WO2024019026A1 - Bioactive peptide-containing formulation - Google Patents
Bioactive peptide-containing formulation Download PDFInfo
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- WO2024019026A1 WO2024019026A1 PCT/JP2023/026181 JP2023026181W WO2024019026A1 WO 2024019026 A1 WO2024019026 A1 WO 2024019026A1 JP 2023026181 W JP2023026181 W JP 2023026181W WO 2024019026 A1 WO2024019026 A1 WO 2024019026A1
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- 239000000203 mixture Substances 0.000 title description 6
- 238000009472 formulation Methods 0.000 title description 3
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- 208000010112 Spinocerebellar Degenerations Diseases 0.000 description 4
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- 229920002261 Corn starch Polymers 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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Images
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
Definitions
- the present invention provides formula (I):
- the present invention relates to a pharmaceutical composition containing a compound represented by formula (I), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (I), etc.). More specifically, the present invention relates to a pharmaceutical composition containing a disintegrant and an excipient, such as a compound represented by formula (I).
- Cited Document 1 thyroid-stimulating hormone-releasing hormone (TRH) derivatives, and have central nervous system activating effects (acetylcholine-releasing effect, anti-reserpine effect, locomotor activity-increasing effect). What is shown is described.
- This document states that the compound represented by formula (I) has an excellent effect of increasing body temperature and promoting spontaneous movement by activating neurons in the dopamine system, norepinephrine system, and acetylcholine system in the brain. It is stated that it can be used to treat various symptoms associated with a decline in system function.
- this document states that the compound represented by formula (I) significantly activates acetylcholine neurons in the cerebral cortex, and therefore various symptoms based on the decline in these functions (e.g., movement disorder, consciousness disorder, senile dementia, It is stated that it can also be used as a treatment for coma, decreased attention span, speech disorders, etc.
- Cited Document 2 describes that the compound represented by formula (I), etc. is useful for the treatment of spinocerebellar degeneration
- Cited Document 3 describes that the compound represented by formula (I), etc. has been described to be useful in the treatment of Parkinson's disease
- Cited Document 4 describes an administration regimen for a therapeutic agent for ataxia in spinocerebellar degeneration.
- the method for producing the compound represented by formula (I) is described in Cited Documents 5 and 6.
- an enteric-coated preparation containing the compound represented by formula (I), etc. is described in Cited Document 7, and is characterized by being coated with an enteric-coated base.
- An orally administered preparation containing the compound represented by formula (I) is described in Cited Document 8, and is characterized by containing medium-chain fatty acid triglyceride.
- An object of the present invention is to provide a pharmaceutical composition containing a compound represented by formula (I).
- the present inventors conducted compatibility tests on various additives, confirmed the content, related substances, and changes in appearance, and found that clear color changes were observed in croscarmellose sodium, sodium carboxymethyl starch, and powdered sugar. In addition, they found that there was little change in color tone especially in partially pregelatinized starch and D-mannitol, and completed the pharmaceutical composition containing the compound represented by formula (I), which is the present invention.
- the present inventors have discovered a pharmaceutical composition containing the compound represented by formula (I) shown below.
- Formula (I) a compound represented by, a salt thereof, or a solvate thereof, and one or more disintegrants selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, and crospovidone.
- the pharmaceutical composition according to (1) above, wherein the disintegrant is partially pregelatinized starch.
- the pharmaceutical composition according to (1) or (2) above, containing a binder and/or a lubricant are examples of the disintegrant selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, and crospovidone.
- Formula (I) Compounds represented by, salts thereof, or solvates thereof, Partially pregelatinized starch as a disintegrant, D-mannitol as excipient, A pharmaceutical composition containing povidone as a binder and magnesium stearate as a lubricant.
- Formula (II) The pharmaceutical composition according to (9) above, which contains a hydrate of the compound represented by:
- the present invention provides a pharmaceutical composition containing a compound represented by formula (I), etc., which does not change in content, has a small amount of related substances, and shows little change in appearance when stored over time.
- the vertical axis is the dissolution rate (unit: %), and the horizontal axis is the time (unit: minutes).
- the present invention relates to a pharmaceutical composition containing a compound represented by formula (I).
- a pharmaceutical composition containing a disintegrant and an excipient such as a compound of formula (I).
- a pharmaceutical composition containing a disintegrant and an excipient such as a compound represented by formula (II).
- a pharmaceutical composition containing a hydrate of the compound represented by formula (II), a disintegrant, and an excipient is containing a hydrate of the compound represented by formula (II), a disintegrant, and an excipient.
- partially pregelatinized starch carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, etc.
- partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, crospovidone, croscarmellose sodium, and sodium carboxymethyl starch are preferred.
- Particularly preferred is partially pregelatinized starch.
- the disintegrant can be used in an amount of 5 to 75% by weight based on the weight of the entire tablet. Preferably it is 20 to 50% by weight. Particularly preferred is 27 to 33% by weight.
- lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, powdered sugar, etc. can be used.
- lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, and cornstarch are preferred.
- Particularly preferred is D-mannitol.
- the excipient can be used in an amount of 10 to 90% by weight based on the total weight of the tablet. Preferably it is 50 to 80% by weight. Particularly preferred is 60 to 73% by weight.
- One embodiment of the present invention is a pharmaceutical composition containing a disintegrant and an excipient, such as a compound of formula (I) containing a binder and/or a lubricant.
- Povidone, hypromellose, etc. can be used as the binder.
- these binders povidone and hypromellose are preferred. Particularly preferred is povidone.
- the binder can be used in an amount of 0.1 to 5.0% by weight based on the weight of the entire tablet. Preferably it is 0.5 to 2.0% by weight. Particularly preferred is 0.8 to 1.0% by weight.
- the lubricant magnesium stearate or the like can be used. Among these lubricants, magnesium stearate is preferred. Particularly preferred is magnesium stearate.
- the lubricant can be used in an amount of 0.1 to 5.0% by weight based on the weight of the entire tablet. Preferably it is 0.5 to 2.0% by weight. Particularly preferred is 0.9 to 1.1% by weight.
- additives used in the pharmaceutical field can be used in the pharmaceutical composition of the present invention.
- it may contain a diluent, a buffer, a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, a solubilizing agent, and the like.
- Examples of the salt of the compound represented by formula (I) or the compound represented by formula (II) include hydrochloride, sulfate, nitrate, acetate, and the like.
- Examples of the solvate of the compound represented by formula (I) or its salt or the compound represented by formula (II) or its salt include hydrates, ethanolates, and the like. Preferably it is a hydrate, particularly preferably a monohydrate, a trihydrate, and even a trihydrate. Particularly preferred is the trihydrate of the compound represented by formula (II).
- the method for producing the monohydrate is described in Cited Document 1, and the method for producing the trihydrate is described in Cited Document 2.
- the compound represented by formula (I) can be used in an amount of 0.5 to 10% by weight based on the weight of the entire tablet. Preferably it is 1 to 5% by weight. Particularly preferred is 1.7 to 2.0% by weight.
- the method for producing the pharmaceutical composition of the present invention includes mixing additives such as a compound represented by formula (I), a disintegrant, an excipient, etc. to produce a mixed powder, and then granulating the mixed powder.
- additives such as a compound represented by formula (I), a disintegrant, an excipient, etc.
- This is preferably a wet granulation method in which granulation is performed by adding water or a solvent containing water or a binder.
- the compound represented by formula (I), etc. can be added to water or a solvent containing water or a binder.
- a V-type mixer, a container blender, and an agitating granulator can be used as a machine for mixing the compound represented by formula (I), additives, etc.
- a fluidized bed granulator or an agitation granulator can be used as a granulating machine.
- the moisture content of the mixed powder during granulation is 10 to 70%, preferably 30 to 50%.
- this is a tableting method in which a disintegrant and a lubricant are mixed with the granules, and the mixed granules are compressed into tablets using a tableting machine.
- a V-type mixer or a container blender can be used as a machine for mixing the granules with the disintegrant and the lubricant.
- the tablet press a single tablet press, a rotary tablet press, etc. can be used as the tablet press.
- the pharmaceutical composition of the present invention is preferably a tablet.
- the pharmaceutical composition of the present invention can contain, but is not particularly limited to, 0.75 to 15 mg of the compound represented by formula (I). Preferably it is 1.5 to 7.5 mg, more preferably 2.25 to 3.0 mg. Particularly preferred is a pharmaceutical composition containing 2.4 mg of the compound represented by formula (I). In this case, the pharmaceutical composition contains 2.745 mg of the trihydrate of the compound represented by formula (II).
- the pharmaceutical composition of the present invention can be administered orally.
- the compound represented by formula (I) can be administered in an amount of 0.1 to 10 mg/day. Preferably it is 1 to 5 mg/day. Particularly preferably, 1.6 to 3.2 mg/day can be administered.
- the total weight of the pharmaceutical composition of the present invention is not particularly limited, but is 50 to 250 mg, more preferably 100 to 200 mg, particularly preferably 150 mg.
- the pharmaceutical composition of the present invention can be used for any of the uses described in Cited Documents 1 to 3. For example, it can be used for the prevention and/or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease.
- one embodiment of the present invention is a pharmaceutical composition that does not have a coating layer.
- one embodiment of the present invention is a pharmaceutical composition in which color change is reduced. Under the storage conditions described herein, reduction in color tone change can be confirmed.
- one embodiment of the present invention is a pharmaceutical composition in which the increase in related substances is reduced. Under the storage conditions described herein, a reduction in the increase in related substances can be confirmed.
- Example 1 A compatibility test was conducted between the hydrate of the compound represented by formula (II) and each additive.
- Table 2 shows the drying loss of the compatibility test samples prepared by wet method.
