WO2009104739A1 - 経口投与用固形製剤 - Google Patents
経口投与用固形製剤 Download PDFInfo
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- WO2009104739A1 WO2009104739A1 PCT/JP2009/053039 JP2009053039W WO2009104739A1 WO 2009104739 A1 WO2009104739 A1 WO 2009104739A1 JP 2009053039 W JP2009053039 W JP 2009053039W WO 2009104739 A1 WO2009104739 A1 WO 2009104739A1
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- tablet
- excipient
- starch
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- KPWSJANDNDDRMB-UHFFFAOYSA-N CN(C)C(NC1CCC(CCN(CC2)CCN2c2cccc(Cl)c2Cl)CC1)=O Chemical compound CN(C)C(NC1CCC(CCN(CC2)CCN2c2cccc(Cl)c2Cl)CC1)=O KPWSJANDNDDRMB-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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 a solid preparation for oral administration of cariprazine hydrochloride useful as a therapeutic agent for schizophrenia and the like.
- Patent Document 1 describes that cariprazine hydrochloride of the following formula is a D3 / D2 receptor antagonist and is useful as a therapeutic agent for schizophrenia and the like.
- a formulation example of a tablet containing a compound of general formula (I) containing cariprazine hydrochloride as an active ingredient and containing cyclodextrin is disclosed as follows.
- cyclodextrin has effects such as improving the solubility of pharmaceutical compounds in water, improving bioavailability, and reducing bitterness (masking), and is applied to pharmaceuticals.
- cyclodextrin is expected to have a stabilizing effect
- when cyclodextrin is used as a pharmaceutical additive the effects on the pharmacokinetics and efficacy of drug inclusion and other concomitant drugs are unclear. is there. From these points, a solid preparation for oral administration which does not contain cyclodextrin and can stably store cariprazine hydrochloride is desired.
- the subject of this invention is providing the said solid preparation for oral administration.
- cariprazine hydrochloride As a result of intensive studies on various solid preparations containing cariprazine hydrochloride, the present inventors have found that when mannitol or anhydrous calcium hydrogen phosphate is partly used as an excipient and only crystalline cellulose is used, the related substances are Although it was produced in large quantities, it was found that if lactose was used as the main excipient, cariprazine hydrochloride could be stably stored without adding cyclodextrin, and the present invention was completed.
- the present invention is as follows.
- the solid preparation for oral administration of the present invention can stably store cariprazine hydrochloride without adding cyclodextrin.
- FIG. It is a figure which shows the time-dependent change of the analog in the tablet obtained in Example 4.
- FIG. It is a figure which shows the time-dependent change of the analog in the tablet obtained in Example 8. It is a figure which shows the time-dependent change of the analog in the tablet obtained in Example 9. It is a figure which shows the time-dependent change of the analog in the tablet obtained in Example 10. It is a figure which shows the time-dependent hardness change in the tablet obtained in Example 18 and 20.
- the compounding amount of cariprazine hydrochloride is usually 0.01 to 70% by weight per tablet, preferably 0.1 to 50% by weight, more preferably 0.4 to 10% by weight.
- the main excipient refers to an excipient contained in the excipient in an amount of 50% by weight or more, and lactose is used as the main excipient in the solid preparation of the present invention.
- Other excipients used include crystalline cellulose and starch (such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and porous starch).
- Crystalline cellulose and starch have water retention properties, and by adding some of these to excipients, variation between production lots of solid preparations during wet granulation can be suppressed, and filling into the die during tableting Is improved.
- Preferred excipients are: (a) an excipient in which 50-100% by weight of lactose is lactose, 0-50% by weight is crystalline cellulose, and 0-35% by weight is starch, (B) In the total amount of excipient, 60 to 100% by weight is lactose, 0 to 29% by weight is crystalline cellulose, and 0 to 11% by weight is starch, (c) Total amount of excipient Among them, an excipient in which 70 to 100% by weight is lactose, 0 to 25% by weight is crystalline cellulose, and 0 to 5% by weight is starch, (d) 80 to 95% by weight in the total amount of the excipient Include lactose, 5-20% by weight crystalline cellulose, and excip
- the excipient can be used in an amount of 5 to 99.9% by weight, preferably 80 to 95% by weight per tablet.
- binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, polyvinylpyrrolidone, popidone, polyvinyl alcohol, gum arabic powder, gelatin, pullulan and the like, preferably hydroxypropylcellulose. These can be used in an amount of 0.5 to 10% by weight, preferably 1 to 5% by weight per tablet.
- disintegrant carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, agar powder, etc. are used, preferably carboxymethyl starch sodium, croscarmellose sodium, low-substituted Degree hydroxypropylcellulose and the like. These are 0.1 to 15% by weight, preferably 1 to 5% by weight, per tablet.
- the preparation of the present invention may contain an appropriate amount of a fragrance, a lubricant, a colorant and the like and various additives used for the production of general preparations as long as the effect of the invention is not hindered.
- the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium stearyl fumarate and the like.
- the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and iron sesquioxide.
- the solid preparation of the present invention when produced, it is known for the purpose of further masking of taste and odor, enteric or sustained release, etc., after coating fine cores with active ingredients, additives, etc. You may mix and use the thing coated by the method of.
- Examples of the solid preparation of the present invention include tablets, capsules, granules, pills, etc. Among them, tablets are preferable.
- the shape of the tablet is not particularly limited, and it may be any of a tablet such as a round tablet, an oval tablet, an oblong tablet, and a coated tablet thereof.
- the solid preparation of the present invention may be a grouped tablet formed by mixing two or more types of granules: a multi-layered tablet such as a double-layered tablet or a three-layered tablet: a dry-coated tablet: a press-coated tablet.
- the solid preparation of the present invention comprises, for example, cariprazine hydrochloride, an excipient, a binder and / or a disintegrant, a high-speed stirring granulator, a fluidized bed granulator / dryer, a centrifugal rolling fluidized bed granulated coating machine or a kneader. It can be produced by wet granulation using water or a binder solution using a device such as the above, mixing / spraying a lubricant on this, and then compression molding.
- cariprazine hydrochloride, an excipient and / or a binder are dry granulated using an apparatus such as a roller compactor, and then a disintegrating agent (further containing a lubricant, etc.). Or may be produced by compression molding after mixing / spraying.
- V-type mixer a VM-10 manufactured by Fuji Paudal or a TCV-20 manufactured by Deoksugaku Kosakusho was used.
- tableting machine AQUA0518SS2AII or VIRG0518SS2AZ manufactured by Kikusui Seisakusho was used.
- unit of compression pressure stampUA: kgf, VIRG: kN.
- Example 1 Each component described in the column of dry powder in Table 1 was charged into a high speed stirring and mixing granulator, mixed, and then granulated by adding water. This was dried with a rolling fluidized bed granulator / dryer to obtain a dry powder. The obtained dry powder and each component described in Table 1 were mixed with a V-type mixer to obtain a tablet powder. This tablet bulk powder was compression-molded (tablet diameter 7 mm, curvature radius 10 mm) to produce tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet.
- Example 2 The ingredients listed in Table 1 were mixed, and tablets (120 mg) containing 2.5 mg of cariprazine hydrochloride per tablet were produced in the same manner as in Example 1 (high-speed stirring granulation method).
- Example 3 Each component (excluding the binder) described in the column of dry powder in Table 1 was charged into a high-speed stirring mixing granulator and mixed. This mixed product was charged and fluidized in a fluidized bed granulator / dryer, and fluidized bed granulated using a binding liquid adjusted with the binder amount shown in Table 1, and then dried in a layer to obtain a dry powder. The dried powder was sized with a sizing machine, and the obtained sized powder and each component described in Table 1 were mixed with a V-type mixer to obtain a tablet raw powder. This tablet bulk powder was compression-molded (tablet diameter 7 mm, curvature radius 10 mm) to produce tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet.
- Example 4 The ingredients listed in Table 1 were mixed, and tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet were produced by the same method as in Example 3 (fluidized bed granulation method).
