JP2009221199A - Peroral liquid composition containing sulfodehydroabietic acid having adjusted particle size and reduced in bitter taste - Google Patents
Peroral liquid composition containing sulfodehydroabietic acid having adjusted particle size and reduced in bitter taste Download PDFInfo
- Publication number
- JP2009221199A JP2009221199A JP2009057198A JP2009057198A JP2009221199A JP 2009221199 A JP2009221199 A JP 2009221199A JP 2009057198 A JP2009057198 A JP 2009057198A JP 2009057198 A JP2009057198 A JP 2009057198A JP 2009221199 A JP2009221199 A JP 2009221199A
- Authority
- JP
- Japan
- Prior art keywords
- liquid
- sulfodehydroabietic acid
- particle size
- acid
- crospovidone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000002253 acid Substances 0.000 title claims abstract description 43
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000001509 sodium citrate Substances 0.000 claims abstract description 21
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 21
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- 230000028327 secretion Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- 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
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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
- A61K47/40—Cyclodextrins; 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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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
- A61K9/08—Solutions
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Abstract
Description
本発明は、苦味が低減され安全性を持つスルホデヒドロアビエチン酸またはその薬学的に許容可能な塩、水和物、溶媒化物の経口用液状製剤に関するものである。 The present invention relates to an oral liquid preparation of sulfodehydroabietic acid or a pharmaceutically acceptable salt, hydrate or solvate thereof having reduced bitterness and safety.
スルホデヒドロアビエチン酸またはこの塩は、酸分泌またはペプシン分泌などの抑制作用を示し、消化性潰瘍(胃潰瘍、十二指腸潰瘍)または胃炎の予防または治療剤として有用な薬物である。 Sulfodehydroabietic acid or a salt thereof exhibits a suppressive action such as acid secretion or pepsin secretion, and is a drug useful as a preventive or therapeutic agent for peptic ulcer (gastric ulcer, duodenal ulcer) or gastritis.
スルホデヒドロアビエチン酸の薬学的に許容可能な塩としては、例えば、アルカリ金属(例えば、ソジウム、リチウム、カリウムなど)課の塩、アルカリ土類金属 (例えば、マグネシウム、カルシウムなど)課の塩、及びアルミニウムのようなと同じ金属課の塩がある。これらの中で、好ましい塩はスルホデヒドロアビエチン酸のソジウム塩、特にこのモノソジウム塩またはディソジウム塩で、最も好ましい塩はスルホデヒドロアビエチン酸モノソジウム塩である。 Examples of pharmaceutically acceptable salts of sulfodehydroabietic acid include, for example, alkali metal (for example, sodium, lithium, potassium, etc.), alkaline earth metal (for example, magnesium, calcium, etc.), and There is the same metal section salt as aluminum. Among these, a preferred salt is a sodium salt of sulfodehydroabietic acid, particularly the monosodium salt or disodium salt, and the most preferred salt is monosodium sulfodehydroabietic acid.
日本公開特許公報昭和第６３-１６５３６１号にはスルホデヒドロアビエチン酸モノソジウム塩は低吸湿性でさらに安定しておりディソジウム塩よりさらに有利だと報告されている。また、スルホデヒドロアビエチン酸の薬学的に許容可能な塩は、水和物の形態として存在でき、スルホデヒドロアビエチン酸モノソジウム塩の水和物は、例えば、この５水和物、つまり、スルホデヒドロアビエチン酸モノソジウム塩５水和物でありえる。下記化学式Ｉのスルホデヒドロアビエチン酸のモノソジウム塩５水和物(化学名:(+)-(１R,４aS,１０aR)-１,２,３,４,４a,９,１０,１０a-オクタヒドロ-１,４a-ディメチル-７-(１-メチルエチル)-６-スルホ-１-フェナントレンカルボキシル酸-６-ソジウム塩５水和物)はエカベッソジウムであり公知化合物である。 Japanese published patent publication No. 63-165361 reports that monosodium sulphodehydroabietic acid is more hygroscopic and more stable and more advantageous than disodium salt. Also, a pharmaceutically acceptable salt of sulfodehydroabietic acid can exist in the form of a hydrate, and a hydrate of sulfodehydroabietic acid monosodium salt is, for example, the pentahydrate, ie, sulfodehydroabietic acid. It can be acid monosodium salt pentahydrate. Monosodium salt pentahydrate of sulfodehydroabietic acid having the following chemical formula I (chemical name: (+)-(1R, 4aS, 10aR) -1,2,3,4,4a, 9,10,10a-octahydro-1) , 4a-Dimethyl-7- (1-methylethyl) -6-sulfo-1-phenanthrenecarboxylic acid-6-sodium salt pentahydrate) is ecabesodium and is a known compound.
＜化Ｉ＞
最近、大韓民国登録特許第６０６６２１号にスルホデヒドロアビエチン酸ソジウムを２〜４W/V%の濃度含有量を含有した水溶液製剤の特許が公示されており、前記水溶液製剤は直腸または結腸に投与したり人工肛門から腸管内に投与する方法による炎症性腸疾患治療用の製剤である。 Recently, Korean Patent No. 606621 has published a patent for an aqueous solution formulation containing 2-4 W / V% of sodium sulfodehydroabietic acid, and the aqueous solution formulation can be administered to the rectum or colon or artificially. It is a preparation for the treatment of inflammatory bowel disease by a method of administration into the intestinal tract from the anus.