- Example 2 Based on the results of Example 1 above, using partially pregelatinized starch as a disintegrant, D-mannitol as an excipient, povidone as a binder, and magnesium stearate as a lubricant, a compound of formula (II) was prepared. A pharmaceutical composition containing a hydrate was prepared. Partially pregelatinized starch and D-mannitol were mixed in a stirring granulator to produce a mixed powder. Thereafter, water containing povidone, a hydrate of the compound represented by formula (II), was added to the mixed powder in a stirring granulator, and wet granulation was performed to produce granules. Furthermore, partially pregelatinized starch and magnesium stearate were mixed with the granules using a container blender to produce mixed granules. The mixed granules were compressed using a rotary tablet machine to produce tablets.
- Example 3 A stability test over time was conducted on the pharmaceutical composition of Example 2. As a result, no problems were found in terms of content, related substances, or changes in appearance.
- Example 4 Regarding the pharmaceutical composition of Example 2, the disintegration time was measured using a disintegration tester according to the Japanese Pharmacopoeia General Test Method "Disintegration Test Method". No auxiliary panel was used, and purified water was used as the test liquid. As a result of measurement of six pharmaceutical compositions of Example 2, the disintegration time was 3 minutes 23 seconds to 4 minutes 5 seconds, indicating good disintegration properties.
- Example 5 A dissolution test was conducted on the pharmaceutical composition of Example 2. Using 900 mL of water as the test solution, the test was conducted at 50 revolutions per minute by the paddle method. One piece of the pharmaceutical composition of Example 2 was taken, the test was started, and after 5, 10, 15, and 30 minutes, 4 mL of each eluate was accurately taken, filtered through a membrane filter with a pore size of 0.45 ⁇ m, and 2 mL of the initial filtrate was The following filtrate was used as the test solution. Separately, about 25 mg of a hydrate standard substance of the compound represented by formula (II) was accurately weighed and dissolved in water to make exactly 50 mL. 5 mL of this liquid was accurately measured and water was added to make 50 mL.
- a hydrate standard substance of the compound represented by formula (II) was accurately weighed and dissolved in water to make exactly 50 mL. 5 mL of this liquid was accurately measured and water was added to make 50 mL.
- Test conditions Detector Ultraviolet absorption photometer (measurement wavelength: 210mm)
- Column A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 cm filled with 3 ⁇ m octadecylsilylated silica gel for liquid chromatography (Develosil ODS-HG (Nomura Chemical) or equivalent
- Column temperature Constant temperature around 45°C Movement Phase: water/acetonitrile solution for liquid chromatography (83:17)
- Liquid amount Adjusted so that the retention time of the compound represented by formula (II) was about 4 minutes.
- the pharmaceutical composition of the present invention showed rapid dissolution behavior. The results are shown in Figure 1.
- the pharmaceutical composition of the present invention is useful in the prevention and/or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease.
Abstract
The present invention provides a pharmaceutical composition containing a compound represented by formula (I), a salt thereof, or a solvate thereof. The present invention uses, as a disintegrant, a partially pregelatinized starch, carmellose calcium, a low-substituted hydroxypropyl cellulose, carmellose, and/or crospovidone, and uses D-mannitol as an excipient. As a result, it is possible to produce a pharmaceutical composition in which a change in contents, an increase in analogs, and a change in color tone occur less.
Description
本発明は、式（Ｉ）：
で示される化合物、その塩、またはそれらの溶媒和物（以下、式（Ｉ）で示される化合物等という。）を含有する医薬組成物に関する。さらに詳しくは、式（Ｉ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物に関する。 The present invention provides formula (I):
The present invention relates to a pharmaceutical composition containing a compound represented by formula (I), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (I), etc.). More specifically, the present invention relates to a pharmaceutical composition containing a disintegrant and an excipient, such as a compound represented by formula (I).
で示される化合物、その塩、またはそれらの溶媒和物（以下、式（Ｉ）で示される化合物等という。）を含有する医薬組成物に関する。さらに詳しくは、式（Ｉ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物に関する。 The present invention provides formula (I):
The present invention relates to a pharmaceutical composition containing a compound represented by formula (I), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (I), etc.). More specifically, the present invention relates to a pharmaceutical composition containing a disintegrant and an excipient, such as a compound represented by formula (I).
式（Ｉ）で示される化合物等は、甲状腺刺激ホルモン放出ホルモン（ＴＲＨ）誘導体として、引用文献１に記載されており、中枢神経賦活作用（アセチルコリン放出作用、抗レセルピン作用、自発運動増加作用）を示すことが記載されている。当該文献には、式（Ｉ）で示される化合物等が脳内のドーパミン系、ノルエピネフリン系、アセチルコリン系のニューロンの賦活化による優れた体温上昇作用、自発運動促進作用を有することから、これらの神経系の機能低下に伴う諸症状の治療に使用することができる旨が記載されている。また、当該文献には、式（Ｉ）で示される化合物等が大脳皮質アセチルコリンニューロンを顕著に賦活することから、これらの機能低下に基づく諸症状（例えば運動障害、意識障害、老人性痴呆症、昏睡、注意力減退、言語障害等）の治療薬としても使用することができる旨が記載されている。
The compounds represented by formula (I) are described in Cited Document 1 as thyroid-stimulating hormone-releasing hormone (TRH) derivatives, and have central nervous system activating effects (acetylcholine-releasing effect, anti-reserpine effect, locomotor activity-increasing effect). What is shown is described. This document states that the compound represented by formula (I) has an excellent effect of increasing body temperature and promoting spontaneous movement by activating neurons in the dopamine system, norepinephrine system, and acetylcholine system in the brain. It is stated that it can be used to treat various symptoms associated with a decline in system function. In addition, this document states that the compound represented by formula (I) significantly activates acetylcholine neurons in the cerebral cortex, and therefore various symptoms based on the decline in these functions (e.g., movement disorder, consciousness disorder, senile dementia, It is stated that it can also be used as a treatment for coma, decreased attention span, speech disorders, etc.
また、引用文献２には、式（Ｉ）で示される化合物等が脊髄小脳変性症の治療に有用であることが記載されており、引用文献３には、式（Ｉ）で示される化合物等がパーキンソン病の治療に有用であることが記載されている。また、引用文献４には、脊髄小脳変性症における運動失調の治療剤の投与レジメンが記載されている。
また、式（Ｉ）で示される化合物等の製造方法については、引用文献５及び６に記載されている。
また、式（Ｉ）で示される化合物等を含有する腸溶性製剤は、引用文献７に記載されており、腸溶基剤でコーティングされていることを特徴としている。式（Ｉ）で示される化合物等を含有する経口投与製剤は、引用文献８に記載されており、中鎖脂肪酸トリグリセリドを含有することを特徴としている。
しかし、いずれの引用文献においても、本発明の製剤は開示されていない。 Furthermore, Cited Document 2 describes that the compound represented by formula (I), etc. is useful for the treatment of spinocerebellar degeneration, and Cited Document 3 describes that the compound represented by formula (I), etc. has been described to be useful in the treatment of Parkinson's disease. Furthermore, Cited Document 4 describes an administration regimen for a therapeutic agent for ataxia in spinocerebellar degeneration.
Furthermore, the method for producing the compound represented by formula (I) is described in Cited Documents 5 and 6.
Further, an enteric-coated preparation containing the compound represented by formula (I), etc. is described in Cited Document 7, and is characterized by being coated with an enteric-coated base. An orally administered preparation containing the compound represented by formula (I) is described in Cited Document 8, and is characterized by containing medium-chain fatty acid triglyceride.
However, none of the cited documents disclose the formulation of the present invention.
また、式（Ｉ）で示される化合物等の製造方法については、引用文献５及び６に記載されている。
また、式（Ｉ）で示される化合物等を含有する腸溶性製剤は、引用文献７に記載されており、腸溶基剤でコーティングされていることを特徴としている。式（Ｉ）で示される化合物等を含有する経口投与製剤は、引用文献８に記載されており、中鎖脂肪酸トリグリセリドを含有することを特徴としている。
しかし、いずれの引用文献においても、本発明の製剤は開示されていない。 Furthermore, Cited Document 2 describes that the compound represented by formula (I), etc. is useful for the treatment of spinocerebellar degeneration, and Cited Document 3 describes that the compound represented by formula (I), etc. has been described to be useful in the treatment of Parkinson's disease. Furthermore, Cited Document 4 describes an administration regimen for a therapeutic agent for ataxia in spinocerebellar degeneration.
Furthermore, the method for producing the compound represented by formula (I) is described in Cited Documents 5 and 6.
Further, an enteric-coated preparation containing the compound represented by formula (I), etc. is described in Cited Document 7, and is characterized by being coated with an enteric-coated base. An orally administered preparation containing the compound represented by formula (I) is described in Cited Document 8, and is characterized by containing medium-chain fatty acid triglyceride.
However, none of the cited documents disclose the formulation of the present invention.
本発明の目的は、式（Ｉ）で示される化合物等を含有する医薬組成物を提供することにある。
An object of the present invention is to provide a pharmaceutical composition containing a compound represented by formula (I).
本発明者らは、各種の添加剤に関し配合性試験を行い、含量、類縁物質、外観変化を確認し、クロスカルメロースナトリウム、カルボキシメチルデンプンナトリウム、粉糖において明らかな色調変化ことが観察されること、及び特に部分アルファー化デンプン、Ｄ－マンニトールにおいて色調変化が少ないことを見出し、本発明である式（Ｉ）で示される化合物等を含有する医薬組成物を完成させた。
The present inventors conducted compatibility tests on various additives, confirmed the content, related substances, and changes in appearance, and found that clear color changes were observed in croscarmellose sodium, sodium carboxymethyl starch, and powdered sugar. In addition, they found that there was little change in color tone especially in partially pregelatinized starch and D-mannitol, and completed the pharmaceutical composition containing the compound represented by formula (I), which is the present invention.
