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WO2007007971A1 - Compositions pharmaceutiques comprenant de la sibutramine - Google Patents

Compositions pharmaceutiques comprenant de la sibutramine Download PDF

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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
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.)
Ceased
Application number
PCT/KR2006/002618
Other languages
English (en)
Inventor
Young-Joon Park
Yoen-Ju Son
Hyun-Jun Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yuhan Corp
Original Assignee
Yuhan Corp
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 Corp filed Critical Yuhan Corp
Publication of WO2007007971A1 publication Critical patent/WO2007007971A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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.

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  • 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 Ceased WO2007007971A1 (fr)

Applications Claiming Priority (2)

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

Publications (1)

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

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ID=37637313

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

Country Status (2)

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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
KR100781882B1 (ko) 2007-12-05
KR20070008787A (ko) 2007-01-18

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