一方、消化性潰瘍(胃潰瘍、十二指腸潰瘍)または胃炎の予防または治療剤としては日本公開特許公報昭和第５８-７７８１４号、日本公開特許公報昭和第６３-１６５３６１号及び日本公開特許公報平成第２-１６７２５８号には一般的な顆粒剤形として公示されていて、現在市販中のガストレックス（登録商標）製剤も顆粒剤として市販されている。 On the other hand, as a preventive or therapeutic agent for peptic ulcer (gastric ulcer, duodenal ulcer) or gastritis, Japanese Patent Publication No. Showa 58-77814, Japanese Patent Publication No. Showa 63-165361 and Japanese Patent Publication No. Heisei 2- No. 167258 is publicly known as a general granule dosage form, and a commercially available GASTREX (registered trademark) formulation is also marketed as a granule.
ところで、スルホデヒドロアビエチン酸は苦味の故に服用がうとまれる傾向があり、患者らが服用を避ける現象が著しく、苦味を低減させる経口用製剤の開発が必要とされる分野である。 By the way, sulfodehydroabietic acid has a tendency to be taken due to bitterness, and the phenomenon that patients avoid taking it is remarkable, and development of an oral preparation for reducing bitterness is required.
大韓民国特許出願第２００７-７０２３０７７号には、プランルカスト水和物を含有する顆粒及びその顆粒を含有してなる製剤(口腔内の速崩錠)を提供するにおけるプランルカスト水和物の平均粒子直径を小さくすることによって、苦味を低減させらることができると公示されており、大韓民国特許出願第１９９４-３４７０７号にはアセトアミノフェンをボールミルをもって粉砕した後、クエン酸などを混合し苦味が隠蔽されたアセトアミノフェン剤形が開始されており、大韓民国特許出願第２００２-５４８２３号にはセフロキシム・アキセチルの苦味を遮断するために５９０μｍ以下の粒子を６０%以上占め、クエン酸を添加した例が公示されている。 Korean Patent Application No. 2007-70203077 discloses the average of pranlukast hydrate in providing granule containing pranlukast hydrate and a preparation containing the granule (fast-disintegrating tablet in the oral cavity) It has been announced that the bitterness can be reduced by reducing the particle diameter. Korean Patent Application No. 1994-34707 pulverizes acetaminophen with a ball mill and then mixes with citric acid or the like to give a bitter taste. In order to block the bitter taste of cefuroxime and axetil, Korean patent application No. 2002-54823 contained 60% or more of particles of 590 μm or less, and citric acid was added. An example is published.
一般的に苦味を有する薬物は平均粒子直径が小さいと、粒子自体の数が増加するという点で表面積が大きくなるため、苦味が増大するが、特異に一部の薬物は小さい平均粒子直径を有する際、苦味の低減効果を有する逆相関がある。 In general, drugs with bitter taste have a small average particle diameter, but the bitterness increases because the surface area increases in terms of the number of particles themselves, but some drugs have a small average particle diameter. In particular, there is an inverse correlation having a bitter taste reducing effect.
また、大韓民国特許出願第２００１-７３２３６号には、特有の苦味を有するレボスルピリドをマスキングし、液剤化するためにクエン酸及びシクロデキストリンを使った例が公示されており、大韓民国特許出願第１９９７-２２９６８号にはアセトアミノフェンの苦味を隠蔽させるためにデキストリン類を使った例が開示されている。 In addition, in Korean Patent Application No. 2001-73236, an example of using citric acid and cyclodextrin for masking and liquidating levosulpiride having a peculiar bitter taste is disclosed, and Korean Patent Application No. 1997- No. 22968 discloses an example using dextrins to mask the bitter taste of acetaminophen.
本発明者らは今まで消化性潰瘍または胃炎に効果を有するスルホデヒドロアビエチン酸の苦味を遮蔽した経口用液状組成物及びその卓越した安全性改善効果について報告されたり提案または実験から立証されたことがないということに注目し研究した。 The present inventors have reported, proved or proposed from experiments or experiments about the liquid composition for oral use that masked the bitter taste of sulfodehydroabietic acid having an effect on peptic ulcer or gastritis and its excellent safety improvement effect. I paid attention to the fact that there was no research.
驚くべきことに、本発明者らはスルホデヒドロアビエチン酸が特定微細粒子の大きさで苦味を低減さることができると分かり、特に賦形剤としてよく使われているクエン酸ナトリウム、クロスポビドン、液状シクロデキストリンは個別に添加される場合には苦味を遮断する効果が殆どないが、必須にこれらの混合物では苦味低減効果が優れていることを発見し、これら賦形剤の混合物は特定割合で混合されるべきであり、pH５.０〜５.５で液状製剤の変質化を防止することができるということを確認し、苦味が遮蔽され安定化したスルホデヒドロアビエチン酸の経口用液状組成物を開発して本発明を完成した。 Surprisingly, the present inventors have found that sulfodehydroabietic acid can reduce bitterness at a specific fine particle size, and particularly sodium citrate, crospovidone, liquid, which are often used as excipients. Cyclodextrins have little effect on blocking bitterness when added individually, but it has been found that these mixtures have an excellent bitterness-reducing effect, and a mixture of these excipients is mixed at a specific ratio. Developed a liquid composition for oral use of sulfodehydroabietic acid that has been confirmed to be able to prevent deterioration of the liquid formulation at pH 5.0 to 5.5 and has a bitter taste masked and stabilized. Thus, the present invention has been completed.