本発明者らは、以下に示す、式（Ｉ）で示される化合物等を含有する医薬組成物を見出した。
（１）式（Ｉ）：
で示される化合物、その塩、またはそれらの溶媒和物、及び
部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース及びクロスポビドンからなる群から選択される１又はそれ以上の崩壊剤を含有し、
賦形剤としてＤ－マンニトールを含有する医薬組成物。
（２）崩壊剤が部分アルファー化デンプンである、上記（１）記載の医薬組成物。
（３）結合剤及び／又は滑沢剤を含有する、上記（１）または（２）記載の医薬組成物。
（４）結合剤を含有し、当該結合剤が、ポビドン及び／又はヒプロメロースである、上記（３）記載の医薬組成物。
（５）結合剤がポビドンである、上記（４）記載の医薬組成物。
（６）滑沢剤を含有し、当該滑沢剤がステアリン酸マグネシウムである、上記（３）～（５）のいずれかに記載の医薬組成物。
（７）式（ＩＩ）：
で示される化合物、その塩、またはそれらの溶媒和物（以下、式（ＩＩ）で示される化合物等という。）を含有する、上記（１）～（６）のいずれかに記載の医薬組成物。
（８）式（ＩＩ）で示される化合物の水和物を含有する、上記（７）記載の医薬組成物。
（９）式（Ｉ）：
で示される化合物、その塩、またはそれらの溶媒和物、
崩壊剤として部分アルファー化デンプン、
賦形剤としてＤ－マンニトール、
結合剤としてポビドン、及び
滑沢剤としてステアリン酸マグネシウムを含有する医薬組成物。
（１０）式（ＩＩ）：
で示される化合物の水和物を含有する、上記（９）記載の医薬組成物。 The present inventors have discovered a pharmaceutical composition containing the compound represented by formula (I) shown below.
(1) Formula (I):
a compound represented by, a salt thereof, or a solvate thereof, and one or more disintegrants selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, and crospovidone. Contains
A pharmaceutical composition containing D-mannitol as an excipient.
(2) The pharmaceutical composition according to (1) above, wherein the disintegrant is partially pregelatinized starch.
(3) The pharmaceutical composition according to (1) or (2) above, containing a binder and/or a lubricant.
(4) The pharmaceutical composition according to (3) above, which contains a binder, and the binder is povidone and/or hypromellose.
(5) The pharmaceutical composition according to (4) above, wherein the binder is povidone.
(6) The pharmaceutical composition according to any one of (3) to (5) above, which contains a lubricant, and the lubricant is magnesium stearate.
(7) Formula (II):
The pharmaceutical composition according to any one of (1) to (6) above, containing a compound represented by formula (II), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (II), etc.) .
(8) The pharmaceutical composition described in (7) above, which contains a hydrate of the compound represented by formula (II).
(9) Formula (I):
Compounds represented by, salts thereof, or solvates thereof,
Partially pregelatinized starch as a disintegrant,
D-mannitol as excipient,
A pharmaceutical composition containing povidone as a binder and magnesium stearate as a lubricant.
(10) Formula (II):
The pharmaceutical composition according to (9) above, which contains a hydrate of the compound represented by:
（１）式（Ｉ）：
で示される化合物、その塩、またはそれらの溶媒和物、及び
部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース及びクロスポビドンからなる群から選択される１又はそれ以上の崩壊剤を含有し、
賦形剤としてＤ－マンニトールを含有する医薬組成物。
（２）崩壊剤が部分アルファー化デンプンである、上記（１）記載の医薬組成物。
（３）結合剤及び／又は滑沢剤を含有する、上記（１）または（２）記載の医薬組成物。
（４）結合剤を含有し、当該結合剤が、ポビドン及び／又はヒプロメロースである、上記（３）記載の医薬組成物。
（５）結合剤がポビドンである、上記（４）記載の医薬組成物。
（６）滑沢剤を含有し、当該滑沢剤がステアリン酸マグネシウムである、上記（３）～（５）のいずれかに記載の医薬組成物。
（７）式（ＩＩ）：
で示される化合物、その塩、またはそれらの溶媒和物（以下、式（ＩＩ）で示される化合物等という。）を含有する、上記（１）～（６）のいずれかに記載の医薬組成物。
（８）式（ＩＩ）で示される化合物の水和物を含有する、上記（７）記載の医薬組成物。
（９）式（Ｉ）：
で示される化合物、その塩、またはそれらの溶媒和物、
崩壊剤として部分アルファー化デンプン、
賦形剤としてＤ－マンニトール、
結合剤としてポビドン、及び
滑沢剤としてステアリン酸マグネシウムを含有する医薬組成物。
（１０）式（ＩＩ）：
で示される化合物の水和物を含有する、上記（９）記載の医薬組成物。 The present inventors have discovered a pharmaceutical composition containing the compound represented by formula (I) shown below.
(1) Formula (I):
a compound represented by, a salt thereof, or a solvate thereof, and one or more disintegrants selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, and crospovidone. Contains
A pharmaceutical composition containing D-mannitol as an excipient.
(2) The pharmaceutical composition according to (1) above, wherein the disintegrant is partially pregelatinized starch.
(3) The pharmaceutical composition according to (1) or (2) above, containing a binder and/or a lubricant.
(4) The pharmaceutical composition according to (3) above, which contains a binder, and the binder is povidone and/or hypromellose.
(5) The pharmaceutical composition according to (4) above, wherein the binder is povidone.
(6) The pharmaceutical composition according to any one of (3) to (5) above, which contains a lubricant, and the lubricant is magnesium stearate.
(7) Formula (II):
The pharmaceutical composition according to any one of (1) to (6) above, containing a compound represented by formula (II), a salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by formula (II), etc.) .
(8) The pharmaceutical composition described in (7) above, which contains a hydrate of the compound represented by formula (II).
(9) Formula (I):
Compounds represented by, salts thereof, or solvates thereof,
Partially pregelatinized starch as a disintegrant,
D-mannitol as excipient,
A pharmaceutical composition containing povidone as a binder and magnesium stearate as a lubricant.
(10) Formula (II):
The pharmaceutical composition according to (9) above, which contains a hydrate of the compound represented by:
本発明により、経時保存した時に、含量の変化がなく、類縁物質の量が少なく、外観変化の少ない、式（Ｉ）で示される化合物等を含有する医薬組成物が提供される。
The present invention provides a pharmaceutical composition containing a compound represented by formula (I), etc., which does not change in content, has a small amount of related substances, and shows little change in appearance when stored over time.
以下に本発明を詳細に説明する。
The present invention will be explained in detail below.
本発明は、式（Ｉ）で示される化合物等を含有する医薬組成物に関する。
本発明の一つの態様は、式（Ｉ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物である。
また、本発明の一つの態様は、式（ＩＩ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物である。
また、本発明の一つの態様は、式（ＩＩ）で示される化合物の水和物、崩壊剤及び賦形剤を含有する医薬組成物である。 The present invention relates to a pharmaceutical composition containing a compound represented by formula (I).
One aspect of the invention is a pharmaceutical composition containing a disintegrant and an excipient, such as a compound of formula (I).
Further, one embodiment of the present invention is a pharmaceutical composition containing a disintegrant and an excipient, such as a compound represented by formula (II).
Further, one embodiment of the present invention is a pharmaceutical composition containing a hydrate of the compound represented by formula (II), a disintegrant, and an excipient.
本発明の一つの態様は、式（Ｉ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物である。
また、本発明の一つの態様は、式（ＩＩ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物である。
また、本発明の一つの態様は、式（ＩＩ）で示される化合物の水和物、崩壊剤及び賦形剤を含有する医薬組成物である。 The present invention relates to a pharmaceutical composition containing a compound represented by formula (I).
One aspect of the invention is a pharmaceutical composition containing a disintegrant and an excipient, such as a compound of formula (I).
Further, one embodiment of the present invention is a pharmaceutical composition containing a disintegrant and an excipient, such as a compound represented by formula (II).
Further, one embodiment of the present invention is a pharmaceutical composition containing a hydrate of the compound represented by formula (II), a disintegrant, and an excipient.
崩壊剤としては、部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース、クロスポビドン、クロスカルメロースナトリウム、カルボキシメチルデンプンナトリウム等を用いることができる。それらの崩壊剤のうち、部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース、クロスポビドン、クロスカルメロースナトリウム、カルボキシメチルデンプンナトリウムが好ましい。特に、部分アルファー化デンプンが好ましい。
崩壊剤は、錠剤全体の重量に対して、５～７５重量％用いることができる。好ましくは、２０～５０重量％である。特に好ましくは、２７～３３重量％である。 As the disintegrant, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, etc. can be used. Among these disintegrants, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, crospovidone, croscarmellose sodium, and sodium carboxymethyl starch are preferred. Particularly preferred is partially pregelatinized starch.
The disintegrant can be used in an amount of 5 to 75% by weight based on the weight of the entire tablet. Preferably it is 20 to 50% by weight. Particularly preferred is 27 to 33% by weight.
崩壊剤は、錠剤全体の重量に対して、５～７５重量％用いることができる。好ましくは、２０～５０重量％である。特に好ましくは、２７～３３重量％である。 As the disintegrant, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, etc. can be used. Among these disintegrants, partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, crospovidone, croscarmellose sodium, and sodium carboxymethyl starch are preferred. Particularly preferred is partially pregelatinized starch.
The disintegrant can be used in an amount of 5 to 75% by weight based on the weight of the entire tablet. Preferably it is 20 to 50% by weight. Particularly preferred is 27 to 33% by weight.
