+

WO1999053941A1 - Preparations orales contenant des derives de trh - Google Patents

Preparations orales contenant des derives de trh Download PDF

Info

Publication number
WO1999053941A1
WO1999053941A1 PCT/JP1999/002006 JP9902006W WO9953941A1 WO 1999053941 A1 WO1999053941 A1 WO 1999053941A1 JP 9902006 W JP9902006 W JP 9902006W WO 9953941 A1 WO9953941 A1 WO 9953941A1
Authority
WO
WIPO (PCT)
Prior art keywords
lecithin
medium
preparation
formulation
fatty acid
Prior art date
Application number
PCT/JP1999/002006
Other languages
English (en)
Japanese (ja)
Inventor
Katsuji Sugita
Norihito Satoh
Takanori Yoshikawa
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Publication of WO1999053941A1 publication Critical patent/WO1999053941A1/fr

Links

Classifications

    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K38/066—TRH, thyroliberin, thyrotropin releasing hormone
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids

Definitions

  • the present invention relates to an oral administration preparation containing thyrotropin releasing hormone (hereinafter, abbreviated as “TRH”) or a derivative thereof.
  • TRH thyrotropin releasing hormone
  • TRH is a discovered hormone from the hypothalamus, the structure, L one Piroguruta mill one L one Hisuchijiru L- Purorin'ami de - a (p- G lu- H is P ro- NH 2). It is known that T RH exerts various pharmacological effects by acting on the central nervous system as well as promoting the release of thyroid stimulating hormone and prolactin in the pituitary gland (Medical Topics Series, Neurobeptide'9). 1, Medical Review). TRH derivatives that have enhanced effects on the central nervous system also generally consist of three amino acids or their derivatives, similar to TRH, and most of them have a molecular weight of about 370-430. And described in, for example, the following literature [J. Med.
  • TRH derivatives are generally stable to enzymes in the gastrointestinal tract, but are absorbed from the gastrointestinal tract because of their high water solubility. Poor sex.
  • TRH derivatives Tartirelin
  • TRH has been reported to have a low bioavailability of 3.9% after oral administration to rats (pharmacokinetics 12 (5) 460-474 (1997)). Therefore, most TRH derivatives have to be developed or used as injections, not as oral preparations. TRH has also been approved for the treatment of ataxia in spinocerebellar degeneration, for example, but due to oral absorption problems, patients with this disease need to be visited daily for treatment by injection. However, for patients with spinocerebellar degeneration with gait disturbance as the main symptom, daily medications at hospital visits pose difficulties in social life, and development of oral preparations is desired from clinical practice.
  • Japanese Unexamined Patent Publication (Kokai) No. 1-257715 discloses that esters and amides which are easily decomposable for enzymes in the digestive tract are dissolved or suspended in medium-chain fatty acid triglycerides. Oral preparations with reduced enzymatic degradation are described.
  • Japanese Patent Application Laid-Open No. Hei 8-92288 discloses that a dihydrochenopyridine derivative, which is a poorly water-soluble drug, is mixed with a medium-chain fatty acid triglyceride and lecithin to improve the solubility and absorbability. Oral preparations with improved properties are described.
  • WO 88/78771 describes a pharmaceutical composition containing lecithin and adapted for transdermal or transmucosal administration.
  • a method for improving the oral absorbability of a TRH derivative In general, the oral absorption of drugs depends on their solubility in water and enzymes in the gastrointestinal tract. Various physical properties such as stability are involved, and even a person skilled in the art can improve the oral absorption of a specific drug only after intensive examination in view of the individual physical properties. There is no suggestion of improvement in oral absorption of the substance from the above-mentioned literature. Disclosure of the invention