本発明はスルホデヒドロアビエチン酸による苦味を持続的に遮蔽できる液状製剤を提供することである。また、本発明は保管安全性が優れたスルホデヒドロアビエチン酸を液状製剤を提供することにその目的がある。 This invention is providing the liquid formulation which can mask continuously the bitter taste by sulfodehydroabietic acid. Another object of the present invention is to provide a liquid preparation of sulfodehydroabietic acid having excellent storage safety.
以下、本発明に対し詳細に説明する。前記の技術的課題を達成するためには、スルホデヒドロアビエチン酸が含有された経口用液状製剤は下記のような条件を満足させなければならない。第一、スルホデヒドロアビエチン酸またはその薬学的に許容可能な塩、水和物、溶媒化物の苦味を低減させるべきであり、第二、経口用液状製剤の保管安全性が確保されなければならない。 Hereinafter, the present invention will be described in detail. In order to achieve the above technical problem, an oral liquid preparation containing sulfodehydroabietic acid must satisfy the following conditions. First, the bitter taste of sulfodehydroabietic acid or a pharmaceutically acceptable salt, hydrate or solvate thereof should be reduced, and second, the storage safety of the oral liquid preparation should be ensured.
本発明は、(A)スルホデヒドロアビエチン酸またはその薬学的に許容可能な塩、水和物、溶媒化物、(B) １０μｍ乃至１００μｍ粒子大きさ、(C)必須にクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリン混合物の含有、(D) pHを５.０〜５.５で調節させた経口用スルホデヒドロアビエチン酸含有液状製剤を提供する。ここで、スルホデヒドロアビエチン酸含有液状製剤は、スルホデヒドロアビエチン酸またはその薬学的に許容可能な塩、水和物、溶媒化物を包含する。 The present invention comprises (A) sulfodehydroabietic acid or a pharmaceutically acceptable salt, hydrate, solvate thereof, (B) 10 μm to 100 μm particle size, (C) essentially sodium citrate, crospovidone and Provided is an oral sulfodehydroabietic acid-containing liquid preparation containing a liquid cyclodextrin mixture and (D) having a pH adjusted to 5.0 to 5.5. Here, the sulfodehydroabietic acid-containing liquid preparation includes sulfodehydroabietic acid or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
本発明によるスルホデヒドロアビエチン酸含有経口用液状製剤は、苦味を持続的に遮蔽でき、製剤の服用時には拒否感なく、保管時に安定した状態を保つ新しい製剤の特徴を有する。 The liquid preparation for oral use containing sulfodehydroabietic acid according to the present invention has the characteristics of a new preparation that can continuously mask bitterness, has no refusal when taking the preparation, and remains stable during storage.
本発明によるスルホデヒドロアビエチン酸は、粒子の大きさは０.２〜４６６.８μｍで好ましくは、７〜１０５.２μｍで、さらに好ましくは１０〜１００μｍの粒子の大きさを有する。 The sulfodehydroabietic acid according to the present invention has a particle size of 0.2 to 466.8 μm, preferably 7 to 105.2 μm, and more preferably 10 to 100 μm.
また本発明は、賦形剤として必須にクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリン混合物を含有し、好ましくは粒子の大きさが調節されたスルホデヒドロアビエチン酸１重量部に対し賦形剤クエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンは、０.２:０.５〜０.６:１の重量比で含まれることで苦味を十分に低減させることができる。 In addition, the present invention essentially contains sodium citrate, crospovidone and a liquid cyclodextrin mixture as an excipient, and preferably an excipient citric acid with respect to 1 part by weight of sulfodehydroabietic acid whose particle size is adjusted. By including sodium, crospovidone and liquid cyclodextrin in a weight ratio of 0.2: 0.5 to 0.6: 1, the bitterness can be sufficiently reduced.
本発明は、またpHを調節することにより経口用液状製剤の保管安全性を増進させることができ、特にpH５.０〜５.５で安定しており、pH調節剤としてはクエン酸、フマル酸、乳酸、酒石酸、琥珀酸、マレイン酸、酢酸、シュウ酸、燐酸及び塩酸などからなる群から選択され、好ましくはクエン酸が選択されることがある。 The present invention can also improve the storage safety of oral liquid preparations by adjusting the pH, and is particularly stable at pH 5.0 to 5.5. Examples of pH regulators include citric acid and fumaric acid. , Lactic acid, tartaric acid, succinic acid, maleic acid, acetic acid, oxalic acid, phosphoric acid, hydrochloric acid and the like, preferably citric acid.
本発明において、スルホデヒドロアビエチン酸と賦形剤として必須にクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリン混合物を溶かした時のpHは、約pH５.０以下またはpH６.０以上であり、室温及び加速保管時３０日で性状が変化し、含有量の多くが減少して柔軟物質を増加させるという問題が発生することがあるので、本発明の組成物は保管安全性を増進させるためにpH調節剤によってpHをpH５.０〜５.５に調節することが 望ましい。 In the present invention, when sulfodehydroabietic acid and sodium citrate, crospovidone, and liquid cyclodextrin mixture are dissolved as essential excipients, the pH is about pH 5.0 or lower or pH 6.0 or higher at room temperature and acceleration. Since the properties change after 30 days of storage, and the content may decrease and increase the amount of flexible material, the composition of the present invention may be used as a pH regulator to enhance storage safety. It is desirable to adjust the pH to between 5.0 and 5.5.