賦形剤としては、乳糖、精製白糖、Ｄ－マンニトール、キシリトール、結晶セルロース、無水リン酸水素カルシウム、コーンスターチ、粉糖等を用いることができる。それらの賦形剤のうち、乳糖、精製白糖、Ｄ－マンニトール、キシリトール、結晶セルロース、無水リン酸水素カルシウム、コーンスターチが好ましい。特に、Ｄ－マンニトールが好ましい。
賦形剤は、錠剤全体の重量に対して、１０～９０重量％用いることができる。好ましくは、５０～８０重量％である。特に好ましくは、６０～７３重量％である。 As excipients, lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, powdered sugar, etc. can be used. Among these excipients, lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, and cornstarch are preferred. Particularly preferred is D-mannitol.
The excipient can be used in an amount of 10 to 90% by weight based on the total weight of the tablet. Preferably it is 50 to 80% by weight. Particularly preferred is 60 to 73% by weight.
賦形剤は、錠剤全体の重量に対して、１０～９０重量％用いることができる。好ましくは、５０～８０重量％である。特に好ましくは、６０～７３重量％である。 As excipients, lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, powdered sugar, etc. can be used. Among these excipients, lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, and cornstarch are preferred. Particularly preferred is D-mannitol.
The excipient can be used in an amount of 10 to 90% by weight based on the total weight of the tablet. Preferably it is 50 to 80% by weight. Particularly preferred is 60 to 73% by weight.
本発明の一つの態様は、結合剤及び／又は滑沢剤を含有する、式（Ｉ）で示される化合物等、崩壊剤及び賦形剤を含有する医薬組成物である。
One embodiment of the present invention is a pharmaceutical composition containing a disintegrant and an excipient, such as a compound of formula (I) containing a binder and/or a lubricant.
結合剤としては、ポビドン、ヒプロメロース等を用いることができる。それらの結合剤のうち、ポビドン、ヒプロメロースが好ましい。特に、ポビドンが好ましい。
結合剤は、錠剤全体の重量に対して、０．１～５．０重量％用いることができる。好ましくは、０．５～２．０重量％である。特に好ましくは、０．８～１．０重量％である。
滑沢剤としては、ステアリン酸マグネシウム等を用いることができる。それらの滑沢剤のうち、ステアリン酸マグネシウムが好ましい。特に、ステアリン酸マグネシウムが好ましい。
滑沢剤は、錠剤全体の重量に対して、０．１～５．０重量％用いることができる。好ましくは、０．５～２．０重量％である。特に好ましくは、０．９～１．１重量％である。 Povidone, hypromellose, etc. can be used as the binder. Among these binders, povidone and hypromellose are preferred. Particularly preferred is povidone.
The binder can be used in an amount of 0.1 to 5.0% by weight based on the weight of the entire tablet. Preferably it is 0.5 to 2.0% by weight. Particularly preferred is 0.8 to 1.0% by weight.
As the lubricant, magnesium stearate or the like can be used. Among these lubricants, magnesium stearate is preferred. Particularly preferred is magnesium stearate.
The lubricant can be used in an amount of 0.1 to 5.0% by weight based on the weight of the entire tablet. Preferably it is 0.5 to 2.0% by weight. Particularly preferred is 0.9 to 1.1% by weight.
結合剤は、錠剤全体の重量に対して、０．１～５．０重量％用いることができる。好ましくは、０．５～２．０重量％である。特に好ましくは、０．８～１．０重量％である。
滑沢剤としては、ステアリン酸マグネシウム等を用いることができる。それらの滑沢剤のうち、ステアリン酸マグネシウムが好ましい。特に、ステアリン酸マグネシウムが好ましい。
滑沢剤は、錠剤全体の重量に対して、０．１～５．０重量％用いることができる。好ましくは、０．５～２．０重量％である。特に好ましくは、０．９～１．１重量％である。 Povidone, hypromellose, etc. can be used as the binder. Among these binders, povidone and hypromellose are preferred. Particularly preferred is povidone.
The binder can be used in an amount of 0.1 to 5.0% by weight based on the weight of the entire tablet. Preferably it is 0.5 to 2.0% by weight. Particularly preferred is 0.8 to 1.0% by weight.
As the lubricant, magnesium stearate or the like can be used. Among these lubricants, magnesium stearate is preferred. Particularly preferred is magnesium stearate.
The lubricant can be used in an amount of 0.1 to 5.0% by weight based on the weight of the entire tablet. Preferably it is 0.5 to 2.0% by weight. Particularly preferred is 0.9 to 1.1% by weight.
本発明の医薬組成物については、上記の崩壊剤、賦形剤、結合剤、滑沢剤以外に、製薬分野において使用される添加剤を用いることができる。たとえば、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤等を含有することができる。
In addition to the above-mentioned disintegrants, excipients, binders, and lubricants, additives used in the pharmaceutical field can be used in the pharmaceutical composition of the present invention. For example, it may contain a diluent, a buffer, a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, a solubilizing agent, and the like.
式（Ｉ）で示される化合物又は式（ＩＩ）で示される化合物の塩としては、塩酸塩、硫酸塩、硝酸塩、酢酸塩等が挙げられる。
式（Ｉ）で示される化合物若しくはその塩又は式（ＩＩ）で示される化合物若しくはその塩の溶媒和物としては、水和物、エタノール和物等が挙げられる。好ましくは、水和物であり、特に好ましくは、一水和物、三水和物であり、さらには三水和物である。特に、式（ＩＩ）で示される化合物の三水和物が好ましい。一水和物の製法については引用文献１に記載されており、三水和物の製法については引用文献２に記載されている。
式（Ｉ）で示される化合物等は、錠剤全体の重量に対して、０.５～１０重量％用いることができる。好ましくは、１～５重量％である。特に好ましくは、１．７～２．０重量％である。 Examples of the salt of the compound represented by formula (I) or the compound represented by formula (II) include hydrochloride, sulfate, nitrate, acetate, and the like.
Examples of the solvate of the compound represented by formula (I) or its salt or the compound represented by formula (II) or its salt include hydrates, ethanolates, and the like. Preferably it is a hydrate, particularly preferably a monohydrate, a trihydrate, and even a trihydrate. Particularly preferred is the trihydrate of the compound represented by formula (II). The method for producing the monohydrate is described in Cited Document 1, and the method for producing the trihydrate is described in Cited Document 2.
The compound represented by formula (I) can be used in an amount of 0.5 to 10% by weight based on the weight of the entire tablet. Preferably it is 1 to 5% by weight. Particularly preferred is 1.7 to 2.0% by weight.
式（Ｉ）で示される化合物若しくはその塩又は式（ＩＩ）で示される化合物若しくはその塩の溶媒和物としては、水和物、エタノール和物等が挙げられる。好ましくは、水和物であり、特に好ましくは、一水和物、三水和物であり、さらには三水和物である。特に、式（ＩＩ）で示される化合物の三水和物が好ましい。一水和物の製法については引用文献１に記載されており、三水和物の製法については引用文献２に記載されている。
式（Ｉ）で示される化合物等は、錠剤全体の重量に対して、０.５～１０重量％用いることができる。好ましくは、１～５重量％である。特に好ましくは、１．７～２．０重量％である。 Examples of the salt of the compound represented by formula (I) or the compound represented by formula (II) include hydrochloride, sulfate, nitrate, acetate, and the like.
Examples of the solvate of the compound represented by formula (I) or its salt or the compound represented by formula (II) or its salt include hydrates, ethanolates, and the like. Preferably it is a hydrate, particularly preferably a monohydrate, a trihydrate, and even a trihydrate. Particularly preferred is the trihydrate of the compound represented by formula (II). The method for producing the monohydrate is described in Cited Document 1, and the method for producing the trihydrate is described in Cited Document 2.
The compound represented by formula (I) can be used in an amount of 0.5 to 10% by weight based on the weight of the entire tablet. Preferably it is 1 to 5% by weight. Particularly preferred is 1.7 to 2.0% by weight.
本発明の医薬組成物の製造方法は、式（Ｉ）で示される化合物等、崩壊剤、賦形剤等の添加剤を混合して、混合末を製造後、当該混合末を造粒する方法であり、好ましくは水や結合剤を含有する水や溶媒を添加して造粒する湿式造粒法である。式（Ｉ）で示される化合物等は水や結合剤を含有する水や溶媒に加えることができる。式（Ｉ）で示される化合物等や添加剤等を混合する機械として、Ｖ型混合機、コンテナブレンダー、攪拌造粒機を使用することができる。また、造粒する機械としては、流動層造粒機、撹拌造粒機を使用することができる。混合末に対する造粒時の水分は、１０～７０％、好ましくは３０～５０％である。さらに、この顆粒に対して、崩壊剤及び滑沢剤を混合し、当該混合顆粒を打錠機で打錠する打錠法である。顆粒と崩壊剤及び滑沢剤を混合する機械として、Ｖ型混合機やコンテナブレンダーを使用することができる。また、打錠機としては、単発打錠機、ロータリー式打錠機等を使用することができる。
本発明の医薬組成物としては、錠剤が好ましい。
本発明の医薬組成物は、特に限定するものではないが、式（Ｉ）で示される化合物等を０．７５～１５ｍｇ含むことができる。好ましくは、１．５～７．５ｍｇであり、さらには、２．２５～３．０ｍｇである。特に好ましくは、式（Ｉ）で示される化合物として２．４ｍｇ含む医薬組成物である。この場合、当該医薬組成物は、式（ＩＩ）で示される化合物の三水和物を２．７４５ｍｇ含む。
本発明の医薬組成物は、経口で投与することができる。特に限定するものではないが、式（Ｉ）で示される化合物として、０．１～１０ｍｇ／日投与することができる。好ましくは、１～５ｍｇ／日である。特に好ましくは、１．６～３．２ｍｇ／日投与することができる。
本発明の医薬組成物の全重量は、特に限定するものではないが、５０～２５０ｍｇであり、より好ましくは１００～２００ｍｇであり、特に好ましくは、１５０ｍｇである。
本発明の医薬組成物は、引用文献１～３のいずれかに記載の用途に用いることができる。例えば、脊髄小脳変性症、パーキンソン病等の中枢神経系の疾患の予防及び／又は治療に用いることができる。
また、本発明の一つの態様は、コーティング層を有しない医薬組成物である。
また、本発明の一つの態様は、色調変化が軽減された医薬組成物である。本明細書記載の保存条件において、色調変化の軽減を確認することができる。
また、本発明の一つの態様は、類縁物質の増加が軽減された医薬組成物である。本明細書記載の保存条件において、類縁物質の増加の軽減を確認することができる。 The method for producing the pharmaceutical composition of the present invention includes mixing additives such as a compound represented by formula (I), a disintegrant, an excipient, etc. to produce a mixed powder, and then granulating the mixed powder. This is preferably a wet granulation method in which granulation is performed by adding water or a solvent containing water or a binder. The compound represented by formula (I), etc. can be added to water or a solvent containing water or a binder. As a machine for mixing the compound represented by formula (I), additives, etc., a V-type mixer, a container blender, and an agitating granulator can be used. Further, as a granulating machine, a fluidized bed granulator or an agitation granulator can be used. The moisture content of the mixed powder during granulation is 10 to 70%, preferably 30 to 50%. Furthermore, this is a tableting method in which a disintegrant and a lubricant are mixed with the granules, and the mixed granules are compressed into tablets using a tableting machine. A V-type mixer or a container blender can be used as a machine for mixing the granules with the disintegrant and the lubricant. Furthermore, as the tablet press, a single tablet press, a rotary tablet press, etc. can be used.
