability by suspending the pharmaceutical product of the present invention in tap water was investigated.
• Test method 1.875 g of the preparation containing additives other than the tosylate of compound A and the stabilizer in Table 1 and a predetermined amount of the stabilizer were put into a 100 mL container. About 70 g of tap water was put into this container and stirred. After stirring, tap water was additionally added so that the total amount of tap water added was 75 g, and a suspension was obtained.
• sample solution preparation method 6 mL of the sample was collected with a whole pipette and put into a centrifuge tube. 4 mL of a solution prepared by dissolving 1.0 g of L-ascorbic acid in 400 mL of a water / methanol (150: 250) mixture was accurately weighed and placed in a centrifuge tube containing a sample. The centrifuge tube was shaken at room temperature for 5 minutes, and then ultrasonically irradiated for 2 minutes with occasional shaking.
• ⁇ Detector Ultraviolet absorptiometer (measurement wavelength: 240 nm)
• Column L-colum ODS (filler 3 ⁇ m, 3.0 ⁇ 100 mm, manufactured by Chemical Substance Evaluation Research Organization)
• -Column temperature constant temperature around 45 ° C.
• -Mobile phase 20 mmol / L phosphate buffer solution at pH 6.1 / acetonitrile for HPLC / methanol mixture for HPLC (13: 6: 1)
• -Motor phase feed 0.4 mL / classified margin substance amount was calculated as a ratio (%) to the total peak area of the chromatogram of the HPLC chart as 100%.
• Results A sample was taken from the central part of the container 3 hours after the addition of the pharmaceutical product of the present invention, and the amount of a related substance of the compound represented by the formula (IA) in the sample was measured. Tables 13 to 18 show the stabilizers, the maximum value (%) of the amount of each related substance, and the related substances showing the maximum value. As a result, in the formulations of Examples 1 to 9, the maximum amount of each related substance is less than 1.0%, and this amount is the threshold value for safety confirmation of the ICH (International Council for Harmonization of Pharmaceutical Regulations) Q3B guideline. It was the one that satisfied.
• ICH International Council for Harmonization of Pharmaceutical Regulations
• the maximum amount of each related substance was 1.0% or more, and both showed high values. Further, when the preparations of Comparative Examples 1, 3, 5, 7, 9 and 12 were stored at 50 ° C. for 2 weeks, the maximum value of the amount of each related substance was 1.0% or less as described above. When these preparations were suspended in water at room temperature for 3 hours, the maximum value of the amount of individual related substances was 1.0% or more.
• the related substance showing the maximum value may differ depending on whether the product is stored at 50 ° C. for 2 weeks or suspended in water for 3 hours. From the above, the stability when suspended in water for 3 hours at room temperature may differ from the stability when stored at 50 ° C. for 2 weeks, and the stability in water should be predicted from the stability test over time. Was considered difficult.
• the tosylate of the compound represented by formula (IA) was sieved through a 60 mesh sieve. Some D-mannitol and tosylate of the compound represented by the formula (IA) were premixed in a polyethylene bag and then sieved through a 30 mesh sieve. The wire mesh and receiving container were rinsed with some D-mannitol. D-mannitol used for rinsing was included and premixed in a polyethylene bag. This mixed powder is hereinafter referred to as "drug substance premixed powder". The drug substance premixed powder and some D-mannitol, antioxidant mixed powder, croscarmellose sodium, and hypromellose were mixed in a polyethylene bag. Then, magnesium stearate and talc were put into a bag and mixed.
• test method The pharmaceutical product of the present invention was stored in a brown glass bottle opened at 40 ° C. and 75% relative humidity for 1 week. A predetermined amount of the pharmaceutical product of the present invention was collected, and the amount of a related substance of the compound represented by the formula (IA) in the sample was measured.
• sample solution preparation method 0.5 g of a sample was collected and placed in a centrifuge tube. 10 mL of a solution prepared by dissolving 1.0 g of L-ascorbic acid in 1000 mL of a water / methanol (3: 1) mixed solution was accurately weighed and placed in a centrifuge tube containing a sample.