また、本発明は適量の増粘剤、懸濁剤、甘味剤と、その他、薬学的に許容可能な担体及び精製水を含むことができ、増粘剤は一般的にグアーガム、カラギーナン、カラヤガム、キサンタンガム、アラビアガム、アルギン酸ナトリウム、デンプン、キトサン、ゼラチン、ポリビニルアルコール、ポリアクリル酸、ポリエチレングリコール、ポリビニルピロリドン、架橋されたポリビニルピロリドン、エチルセルロース、ゼイン、シェラック、カルボマーなどがあり、好ましくはキサンタンガムである。 The present invention can also include appropriate amounts of thickeners, suspensions, sweeteners, as well as other pharmaceutically acceptable carriers and purified water, where the thickeners are generally guar gum, carrageenan, caraya gum, There are xanthan gum, gum arabic, sodium alginate, starch, chitosan, gelatin, polyvinyl alcohol, polyacrylic acid, polyethylene glycol, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, ethyl cellulose, zein, shellac, carbomer , and preferably xanthan gum.
本発明で使用した懸濁化剤は、一般的にカルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルプセルロース、ハイプロメルロース、メチルセルロース、微結晶セルロース、微結晶セルロース・カルボキシメチルセルロースナトリウム、ポリビニルピロリドン、ソジウムスターチ・グリコネートなどがあり、微結晶セルロース・カルボキシメチルセルロースナトリウムが望ましい。 The suspending agents used in the present invention are generally carboxymethylcellulose calcium, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hypromelulose, methylcellulose, microcrystalline cellulose, microcrystalline cellulose and carboxymethylcellulose. Sodium, polyvinyl pyrrolidone, sodium starch / glyconate, etc. are preferable, and microcrystalline cellulose / sodium carboxymethylcellulose is desirable.
本発明で使用した甘味剤は、一般的にデクストロース、キシリトール、アスパルテーム、アセスルファムカリウム、アンモニウムグリチルリチネイト、サッカリン、サッカリンナトリウム、ソルビトール、白糖、スクラロース、ソジウムシクラメイト、ソーマチンなどが使用可能で、この中でアスパルテーム、アセスルファムカリウム、白糖、キシリトールが望ましい。 As the sweetening agent used in the present invention, dextrose, xylitol, aspartame, acesulfame potassium, ammonium glycyrrhizinate, saccharin, saccharin sodium, sorbitol, sucrose, sucralose, sodium cyclamate, thaumatin and the like can be used. Of these, aspartame, acesulfame potassium, sucrose, and xylitol are desirable.
また、本発明では薬学的に許容可能な通常の担体として保存剤、着香剤などを混合して経口投与用液状製剤を製造することができる。 In the present invention, a liquid preparation for oral administration can be produced by mixing a preservative, a flavoring agent and the like as a normal pharmaceutically acceptable carrier.
また、本発明における経口用液状製剤としては 懸濁剤、シロップ剤、乳剤、エキス剤、リモナーデ剤、流エキス剤、チンキ剤、エリクシール剤などあり、好ましくは懸濁剤、シロップ剤、乳剤、エキス剤があり、より好ましくは 懸濁剤またはシロップ剤を特徴とする。 Further, the oral liquid preparations in the present invention include suspensions, syrups, emulsions, extracts, limonades, flow extracts, tinctures, elixirs, etc., preferably suspensions, syrups, emulsions, extracts. And is more preferably characterized by a suspension or syrup.
本発明の組成物は、下記の実施例記載の通り、通常の製造方法でとても容易に製造することができる。 The composition of the present invention can be produced very easily by a usual production method as described in the following examples.
本発明は、スルホデヒドロアビエチン酸またはその薬学的に許容可能な塩、水和物、溶媒化物の粒子の大きさを調節し必須にクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンを混合して苦味が低減された消化性胃潰瘍、胃炎または炎症性腸疾患治療に効果のある経口用液状製剤を提供し、服用の順応度と服用の便利性を改善させた製剤であり、液状組成物のpHを調節することによって、保管の安全性が優れたスルホデヒドロアビエチン酸が含有された経口用の液状製剤である。 The present invention adjusts the particle size of sulfodehydroabietic acid or a pharmaceutically acceptable salt, hydrate or solvate thereof, and essentially mixes sodium citrate, crospovidone and liquid cyclodextrin to reduce the bitterness. Providing oral liquid preparations that are effective in treating reduced peptic gastric ulcer, gastritis, or inflammatory bowel disease, improving dosage flexibility and convenience, and adjusting the pH of liquid compositions By doing so, it is a liquid preparation for oral use containing sulfodehydroabietic acid having excellent storage safety.
以下、本発明を実施例及び実験例に依拠して詳しく説明する。ただし、下記の実施例及び実験例は本発明を例示するだけで本発明の内容が下記の実施例及び実験例に限定されるものではない。 Hereinafter, the present invention will be described in detail based on examples and experimental examples. However, the following examples and experimental examples only illustrate the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.
１.粒子の大きさによる苦味の低減程度評価
本実験は、スルホデヒドロアビエチン酸モノソジウム塩５水和物の粒子の大きさによる苦味の低減程度を評価するためのものである。
1. Evaluation of degree of bitterness reduction by particle size This experiment is for evaluating the degree of bitterness reduction by the particle size of sulfodehydroabietic acid monosodium salt pentahydrate.
