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WO2006090999A1 - Malates de sibutramine anhydres et procede de preparation - Google Patents

Malates de sibutramine anhydres et procede de preparation Download PDF

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Publication number
WO2006090999A1
WO2006090999A1 PCT/KR2006/000578 KR2006000578W WO2006090999A1 WO 2006090999 A1 WO2006090999 A1 WO 2006090999A1 KR 2006000578 W KR2006000578 W KR 2006000578W WO 2006090999 A1 WO2006090999 A1 WO 2006090999A1
Authority
WO
WIPO (PCT)
Prior art keywords
sibutramine
malate
anhydrous
solvent
crystalline
Prior art date
Application number
PCT/KR2006/000578
Other languages
English (en)
Inventor
Tae-Won Kang
Kwan-Jun Jeon
Hoee-Joo Shon
Won-Kyu Choi
Kwan-Young Chang
Kyung-Yong Jin
Kwang-Seob Lee
Original Assignee
Ckd Bio 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 Ckd Bio Corp filed Critical Ckd Bio Corp
Publication of WO2006090999A1 publication Critical patent/WO2006090999A1/fr

Links

Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24C—DOMESTIC STOVES OR RANGES ; DETAILS OF DOMESTIC STOVES OR RANGES, OF GENERAL APPLICATION
    • F24C7/00—Stoves or ranges heated by electric energy
    • F24C7/04—Stoves or ranges heated by electric energy with heat radiated directly from the heating element
    • F24C7/043—Stoves
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24C—DOMESTIC STOVES OR RANGES ; DETAILS OF DOMESTIC STOVES OR RANGES, OF GENERAL APPLICATION
    • F24C7/00—Stoves or ranges heated by electric energy
    • F24C7/08—Arrangement or mounting of control or safety devices
    • F24C7/081—Arrangement or mounting of control or safety devices on stoves
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to an anhydride of sibutramine acid addition salt
  • osteoarthritis anxiety disorder, somnipathy, sexual dysfunction, chronic fatigue
  • sibutramine should be used in the form of acid
  • GB patent No.2,098,602 discloses methods for preparing sibutramine
  • anhydrous sibutramine hydrochloride is highly hygroscopic.
  • Hygroscopic material is undesirable in preparing drugs because of difficulties in
  • sibutramine acid addition salt has been developed as a hydrate form, which is the final
  • composition such as Meradia and Reductile known for treating obesity.
  • solubility must be great over a broad pH range which highly influences on release rate
  • compositions in diverse conditions e.g., stomach, gut or blood when it is administered,
  • sibutramine hydrochloride monohydrate shows a low solubility in
  • sibutramine is also an important factor for a pharmaceutical
  • sibutramine having a high solubility in water or aqueous solution over a broad pH range
  • composition comprising said anhydrous sibutramine malate as an active ingredient.
  • Fig. 1 is a flow chart illustrating a preparation process of an anhydrous
  • sibutramine malate from sibutramine and malic acid according to the present invention.
  • Fig. 2 is a representative X-ray diffraction spectrum of the anhydrous
  • sibutramine malate crystalline I according to the present invention.
  • Fig. 3 is a representative differential scanning calorimetry (DSC) of the
  • Fig. 4 is a representative X-ray diffraction spectrum of the anhydrous
  • sibutramine malate crystalline II according to the present invention.
  • Fig. 5 is a representative differential scanning calorimetry (DSC) of the
  • the present invention provides an anhydrous sibutramine malate of formula (I)
  • the present invention further provides a method for preparing the anhydrous
  • the present invention further provides a pharmaceutical composition
  • sibutramine malate a product of salt-forming reaction between malic acid and
  • sibutramine function like hydroxyl group of H 2 O, and solved the hydroscopicity of
  • sibutraimine salt anhydride using "non-hydration” property of sibutramine malate
  • the present invention provides anhydrous sibutramine malate crystallines I and
  • the anhydrous sibutramine malate of the present invention has solved
  • anhydrous sibutramine malate of the present invention also has a high
  • solubility over a broad pH range e.g., stomach, gut or blood in respect of internal
  • the present inventors tried to obtain hydrate of sibutramine malate by exposing
  • sibutramine malate to excess amount of water intentionally or by contacting with water
  • malate of the present invention is not formed by any known method, so that it may be
  • sibutramine malate according to the present invention has innate "non-reacted sibutramine malate according to the present invention
  • sibutramine salts which are converted to the corresponding hydrate salts when they
  • the anhydrous sibutramine malate according to the present invention has a high
  • malate according to the present invention prevents humidity from causing hydrolysis
  • invention comprises the steps of:
  • Fig. 1 is a flow chart of a preparation process of the anhydrous sibutramine
  • the first solvent is one or more alcohols selected from the group consisting of
  • solvent water may be add to the solvent.
  • the second solvent used in the preparation of the crystalline I is one or more
  • ketones which are hydrophilic selected from the group consisting of acetone, methyl
  • the second solvent used in the preparation of the crystalline II is one or more
  • esters which are non-hydrophilic selected from the group consisting of ethyl acetate, n-
  • hydrophilic selected from the group consisting of diethyl ether, isopropyl ether and t-
  • the first solvent may be employed in an amount of 5-20
  • the second solvent may be
  • sibutramine of formula (II) based on 1 part by weight of sibutramine of formula (II).
  • reaction temperature and reaction time are
  • reaction is performed at
  • reaction temperature ranging from 0 ° C to the boiling point of the solvent, preferably
  • the precipitating process may be performed at -15 ° C to 65 ° C, preferably at
  • Malic acid in the forms of D-malic acid, L-malic acid or D-,L-malic acid may be any suitable malic acid in the forms of D-malic acid, L-malic acid or D-,L-malic acid.
  • the anhydrous sibutramine malate according to the present invention can be any organic sibutramine malate according to the present invention.
  • the present invention provides a pharmaceutical composition
  • composition of the present invention may further comprise pharmaceutically acceptable
  • the pharmaceutical composition of the invention is a pharmaceutical composition of the following abbreviations: a pharmaceutically acceptable diluents and excipients.
  • the pharmaceutical composition of the invention is a pharmaceutically acceptable diluents and excipients.
  • present invention is administrated orally in the form of a tablet or a capsule.
  • Anhydrous sibutramine hydrochloride was prepared according to the method
  • sibutramine was dissolved in 50ml of methanol and 2.6g of L-malic acid
  • Fig. 2 shows a representative X-ray diffraction spectrum of the
  • sibutramine malate 7.7 ⁇ 0.2, 10.4 ⁇ 0.2, 11.5 ⁇ 0.2, 12.4 ⁇ 0.2, 13.5 ⁇ 0.2, 14.1 ⁇ 0.2,
  • Fig. 4 shows a representative X-ray diffraction spectrum of the
  • sibutramine malate crystalline II according to the present invention. According to Fig.
  • sibutramine malate 8.4 ⁇ 0.2, 8.7 ⁇ 0.2, 9.7 ⁇ 0.2, 10.0 ⁇ 0.2, 11.4 ⁇ 0.2, 11.6 ⁇ 0.2, 12.1 ⁇ 0.2,
  • Example 8 Formulation in capsule containing sibutramine malate
  • Non-hygroscopic salt is desirable for stable formulation and constant content of a
  • the present invention resolved hygroscopic problems of conventional sibutramine acid-
  • the compound were measured by employing a Kaal-Fisher moisture analyzer.
  • the compound were measured by employing a Kaal-Fisher moisture analyzer.
  • present invention exhibits unique non-hydration property which is not provided in any
  • preparation example 1 were compared with one another within a pH range required for
  • sibutramine malate of the present invention is more stable than the conventional
  • sibutramine hydrochloride monohydrate by testing the salt in stringent condition
  • the anhydrous sibutramine malate according to the present invention shows
  • sibutramine salts so that it fundamentally eliminates the hygroscopic property of a
  • sibutramine malate of the present invention may be used in the pharmaceutical composition for the treatment or prevention of various diseases,
  • sibutramine is used as a pharmaceutically active ingredient.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Combustion & Propulsion (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un malate de sibutramine anhydre, hygroscopique, hautement soluble et stable représenté par la formule (1), ainsi que son procédé de préparation. Selon l'invention, le malate de sibutramine anhydre non hygroscopique est hautement soluble dans l'eau à divers pH et présente une stabilité améliorée à l'humidité et aux températures élevées, ce qui, par conséquent, le rend utile dans la préparation d'une composition pharmaceutique destinée à traiter une maladie telle que l'obésité.
PCT/KR2006/000578 2005-02-22 2006-02-21 Malates de sibutramine anhydres et procede de preparation WO2006090999A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020050014642A KR20060093564A (ko) 2005-02-22 2005-02-22 무수 시부트라민 말산염 및 이의 제조 방법
KR10-2005-0014642 2005-02-22