The pharmaceutical composition of the present invention is preferably a tablet.
The pharmaceutical composition of the present invention can contain, but is not particularly limited to, 0.75 to 15 mg of the compound represented by formula (I). Preferably it is 1.5 to 7.5 mg, more preferably 2.25 to 3.0 mg. Particularly preferred is a pharmaceutical composition containing 2.4 mg of the compound represented by formula (I). In this case, the pharmaceutical composition contains 2.745 mg of the trihydrate of the compound represented by formula (II).
The pharmaceutical composition of the present invention can be administered orally. Although not particularly limited, the compound represented by formula (I) can be administered in an amount of 0.1 to 10 mg/day. Preferably it is 1 to 5 mg/day. Particularly preferably, 1.6 to 3.2 mg/day can be administered.
The total weight of the pharmaceutical composition of the present invention is not particularly limited, but is 50 to 250 mg, more preferably 100 to 200 mg, particularly preferably 150 mg.
The pharmaceutical composition of the present invention can be used for any of the uses described in Cited Documents 1 to 3. For example, it can be used for the prevention and/or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease.
Moreover, one embodiment of the present invention is a pharmaceutical composition that does not have a coating layer.
Further, one embodiment of the present invention is a pharmaceutical composition in which color change is reduced. Under the storage conditions described herein, reduction in color tone change can be confirmed.
Furthermore, one embodiment of the present invention is a pharmaceutical composition in which the increase in related substances is reduced. Under the storage conditions described herein, a reduction in the increase in related substances can be confirmed.
本発明の医薬組成物としては、錠剤が好ましい。
本発明の医薬組成物は、特に限定するものではないが、式（Ｉ）で示される化合物等を０．７５～１５ｍｇ含むことができる。好ましくは、１．５～７．５ｍｇであり、さらには、２．２５～３．０ｍｇである。特に好ましくは、式（Ｉ）で示される化合物として２．４ｍｇ含む医薬組成物である。この場合、当該医薬組成物は、式（ＩＩ）で示される化合物の三水和物を２．７４５ｍｇ含む。
本発明の医薬組成物は、経口で投与することができる。特に限定するものではないが、式（Ｉ）で示される化合物として、０．１～１０ｍｇ／日投与することができる。好ましくは、１～５ｍｇ／日である。特に好ましくは、１．６～３．２ｍｇ／日投与することができる。
本発明の医薬組成物の全重量は、特に限定するものではないが、５０～２５０ｍｇであり、より好ましくは１００～２００ｍｇであり、特に好ましくは、１５０ｍｇである。
本発明の医薬組成物は、引用文献１～３のいずれかに記載の用途に用いることができる。例えば、脊髄小脳変性症、パーキンソン病等の中枢神経系の疾患の予防及び／又は治療に用いることができる。
また、本発明の一つの態様は、コーティング層を有しない医薬組成物である。
また、本発明の一つの態様は、色調変化が軽減された医薬組成物である。本明細書記載の保存条件において、色調変化の軽減を確認することができる。
また、本発明の一つの態様は、類縁物質の増加が軽減された医薬組成物である。本明細書記載の保存条件において、類縁物質の増加の軽減を確認することができる。 The method for producing the pharmaceutical composition of the present invention includes mixing additives such as a compound represented by formula (I), a disintegrant, an excipient, etc. to produce a mixed powder, and then granulating the mixed powder. This is preferably a wet granulation method in which granulation is performed by adding water or a solvent containing water or a binder. The compound represented by formula (I), etc. can be added to water or a solvent containing water or a binder. As a machine for mixing the compound represented by formula (I), additives, etc., a V-type mixer, a container blender, and an agitating granulator can be used. Further, as a granulating machine, a fluidized bed granulator or an agitation granulator can be used. The moisture content of the mixed powder during granulation is 10 to 70%, preferably 30 to 50%. Furthermore, this is a tableting method in which a disintegrant and a lubricant are mixed with the granules, and the mixed granules are compressed into tablets using a tableting machine. A V-type mixer or a container blender can be used as a machine for mixing the granules with the disintegrant and the lubricant. Furthermore, as the tablet press, a single tablet press, a rotary tablet press, etc. can be used.
The pharmaceutical composition of the present invention is preferably a tablet.
The pharmaceutical composition of the present invention can contain, but is not particularly limited to, 0.75 to 15 mg of the compound represented by formula (I). Preferably it is 1.5 to 7.5 mg, more preferably 2.25 to 3.0 mg. Particularly preferred is a pharmaceutical composition containing 2.4 mg of the compound represented by formula (I). In this case, the pharmaceutical composition contains 2.745 mg of the trihydrate of the compound represented by formula (II).
The pharmaceutical composition of the present invention can be administered orally. Although not particularly limited, the compound represented by formula (I) can be administered in an amount of 0.1 to 10 mg/day. Preferably it is 1 to 5 mg/day. Particularly preferably, 1.6 to 3.2 mg/day can be administered.
The total weight of the pharmaceutical composition of the present invention is not particularly limited, but is 50 to 250 mg, more preferably 100 to 200 mg, particularly preferably 150 mg.
The pharmaceutical composition of the present invention can be used for any of the uses described in Cited Documents 1 to 3. For example, it can be used for the prevention and/or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease.
Moreover, one embodiment of the present invention is a pharmaceutical composition that does not have a coating layer.
Further, one embodiment of the present invention is a pharmaceutical composition in which color change is reduced. Under the storage conditions described herein, reduction in color tone change can be confirmed.
Furthermore, one embodiment of the present invention is a pharmaceutical composition in which the increase in related substances is reduced. Under the storage conditions described herein, a reduction in the increase in related substances can be confirmed.
以下に本発明を実施例により具体的に説明するが、本発明の範囲はこれら実施例に限定されるものではない。
The present invention will be specifically explained below using Examples, but the scope of the present invention is not limited to these Examples.
（実施例１）
式（ＩＩ）で示される化合物の水和物と各添加剤との配合性試験を実施した。 (Example 1)
A compatibility test was conducted between the hydrate of the compound represented by formula (II) and each additive.
式（ＩＩ）で示される化合物の水和物と各添加剤との配合性試験を実施した。 (Example 1)
A compatibility test was conducted between the hydrate of the compound represented by formula (II) and each additive.
（Ａ）実験材料
実験には以下に示す試薬、添加剤を用いた。
（崩壊剤）
部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース、クロスポビドン、クロスカルメロースナトリウム、カルボキシメチルデンプンナトリウム
（賦形剤）
乳糖、精製白糖、Ｄ－マンニトール、キシリトール、結晶セルロース、無水リン酸水素カルシウム、コーンスターチ、粉糖
（結合剤）
ポビドン、ヒプロメロース
（滑沢剤）
ステアリン酸マグネシウム (A) Experimental Materials The following reagents and additives were used in the experiment.
(disintegrant)
Partially pregelatinized starch, carmellose calcium, low substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium (excipient)
Lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, powdered sugar (binder)
Povidone, hypromellose (lubricant)
Magnesium stearate
実験には以下に示す試薬、添加剤を用いた。
（崩壊剤）
部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース、クロスポビドン、クロスカルメロースナトリウム、カルボキシメチルデンプンナトリウム
（賦形剤）
乳糖、精製白糖、Ｄ－マンニトール、キシリトール、結晶セルロース、無水リン酸水素カルシウム、コーンスターチ、粉糖
（結合剤）
ポビドン、ヒプロメロース
（滑沢剤）
ステアリン酸マグネシウム (A) Experimental Materials The following reagents and additives were used in the experiment.
