WO2005080383A1 - Chlorhydrate d'itraconazole, sa preparation et composition orale solide associee - Google Patents

Chlorhydrate d'itraconazole, sa preparation et composition orale solide associee Download PDF

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Publication number
WO2005080383A1
WO2005080383A1 PCT/CN2004/000474 CN2004000474W WO2005080383A1 WO 2005080383 A1 WO2005080383 A1 WO 2005080383A1 CN 2004000474 W CN2004000474 W CN 2004000474W WO 2005080383 A1 WO2005080383 A1 WO 2005080383A1
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WO
WIPO (PCT)
Prior art keywords
itraconazole
cyclodextrin
hydrochloride
solid composition
oral solid
Prior art date
Application number
PCT/CN2004/000474
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English (en)
Chinese (zh)
Inventor
Tao Tao
Baoyuan He
Yulan Gu
Weideng Zhou
Liangan Huang
Original Assignee
Shanghai Institute Of Pharmaceutical Industry
Shanghai Modern Pharmaceutical 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 Shanghai Institute Of Pharmaceutical Industry, Shanghai Modern Pharmaceutical Co., Ltd. filed Critical Shanghai Institute Of Pharmaceutical Industry
Publication of WO2005080383A1 publication Critical patent/WO2005080383A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • Itraconazole hydrochloride its oral solid composition and preparation method
  • the invention relates to an itraconazole salt and a preparation thereof, in particular to an oral solid composition containing itraconazole hydrochloride and a preparation method thereof.
  • Itraconazole is (shi) -cis-4- [4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1 ⁇ -1,2,4-tri Azol-1-yl-methyl) -1,3-dioxolane-4-yl] methoxy] phenyl] piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one is a broad-spectrum antifungal compound for oral, parenteral, and topical use.
  • WO94 / 05263 discloses a coated pellet in which a sugar pellet of 600 to 700 ⁇ m is built in a fluidized bed granulator, and after it is preheated, itraconazole and hydroxypropyl methylcellulose (1: 1.5) The mixture of dichloromethane and anhydrous ethanol solution is sprayed on the medicine, and after vacuum drying, it is coated with a solution of polyethylene glycol 20000 in dichloromethane, and finally the coated pellets are filled into hard capsules.
  • This is the production process of Janssen Pharmaceutica (Beerse, Belgium) Sporanox® capsules. This process requires the use of toxic and harmful dichloromethane as a solvent. The process parameters are complex and the production cycle is long. It also requires Explosion-proof equipment. Sporanox® capsules have been reported to have an absolute absolute bioavailability of about 30% orally, vary widely within individuals and individuals, and are also affected by food intake.
  • WO95 / 08993, CN 1086579C discloses an itraconazole oral solution prepared by using hydroxypropyl- ⁇ -cyclodextrin as a solubilizer. This is the prescription process for Sporanox® oral solution from Janssen, Belgium. The oral solution uses 40 to 60% of hydroxypropyl- ⁇ -cyclodextrin, which is expensive.
  • WO97 / 44014 discloses a solid dispersion of itraconazole and hydroxypropyl methylcellulose prepared by a melt extrusion method.
  • the high temperature of 245 ⁇ 265 ° C will affect the stability of the drug, and the process parameters are complicated, requiring special melting-extrusion equipment.
  • W098 / 57967, CN 1262682 A discloses a method for reducing the average particle size of itraconazole from a conventional 24.5 ⁇ m to 3.7 m by a spray drying method. Although it can increase the water solubility and dissolution rate of itraconazole, In 37 ° C artificial gastric juice at pH 1.2, it only dissolves ⁇ 85% in 2h, and it cannot meet the dissolution requirements prescribed by the Pharmacopoeia.
  • W099 / 33467, CN 1285746A discloses an itraconazole and a pH-dependent hydrophilic polymer prepared by a spray drying method, polyvinylacetal diethylamine acetate (AEA) and dimethyl methacrylate
  • AEA polyvinylacetal diethylamine acetate
  • Eudragit E100 A solid dispersion of aminoethyl-neutral methacrylate copolymer (Eudragit E100).
  • AEA and Eudragit E100 are hydrophilic polymers with quaternary ammonium functional groups. They can dissolve in gastric juice with a pH value lower than 5 and solubilize itraconazole. However, when the fasting gastric emptying is fast or for patients with hypoacidity, the drug cannot be completely dissolved in the stomach. When the solid dispersion enters the small intestine, the pH of the polymer will be higher than 5, and the insolubilization of the polymer will block the drug Dissolve.
  • WO00 / 76520, CN 1390127A discloses itraconazole, hydroxypropyl methylcellulose, poloxamer, sodium chloride and magnesium stearate (1: 1: 0.07: 0.01) prepared by a spray drying method. : 0.01) mixture solid dispersion. Allegedly, the above spray-dried mixture was appropriately shaped After the formulations were made into tablets, 10 healthy subjects were subjected to a relative bioavailability study. The AUC and C max of oral 50 mg tablets and oral commercial 100 mg Sporanox® capsules were basically the same, but the individual differences were significantly reduced; oral 100 mg The tablets have twice the AUC and Cmax than the oral same-dose Spomnox® tablets.
  • the invention adopts a spray drying method, which requires the use of toxic and harmful methylene chloride as a solvent, requires an explosion-proof spray drying device, and has a long process.
  • WO01 / 41765, CN 1398184A discloses a fused mixture of itraconazole and phosphoric acid. After mixing itraconazole and phosphoric acid 85% (1: 1.5), it is heated to 160 ° C to make the mixture melt. During the cooling process, Poloxamer® 407, Cromophor® RH40, hydroxypropyl methylcellulose and hydrotalcite were added. After cooling, a fused mixture was obtained. It is said that higher bioavailability was measured in rats than Sporanox® tablets. . Although the invention has a lower heating temperature than WO97 / 44014, it has no industrial setting equipment.
  • the technical problem to be solved by the present invention is to disclose an itraconazole hydrochloride, an oral solid composition thereof, and a preparation method thereof, so as to overcome the above-mentioned defects existing in the prior art.
  • the itraconazole hydrochloride in the present invention is a compound having the following general formula:
  • the itraconazole oral solid composition according to the present invention is characterized by comprising a therapeutically effective amount of itraconazole hydrochloride and a sufficient amount of cyclodextrin.
  • the oral solid composition of itraconazole hydrochloride of the present invention includes 20 to 50% by weight of a pharmaceutically active ingredient and 50 to 80% by weight of a cyclodextrin.
  • the active pharmaceutical ingredient is itraconazole hydrochloride
  • the cyclodextrin includes one or more of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydrazone-cyclodextrin, hydroxypropyl-3 -cyclodextrin, and methyl- ⁇ -cyclodextrin. .
  • the oral solid composition according to the present invention can be prepared into capsules such as immediate release capsules, sustained release capsules or controlled release capsules and tablets such as immediate release tablets, orally soluble tablets, chewable tablets, dispersible tablets, Sustained-release tablets, controlled-release tablets, etc.
  • the dissolution rate of the itraconazole oral solid composition of the present invention in 900 ml of a hydrochloric acid solution (9-1000) can reach a drug dissolution rate of 90 to 100% in 45 minutes.
  • the method for preparing the itraconazole hydrochloride oral solid composition includes the steps of first preparing the drug as a hydrochloride, and then mixing the drug with a sufficient amount of cyclodextrin. Because itraconazole is a weak base, its hydrochloride salt is difficult to obtain according to the conventional preparation method, or the obtained product is easy to absorb water and is unstable. Therefore, the preferred preparation method includes the following steps:
  • the organic solvents mentioned include alcoholic solvents containing 1 to 4 carbon atoms, such as methanol and ethanol; ketone solvents containing 3 to 5 carbon atoms, such as acetone and methyl ethyl ketone;
  • the temperature of the salt formation reaction is from room temperature to 100 ° C, preferably 60 to 80 ° C.
  • Figure 1 is the cumulative dissolution curve (1 is itraconazole hydrochloride capsules, 2 is spinenol gum.
  • Figure 2 is a sample of 20 healthy volunteers taking a single dose of 200 mg itraconazole hydrochloride capsule test preparation and sperren The mean plasma concentration-time curve after the Nuo® capsule reference preparation. The following examples are used to illustrate the present invention, but are not meant to limit the present invention in any way.
  • Dissolution test of itraconazole hydrochloride capsules According to the dissolution test method of the two parts of the Chinese Pharmacopoeia 2000, the dissolution curves of Example 3 and Spiranox® capsules (distributed by Xi'an Yangsen Pharmaceutical Co., Ltd., batch number 000322098) were determined according to law.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le chlorhydrate d'itraconazole, sa préparation et la composition orale solide associée. L'itraconazole peut être converti en chlorhydrate avec une meilleure hydrosolubilité par réaction d'un gaz HCI dans un solvant organique. Cette composition orale solide peut être obtenue par mélange du sel susmentionné et d'une quantité appropriée de cyclodextrine, la solubilité et la biodisponibilité du composé actif étant alors considérablement améliorées.
PCT/CN2004/000474 2004-02-23 2004-05-12 Chlorhydrate d'itraconazole, sa preparation et composition orale solide associee WO2005080383A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410016484.5 2004-02-23
CNB2004100164845A CN1285590C (zh) 2004-02-23 2004-02-23 伊曲康唑盐酸盐口服固体组合物和制备方法