＜実施例１＞ Haｍｍer ｍillを利用した粒子を含有する溶液の製造(１)
スルホデヒドロアビエチン酸モノソジウム塩５水和物(分子量４９２.５６,５H２０)をHaｍｍer ｍill(Dalton Inc,Atoｍizer（登録商標）)を通して１.０ｍｍのスクリーンを使い、中速で粉砕し粒子の大きさが１４.４〜１０５.２μｍ(平均粒子大４３.７μｍ)の微粒子粉末を製造し前記微粒子粉末１０ｍgを取って７０℃で加温した精製水に溶解させ溶液を製造した。
<Example 1> Production of solution containing particles using Hammer mill (1)
Sulfodehydroabietic acid Monosojiumu salt pentahydrate (molecular weight 492.56,5H 2 0) a Hammer mill using a 1.0mm screen through (Dalton Inc, Atomizer (registered trademark)), the milled at medium speed particle size A fine particle powder having an average particle size of 14.4 to 105.2 μm (average particle size: 43.7 μm) was produced, 10 mg of the fine particle powder was taken and dissolved in purified water heated at 70 ° C. to produce a solution.
＜実施例２＞ Haｍｍer ｍillを利用した粒子を含有する溶液の製造(２)
スルホデヒドロアビエチン酸モノソジウム塩５水和物をHaｍｍer ｍill(Dalton Inc,AtoｍizerR)を通して、１.０ｍｍスクリーンを使い、高速で粉砕し粒子の大きさが７.５〜６２.３μｍ(平均粒子大２０.４μｍ)の微粒子粉末を製造して実施例１と同様の方法で溶液を製造した。
<Example 2> Production of solution containing particles using Hammer mill (2)
Sulfodehydroabietic acid monosodium salt pentahydrate was passed through a Hammer mill (Dalton Inc, Atomizer®) using a 1.0 mm screen and pulverized at a high speed to a particle size of 7.5 to 62.3 μm (average particle size of 20. 4 μm) fine particle powder was produced, and a solution was produced in the same manner as in Example 1.
〈比較例１＞ Air-jet ｍillを利用した粒子を含有する溶液の製造
スルホデヒドロアビエチン酸モノソジウム塩５水和物をAir-jet ｍill(STURTEVANT Inc,ＭicronizerR)を使い、微細粉砕して粒子の大きさが０.２〜１５.８μｍ(平均粒子大きさ７.１１μｍ)のスルホデヒドロアビエチン酸モノソジウム塩５水和物の微粒子を製造して実施例１と同様の方法で溶液を製造した。
<Comparative Example 1> Production of solution containing particles using Air-jet mill Monosulfodehydroabietic acid monosodium salt pentahydrate is finely pulverized using Air-jet mill (STURTEVANT Inc, Micronizer®). In this manner, fine particles of sulfodehydroabietic acid monosodium salt pentahydrate having a particle size of 0.2 to 15.8 μm (average particle size of 7.11 μm) are produced, and a solution is produced in the same manner as in Example 1. did.
＜比較例２＞ピンミルを利用した粒子を含有する溶液の製造
スルホデヒドロアビエチン酸モノソジウム塩５水和物をピンミル(へドンプラント社、PincrusherR)を使用して粉砕し、前記製造例１のごとく粒子の大きさを測定して粒子の大きさが７６〜４６６.８μｍ(平均粒子大２１３.２μｍ)の微粒子粉末を製造して実施例１と同様の方法で溶液を製造した。
<Comparative Example 2> pin mill containing particles using a solution of preparation <br/> sulfodehydroabietic acid Monosojiumu salt pentahydrate pin mills (the Don plant Co., Pincrusher R) and ground using a the production The particle size was measured as in Example 1 to produce fine particle powder having a particle size of 76 to 466.8 μm (average particle size of 213.2 μm), and a solution was prepared in the same manner as in Example 1.
＜比較例３ ＞粒子が調節されなかった顆粒剤を利用した溶液の製造
粒子の大きさが調節されていない製剤(顆粒剤)のスルホデヒドロアビエチン酸モノソジウム塩５水和物１０ｍgに該当する量を取って実施例１と同様の方法で製造した。
<Comparative example 3> Preparation of solution using granules whose particles were not adjusted To 10 mg of sulfodehydroabietic acid monosodium salt pentahydrate of a formulation (granules) whose particle size was not adjusted A corresponding amount was taken and manufactured in the same manner as in Example 1.
＜実験例１＞粒子の大きさによる苦味の低減程度評価
実施例１、２及び比較例１ないし３で製造された溶液を利用しスルホデヒドロアビエチン酸モノソジウム塩５水和物の粒子の大きさによる苦味の遮蔽程度を確認した。実験方法は、実験者１０人に各々実施例１、２及び比較例１乃至３で製造されたスルホデヒドロアビエチン酸モノソジウム塩５水和物溶液１０ｍLを５秒程度口中に入れ、その味を評価する方法で苦味の程度を評価しその結果を下記の[表１]に示した。評価点数は１-１０に１０等分して一番低い点数と最も高い点数を引いた残りの８人の評価点数をもって平均を出して評価した。
<Experimental Example 1> Evaluation of degree of bitterness reduction by particle size Particles of sulfodehydroabietic acid monosodium salt pentahydrate using the solutions prepared in Examples 1 and 2 and Comparative Examples 1 to 3 The degree of bitterness shielding by the size of the was confirmed. In the experiment method, 10 ml of the sulfodehydroabietic acid monosodium salt pentahydrate solution prepared in each of Examples 1 and 2 and Comparative Examples 1 to 3 was put in the mouth for about 5 seconds, and the taste was evaluated. The degree of bitterness was evaluated by the method, and the results are shown in [Table 1] below. The evaluation score was divided into 1-10 and divided into 10 equal parts, and the average was obtained with the remaining 8 evaluation scores obtained by subtracting the lowest score and the highest score.
