WO2007007971A1 - Compositions pharmaceutiques comprenant de la sibutramine - Google Patents

Compositions pharmaceutiques comprenant de la sibutramine Download PDF

Info

Publication number
WO2007007971A1
WO2007007971A1 PCT/KR2006/002618 KR2006002618W WO2007007971A1 WO 2007007971 A1 WO2007007971 A1 WO 2007007971A1 KR 2006002618 W KR2006002618 W KR 2006002618W WO 2007007971 A1 WO2007007971 A1 WO 2007007971A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
sibutramine
mixture
group
acid
Prior art date
Application number
PCT/KR2006/002618
Other languages
English (en)
Inventor
Young-Joon Park
Yoen-Ju Son
Hyun-Jun Kim
Original Assignee
Yuhan Corporation
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 Yuhan Corporation filed Critical Yuhan Corporation
Publication of WO2007007971A1 publication Critical patent/WO2007007971A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising sibutramine or a salt thereof as an active ingredient.
  • Sibutramine is known as an inhibitor of 5 -hydroxy tryptamine (5-HT) and noradrenaline reuptake in vivo ⁇ Prog. Neuro-Psychopharmacol. Biol. Psychiast. 12, 575-584, Neuropharmacology, 28, 129-134). Sibutramine is also known to have a therapeutic effect against a Parkinson's disease, obesity, or depression (WO 88/06444, U.S. Pat. No. 4,814,352, and WO 90/06110] and to reduce insulin resistance or improve glucose tolerance (U.S. Pat. No. 6,174,925 and No. 6,187,820).
  • Sibutramine in a free base form is hardly soluble in water or a basic solvent.
  • sibutramine as an acid addition salt form, e.g., hydrochloride, methanesulfonate, or a monno- or hemi-hydrate thereof is disclosed (EP0230742 and U.S. Pat. Laid-Open Pub. No. 20040068018).
  • sibutramine hydrochloride monohydrate is used as an active ingredient of
  • Reductil Although commercially available Reductil exhibits a markedly improved dissolution property in water, it still shows a dissolution pattern of a poorly soluble drug, i.e., less than 50% initial release (within 15 minutes) and about 70% subsequent release (within one hour after the initial release).
  • the present invention provides a pharmaceutical composition for enhancing a dissolution rate of sibutramine in an aqueous medium, comprising sibutramine in a free base form as an active ingredient, and a pharmaceutical composition with improved stability, comprising sibutramine or its salt. [7] That is, the present invention provides a pharmaceutical composition comprising sibutramine in a free base form as an active ingredient.
  • the present invention also provides a pharmaceutical composition with improved stability, including sibutramine or its salt.
  • a pharmaceutical composition for oral administration comprising: sibutramine in a free base form; an acidifying agent selected from the group consisting of citric acid, succinic acid, malic acid, maleic acid, and a mixture thereof; and a surfactant.
  • a pharmaceutical composition comprising a sibutramine salt and an alkaline earth metal-free pharmaceutically acceptable additive.
  • the present invention provides a pharmaceutical composition including sibutramine in a free base form.
  • the sibutramine in the free base form is formulated together with an acidifying agent and a surfactant. Therefore, it is possible to solve the problem of a residual solvent caused in a separate process for the conversion of sibutramine to an acid addition salt form, and to achieve a satisfactory dissolution rate of sibutramine in an aqueous medium.
  • the sibutramine in the free base form is used as an active ingredient.
  • the sibutramine in the free base form can be used in a therapeutically effective amount.
  • a unit dosage form may include 5 - 50 mg, preferably about 8 - 20 mg of the sibutramine in the free base form.
  • the content of the sibutramine in the free base form may be 1 - 10 wt%, preferably 1 - 5 wt%, based on the total weight of the composition.
  • the acidifying agent included in the pharmaceutical composition of the present invention is selected from the group consisting of citric acid, succinic acid, malic acid, maleic acid, and a mixture thereof.
  • the content of the acidifying agent may be 1 - 20 wt%, preferably 2 - 5 wt%, based on the total weight of the composition.
  • the surfactant may be selected from the group consisting of polyoxyethylene castor oil derivatives, polyoxyethylene-polyoxypropylene block copolymers, sucrose fatty acid esters, sodium dioctyl sulfosuccinate, metal salts of alkyl sulfate, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.
  • the metal salts of alkyl sulfate may include sodium lauryl sulfate, sodium dodecyl sulfate, etc.
  • the sorbitan fatty acid esters may include commercially available Span series surfactants
  • the polyoxyethylene sorbitan fatty acid esters may include commercially available Tween series surfactants.
  • the content of the surfactant may be 1 - 30 wt%, preferably 1 - 10 wt%, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive.
  • a pharmaceutically acceptable additive e.g., the present inventor found that inte raction of sibutramine or its salt with an alkaline earth metal (e.g., magnesium, barium, strontium, or calcium) produced impurities (e.g., desmethyl-sibutramine (Ml) produced in the presence of an alkaline earth metal-containing excipient), thereby resulting in a significant reduction in stability.
  • an alkaline earth metal e.g., magnesium, barium, strontium, or calcium