- Example 5 Each component (excluding the binder) described in the column of dry powder in Table 2 was charged into a high-speed stirring mixing granulator and mixed. This mixed product was charged and fluidized in a fluidized bed granulator / dryer, fluidized bed granulated using a binding solution adjusted with the binder amount shown in the table, and then dried in a layer to obtain a dry powder. The dried powder was sized with a sizing machine, and the obtained sized powder and each component described in the column of tablet raw powder mixing in Table 2 were mixed with a V-type mixer to obtain a tablet raw powder. This tablet bulk powder was compression-molded (tablet diameter 7 mm flat corner) to produce tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet.
- Example 6 to 19 The components listed in Table 2 were mixed and produced by the same method as in Example 5 (fluidized bed granulation method).
- the tablet mass per tablet was 120 mg, and the content was produced according to the component contents shown in Table 2.
- Examples 20-33 The components listed in Table 3 were mixed and produced by the same method as in Example 5 (fluidized bed granulation method).
- the tablet mass per tablet was 120 mg, and the content was produced according to the component contents shown in Table 3.
- This tablet bulk powder was compression-molded (tablet diameter 7 mm flat corner) to produce tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet. Except for changing lactose hydrate to D-mannitol, the blending amount and production method are the same as those in Example 5.
- Comparative Example 2 Ingredients listed in Table 4 were charged into a laboratory universal powder processing apparatus and mixed to obtain a tablet bulk powder. This tablet bulk powder was compression-molded (tablet diameter 7 mm flat corner) to produce tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet.
- Comparative Example 3 Ingredients listed in Table 4 were charged into a laboratory universal powder processing apparatus and mixed to obtain a tablet bulk powder. This tablet bulk powder was compression-molded (tablet diameter 7 mm flat corner) to produce tablets (120 mg) containing 0.5 mg of cariprazine hydrochloride per tablet.
- Example 1 Stability test The tablets obtained in Example 4 were subjected to PTP (PVC) blister packaging (PVC molded sheet: Daiwa Kasei Kogyo, PVC aluminum foil: Daiwa Kasei Kogyo, 10 tablets / sheet), and PTP packaging I got a product.
- PTP PVC
- PVC PVC blister packaging
- PVC aluminum foil Daiwa Kasei Kogyo
- 10 tablets / sheet PTP packaging I got a product.
- PTP aluminum bags can be obtained by placing 10 sheets in an aluminum gusset bag (Okada Paper Industry) and heat-sealing with a heat sealer (Fuji Impulse).
- Example 2 Stability Test The tablets obtained in Example 8, Example 9 and Example 10 were packaged in the same manner as in Experimental Example 1 to obtain a PTP packaged product and a PTP aluminum packaged product. About the obtained PTP packaged product and PTP aluminum bag packaged product, the stability test was implemented by storing in a constant temperature and humidity chamber at a temperature of 40 ° C. and a relative humidity of 75%. The storage period is 1 month, 2 months, 3 months and 6 months for all packaging forms, and the related substances are taken out and confirmed by high performance liquid chromatography. The difference in the ratio of related substances at each time point from the start of storage was observed over time (FIGS. 2, 3 and 4). As shown in FIGS. 1, 2, 3 and 4 obtained in Experimental Examples 1 and 2, all of the tablets of Examples 4, 8, 9 and 10 did not produce much related substances and were stable in storage. Is excellent. In addition, the packaging form with higher moisture-proof property tended to produce more related substances.
- Comparative Example 3 the related substance 2 was remarkably increased. From the above, when mannitol, anhydrous calcium hydrogen phosphate is used as an excipient, or when only crystalline cellulose is used, a large amount of analogs are produced, and it is not preferable to use these as excipients. Was confirmed. On the other hand, it was found that if lactose was used as the main excipient, cariprazine hydrochloride could be stored chemically and stably.