[表１]から分かるように、スルホデヒドロアビエチン酸モノソジウム塩５水和物は粒子の大きさにより苦い味を低減させることができる差異を示すことが分かり、特に、粒子の大きさを調節しない薬物である比較例３は苦味がほとんど低減されないものとして評価されたが、本発明による実施例１及び２は苦味に対する感覚が低減されるという評価を表した。特に、スルホデヒドロアビエチン酸モノソジウム塩５水和物は粒子の大きさによって苦味を低減させることができるが、比較例１のように微細粒子が非常に小さい粒子を有する場合では、むしろ苦味を大きく低減させることができず、また比較例２のように粒子の大きさが７６〜４６６.８μｍ(平均粒子大２１３.２μｍ)の場合にも苦味の程度を大きくは減少させることができなかった。 As can be seen from [Table 1], sulfodehydroabietic acid monosodium salt pentahydrate shows a difference that can reduce the bitter taste depending on the size of the particles, and in particular, a drug that does not regulate the size of the particles. Comparative Example 3 was evaluated as one in which the bitterness was hardly reduced, but Examples 1 and 2 according to the present invention expressed an evaluation that the sense of bitterness was reduced. In particular, sulfodehydroabietic acid monosodium salt pentahydrate can reduce the bitterness depending on the size of the particles, but when the fine particles have very small particles as in Comparative Example 1, the bitterness is greatly reduced. In addition, even when the particle size was 76 to 466.8 μm (average particle size 213.2 μm) as in Comparative Example 2, the degree of bitterness could not be greatly reduced.
したがって、本発明はスルホデヒドロアビエチン酸モノソジウム塩５水和物の粒子の大きさによって、苦味を低減させることができる効果を示すことが分かり、前記実験結果からスルホデヒドロアビエチン酸モノソジウム塩５水和物約１０〜１００μｍ粒子の大きさを持つ場合に苦味を最も低減させることができると判断される。 Therefore, it can be seen that the present invention shows the effect of reducing bitterness depending on the particle size of sulfodehydroabietic acid monosodium salt pentahydrate. From the experimental results, sulfodehydroabietic acid monosodium salt pentahydrate is obtained. It is judged that the bitterness can be reduced most when the particle size is about 10 to 100 μm.
２.賦形剤の添加による苦味の低減程度及び性状変化評価
本実験は、賦形剤クエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンの濃度含有量変化により苦味の低減程度及び性状変化を評価するためのものである。本実験では前記実験結果によりスルホデヒドロアビエチン酸モノソジウム塩５水和物の苦味の低減効果を示す実施例２で製造された粒子をもって苦味の低減程度を評価した。
2. Degree of bitterness reduction and evaluation of changes in properties due to the addition of excipients This experiment is based on changes in the concentration and content of excipients sodium citrate, crospovidone and liquid cyclodextrin. It is for evaluating. In this experiment, the degree of bitterness reduction was evaluated using the particles produced in Example 2 showing the bitterness reducing effect of sulfodehydroabietic acid monosodium salt pentahydrate based on the experimental results.
＜実施例３＞本発明による賦形剤含有量を有する溶液の製造(１)
クエン酸ナトリウム２ｍgを７０℃で加温した精製水１００ｍLに溶解させた後、実施例２で製造された粒子の大きさを有するスルホデヒドロアビエチン酸モノソジウム塩５水和物微細粉末１０ｍgを添加して撹拌した。クロスポビドン６ｍg及び液状シクロデキストリン１０ｍgを溶かした後、投入して十分に撹拌して溶液を製造した。
<Example 3> Production of a solution having an excipient content according to the present invention (1)
After dissolving 2 mg of sodium citrate in 100 ml of purified water heated at 70 ° C., 10 mg of fine powder of sulfodehydroabietic acid monosodium salt pentahydrate having the particle size produced in Example 2 was added. Stir. After dissolving 6 mg of crospovidone and 10 mg of liquid cyclodextrin, it was added and stirred sufficiently to prepare a solution.
＜実施例４＞本発明による賦形剤の含有量を有する溶液の製造(２)
クエン酸ナトリウム２ｍgを７０℃で加温した精製水１００ｍLに溶解させた後、実施例２で製造された粒子の大きさを有するスルホデヒドロアビエチン酸モノソジウム塩５水和物微細粉末１０ｍgを添加して撹拌した。クロスポビドン５ｍg及び液状シクロデキストリン１０ｍgを溶かした後、投入して十分に撹拌して溶液を製造した。
<Example 4> Production of a solution having an excipient content according to the present invention (2)
After dissolving 2 mg of sodium citrate in 100 ml of purified water heated at 70 ° C., 10 mg of fine powder of sulfodehydroabietic acid monosodium salt pentahydrate having the particle size produced in Example 2 was added. Stir. After dissolving 5 mg of crospovidone and 10 mg of liquid cyclodextrin, it was added and stirred well to prepare a solution.
＜実施例５-１０＞本発明による賦形剤の含有量を有する溶液の製造(３)
表２に示す賦形剤含有量別に本発明による実施例３と同様の方法によって、それぞれの実施例５-１０の溶液を製造した。
<Example 5-10> Production of a solution having an excipient content according to the present invention (3)
The solutions of Examples 5-10 were prepared in the same manner as in Example 3 according to the present invention, depending on the excipient content shown in Table 2.
＜比較例４-９＞賦形剤含有量別溶液の製造(１)
表２に示す組成成分を実施例３と同様の方法で溶液を製造して各々比較例とした。
<Comparative Example 4-9> Production of solution according to excipient content (1)
A solution was prepared from the composition components shown in Table 2 in the same manner as in Example 3, and each was used as a comparative example.