(disintegrant)
Partially pregelatinized starch, carmellose calcium, low substituted hydroxypropyl cellulose, carmellose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium (excipient)
Lactose, refined white sugar, D-mannitol, xylitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, cornstarch, powdered sugar (binder)
Povidone, hypromellose (lubricant)
Magnesium stearate
（Ｂ）製造設備
通気乾燥機 ＰＭＮｏ．ＴＲＶ１４１ (B) Manufacturing equipment Ventilation dryer PM No. TRV141
通気乾燥機 ＰＭＮｏ．ＴＲＶ１４１ (B) Manufacturing equipment Ventilation dryer PM No. TRV141
（Ｃ）試験法
乾燥減量：電子水分計 ＰＭＮｏ．ＡＥＨ１１２２（加熱温度１０５℃）
含量：ＨＰＬＣ法
カラム：Ｍｉｇｈｔｙｓｉｌ ＲＰ－１８ＧＰ（１５０ｍｍ×４．６ｍｍ）Ｓ－３μｍ（関東化学）
カラム温度：４０℃
移動相：ＰＩＣ Ｂ－５（Ｌｏｗ ＵＶ）／アセトニトリル＝８／２混液
検出波長：２２０ｎｍ
流量：約１．０ｍＬ／ｍｉｎ
注入量：１００μＬ
ポンプ：Ｗａｔｅｒｓ ６００
注入装置：Ｗａｔｅｒｓ ７１７ｐｌｕｓ
検出器：Ｗａｔｅｒｓ ２４８７
色差：分光高度計 ＳＥ－２０００（日本電色）
視野選択：反射光測定
測定条件：２度視野、標準光
類縁物質：ＨＰＬＣ法 (C) Test method Loss on drying: Electronic moisture meter PM No. AEH1122 (heating temperature 105℃)
Content: HPLC method Column: Mightysil RP-18GP (150mm x 4.6mm) S-3μm (Kanto Chemical)
Column temperature: 40℃
Mobile phase: PIC B-5 (Low UV)/acetonitrile = 8/2 mixture Detection wavelength: 220 nm
Flow rate: Approximately 1.0mL/min
Injection volume: 100μL
Pump: Waters 600
Injection device: Waters 717plus
Detector: Waters 2487
Color difference: Spectroscopic altimeter SE-2000 (Nippon Denshoku)
Field of view selection: Reflected light measurement Measurement conditions: 2 degree field of view, standard light Related substances: HPLC method
乾燥減量：電子水分計 ＰＭＮｏ．ＡＥＨ１１２２（加熱温度１０５℃）
含量：ＨＰＬＣ法
カラム：Ｍｉｇｈｔｙｓｉｌ ＲＰ－１８ＧＰ（１５０ｍｍ×４．６ｍｍ）Ｓ－３μｍ（関東化学）
カラム温度：４０℃
移動相：ＰＩＣ Ｂ－５（Ｌｏｗ ＵＶ）／アセトニトリル＝８／２混液
検出波長：２２０ｎｍ
流量：約１．０ｍＬ／ｍｉｎ
注入量：１００μＬ
ポンプ：Ｗａｔｅｒｓ ６００
注入装置：Ｗａｔｅｒｓ ７１７ｐｌｕｓ
検出器：Ｗａｔｅｒｓ ２４８７
色差：分光高度計 ＳＥ－２０００（日本電色）
視野選択：反射光測定
測定条件：２度視野、標準光
類縁物質：ＨＰＬＣ法 (C) Test method Loss on drying: Electronic moisture meter PM No. AEH1122 (heating temperature 105℃)
Content: HPLC method Column: Mightysil RP-18GP (150mm x 4.6mm) S-3μm (Kanto Chemical)
Column temperature: 40℃
Mobile phase: PIC B-5 (Low UV)/acetonitrile = 8/2 mixture Detection wavelength: 220 nm
Flow rate: Approximately 1.0mL/min
Injection volume: 100μL
Pump: Waters 600
Injection device: Waters 717plus
Detector: Waters 2487
Color difference: Spectroscopic altimeter SE-2000 (Nippon Denshoku)
Field of view selection: Reflected light measurement Measurement conditions: 2 degree field of view, standard light Related substances: HPLC method
（Ｄ）配合性試験用検体
（Ｄ－１）配合比率
添加物の配合比率は、以下の通りとした。式（ＩＩ）で示される化合物として１にするため、水分補正を行い、式（ＩＩ）で示される化合物の水和物として１．１５添加した。
（崩壊剤）
式（ＩＩ）で示される化合物：添加剤＝１：１０
（賦形剤）
式（ＩＩ）で示される化合物：添加剤＝１：１０
（結合剤）
式（ＩＩ）で示される化合物：添加剤＝１：１
（滑沢剤）
式（ＩＩ）で示される化合物：添加剤＝１：１ (D) Specimen for Compatibility Test (D-1) Compounding Ratio The blending ratio of additives was as follows. In order to make the compound represented by formula (II) 1, water content was corrected and 1.15 was added as a hydrate of the compound represented by formula (II).
(disintegrant)
Compound represented by formula (II): additive = 1:10
(Excipient)
Compound represented by formula (II): additive = 1:10
(Binder)
Compound represented by formula (II): additive = 1:1
(lubricant)
Compound represented by formula (II): additive = 1:1
（Ｄ－１）配合比率
添加物の配合比率は、以下の通りとした。式（ＩＩ）で示される化合物として１にするため、水分補正を行い、式（ＩＩ）で示される化合物の水和物として１．１５添加した。
（崩壊剤）
式（ＩＩ）で示される化合物：添加剤＝１：１０
（賦形剤）
式（ＩＩ）で示される化合物：添加剤＝１：１０
（結合剤）
式（ＩＩ）で示される化合物：添加剤＝１：１
（滑沢剤）
式（ＩＩ）で示される化合物：添加剤＝１：１ (D) Specimen for Compatibility Test (D-1) Compounding Ratio The blending ratio of additives was as follows. In order to make the compound represented by formula (II) 1, water content was corrected and 1.15 was added as a hydrate of the compound represented by formula (II).
(disintegrant)
Compound represented by formula (II): additive = 1:10
(Excipient)
Compound represented by formula (II): additive = 1:10
(Binder)
Compound represented by formula (II): additive = 1:1
(lubricant)
Compound represented by formula (II): additive = 1:1
（Ｄ－２）湿式処理品
滑沢剤のステアリン酸マグネシウムを除く添加剤は、湿式処理し経時試験を実施した。
（１）式（ＩＩ）で示される化合物１：添加剤１０若しくは式（ＩＩ）で示される化合物１：添加剤１の割合で秤取し、メノウ乳鉢で混合後、精製水を徐々に加え混合操作を行った。
（２）さらに、湿潤練合物をトレイに展張し、１２０分間４５℃で通気乾燥した。 (D-2) Wet-processed product Additives other than the lubricant magnesium stearate were wet-processed and tested over time.
(1) Weigh out the compound represented by formula (II) at a ratio of 1:10 additive or the compound represented by formula (II) at a ratio of 1:1 additive, mix in an agate mortar, and then gradually add purified water and mix. performed the operation.
(2) Furthermore, the wet kneaded product was spread on a tray and air-dried at 45° C. for 120 minutes.
滑沢剤のステアリン酸マグネシウムを除く添加剤は、湿式処理し経時試験を実施した。
（１）式（ＩＩ）で示される化合物１：添加剤１０若しくは式（ＩＩ）で示される化合物１：添加剤１の割合で秤取し、メノウ乳鉢で混合後、精製水を徐々に加え混合操作を行った。
（２）さらに、湿潤練合物をトレイに展張し、１２０分間４５℃で通気乾燥した。 (D-2) Wet-processed product Additives other than the lubricant magnesium stearate were wet-processed and tested over time.
(1) Weigh out the compound represented by formula (II) at a ratio of 1:10 additive or the compound represented by formula (II) at a ratio of 1:1 additive, mix in an agate mortar, and then gradually add purified water and mix. performed the operation.
(2) Furthermore, the wet kneaded product was spread on a tray and air-dried at 45° C. for 120 minutes.
（Ｄ－３）物理混合品
ステアリン酸マグネシウムは、式（ＩＩ）で示される化合物１：添加剤１の割合で秤取し、メノウ乳鉢で乾式混合した。 (D-3) Physical mixture Magnesium stearate was weighed out at a ratio of 1:1 additive represented by formula (II) and dry mixed in an agate mortar.
ステアリン酸マグネシウムは、式（ＩＩ）で示される化合物１：添加剤１の割合で秤取し、メノウ乳鉢で乾式混合した。 (D-3) Physical mixture Magnesium stearate was weighed out at a ratio of 1:1 additive represented by formula (II) and dry mixed in an agate mortar.
（Ｄ－４）経時試験
配合性試験用に調製した検体を秤取し、表１に示す条件の経時試験を実施した。 (D-4) Time-lapse test Specimens prepared for the compatibility test were weighed, and a time-course test was conducted under the conditions shown in Table 1.
配合性試験用に調製した検体を秤取し、表１に示す条件の経時試験を実施した。 (D-4) Time-lapse test Specimens prepared for the compatibility test were weighed, and a time-course test was conducted under the conditions shown in Table 1.
配合性検体の調製
湿式で調製した配合性試験検体の乾燥減量を表２に示す。 Preparation of compatibility test samples Table 2 shows the drying loss of the compatibility test samples prepared by wet method.
湿式で調製した配合性試験検体の乾燥減量を表２に示す。 Preparation of compatibility test samples Table 2 shows the drying loss of the compatibility test samples prepared by wet method.
（結果）
（Ｄ－４）で示す加速条件で経時試験を実施し、含量、類縁物質及び外観変化を確認した。
（含量）各経時試験の開始時と終了時の含量変化を確認した。いずれの添加剤についても大きな含量低下を認めなかった。
（類縁物質）各経時試験の開始時と終了時の類縁物質の量の変化を確認した。開始時の類縁物質の量は０．０２％程度であり、終了時においても０．０２～０．０３％程度であった。なお、カルメロース、クロスカルメロースナトリウム、乳糖、キシリトール、無水リン酸水素カルシウム、粉糖、ヒプロメロースにおいて、僅かに類縁物質が増加する傾向を認めた。
（外観変化）各経時試験の開始時と終了時の色差を確認した。色差はΔＥで表した。ΔＥは以下の式から算出した。ただし、Ｌは明度、ａは色度 （＋：赤色度、－：緑色度）、ｂは色度 （＋：黄色度、－：青色度）を示す。また、表３に色差計による外観判定基準を示す。
ΔＥ＝{(ΔＬ)2＋(Δａ)2＋(Δｂ)2}1/2 (result)
A time-lapse test was conducted under the accelerated conditions shown in (D-4), and the content, related substances, and changes in appearance were confirmed.