- Experimental Example 4 For the tablets obtained in Examples 18 and 20, a PTP packaged product, a PTP aluminum bag packaged product, and a PTP silica gel aluminum bag packaged product were obtained in the same manner as in Experimental Example 1. Each obtained packaged product was stored in a constant temperature and humidity chamber at a temperature of 40 ° C. and a relative humidity of 75%, and a stability test was performed. The storage period was 6 months, and the water activity value of the tablets was measured after each removal. The analog was then confirmed by high performance liquid chromatography. Table 6 shows the water activity value of the tablet in Example 18 and the production amount of the related substance, and Table 7 shows the water activity value of the tablet in Example 20 and the production amount of the related substance.
- Example 18 is the same prescription and manufacturing method except the point which increased the binding liquid addition amount of Example 14 from 2% to 3% of the whole, and reduced the amount of the increase corn starch. As shown in Tables 6 and 7, it was confirmed that the tablet of Example 20 was more stable than the tablet of Example 18, was particularly stable under low humidity, and was less dependent on humidity. That is, it turned out that the tablet which does not use starch as an excipient
- Experimental Example 5 Stability Test The PTP packaged product (Examples 18 and 20) used in Experimental Example 4 was stored in a constant temperature and humidity room at a temperature of 40 ° C. and a relative humidity of 75%, and a stability test was performed. The storage period was 0.25, 0.5, 1, 2, 3, 6 months, the hardness was measured after removal, and the change in hardness over time was observed (FIG. 5). As shown in FIG. 5, the tablet of Example 18 showed a significant decrease in hardness. Usually, since 20N or more is desired as a hardness that does not cause a problem in handling, this tablet may have a problem in storage in a high humidity environment. On the other hand, with the tablet of Example 20, the result of staying within the allowable hardness reduction was obtained.
- filler is more excellent.
- the compression pressure at the time of tableting can give the same hardness with the direction of Example 20 being low pressure, and has the outstanding manufacturability.