  • the present inventors have conducted various studies on a method for improving the oral absorbability of a TRH derivative, and as a result, have found that a combination use with a medium-chain fatty acid triglyceride is very preferable. Furthermore, they found that oral administration of a combination of lecithin and triglyceride of medium-chain fatty acid improved oral absorption of TRH derivatives, and thus completed the present invention described below.
  • H et 1 and H et 2 each represent any of the following groups.
  • R 1 is hydrogen or alkyl; X is CH 2 or ⁇ );
  • Z is CH 2 or S
  • R 2 is alkyl, one CH 2 OR 3 , one C ⁇ NHR 4 , one COOR 5 or —CN (R 3 , R 4 and R 5 are each independently hydrogen, optionally substituted alkyl or substituted Or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • the rate of increase in body temperature after oral administration to reserpine-pretreated mice is about twice or more as compared with a preparation containing no medium-chain fatty acid triglyceride and lecithin, as described in (1) to (6) above.
  • the preparation according to any one of the above.
  • the bioavailability in a rat is about 30 times or more as compared with a preparation containing no medium-chain fatty acid triglyceride and lecithin.
  • the TRH derivative which is the main drug of the present preparation include various TRH derivatives described in the above-mentioned literatures, including the compound (I) represented by the formula (I).
  • alkyl in R 1 and R 2 independently includes straight-chain or branched alkyl having 1 to 10 carbon atoms, and includes methyl, ethyl, n-propyl, and isopropyl.
  • Alkyl at R 3 , R 4 and R 5 includes linear or branched alkyl having 1 to 16 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl Hexyl, octyl, nonanyl, decanyl, pendenyl, dodecanyl, tridecanyl, tetradecanyl, pentadecanyl, hexadenicil, etc. Is methyl, ethyl, propyl and the like.
  • the alkyl may be substituted by a substituent such as halogen (eg, F, C1, Br, I), hydroxy, amino, carboxyl, nitro and the like.
  • R 3 , R 4 and R 5 may be substituted by the same substituents as in the above alkyl.
  • salts such as acid addition salts (eg, tartaric acid, oxalic acid, fumaric acid, cunic acid, lingoic acid, lactic acid, oleic acid, palmitic acid, acetic acid, Hydrochloric acid, sulfuric acid, etc.).
  • acid addition salts eg, tartaric acid, oxalic acid, fumaric acid, cunic acid, lingoic acid, lactic acid, oleic acid, palmitic acid, acetic acid, Hydrochloric acid, sulfuric acid, etc.
  • the content of the TRH derivative in the present preparation is usually about 0.1 to 20% by weight, preferably about 0.5 to 20% by weight, more preferably about 1 to 10% by weight, based on the whole preparation.
  • the medium chain fatty acid triglyceride preferably has 8 to 12 carbon atoms in each fatty acid, such as ODO (Nisshin Oil), Migliool (Mitsuba Trading), Bana Sate (Nippon Yushi), Cocona Examples include Ido (Kao), Myritol GM (Henkel Hakusui), TCG (higher alcohol industry), San Fat MCT-6 (Taiyo Chemical), and Factor (RIKEN Vitamin).
  • the content of the medium-chain triglyceride is usually about 50 to 99% by weight, preferably about 80 to 99% by weight, more preferably about 90 to 98% by weight, based on the whole preparation.
  • the weight ratio is usually about 1 to 200 times, preferably about 5 to 100 times, more preferably about 10 to 50 times, and more preferably about 20 to 30 times the weight of the main drug. If the content of the medium-chain fatty acid triglyceride is too large, the desired pharmacological effect may not be obtained due to the low concentration of the active drug, while if the content is too small, sufficient oral absorption is not achieved. Pharmacological effect of No result.
  • lecithin In order to further enhance the oral absorption of the TRH derivative in the present preparation, it is preferable to add lecithin.
  • lecithin include natural egg yolk lecithin, soybean lecithin, hydrogenated lecithin thereof, synthetic phosphatidylcholine, and the like, and preferably soybean lecithin.
  • its content is usually about 0.1 to 20% by weight, preferably about 0.5 to 15% by weight, more preferably about 1 to 10% by weight, based on the whole preparation. %.
  • the weight ratio is usually about 0.1 to 10 times, preferably about 0.5 to 5 times, more preferably about 1 to 3 times the weight of the active ingredient.