(Content) Changes in content were confirmed at the start and end of each time-course test. No significant decrease in content was observed for any of the additives.
(Related substances) Changes in the amount of related substances at the start and end of each time-course test were confirmed. The amount of related substances at the beginning was about 0.02%, and at the end it was also about 0.02 to 0.03%. In addition, a slight tendency for related substances to increase was observed in carmellose, croscarmellose sodium, lactose, xylitol, anhydrous calcium hydrogen phosphate, powdered sugar, and hypromellose.
(Appearance change) The color difference at the beginning and end of each aging test was confirmed. Color difference was expressed as ΔE. ΔE was calculated from the following formula. Here, L indicates lightness, a indicates chromaticity (+: redness, -: greenness), and b indicates chromaticity (+: yellowness, -: blueness). Furthermore, Table 3 shows the appearance criteria determined by a color difference meter.
ΔE={(ΔL) 2 +(Δa) 2 +(Δb) 2 } 1/2
（Ｄ－４）で示す加速条件で経時試験を実施し、含量、類縁物質及び外観変化を確認した。
（含量）各経時試験の開始時と終了時の含量変化を確認した。いずれの添加剤についても大きな含量低下を認めなかった。
（類縁物質）各経時試験の開始時と終了時の類縁物質の量の変化を確認した。開始時の類縁物質の量は０．０２％程度であり、終了時においても０．０２～０．０３％程度であった。なお、カルメロース、クロスカルメロースナトリウム、乳糖、キシリトール、無水リン酸水素カルシウム、粉糖、ヒプロメロースにおいて、僅かに類縁物質が増加する傾向を認めた。
（外観変化）各経時試験の開始時と終了時の色差を確認した。色差はΔＥで表した。ΔＥは以下の式から算出した。ただし、Ｌは明度、ａは色度 （＋：赤色度、－：緑色度）、ｂは色度 （＋：黄色度、－：青色度）を示す。また、表３に色差計による外観判定基準を示す。
ΔＥ＝{(ΔＬ)2＋(Δａ)2＋(Δｂ)2}1/2 (result)
A time-lapse test was conducted under the accelerated conditions shown in (D-4), and the content, related substances, and changes in appearance were confirmed.
(Content) Changes in content were confirmed at the start and end of each time-course test. No significant decrease in content was observed for any of the additives.
(Related substances) Changes in the amount of related substances at the start and end of each time-course test were confirmed. The amount of related substances at the beginning was about 0.02%, and at the end it was also about 0.02 to 0.03%. In addition, a slight tendency for related substances to increase was observed in carmellose, croscarmellose sodium, lactose, xylitol, anhydrous calcium hydrogen phosphate, powdered sugar, and hypromellose.
(Appearance change) The color difference at the beginning and end of each aging test was confirmed. Color difference was expressed as ΔE. ΔE was calculated from the following formula. Here, L indicates lightness, a indicates chromaticity (+: redness, -: greenness), and b indicates chromaticity (+: yellowness, -: blueness). Furthermore, Table 3 shows the appearance criteria determined by a color difference meter.
ΔE={(ΔL) 2 +(Δa) 2 +(Δb) 2 } 1/2
試験の結果、クロスカルメロースナトリウム、カルボキシメチルデンプンナトリウム、粉糖は明らかな色調変化を認めた。また、製剤中への含有量が多くなる賦形剤においては、粉糖ほどではないが、Ｄ－マンニトール以外の賦形剤において、色調変化が観察された。賦形剤の中では、Ｄ－マンニトールの色調変化がもっとも少なかった。結果を表４に示す。
As a result of the test, clear color changes were observed for croscarmellose sodium, carboxymethyl starch sodium, and powdered sugar. Further, among excipients whose content in the formulation is increased, color changes were observed for excipients other than D-mannitol, although not as much as powdered sugar. Among the excipients, D-mannitol caused the least color change. The results are shown in Table 4.
（実施例２）
上記実施例１の結果に基づき、崩壊剤として部分アルファー化デンプン、賦形剤としてＤ－マンニトール、結合剤としてポビドン、滑沢剤としてステアリン酸マグネシウムを用いて、式（ＩＩ）で示される化合物の水和物を含有する医薬組成物を製造した。
部分アルファー化デンプン、Ｄ－マンニトールを攪拌造粒機で混合して、混合末を製造した。その後、撹拌造粒機において、当該混合末に、式（ＩＩ）で示される化合物の水和物、ポビドンを含有する水を添加して、湿式造粒し、顆粒を製造した。さらに、当該顆粒に対して、部分アルファー化デンプンおよびステアリン酸マグネシウムをコンテナブレンダーで混合し、混合顆粒を製造した。当該混合顆粒をロータリー式打錠機で打錠し、錠剤を製造した。 (Example 2)
Based on the results of Example 1 above, using partially pregelatinized starch as a disintegrant, D-mannitol as an excipient, povidone as a binder, and magnesium stearate as a lubricant, a compound of formula (II) was prepared. A pharmaceutical composition containing a hydrate was prepared.
Partially pregelatinized starch and D-mannitol were mixed in a stirring granulator to produce a mixed powder. Thereafter, water containing povidone, a hydrate of the compound represented by formula (II), was added to the mixed powder in a stirring granulator, and wet granulation was performed to produce granules. Furthermore, partially pregelatinized starch and magnesium stearate were mixed with the granules using a container blender to produce mixed granules. The mixed granules were compressed using a rotary tablet machine to produce tablets.
上記実施例１の結果に基づき、崩壊剤として部分アルファー化デンプン、賦形剤としてＤ－マンニトール、結合剤としてポビドン、滑沢剤としてステアリン酸マグネシウムを用いて、式（ＩＩ）で示される化合物の水和物を含有する医薬組成物を製造した。
部分アルファー化デンプン、Ｄ－マンニトールを攪拌造粒機で混合して、混合末を製造した。その後、撹拌造粒機において、当該混合末に、式（ＩＩ）で示される化合物の水和物、ポビドンを含有する水を添加して、湿式造粒し、顆粒を製造した。さらに、当該顆粒に対して、部分アルファー化デンプンおよびステアリン酸マグネシウムをコンテナブレンダーで混合し、混合顆粒を製造した。当該混合顆粒をロータリー式打錠機で打錠し、錠剤を製造した。 (Example 2)
Based on the results of Example 1 above, using partially pregelatinized starch as a disintegrant, D-mannitol as an excipient, povidone as a binder, and magnesium stearate as a lubricant, a compound of formula (II) was prepared. A pharmaceutical composition containing a hydrate was prepared.
Partially pregelatinized starch and D-mannitol were mixed in a stirring granulator to produce a mixed powder. Thereafter, water containing povidone, a hydrate of the compound represented by formula (II), was added to the mixed powder in a stirring granulator, and wet granulation was performed to produce granules. Furthermore, partially pregelatinized starch and magnesium stearate were mixed with the granules using a container blender to produce mixed granules. The mixed granules were compressed using a rotary tablet machine to produce tablets.
医薬組成物中の各含量を表５に示す。
The respective contents in the pharmaceutical composition are shown in Table 5.
（実施例３）
実施例２の医薬組成物について、経時安定性試験を実施した。その結果、含量、類縁物質、外観変化とも、問題を認めなかった。 (Example 3)
A stability test over time was conducted on the pharmaceutical composition of Example 2. As a result, no problems were found in terms of content, related substances, or changes in appearance.
実施例２の医薬組成物について、経時安定性試験を実施した。その結果、含量、類縁物質、外観変化とも、問題を認めなかった。 (Example 3)
A stability test over time was conducted on the pharmaceutical composition of Example 2. As a result, no problems were found in terms of content, related substances, or changes in appearance.
（実施例４）
実施例２の医薬組成物について、日本薬局方一般試験法「崩壊試験法」に従い、崩壊試験器を用いて崩壊時間を測定した。補助盤は使用せず、試験液には精製水を用いた。実施例２の医薬組成物６個について測定した結果，崩壊時間は３分２３秒～４分５秒であり，良好な崩壊性を示した。 (Example 4)
Regarding the pharmaceutical composition of Example 2, the disintegration time was measured using a disintegration tester according to the Japanese Pharmacopoeia General Test Method "Disintegration Test Method". No auxiliary panel was used, and purified water was used as the test liquid. As a result of measurement of six pharmaceutical compositions of Example 2, the disintegration time was 3 minutes 23 seconds to 4 minutes 5 seconds, indicating good disintegration properties.
実施例２の医薬組成物について、日本薬局方一般試験法「崩壊試験法」に従い、崩壊試験器を用いて崩壊時間を測定した。補助盤は使用せず、試験液には精製水を用いた。実施例２の医薬組成物６個について測定した結果，崩壊時間は３分２３秒～４分５秒であり，良好な崩壊性を示した。 (Example 4)
Regarding the pharmaceutical composition of Example 2, the disintegration time was measured using a disintegration tester according to the Japanese Pharmacopoeia General Test Method "Disintegration Test Method". No auxiliary panel was used, and purified water was used as the test liquid. As a result of measurement of six pharmaceutical compositions of Example 2, the disintegration time was 3 minutes 23 seconds to 4 minutes 5 seconds, indicating good disintegration properties.