＜実験例２＞賦形剤含有量による苦味の低減程度評価
実施例２-１０及び比較例４-９で製造された溶液を利用しスルホデヒドロアビエチン酸モノソジウム塩５水和物に含まれる賦形剤含有量による苦味の低減程度を確認して表２に示した。実験の方法は実験例１と同様であった。
<Experimental example 2> Evaluation of degree of bitterness reduction by excipient content To the monosodium sulfodehydroabietic acid pentahydrate using the solutions prepared in Example 2-10 and Comparative Example 4-9 The degree of bitterness reduction due to the contained excipient content was confirmed and shown in Table 2. The experimental method was the same as in Experimental Example 1.
+++：層分離、++++：変色、固まり、層分離
+++: Layer separation, ++++: Discoloration, mass, layer separation
[表２]から分かるように、スルホデヒドロアビエチン酸モノソジウム塩５水和物は粒子の大きさだけでなく、賦形剤の添加により苦味を低減させることができる差異を示しており、但し、賦形剤の添加程度によって溶液の性状に大きな変化があった。 As can be seen from [Table 2], sulfodehydroabietic acid monosodium salt pentahydrate shows not only the size of the particles but also the difference that bitterness can be reduced by the addition of excipients. There was a great change in the properties of the solution depending on the degree of addition of the formulation.
特に、本実験を通してスルホデヒドロアビエチン酸モノソジウム塩５水和物含有溶液はクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンを各々単独で使うか混合して使うかで苦味の低減程度に大きな差異を示すだけではなく、前記賦形剤らがスルホデヒドロアビエチン酸モノソジウム塩５水和物含有溶液の性状に非常に大きな影響を及ぼすことが分かる。つまり、クエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンを各々単独で使った比較例４-６とクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンの２種類混合物を使った比較例７-９では賦形剤を添加しなかった実施例２と苦味の低減程度の差異はなかったが、クエン酸ナトリウム、クロスポビドン及び液状シクロデキストリン混合組成物を添加した本発明による実施例３-１０では苦味の低減効果が非常に大きく示され、スルホデヒドロアビエチン酸モノソジウム塩５水和物の含有溶液は必須にクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリンの混合賦形剤によって、苦味の低減効果を有することが分かる。 In particular, the sulfodehydroabietic acid monosodium salt pentahydrate-containing solution throughout this experiment shows only a significant difference in the bitterness reduction depending on whether sodium citrate, crospovidone and liquid cyclodextrin are used alone or in combination. However, it can be seen that the excipients have a great influence on the properties of the sulfodehydroabietic acid monosodium salt pentahydrate-containing solution. That is, in Comparative Example 4-6 using each of sodium citrate, crospovidone and liquid cyclodextrin alone and in Comparative Example 7-9 using a mixture of two kinds of sodium citrate, crospovidone and liquid cyclodextrin, excipients Although there was no difference in the degree of bitterness reduction from Example 2 in which no addition was made, Example 3-10 according to the present invention in which sodium citrate, crospovidone and liquid cyclodextrin mixed composition were added had an effect of reducing bitterness. It is very large and it can be seen that the solution containing sulfodehydroabietic acid monosodium salt pentahydrate has an effect of reducing bitterness by the mixed excipient of sodium citrate, crospovidone and liquid cyclodextrin.
但し、本発明による実施例３及び４とは違い、実施例５ないし実施例１０では苦味の低減効果を示しながらスルホデヒドロアビエチン酸モノソジウム塩５水和物含有溶液の性状に影響を及ぼしていることを確認した。 However, unlike Examples 3 and 4 according to the present invention, Examples 5 to 10 affect the properties of the solution containing sulfodehydroabietic acid monosodium salt pentahydrate while showing the effect of reducing bitterness. It was confirmed.
したがって、スルホデヒドロアビエチン酸モノソジウム塩５水和物含有溶液は賦形剤によって、苦味の低減効果は有するが、溶液の性状が不安定で保管安全性に問題が発生する恐れがあるということが分かる。 Therefore, it can be seen that the solution containing sulfodehydroabietic acid monosodium salt pentahydrate has an effect of reducing bitterness depending on the excipient, but the properties of the solution are unstable and there is a risk of problems in storage safety. .
３. pH変化による影響
＜実験例３＞pH変化による性状変化
本実験は、pH変化による保管安全性を評価した実験である。前記実験で本発明による実施例３及び４は性状変化が示されていなかったが、他の実施例５ないし実施例１０で性状変化を示すことによって、本発明による液状製剤のpH変化別性状変化を測定した。
3. Effect of pH change
<Experimental example 3> Property change due to pH change This experiment was an evaluation of storage safety due to pH change. In the experiments, Examples 3 and 4 according to the present invention did not show changes in properties. However, by showing changes in properties in other Examples 5 to 10, the changes in the properties of the liquid preparations according to the present invention were changed. Was measured.
別に加温した精製水に適量の懸濁化剤、甘味剤及び増粘剤及び薬剤学的に許容可能な担体を入れて十分に撹拌した後、本発明による実施例３、６、８及び１０の溶液と混合・撹拌して保存剤及び着香剤を入れ標線を合わせて十分に撹拌してから懸濁剤を製造し前記液状製剤にpH調節剤としてクエン酸を適量添加しpHを３.３-６.０別にpHを調節した後、pHの影響による安全性は室温、加速(４０度７５% RH)で比較評価して表３に示した。 Separately warmed purified water was charged with appropriate amounts of a suspending agent, sweetener and thickener and pharmaceutically acceptable carrier, and after sufficient stirring, Examples 3, 6, 8 and 10 according to the present invention. Mix and agitate with the above solution, add a preservative and a flavoring agent, and adjust the mark carefully. Then, a suspension is prepared and an appropriate amount of citric acid is added to the liquid preparation as a pH regulator to adjust the pH to 3. After adjusting pH separately for 3-6.0, the safety under the influence of pH is shown in Table 3 as a comparative evaluation at room temperature and acceleration (40 degrees 75% RH).