- the present invention provides a solid preparation for oral administration which can stably store cariprazine hydrochloride without adding cyclodextrin.
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Abstract
Description
同公報の第27頁には、塩酸カリプラジンを含む一般式(I)の化合物を有効成分とし、シクロデキストリンを含有する錠剤の処方例が下記の通り、開示されている。
「式(I)の化合物 1~40mg
希釈剤/充填剤(シクロデキストリンも含み得る) 50~250mg
結合剤 5~25mg
崩壊剤(シクロデキストリンも含み得る) 5~50mg
滑剤 1~5mg
シクロデキストリン 1~100mg
希釈剤:例えば微晶質セルロース、ラクトース、デンプン。
結合剤:例えばポリビニルピロリドン、ヒドロキシプロピルメチルセルロース。
崩壊剤:例えばデンプングリコール酸ナトリウム、クロスポピドン。
滑剤 :例えばステアリン酸マグネシウム、ステアリルフマル酸ナトリウム。」
(1) 主賦形剤として乳糖を使用し、塩酸カリプラジンを含有する経口投与用固形製剤。
(2) 乳糖以外に使用される賦形剤が結晶セルロース及び/又はデンプンである(1)記載の固形製剤。
(3) 賦形剤全量中、50~100重量%が乳糖であり、0~50重量%が結晶セルロースであり、0~35重量%がデンプンである(2)記載の固形製剤。
(4) 賦形剤全量中、60~100重量%が乳糖であり、0~29重量%が結晶セルロースであり、0~11重量%がデンプンである(2)記載の固形製剤。
(5) 賦形剤全量中、70~100重量%が乳糖であり、0~25重量%が結晶セルロースであり、0~5重量%がデンプンである(2)記載の固形製剤。
(6) 賦形剤全量中、80~95重量%が乳糖であり、5~20重量%が結晶セルロースであり、デンプンを含まない(2)記載の固形製剤。
(7) ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、エチルセルロース、メチルセルロース、ポビドン及びポリビニルアルコールから少なくとも1種選ばれる結合剤を使用する(1)~(6)のいずれか記載の固形製剤。
(8) カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、カンテン末及びクロスポビドンから少なくとも1種選ばれる崩壊剤を使用する(1)~(7)のいずれか記載の固形製剤。
(9) 塩酸カリプラジン、賦形剤、結合剤、及び必要に応じて崩壊剤を混合及び造粒して、これに崩壊剤及び滑沢剤を混合したのち圧縮成型することを特徴とする錠剤である(1)~(8)のいずれか記載の固形製剤。
主賦形剤とは、賦形剤全量中50重量%以上含まれる賦形剤を言い、本発明の固形製剤において乳糖が主賦形剤として使用される。その他に使用される賦形剤としては、結晶セルロース及びデンプン(トウモロコシデンプン、馬鈴薯デンプン、コムギデンプン、コメデンプン、部分アルファー化デンプン、有孔デンプン等)等が挙げられる。結晶セルロース及びデンプンは保水性を有しており、これらを一部賦形剤に加えることで、湿式造粒の際に固形製剤の製造ロット間のばらつきを抑制でき、打錠時に臼への充填性が向上される。好ましい賦形剤としては、(a)賦形剤全量中、50~100重量%が乳糖であり、0~50重量%が結晶セルロースであり、0~35重量%がデンプンである賦形剤、(b)賦形剤全量中、60~100重量%が乳糖であり、0~29重量%が結晶セルロースであり、0~11重量%がデンプンである賦形剤、(c) 賦形剤全量中、70~100重量%が乳糖であり、0~25重量%が結晶セルロースであり、0~5重量%がデンプンである賦形剤、(d)賦形剤全量中、80~95重量%が乳糖であり、5~20重量%が結晶セルロースであり、デンプンを含まない賦形剤が挙げられる。なお、デンプンを使用しないか、あるいは使用量を低く抑えることで、固形製剤の硬度低下を抑えることができ、また湿度の如何に関わらず、塩酸カリプラジンを安定に保存できるため、好ましい。賦形剤は1錠あたり5~99.9重量%、好ましくは80~95重量%を用いることができる。
崩壊剤としては、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、カンテン末等が用いられ、好ましくはカルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース等が挙げられる。これらは1錠あたり0.1~15重量%、好ましくは1~5重量%である。
高速攪拌混合造粒機は、パウレック社製FM-VG-10又はFM-VG-25を使用した。転動流動層造粒乾燥機は、パウレック社製MP-01を使用した。流動層造粒乾燥機は、フロイント産業社製FLO-5/2SJ、又はパウレック社製MP-01を使用した。整粒機は、パウレック社製QC-197S、0.991mm丸穴スクリーンを使用した。V型混合機は、不二パウダル社製VM-10、又は徳寿工作所製TCV-20を使用した。打錠機は菊水製作所製AQUA0518SS2AII、またはVIRG0518SS2AZを使用した。なお圧縮圧力(打圧)の単位については、機器表示単位(AQUA:kgf、VIRG:kN)にて表中に記載した。