（実施例５）
実施例２の医薬組成物について、溶出試験を実施した。試験液に水９００ｍＬを用い、パドル法により、毎分５０回転で試験を行った。実施例２の医薬組成物１個をとり、試験を開始し、５、１０、１５、３０分後にそれぞれ溶出液４ｍＬを正確にとり、孔径０．４５μｍのメンブランフィルターでろ過し、初めのろ液２ｍＬを除き、次のろ液を試験溶液とした。別に式（ＩＩ）で示される化合物の水和物標準物質約２５ｍｇを精密に量り、水に溶かし、正確に５０ｍＬとした。この液５ｍＬを正確に量り、水を加えて５０ｍＬとした。この液３ｍＬを正確に量り、水を加えて正確に５０ｍＬとし、標準溶液とした。試験溶液及び標準溶液５０μＬずつを正確にとり、次の条件で液体クロマトグラフィーにより試験を行い、それぞれの式（ＩＩ）で示される化合物のピーク面積を測定した。
試験条件
検出器：紫外吸光光度計（測定波長：２１０ｍｍ）
カラム：内径４．６ｍｍ、長さ５ｃｍのステンレス管に３μｍの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填した（Ｄｅｖｅｌｏｓｉｌ ＯＤＳ－ＨＧ（野村化学）又は同等のもの
カラム温度：４５℃付近の一定温度
移動相：水／液体クロマトグラフィー用アセトニトリル溶液（８３：１７）
液量：式（ＩＩ）で示される化合物の保持時間が約４分になるように調整した。
上記試験の結果、本発明の医薬組成物は、速やかな溶出挙動を示した。結果を図１に示す。 (Example 5)
A dissolution test was conducted on the pharmaceutical composition of Example 2. Using 900 mL of water as the test solution, the test was conducted at 50 revolutions per minute by the paddle method. One piece of the pharmaceutical composition of Example 2 was taken, the test was started, and after 5, 10, 15, and 30 minutes, 4 mL of each eluate was accurately taken, filtered through a membrane filter with a pore size of 0.45 μm, and 2 mL of the initial filtrate was The following filtrate was used as the test solution. Separately, about 25 mg of a hydrate standard substance of the compound represented by formula (II) was accurately weighed and dissolved in water to make exactly 50 mL. 5 mL of this liquid was accurately measured and water was added to make 50 mL. Accurately measured 3 mL of this solution, added water to make exactly 50 mL, and used it as a standard solution. Accurately 50 μL each of the test solution and standard solution were taken and tested by liquid chromatography under the following conditions, and the peak area of each compound represented by formula (II) was measured.
Test conditions Detector: Ultraviolet absorption photometer (measurement wavelength: 210mm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 cm filled with 3 μm octadecylsilylated silica gel for liquid chromatography (Develosil ODS-HG (Nomura Chemical) or equivalent Column temperature: Constant temperature around 45°C Movement Phase: water/acetonitrile solution for liquid chromatography (83:17)
Liquid amount: Adjusted so that the retention time of the compound represented by formula (II) was about 4 minutes.
As a result of the above test, the pharmaceutical composition of the present invention showed rapid dissolution behavior. The results are shown in Figure 1.
実施例２の医薬組成物について、溶出試験を実施した。試験液に水９００ｍＬを用い、パドル法により、毎分５０回転で試験を行った。実施例２の医薬組成物１個をとり、試験を開始し、５、１０、１５、３０分後にそれぞれ溶出液４ｍＬを正確にとり、孔径０．４５μｍのメンブランフィルターでろ過し、初めのろ液２ｍＬを除き、次のろ液を試験溶液とした。別に式（ＩＩ）で示される化合物の水和物標準物質約２５ｍｇを精密に量り、水に溶かし、正確に５０ｍＬとした。この液５ｍＬを正確に量り、水を加えて５０ｍＬとした。この液３ｍＬを正確に量り、水を加えて正確に５０ｍＬとし、標準溶液とした。試験溶液及び標準溶液５０μＬずつを正確にとり、次の条件で液体クロマトグラフィーにより試験を行い、それぞれの式（ＩＩ）で示される化合物のピーク面積を測定した。
試験条件
検出器：紫外吸光光度計（測定波長：２１０ｍｍ）
カラム：内径４．６ｍｍ、長さ５ｃｍのステンレス管に３μｍの液体クロマトグラフィー用オクタデシルシリル化シリカゲルを充填した（Ｄｅｖｅｌｏｓｉｌ ＯＤＳ－ＨＧ（野村化学）又は同等のもの
カラム温度：４５℃付近の一定温度
移動相：水／液体クロマトグラフィー用アセトニトリル溶液（８３：１７）
液量：式（ＩＩ）で示される化合物の保持時間が約４分になるように調整した。
上記試験の結果、本発明の医薬組成物は、速やかな溶出挙動を示した。結果を図１に示す。 (Example 5)
A dissolution test was conducted on the pharmaceutical composition of Example 2. Using 900 mL of water as the test solution, the test was conducted at 50 revolutions per minute by the paddle method. One piece of the pharmaceutical composition of Example 2 was taken, the test was started, and after 5, 10, 15, and 30 minutes, 4 mL of each eluate was accurately taken, filtered through a membrane filter with a pore size of 0.45 μm, and 2 mL of the initial filtrate was The following filtrate was used as the test solution. Separately, about 25 mg of a hydrate standard substance of the compound represented by formula (II) was accurately weighed and dissolved in water to make exactly 50 mL. 5 mL of this liquid was accurately measured and water was added to make 50 mL. Accurately measured 3 mL of this solution, added water to make exactly 50 mL, and used it as a standard solution. Accurately 50 μL each of the test solution and standard solution were taken and tested by liquid chromatography under the following conditions, and the peak area of each compound represented by formula (II) was measured.
Test conditions Detector: Ultraviolet absorption photometer (measurement wavelength: 210mm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 cm filled with 3 μm octadecylsilylated silica gel for liquid chromatography (Develosil ODS-HG (Nomura Chemical) or equivalent Column temperature: Constant temperature around 45°C Movement Phase: water/acetonitrile solution for liquid chromatography (83:17)
Liquid amount: Adjusted so that the retention time of the compound represented by formula (II) was about 4 minutes.
As a result of the above test, the pharmaceutical composition of the present invention showed rapid dissolution behavior. The results are shown in Figure 1.
本発明の医薬組成物は、脊髄小脳変性症、パーキンソン病等の中枢神経系の疾患の予防及び／又は治療において有用である。
The pharmaceutical composition of the present invention is useful in the prevention and/or treatment of central nervous system diseases such as spinocerebellar degeneration and Parkinson's disease.
Claims (8)
- 式（Ｉ）：
で示される化合物、その塩、またはそれらの溶媒和物、及び
部分アルファー化デンプン、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、カルメロース及びクロスポビドンからなる群から選択される１又はそれ以上の崩壊剤を含有し、
賦形剤としてＤ－マンニトールを含有する医薬組成物。 Formula (I):
a compound represented by, a salt thereof, or a solvate thereof, and one or more disintegrants selected from the group consisting of partially pregelatinized starch, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, and crospovidone. Contains
A pharmaceutical composition containing D-mannitol as an excipient. - 崩壊剤が部分アルファー化デンプンである、請求項１記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the disintegrant is partially pregelatinized starch.
- 結合剤及び／又は滑沢剤を含有する、請求項１または２記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, which contains a binder and/or a lubricant.
- 結合剤を含有し、当該結合剤が、ポビドン及び／又はヒプロメロースである、請求項３記載の医薬組成物。 The pharmaceutical composition according to claim 3, which contains a binder, and the binder is povidone and/or hypromellose.
- 結合剤がポビドンである、請求項４記載の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the binder is povidone.
- 滑沢剤を含有し、当該滑沢剤がステアリン酸マグネシウムである、請求項３～５のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 3 to 5, which contains a lubricant, and the lubricant is magnesium stearate.
- 式（ＩＩ）：
で示される化合物、その塩、またはそれらの溶媒和物を含有する、請求項１～６のいずれかに記載の医薬組成物。 Formula (II):
The pharmaceutical composition according to any one of claims 1 to 6, containing a compound represented by, a salt thereof, or a solvate thereof. - 式（ＩＩ）で示される化合物の水和物を含有する、請求項７記載の医薬組成物。 The pharmaceutical composition according to claim 7, which contains a hydrate of the compound represented by formula (II).
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| Application Number | Priority Date | Filing Date | Title |
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| JP2022115891 | 2022-07-20 | ||
| JP2022-115891 | 2022-07-20 |
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| WO2024019026A1 true WO2024019026A1 (en) | 2024-01-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2023/026181 WO2024019026A1 (en) | 2022-07-20 | 2023-07-18 | Bioactive peptide-containing formulation |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008867A1 (en) * | 1996-08-28 | 1998-03-05 | Shionogi & Co., Ltd. | Novel peptide derivatives having thiazolyl-alanine residue |
| WO2002004016A1 (en) * | 2000-07-11 | 2002-01-17 | Shionogi & Co., Ltd. | Enteric preparations containing physiologically active peptides |
| JP2017014198A (en) * | 2015-06-26 | 2017-01-19 | キッセイ薬品工業株式会社 | Dosage regimen of therapeutic agent of ataxia in spinocerebellar ataxia |
-
2023
- 2023-07-18 WO PCT/JP2023/026181 patent/WO2024019026A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008867A1 (en) * | 1996-08-28 | 1998-03-05 | Shionogi & Co., Ltd. | Novel peptide derivatives having thiazolyl-alanine residue |
| WO2002004016A1 (en) * | 2000-07-11 | 2002-01-17 | Shionogi & Co., Ltd. | Enteric preparations containing physiologically active peptides |
| JP2017014198A (en) * | 2015-06-26 | 2017-01-19 | キッセイ薬品工業株式会社 | Dosage regimen of therapeutic agent of ataxia in spinocerebellar ataxia |
Non-Patent Citations (1)
| Title |
|---|
| MITSUBISHI TANABE PHARMA CORPORATION: "Medical drug package insert CEREDIST Tablets 5mg/CEREDIST OD Tablets 5mg", MEDICAL DRUG PACKAGE INSERT, PMDA, JP, JP, pages 1 - 3, XP009553474, Retrieved from the Internet <URL:https://www.info.pmda.go.jp/go/pack/1190014F1033_1_06/> * |
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