  • lecithin is preferably in a dissolved state. If the lecithin content is too high, lecithin may not dissolve in the medium-chain fatty acid triglycerides and may adversely interfere with drug absorption.
  • the form of the present preparation is, for example, a liquid, powder, soft capsule, hard capsule, tablet, granule and the like, and preferably a powder, hard capsule and the like. It may also be in the form of a ⁇ WO-type emulsion formed by combining a medium-chain fatty acid triglyceride (preferably ODO) and lecithin.
  • a medium-chain fatty acid triglyceride preferably ODO
  • This preparation can be optionally used with excipients (lactose, starch, microcrystalline cellulose, etc.), binders (hydroxypropylcellulose, etc.), disintegrants (CMC-Na, CMC-Ca, etc.), lubricants (stearin, etc.) Pharmaceutical additives such as magnesium acid), dissolution aids (triethyl citrate, triacetin, etc.), absorption promoters (polycarboxylic acid, oxycarboxylic acid, etc.), stabilizing agents, solubilizing agents, suspending agents, dispersing agents, etc. Can be contained.
  • excipients lactose, starch, microcrystalline cellulose, etc.
  • binders hydroxypropylcellulose, etc.
  • disintegrants CMC-Na, CMC-Ca, etc.
  • lubricants stearin, etc.
  • Pharmaceutical additives such as magnesium acid), dissolution aids (triethyl citrate, triacetin, etc.), absorption promoter
  • the production method of the present preparation is not particularly limited, but usually, the main drug may be dissolved or suspended in medium-chain fatty acid triglyceride. Powders can be prepared using the obtained suspension or the like, or they may be filled in capsules.
  • the dosage varies depending on the disease state, age, administration route, etc., but is usually about 0.1 to 100 mg / day, preferably about 1 to 20 mg / day as the main drug for adults. It is within the range.
  • the bioavailability was significantly improved by adding a very small amount of lecithin to the medium-chain fatty acid triglyceride.
  • the bioavailability was 30- A 40-fold improvement effect was observed.
  • the present preparation has the following characteristics.
  • FIG. 1 is a graph showing the effect of increasing body temperature after oral administration of a TRH inducer in reserpine-pretreated mice performed in Test Example 3.
  • Control 1 aqueous solution
  • test compound 1 O mg was added to 24 O mg of ODO-C (Nisshin Oil), and after ultrasonic irradiation, it was uniformly dispersed by stirring with a magnetic stirrer.
  • This formulation 2 OEO suspension with soy lecithin
  • soy lecithin SLP-White SP, manufactured by Tsuruichi Lecithin Industry Co., Ltd.
  • ODO-C Neshin Oil 180 Omg.
  • the test compound lO Omg was added to this solution, and after ultrasonic irradiation, it was uniformly dispersed by stirring with a magnetic stirrer.
  • Bioavailability indicates the absolute bioavailability calculated by adjusting the dose based on the AUC at the time of the intravenous experiment conducted separately.
  • Example 2 The compound A (10 g), Panacet 800 (manufactured by NOF CORPORATION) (100 g) and soybean lecithin (10 g) are thoroughly mixed with a magnetic stirrer, and the mixture is stirred to obtain a suspension.
  • Example 2 The compound A (10 g), Panacet 800 (manufactured by NOF CORPORATION) (100 g) and soybean lecithin (10 g) are thoroughly mixed with a magnetic stirrer, and the mixture is stirred to obtain a suspension.
  • Example 2 The compound A (10 g), Panacet 800 (manufactured by NOF CORPORATION) (100 g) and soybean lecithin (10 g) are thoroughly mixed with a magnetic stirrer, and the mixture is stirred to obtain a suspension.
  • Example 2 The compound A (10 g), Panacet 800 (manufactured by NOF CORPORATION) (100 g) and soybean lecithin (10 g) are thoroughly mixed with a magnetic stirrer,
  • a suspension was obtained by sufficiently mixing and stirring 10 g of the compound D, 200 g of coconado (Kao) and 10 g of soybean lecithin with a magnetic stirrer. Silica (Carplex # 80, Shionogi) was added to this suspension to prepare a powder, which was filled with a capsule machine to obtain a hard capsule.
  • Silica Carplex # 80, Shionogi