  • impurities e.g., desmethyl-sibutramine (Ml) produced in the presence of an alkaline earth metal-containing excipient
  • the pharmaceutically acceptable additive may be an alkaline earth metal-free pharmaceutically acceptable additive.
  • the pharmaceutically acceptable additive may be a diluent selected from the group consisting of lactose (including hydrous lactose, anhydrous lactose, and direct compression lactose), microcrystalline cellulose, starch, sodium starch glycolate, mannitol, and a mixture thereof; and/or a lubricant selected from the group consisting of silicon dioxide, talc, sodium stearyl fumarate, stearic acid, sugar esters (Ryoto esters, Tokyo), hydrogenated castor oil, and a mixture thereof.
  • the content of the diluent may be 5 - 80 wt%, preferably 10 - 60 wt%, based on the total weight of the composition, and the content of the lubricant may be 0.1 - 5 wt%, preferably 0.1 - 1 wt%, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may further include a disintegrating agent, a flavoring agent, or a sweetener, when needed.
  • composition of the present invention can be formulated into various oral dosage forms, preferably tablets or capsules.
  • the present invention also provides a pharmaceutical composition with improved stability, including a sibutramine salt and an alkaline earth metal-free pharmaceutically acceptable additive.
  • the sibutramine salt may be selected from all known salts, e.g., hydrochlorides, methanesulfonates, and mono- or hemi-hydrates thereof.
  • the alkaline earth metal-free pharmaceutically acceptable additive may be the above-illustrated diluent and/or lubricant, and when needed, may further include a disintegrating agent, a flavoring agent, a sweetener, etc.
  • compositions of the present invention can be prepared according to conventional preparation methods of oral formulations, e.g., direct tableting, wet granulation, or dry granulation.
  • Capsules were prepared with components and contents presented in Table 1 below. Sibutramine in a free base form, colloidal silicon dioxide, starch, and microcrystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.
  • Capsules were prepared with components and contents presented in Table 2 below. Sibutramine in a free base form, colloidal silicon dioxide, and microcrystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.
  • Example 9 [37] Capsules were prepared with components and contents presented in Table 4 below. Sibutramine hydrochloride monohydrate, colloidal silicon dioxide, and micro- crystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.
  • Capsules were prepared with components and contents presented in Table 6 below. Sibutramine in a free base form, colloidal silicon dioxide, and microcrystalline cellulose were mixed, and the other additives (except for magnesium stearate or magnesium trisilicate) were added thereto. The resultant mixture was mixed with magnesium stearate or magnesium trisilicate and filled in No. 2 hard capsules to give capsules.
  • Test Example 1 Dissolution tests
  • the dissolution tests of the capsules prepared in Examples 1, 2, 5, and 6 and the comparative capsules prepared in Comparative Examples 1 - 3, and commercially available capsules (control capsules: Reductil TM, Abbott) were performed according to Dissolution Test Method II (paddle method) described in the General Tests chapter of the Korean pharmacopoeia under the following conditions. The results are summarized in Table 8 below.
  • Dissolution medium deionized purified water
  • Temperature of dissolution medium 37 + 0.5 0 C
  • Rotation speed 50 rpm
  • Analytical method liquid chromatography
  • the capsules of the present invention exhibited a significantly improved dissolution rate in an aqueous medium, relative to the comparative capsules. Furthermore, the capsules of the present invention exhibited about 10% higher dissolution rate than the control capsules (Reductil ).
  • Sibutramine was mixed with each component presented in Table 10 below with a mixture ratio of 1 to 1.
  • the resultant mixtures were stored under acceleration conditions (40 0 C / 75 RH) for 15 days, and the contents of impurities (including desmethyl-sibutramine (Ml)) were measured. The results are summarized in Table 10 below.
  • a pharmaceutical composition of the present invention exhibits a markedly improved dissolution rate of sibutramine in an aqueous medium while it includes sibutramine in a free base form as an active ingredient. Furthermore, the pharmaceutical composition of the present invention can maintain good stability during long-term storage.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur une composition pharmaceutique administrée oralement et comprenant : de la sibutramine sous forme de base libre, un agent acidifiant sélectionné dans un groupe formé de l’acide citrique, l’acide succinique, l’acide malique, l’acide maléique et un mélange de ceux-ci ; et un agent de surface. De plus, la présente invention fournit une composition pharmaceutique dont la stabilité est améliorée et qui comprend un sel de sibutramine et un additif pharmaceutiquement acceptable sans métal alcalino-terreux.
PCT/KR2006/002618 2005-07-12 2006-07-05 Compositions pharmaceutiques comprenant de la sibutramine WO2007007971A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020050062572A KR100781882B1 (ko) 2005-07-12 2005-07-12 시부트라민을 함유하는 약제학적 조성물
KR10-2005-0062572 2005-07-12