表1の乾燥末の欄に記載の各成分を高速攪拌混合造粒機に仕込み、混合した後、水を添加して造粒した。これを転動流動層造粒乾燥機で乾燥し、乾燥末を得た。得られた乾燥末と、表1の錠原末混合の欄に記載の各成分をV型混合機にて混合し、錠原末を得た。この錠原末を圧縮成型(錠剤直径7mm、曲率半径10mm)し、1錠当たり塩酸カリプラジン0.5mgを含有する錠剤(120mg)を製造した。
表1記載の成分を混合し、実施例1と同一の方法(高速攪拌造粒法)にて1錠あたり塩酸カリプラジン2.5mgを含む錠剤(120mg)を製造した。
表1の乾燥末の欄に記載の各成分(結合剤を除く)を高速攪拌混合造粒機に仕込み混合した。この混合品を流動層造粒乾燥機に仕込み流動させ、表1記載の結合剤量にて調整した結合液を用いて流動層造粒した後、層内で乾燥し、乾燥末を得た。乾燥末を整粒機にて整粒し、得られた整粒末と表1の錠原末混合の欄に記載の各成分をV型混合機にて混合し、錠原末を得た。この錠原末を圧縮成型(錠剤直径7mm、曲率半径10mm)し、1錠当たり塩酸カリプラジン0.5mgを含有する錠剤(120mg)を製造した。
表2の乾燥末の欄に記載の各成分(結合剤を除く)を高速攪拌混合造粒機に仕込み混合した。この混合品を流動層造粒乾燥機に仕込み流動させ、表記載の結合剤量にて調整した結合液を用いて流動層造粒した後、層内で乾燥し、乾燥末を得た。乾燥末を整粒機にて整粒し、得られた整粒末と表2の錠原末混合の欄に記載の各成分をV型混合機にて混合し、錠原末を得た。この錠原末を圧縮成型(錠剤直径7mm平面隅角)し、1錠当たり塩酸カリプラジン0.5mgを含有する錠剤(120mg)を製造した。
表2記載の成分を混合し、実施例5と同一の方法(流動層造粒法)にて製造した。1錠あたりの錠剤質量は120mg、含量は表2記載の成分含量に従って製造した。
表4の乾燥末の欄に記載の各成分(結合剤を除く)をラボ用万能粉粒体処理装置(メカノミル、岡田精工)に仕込み混合した。この混合品を流動層造粒乾燥機に仕込み流動させ、表記載の結合剤量にて調整した結合液を用いて流動層造粒した後、層内で乾燥し、乾燥末を得た。乾燥末を整粒機にて整粒し、得られた整粒末と表4の錠原末混合の欄に記載の各成分をV型混合機にて混合し、錠原末を得た。この錠原末を圧縮成型(錠剤直径7mm平面隅角)し、1錠当たり塩酸カリプラジン0.5mgを含有する錠剤(120mg)を製造した。乳糖水和物をD-マンニトールに変更した以外は配合量・製造方法ともに実施例5と同一である。
表4記載の成分をラボ用万能粉粒体処理装置に仕込み混合し、錠原末を得た。この錠原末を圧縮成型(錠剤直径7mm平面隅角)し、1錠あたり塩酸カリプラジン0.5mgを含有する錠剤(120mg)を製造した。
表4記載の成分をラボ用万能粉粒体処理装置に仕込み混合し、錠原末を得た。この錠原末を圧縮成型(錠剤直径7mm平面隅角)し、1錠あたり、塩酸カリプラジン0.5mgを含有する錠剤(120mg)を製造した。
実験例1 安定性試験
実施例4で得た錠剤について、PTP(PVC)ブリスター包装(PVC成形シート:大和化成工業、PVC用アルミ箔:大和化成工業、10錠/シート)を実施し、PTP包装品を得た。また、防湿性の高い包装形態の比較例として、このPTP包装品について、10シートをアルミガゼット袋(岡田紙業)に入れ、ヒートシーラー(不二インパルス)でヒートシールすることにより、PTPアルミ袋包装品を、PTP包装品10シートとシリカゲル(新越化成工業、シリカゲル三方1g)1シートをアルミガゼット袋(岡田紙業)に入れ、ヒートシーラー(不二インパルス)でヒートシールすることによりPTPシリカゲルアルミ袋包装品を得た。PTP包装品、PTPアルミ袋包装品及びPTPシリカゲルアルミ袋包装品について、温度40℃相対湿度75%の恒温恒湿室に保存することで安定性試験を実施した。保存期間はいずれの包装形態も1箇月、2箇月、3箇月及び6箇月とし、それぞれ取り出してその類縁物を高速液体クロマトグラフィーによって確認し、各時点での類縁物割合の保存開始時との差について経時的に観察した(図1)。
実施例8、実施例9及び実施例10で得た錠剤について、実験例1と同様に包装を実施し、PTP包装品とPTPアルミ包装品を得た。得られたPTP包装品及びPTPアルミ袋包装品について、温度40℃相対湿度75%の恒温恒湿室に保存することで安定性試験を実施した。保存期間はいずれの包装形態も1箇月、2箇月、3箇月及び6箇月とし、それぞれ取り出してその類縁物を高速液体クロマトグラフィーによって確認し、各時点での類縁物割合の保存開始時との差について経時的に観察した(図2、図3及び図4)。
実験例1及び2で得られた図1、図2、図3及び図4の結果通り、実施例4、8、9及び10の錠剤はいずれも類縁物の生成は多くは無く、保存安定性に優れている。また、防湿性が高い包装形態ほど類縁物が多く生成する傾向も見られた。
比較例1、2、3、実施例12、14、15で得た製剤について、PTP包装品を温度60℃の恒温層に保存することで安定性試験を実施した。保存期間は2箇月とし、類縁物を高速液体クロマトグラフィーにて確認した。表5に、2箇月60℃保存条件での類縁物の生成量を示す。