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparations conçues pour l'administration orale de dérivés de TRH et contenant ces dérivés de TRH, des triglycérides de chaîne moyenne et, si besoin est, lécithine. L'utilisation de ces préparations permet d'améliorer les caractéristiques d'absorption orale des dérivés de TRH, ce qui élève la biocompatibilité de ces derniers.
PCT/JP1999/002006 1998-04-15 1999-04-15 Preparations orales contenant des derives de trh WO1999053941A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/104993 1998-04-15
JP10499398 1998-04-15

Publications (1)

Publication Number Publication Date
WO1999053941A1 true WO1999053941A1 (fr) 1999-10-28

Family

ID=14395630

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/002006 WO1999053941A1 (fr) 1998-04-15 1999-04-15 Preparations orales contenant des derives de trh

Country Status (1)

Country Link
WO (1) WO1999053941A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003073262A (ja) * 2001-08-30 2003-03-12 Gotoo Corporation:Kk 固型製剤用包摂コーティング剤、固型製剤、その製造方法、及び食品類
WO2006028277A1 (fr) * 2004-09-09 2006-03-16 Shionogi & Co., Ltd. Préparation pharmaceutique pour le traitement de l’ataxie, de l’atrophie multisystémique, ou de troubles de l’équilibre
JP2008512344A (ja) * 2004-09-09 2008-04-24 塩野義製薬株式会社 脊髄小脳変性症治療剤
JP2016509200A (ja) * 2012-12-19 2016-03-24 ザ プロボースト，フェローズ，ファンデーション スカラーズ，アンド ジ アザー メンバーズ オブ ボード，オブ ザ カレッジ オブ ザ ホーリー アンド アンディバイデッド トリニティ オブ クイーン ヒトｃｎｓにおける新規ｔｒｈ結合部位
JP2018533618A (ja) * 2015-08-28 2018-11-15 アマゼンティス エスアーＡｍａｚｅｎｔｉｓ Ｓａ ウロリチン化合物を含む組成物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5517328A (en) * 1978-07-21 1980-02-06 Tanabe Seiyaku Co Ltd Insulin-containing emulsion and its preparation
JPS6023326A (ja) * 1983-07-18 1985-02-05 Takeda Chem Ind Ltd ペプチド含有経口投与製剤
WO1994008605A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Microemulsions therapeutiques
WO1994008603A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Compositions
WO1998008867A1 (fr) * 1996-08-28 1998-03-05 Shionogi & Co., Ltd. Nouveaux derives de peptides presentant un residu de thiazolyle-alanine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5517328A (en) * 1978-07-21 1980-02-06 Tanabe Seiyaku Co Ltd Insulin-containing emulsion and its preparation
JPS6023326A (ja) * 1983-07-18 1985-02-05 Takeda Chem Ind Ltd ペプチド含有経口投与製剤
WO1994008605A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Microemulsions therapeutiques
WO1994008603A1 (fr) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Compositions
WO1998008867A1 (fr) * 1996-08-28 1998-03-05 Shionogi & Co., Ltd. Nouveaux derives de peptides presentant un residu de thiazolyle-alanine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003073262A (ja) * 2001-08-30 2003-03-12 Gotoo Corporation:Kk 固型製剤用包摂コーティング剤、固型製剤、その製造方法、及び食品類
WO2006028277A1 (fr) * 2004-09-09 2006-03-16 Shionogi & Co., Ltd. Préparation pharmaceutique pour le traitement de l’ataxie, de l’atrophie multisystémique, ou de troubles de l’équilibre
JP2008512344A (ja) * 2004-09-09 2008-04-24 塩野義製薬株式会社 脊髄小脳変性症治療剤
US8071633B2 (en) 2004-09-09 2011-12-06 Shionogi & Co., Ltd. Pharmaceutical composition for treating spinocerebellar ataxia
JP2016509200A (ja) * 2012-12-19 2016-03-24 ザ プロボースト，フェローズ，ファンデーション スカラーズ，アンド ジ アザー メンバーズ オブ ボード，オブ ザ カレッジ オブ ザ ホーリー アンド アンディバイデッド トリニティ オブ クイーン ヒトｃｎｓにおける新規ｔｒｈ結合部位
JP2018533618A (ja) * 2015-08-28 2018-11-15 アマゼンティス エスアーＡｍａｚｅｎｔｉｓ Ｓａ ウロリチン化合物を含む組成物
US11925616B2 (en) 2015-08-28 2024-03-12 Amazentis Sa Compositions comprising urolithin compounds