Publications (1)

Publication Number Publication Date
WO2007007971A1 true WO2007007971A1 (fr) 2007-01-18

Family

ID=37637313

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/002618 WO2007007971A1 (fr) 2005-07-12 2006-07-05 Compositions pharmaceutiques comprenant de la sibutramine

Country Status (2)

Country Link
KR (1) KR100781882B1 (fr)
WO (1) WO2007007971A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100886542B1 (ko) * 2007-02-16 2009-03-02 주식회사 드림파마 시부트라민의 가용화 조성물 및 이의 제조방법
KR100913644B1 (ko) * 2007-10-09 2009-08-24 제일약품주식회사 활성성분으로 시부트라민 유리염기를 함유하는 약제학적조성물 및 그 제조방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230742A1 (fr) * 1985-12-17 1987-08-05 The Boots Company PLC Monohydrate du chlorhydrate de N,N-diméthyl-1-[4-chlorophényl)cyclobutyl]-3-méthylbutylamine et compositions pharmaceutiques le contenant
WO2001034140A1 (fr) * 1999-11-06 2001-05-17 Abbott Gmbh & Co. Kg Formulation pharmaceutique
WO2004030663A1 (fr) * 2002-10-05 2004-04-15 Hanmi Pharm. Co., Ltd. Composition pharmaceutique comprenant de l'hemihydrate de methanesulfonate de sibutramine cristallin
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230742A1 (fr) * 1985-12-17 1987-08-05 The Boots Company PLC Monohydrate du chlorhydrate de N,N-diméthyl-1-[4-chlorophényl)cyclobutyl]-3-méthylbutylamine et compositions pharmaceutiques le contenant
WO2001034140A1 (fr) * 1999-11-06 2001-05-17 Abbott Gmbh & Co. Kg Formulation pharmaceutique
WO2004030663A1 (fr) * 2002-10-05 2004-04-15 Hanmi Pharm. Co., Ltd. Composition pharmaceutique comprenant de l'hemihydrate de methanesulfonate de sibutramine cristallin
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant

Also Published As

Publication number Publication date
KR20070008787A (ko) 2007-01-18
KR100781882B1 (ko) 2007-12-05

Similar Documents

Publication Publication Date Title
TWI404534B (zh) 包含氨氯地平（ａｍｌｏｄｉｐｉｎｅ）及洛沙坦（ｌｏｓａｒｔａｎ）且具有經改良穩定性之固體藥學組成物
JP4965130B2 (ja) 乾式直打速崩壊性錠剤
EP2550957B1 (fr) Formulations effervescentes de vildagliptine
US20030190353A1 (en) Low water-soluble venlafaxine salts
WO2010070705A1 (fr) Préparation orale aqueuse stable d'amlodipine
ZA200509155B (en) Pioglitazone salts, such as pioglitazone sulfate, and pharmaceutical compositions and processes using the same
JP5284777B2 (ja) 難溶性薬剤の改善された溶解プロファイルを有する医薬組成物
US20100021543A1 (en) Peroral solid pain killer preparation
JP2019112424A (ja) トホグリフロジンを含有する固形製剤及びその製造方法
KR20090131584A (ko) 매스틱을 포함하는 발포성 속붕해정
EP2563340A2 (fr) Composition pharmaceutique hydrosoluble
WO2007007971A1 (fr) Compositions pharmaceutiques comprenant de la sibutramine
JP2009507014A (ja) Ｓ−クロピドグレルの新規レジネート複合体およびその生成法
JPH1192369A (ja) 医薬品調製物、その製造方法及びシランセトロンの安定化のための酸性添加剤の使用
EP1259261B1 (fr) Compositions pharmaceutiques renfermant du terbinafine
WO2020148219A1 (fr) Procédé de fabrication de composition pharmaceutique comprenant du néfopam et de l'acétaminophène, et composition pharmaceutique ainsi obtenue
JP2005537295A (ja) ビシファジンの製造方法
JP5072748B2 (ja) アムロジピンの安定な液剤とゼリー剤
EP2925320B1 (fr) Procede nouveau pour ameliorer la biodisponibilite des medicaments ayant une faible solubilite aqueuse
AU2020209883A1 (en) A method of manufacturing a pharmaceutical composition comprising nefopam and acetaminophen, and the pharmaceutical composition obtained thereby
JP2006510665A (ja) 新規な経口即時放出型投与剤形
US6784315B2 (en) Stilbene derivative crystal and method for producing the same
CN111065398A (zh) 用于治疗急性心肌梗塞的、具有乙酰水杨酸与柠檬酸、碳酸氢钠和l-茶氨酸的水溶性共晶的舌下制剂
WO2013100871A1 (fr) Formulations effervescentes de rivastigmine
ES2406757T3 (es) Comprimido bucodispersable que contiene una sal de sildenafilo

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06769171

Country of ref document: EP

Kind code of ref document: A1