実施例18、実施例20で得た錠剤について、実験例1と同一の方法にてPTP包装品、PTPアルミ袋包装品、PTPシリカゲルアルミ袋包装品を得た。得られたそれぞれの包装品を温度40℃相対湿度75%の恒温恒湿室に保存することで安定性試験を実施した。保存期間は6箇月とし、それぞれの取り出し後、錠剤の水分活性値を測定した。その後類縁物を高速液体クロマトグラフィーによって確認した。表6に、実施例18での錠剤の水分活性値と、類縁物の生成量を、表7に実施例20での錠剤の水分活性値と類縁物の生成量とを示す。水分活性測定装置には、AQUALAB(series3TE、DECAGON)を使用した。また、水分活性値の測定は、恒温恒湿室から取り出し後12時間以内に実施した。なお、実施例18は実施例14の結合液添加量を全体の2%から3%に増加し、その増加分トウモロコシデンプンを減量した点以外は同一の処方・製法である。
表6及び7の通り、実施例20の錠剤のほうが実施例18の錠剤よりも、安定性が優れており、低湿度下で特に安定であり、湿度依存性が少ないことが確認された。すなわち、賦形剤としてデンプンを用いない錠剤がより優れていることが分かった。
実験例4で使用したPTP包装品(実施例18、実施例20)を温度40℃相対湿度75%の恒温恒湿室に保存し、安定性試験を実施した。保存期間は0.25、0.5、1、2、3、6箇月とし、取り出し後に硬度を測定し、経時的な硬度変化を観察した(図5)。
図5の通り、実施例18の錠剤は著しい硬度低下が生じた。通常、取り扱いに問題がない硬度として20N以上が望まれていることから、本錠剤は高湿度環境下での保存に問題がある可能性がある。他方、実施例20の錠剤では許容範囲内の硬度低下に留まる結果が得られた。以上より、賦形剤としてデンプンを含まない錠剤がより優れていることが分かる。また、打錠時の圧縮圧が実施例20の方が低圧で同様の硬度を出すことができ、優れた製造性を有することが分かった。
Claims (9)
- 主賦形剤として乳糖を使用し、塩酸カリプラジンを含有する経口投与用固形製剤。
- 乳糖以外に使用される賦形剤が結晶セルロース及び/又はデンプンである請求項1記載の固形製剤。
- 賦形剤全量中、50~100重量%が乳糖であり、0~50重量%が結晶セルロースであり、0~35重量%がデンプンである請求項2記載の固形製剤。
- 賦形剤全量中、60~100重量%が乳糖であり、0~29重量%が結晶セルロースであり、0~11重量%がデンプンである請求項2記載の固形製剤。
- 賦形剤全量中、70~100重量%が乳糖であり、0~25重量%が結晶セルロースであり、0~5重量%がデンプンである請求項2記載の固形製剤。
- 賦形剤全量中、80~95重量%が乳糖であり、5~20重量%が結晶セルロースであり、デンプンを含まない請求項2記載の固形製剤。
- ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、エチルセルロース、メチルセルロース、ポビドン及びポリビニルアルコールから少なくとも1種選ばれる結合剤を使用する請求項1~6のいずれか記載の固形製剤。
- カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、カンテン末及びクロスポビドンから少なくとも1種選ばれる崩壊剤を使用する請求項1~7のいずれか記載の固形製剤。
- 塩酸カリプラジン、賦形剤、結合剤、及び必要に応じて崩壊剤を混合及び造粒して、これに崩壊剤及び滑沢剤を混合したのち圧縮成型することを特徴とする錠剤である請求項1~8のいずれか記載の固形製剤。
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CN2009801148592A CN102014909B (zh) | 2008-02-21 | 2009-02-20 | 口服用固体制剂 |
EP09712557A EP2251011B1 (en) | 2008-02-21 | 2009-02-20 | Solid preparation for oral administration |
KR1020137025458A KR20130115393A (ko) | 2008-02-21 | 2009-02-20 | 경구 투여용 고형 제제 |
US12/918,580 US20110059980A1 (en) | 2008-02-21 | 2009-02-20 | Solid preparation for oral administration |
JP2009520724A JP4409630B2 (ja) | 2008-02-21 | 2009-02-20 | 経口投与用固形製剤 |
CA2715760A CA2715760C (en) | 2008-02-21 | 2009-02-20 | Solid preparation for oral administration of cariprazine hydrochloride |
EA201001334A EA023972B1 (ru) | 2008-02-21 | 2009-02-20 | Стабильный твёрдый препарат карипразина для перорального введения и способ его получения |
AT09712557T ATE552002T1 (de) | 2008-02-21 | 2009-02-20 | Feste zubereitung zur oralen verabreichung |