Publications (1)

Publication Number Publication Date
WO2005080383A1 true WO2005080383A1 (fr) 2005-09-01

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CN (1) CN1285590C (fr)
WO (1) WO2005080383A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10166215B2 (en) 2013-06-21 2019-01-01 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG131794A1 (en) * 2005-10-18 2007-05-28 Matsushita Electric Ind Co Ltd Disc changer
CN103788077B (zh) * 2014-02-28 2016-03-09 上海现代哈森（商丘）药业有限公司 一种盐酸伊曲康唑的合成方法
CN110898015A (zh) * 2019-12-31 2020-03-24 上海汉维生物医药科技有限公司 一种伊曲康唑制剂的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097853A1 (fr) * 2000-06-21 2001-12-27 Biochemie Gesellschaft Mbh Amelioration de la biodisponibilite d'itraconazole
CN1398184A (zh) * 1999-12-08 2003-02-19 东亚制药株式会社 具有改善的生物利用度和缩小的个体内和个体间吸收差异的含有伊曲康唑的组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1398184A (zh) * 1999-12-08 2003-02-19 东亚制药株式会社 具有改善的生物利用度和缩小的个体内和个体间吸收差异的含有伊曲康唑的组合物
WO2001097853A1 (fr) * 2000-06-21 2001-12-27 Biochemie Gesellschaft Mbh Amelioration de la biodisponibilite d'itraconazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAO TAO ET AL: "Dissolution of Itraconazole Hydrochloride Capsules.", CHINESE JURNAL OF PHARMACEUTICALS., vol. 34, no. 7, 2003, pages 340 - 342 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10166215B2 (en) 2013-06-21 2019-01-01 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors

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CN1285590C (zh) 2006-11-22
CN1660841A (zh) 2005-08-31

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