+++：層分離、++++：変色、固まり、層分離
+++: Layer separation, ++++: Discoloration, mass, layer separation
本発明によるすべての実施例で苛酷実験で開始時のpHでは性状の差はなく、pH５.１〜５.５で加速保管１ヶ月後にも性状の変化なく一番安定していたが、pH３.５及びpH６.０では性状に影響を大きく及ぼしていることが分かる。 In all the examples according to the present invention, there was no difference in properties at the starting pH in severe experiments, and it was the most stable with no change in properties after one month of accelerated storage at pH 5.1 to 5.5, but pH 3. It can be seen that at 5 and pH 6.0, the properties are greatly affected.
４. 本発明による組成物での安全性評価
＜実験例４＞実施例３及び４の安全性試験
本発明による実施例３及び４の溶液に別に加温した精製水に適量の懸濁化剤、甘味剤及び増粘剤及び薬剤学的に許容可能な担体を入れ十分に撹拌した後、実施例３及び４の液状組成物と混合・撹拌して保存剤及び着香剤を入れ標線を合わせて十分に撹拌し懸濁剤を製造し前記懸濁剤にpH調節剤としクエン酸を適量添加しpHを５.１でpHを調節した液状製剤を通して加速条件(４０℃, 相対湿度８５%)で６ヶ月間安全性試験を行った。また、性状評価は-５℃及び常温で保管し沈殿状態及び変色有無を評価した結果を下記の[表４]に示した。
4. Safety assessment with the composition according to the invention
<Experimental Example 4> Safety test of Examples 3 and 4 Appropriate amounts of suspending agents, sweeteners and thickeners in purified water separately heated to the solutions of Examples 3 and 4 according to the present invention and Add pharmaceutically acceptable carrier and stir well, then mix and stir with the liquid compositions of Examples 3 and 4, add preservative and flavoring agent, align well and stir well A 6-month safety test under accelerated conditions (40 ° C, relative humidity 85%) through a liquid preparation prepared by adding an appropriate amount of citric acid to the suspension and adjusting the pH to 5.1 with a pH regulator Went. In addition, the property evaluation was carried out at -5 ° C and room temperature, and the results of evaluating the precipitation state and the presence or absence of discoloration are shown in [Table 4] below.
[表４]から分かるように、本発明により製造された液状製剤は基準及び試験方法中６ヶ月後の含有量変化試験及び柔軟物質試験法による柔軟物質試験を遂行した結果、６ヶ月後の含有量変化は基準範囲(９５〜１０５%)に適合しており、総柔軟物質もやはり基準値(０.５%)以下で適合したことが分かった。 As can be seen from [Table 4], the liquid preparation produced according to the present invention was subjected to a content change test after 6 months in the standard and test method and a soft material test by the soft material test method. It was found that the amount change was adapted to the reference range (95 to 105%), and the total soft material was also fitted below the reference value (0.5%).
したがって、本発明により製造された液状製剤は韓国食品医薬品安全庁で提示する基準及び試験方法に適合した製剤である。また、６ヶ月後の性状変化もやはり変色、固まり、層分離なしに安定していることを確認し製剤安全性に適合した薬剤学的な組成物であることがわかる。 Therefore, the liquid preparation produced by the present invention is a preparation that conforms to the standards and test methods presented by the Korean Food and Drug Safety Agency. In addition, it was confirmed that the property change after 6 months was also stable without discoloration, solidification, and layer separation, and it was found that the composition was a pharmacological composition suitable for formulation safety.
Claims (5)
(ｉ)スルホデヒドロアビエチン酸またはその薬学的に許容可能な塩、水和物、溶媒化物の粒子の大きさが１０〜１００μｍであり、
(ｉｉ)賦形剤クエン酸ナトリウム、クロスポビドン及び液状シクロデキストリン混合物はスルホデヒドロアビエチン酸１重量部に対しクエン酸ナトリウム、クロスポビドン及び液状シクロデキストリン１:０.２:０.５〜０.６:１重量比で含有し、
(ｉｉｉ) pHが５.０〜５.５として調節された液状製剤。 Sulfodehydroabietic acid or its pharmaceutically acceptable salts, hydrates, solvates and essential excipients such as sodium citrate, crospovidone and liquid cyclodextrin mixture adjust pH and reduce bitterness An oral liquid preparation having the following characteristics (i) to (iii) as an oral liquid preparation for treatment of digestive gastric ulcer, gastritis or inflammatory bowel disease stabilized:
(i) Sulfodehydroabietic acid or a pharmaceutically acceptable salt, hydrate, or solvate thereof has a particle size of 10 to 100 μm,
(ii) Excipient sodium citrate, crospovidone and liquid cyclodextrin mixture is sodium citrate, crospovidone and liquid cyclodextrin 1: 0.2: 0.5-0.6 with respect to 1 part by weight of sulfodehydroabietic acid. : Contained in a weight ratio of 1
(iii) A liquid preparation having a pH adjusted to 5.0 to 5.5.
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| US11091486B2 (en) | 2016-10-26 | 2021-08-17 | Array Biopharma, Inc | Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof |
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