Publications (1)

Publication Number Publication Date
WO2006090999A1 true WO2006090999A1 (fr) 2006-08-31

Family

ID=36927607

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/000578 WO2006090999A1 (fr) 2005-02-22 2006-02-21 Malates de sibutramine anhydres et procede de preparation

Country Status (2)

Country Link
KR (1) KR20060093564A (fr)
WO (1) WO2006090999A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2825215C2 (ru) * 2019-05-31 2024-08-21 Хёндэ Фарм Ко., Лтд. Новая кристаллическая форма производного 3-(4-(бензилокси)фенил)гекс-4-иновой кислоты

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113906015B (zh) * 2019-05-31 2024-03-01 现代药品株式会社 3-(4-(苄氧基)苯基)己-4-炔酸衍生物的新晶型

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013034A1 (fr) * 1996-09-25 1998-04-02 Knoll Aktiengesellschaft Utilisation d'analogues de sibutramine pour abaisser les taux de lipides
WO2000056313A1 (fr) * 1999-03-19 2000-09-28 Knoll Gmbh Procede de lutte contre le gain de poids associe a des medicaments therapeutiques
US6331571B1 (en) * 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998013034A1 (fr) * 1996-09-25 1998-04-02 Knoll Aktiengesellschaft Utilisation d'analogues de sibutramine pour abaisser les taux de lipides
US6331571B1 (en) * 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
WO2000056313A1 (fr) * 1999-03-19 2000-09-28 Knoll Gmbh Procede de lutte contre le gain de poids associe a des medicaments therapeutiques
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2825215C2 (ru) * 2019-05-31 2024-08-21 Хёндэ Фарм Ко., Лтд. Новая кристаллическая форма производного 3-(4-(бензилокси)фенил)гекс-4-иновой кислоты

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KR20060093564A (ko) 2006-08-25

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