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EP (1) | EP2251011B1 (ja) |
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- 2009-11-11 JP JP2009258219A patent/JP2010132654A/ja active Pending
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Cited By (10)
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AU2009270823B2 (en) * | 2008-07-16 | 2014-07-17 | Richter Gedeon Nyrt. | Pharmaceutical formulations containing dopamine receptor ligands |
USRE49110E1 (en) | 2008-07-16 | 2022-06-21 | Richter Gedeon Nyrt. | Pharmaceutical formulations containing dopamine receptor ligands |
USRE49302E1 (en) | 2008-07-16 | 2022-11-15 | Richter Gedeon Nyrt. | Pharmaceutical formulations containing dopamine receptor ligands |
EP3231418A1 (en) | 2016-04-14 | 2017-10-18 | Richter Gedeon Nyrt. | Granule formulation for oral administration |
WO2017178999A1 (en) | 2016-04-14 | 2017-10-19 | Richter Gedeon Nyrt. | Granule formulation for oral administration |
JP2019511513A (ja) * | 2016-04-14 | 2019-04-25 | リチュテル・ゲデオン・ヴェジェーセティ・ジャール・ニュイルヴァーノシャン・ミューコェデー・レースヴェーニュタールシャシャーグRichter Gedeon Nyrt. | 経口投与のための顆粒製剤 |
US11274087B2 (en) | 2016-07-08 | 2022-03-15 | Richter Gedeon Nyrt. | Industrial process for the preparation of cariprazine |
WO2018229641A1 (en) | 2017-06-13 | 2018-12-20 | Richter Gedeon Nyrt. | Solid preparation of cariprazine for oral administration |
JP2020523335A (ja) * | 2017-06-13 | 2020-08-06 | リヒター ゲデオン ニルバーノシャン ミーケデーレスベニュタールシャシャーグ | 経口投与用固形製剤 |
US11547707B2 (en) | 2019-04-10 | 2023-01-10 | Richter Gedeon Nyrt. | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder |
Also Published As
Publication number | Publication date |
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KR20130115393A (ko) | 2013-10-21 |
ATE552002T1 (de) | 2012-04-15 |
KR101563383B1 (ko) | 2015-10-26 |
JP4409630B2 (ja) | 2010-02-03 |
EA023972B1 (ru) | 2016-08-31 |
JPWO2009104739A1 (ja) | 2011-06-23 |
EP2251011B1 (en) | 2012-04-04 |
CN102014909B (zh) | 2013-03-13 |
KR20100117676A (ko) | 2010-11-03 |
EP2251011A4 (en) | 2011-03-02 |
JP2010132654A (ja) | 2010-06-17 |
CA2715760C (en) | 2017-06-13 |
US20110059980A1 (en) | 2011-03-10 |
EA201001334A1 (ru) | 2011-06-30 |
CA2715760A1 (en) | 2009-08-27 |
EP2251011A1 (en) | 2010-11-17 |
CN102014909A (zh) | 2011-04-13 |
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