Similar Documents

Publication Publication Date Title
KR101716878B1 (ko) 글리세롤 지방산에스테르유도체 또는 프로필렌글리콜 지방산에스테르유도체를 함유한 두타스테리드와 타다라필의 복합 캡슐제제 조성물 및 이의 제조방법
TW200302734A (en) Pharmaceutical compositions for hepatitis c viral protease inhibitors
AU2019363244B2 (en) Pharmaceutical formulation
CN106714841A (zh) 治疗肝病的方法
WO2006134864A1 (fr) Preparation d'une solubilisation
BR112019014705A2 (pt) Tratamento que compreende a administração oral ou gástrica de edaravone
Araya et al. The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion I: enhancing effects on oral bioavailability of poorly water soluble compounds in rats and beagle dogs
JP2004520398A (ja) 経口生物学的利用能が改善されたパクリタキセルの化学療法マイクロエマルジョン組成物
TW200843762A (en) Pharmaceutical compositions
AU2003215775A1 (en) Ibuprofen solution for hard shell capsules
WO1999053941A1 (fr) Preparations orales contenant des derives de trh
JPH02326B2 (fr)
JP5613396B2 (ja) 腸管吸収性を改善する医薬組成物
BR112019014712A2 (pt) Tratamento médio que compreende a administração entérica de edaravona
EP1300155A1 (fr) Preparations enteriques contenant des peptides physiologiquement actifs
JP2948111B2 (ja) 経口投与用油性組成物
KR101859200B1 (ko) 모노아세틸디아실글리세롤 화합물의 경구 투여용 조성물 및 고형 제제
EA001905B1 (ru) Лекарственная форма сертралина в виде раствора, заключенного в желатиновые капсулы
EP4493151A2 (fr) Compositions possédant une biodisponibilité améliorée d'agents thérapeutiques et leurs utilisations
WO2014015153A2 (fr) Compositions et méthodes permettant de traiter le sarcome d'ewing et d'autres affections associées à ews-fli1
US20030153585A1 (en) Pharmaceutical preparations containing 2-pyrrolidone as the dissolving intermediary
JP2007504190A (ja) ３−［（２−｛［４−（ヘキシルオキシカルボニルアミノ−イミノ−メチル）−フェニルアミノ］−メチル｝−１−メチル−１ｈ−ベンズイミダゾール−５−カルボニル）−ピリジン−２−イル−アミノ］−エチルプロピオネート及びそれらの塩の新規経口投与形態
EP2699236B1 (fr) Système d'administration de médicament multimodal pharmacologiquement optimisé pour l'acide nordihydroguaiarétique (ndga)
WO2004078173A1 (fr) Comprime a caracteristiques de dissolution ameliorees
JPH09323934A (ja) 保存安定性の改善された坐剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载