• the centrifuge tube was shaken at room temperature for 5 minutes, and then ultrasonically irradiated for 2 minutes with occasional shaking. Then, the supernatant after centrifugation (3000 rpm, 10 minutes) was filtered through a membrane filter (chromatographic disk 25N, non-aqueous system) having a pore size of 0.45 ⁇ m using a syringe, and 3 mL of the initial flow was discarded to prepare a sample solution. (Measuring method) The amount of the compound was measured by a liquid chromatograph according to the following methods and conditions.
• ⁇ Detector Ultraviolet absorptiometer (measurement wavelength: 240 nm)
• -Column L-methanol ODS (filler 5 ⁇ m, 4.6 x 250 mm, manufactured by Chemical Substances Evaluation and Research Institute)
• -Column temperature constant temperature around 45 ° C.
• -Mobile phase 20 mmol / L phosphate buffer solution with pH 6.1 / Acetonitrile for HPLC / Methanol mixture for HPLC (13: 6: 1)
• -Mobile phase feed 1.0 mL /
• the amount of classified related substances is the amount of individual related substances calculated from the following formula (%).
• Results Table 20 shows the total amount of related substances after initials and storage for 1 week when the pharmaceutical product of the present invention was opened in a brown glass bottle at 40 ° C. and 75% relative humidity.
• “initial” means before the start of the stability test over time.
• the total amount of related substances of the preparations of Examples 10 and 11 was 4.0% or less even after being left for one week at the initial stage.
• the remaining D-mannitol and hypromellose were put into a bag and mixed in a polyethylene bag.
• magnesium stearate and talc were put into the bag and mixed in a polyethylene bag.
• the mixed powder and a predetermined amount of ascorbic acid were mixed in a polyethylene bag, sieved through a 30-mesh sieve, and mixed again.
• test method 1.875 g of the pharmaceutical product of the present invention was put into a 100 mL container. About 70 g of tap water was put into this container and stirred. After stirring, tap water was additionally added so that the total amount of tap water added was 75 g, and a suspending agent was obtained. Three hours after the tap water was added, stirring was performed using a stirrer for 30 seconds, a sample was taken from the center of the container, and the amount of a related substance of the compound represented by the formula (IA) in the sample was measured. (Sample solution preparation method) The sample was collected with a 6 mL whole pipette and placed in a centrifuge tube.
• M S weighed amount of standard compound of formula (IA) (mg) AT : Peak area of individual related substances other than those derived from the white sample among the peaks that elute after the hydroxide obtained from the sample solution.
• F Sensitivity coefficient Hydroxide; 1.3, Others;
• 1.0 AS Peak area of compound represented by formula (IA) obtained from standard solution 1/200000: Dilution factor 0.02604: Labeled amount (mg) of the compound represented by the formula (IA) in one unit.
• M t Amount of product contained in the sample collected with a 6 mL volumetric pipette (g)
• Results A sample was taken from the central part of the container 3 hours after the addition of the pharmaceutical product of the present invention, and the amount of a related substance of the compound represented by the formula (IA) in the sample was measured.
• Table 23 shows the total amount of related substances of Reference Examples 1 to 3 and Examples 12 to 14. As a result, the total amount of related substances was detected in the formulations of Reference Examples 1 to 3, but no related substances were detected in any of the formulations of Examples 12 to 14 containing 10 mg or more of ascorbic acid in the formulations. .. Therefore, it was clarified that the total amount of related substances decreased as the amount of ascorbic acid in the pharmaceutical product increased.
• the pharmaceutical product of the present invention containing the compound represented by the formula (IA) or a pharmaceutically acceptable salt thereof can improve the stability in water and the stability over time by examining various stabilizers. did it. As a result, the product of the present invention can be suspended in water, and even a child can easily take the product of the present invention.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pain & Pain Management (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Dispersion Chemistry (AREA)
• Emergency Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=75980561

Family Applications (1)

Country Status (3)

Citations (9)

Family Cites Families (7)

• 2020
  • 2020-11-18 JP JP2021558405A patent/JP7582961B2/ja active Active
  • 2020-11-18 WO PCT/JP2020/042889 patent/WO2021100728A1/ja not_active Ceased
  • 2020-11-18 EP EP20890315.3A patent/EP4062973A4/en active Pending

Patent Citations (10)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events