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High-dose clinorhomboidal adefovir dipivoxil preparation, and preparation method and application thereof

A technology of adefovir dipivoxil and triclinic crystal is applied in the field of high-dose preparations of triclinic adefovir dipivoxil, which can solve the problems that affect the safety of adefovir dipivoxil, the drug is difficult to exert its original crystal form, and the raw material drug Crystal form damage and other problems, to achieve the effect of ensuring the uniformity of tablet weight/grain weight, ensuring production continuity and high safety

Inactive Publication Date: 2012-10-10
CHF SHANGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the production process of preparations adopts wet granulation process to prepare tablets or capsules. In the process of granulation-tabletting / filling capsules, the crystal form of raw materials is destroyed or partially destroyed due to the dissolution or partial dissolution of raw materials, resulting in drug It is difficult to take advantage of the original crystal form in vivo
In the process of granulation and drying, because adefovir dipivoxil is easy to decompose, the related substances are as high as 3%~6%, and the effective content is reduced, which affects the safety of adefovir dipivoxil in clinical use.

Method used

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  • High-dose clinorhomboidal adefovir dipivoxil preparation, and preparation method and application thereof
  • High-dose clinorhomboidal adefovir dipivoxil preparation, and preparation method and application thereof
  • High-dose clinorhomboidal adefovir dipivoxil preparation, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: Preparation of specific triclinic adefovir dipivoxil whose space group is P-1

[0049] Drying Reactor N 2 Protection, heating and dissolving 1000g of the crude product of adefovir dipivoxil in 10L of ethanol, filtering off the insolubles while hot, adding diisopropyl ether at 20~25°C until cloudy, then stirring until crystallization is complete, filtering and vacuum drying for 24 hours, Triclinic crystal adefovir dipivoxil was obtained with a yield of 85-90%, a content of ≥99.0% (HPLC), and a melting point of 99-101°C.

[0050] The obtained triclinic adefovir dipivoxil single crystal X-ray diffraction data are as follows: the crystal belongs to the triclinic system, the space group is P-1, and the unit cell parameters are as follows: α=93.798(6)°.β=97.458(6)°.γ=102.897(6)°.Z=2.

[0051] The data of triclinic adefovir dipivoxil powder X-diffraction are as follows:

[0052]

Embodiment 2

[0053] Example 2: High-dose triclinic adefovir dipivoxil tablet or capsule preparation dry granulation process

[0054] 1. Selection of carriers and excipients:

[0055] Diluent: anhydrous lactose (supplier: Hefei Shanhe Accessories Co., Ltd.; manufacturer: DMV International Co., Ltd.; registration number: F20090027; specification: medicinal (import))

[0056] Adhesive: pregelatinized starch (supplier: Huzhou Zhanwang Pharmaceutical Co., Ltd.; manufacturer: Huzhou Zhanwang Pharmaceutical Co., Ltd.; approval number: Zheyao Zhunzi: F20060057; executive standard: Chinese Pharmacopoeia 2010 edition; specification : medicinal);

[0057] Disintegrant: sodium starch glycolate (supplier: Huzhou Zhanwang Pharmaceutical Co., Ltd.; manufacturer: Huzhou Zhanwang Pharmaceutical Co., Ltd.; approval number: F20060059; executive standard: Chinese Pharmacopoeia 2010 edition; specification: medicinal) ;

[0058] Lubricant: Talc powder (supplier: Shanghai New Pioneer Huakang Pharmaceutical Co...

Embodiment 3

[0078] Embodiment 3: triclinic adefovir dipivoxil tablet or capsule and content detection of related substances:

[0079] Determination according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix VD).

[0080] Chromatographic conditions and system suitability test use mixed anion exchange carbon octaalkyl bonded silica gel as filler (such as Alltech, Mix-modeC8 / Anion, 7μm, 25cm×4.6mm); use 0.2moL / L phosphate buffer ( Take 9.2g of anhydrous dipotassium hydrogen phosphate and 47.2g of anhydrous potassium dihydrogen phosphate, add water to dissolve and dilute to 2000ml, adjust the pH value to 6.0 with phosphoric acid or potassium hydroxide solution)-acetonitrile (70:30) as mobile phase A , using 0.2moL / L phosphate buffer (PH 6.0)-acetonitrile (50:50) as mobile phase B, perform linear gradient elution according to the following procedure, the flow rate is 1.2ml per minute; the detection wavelength is 260nm.

[0081] Determination method Ta...

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Abstract

The invention relates to a clinorhomboidal adefovir dipivoxil preparation. The clinorhomboidal adefovir dipivoxil preparation is characterized in that each unit of the clinorhomboidal adefovir dipivoxil preparation comprises 15 to 25mg of clinorhomboidal adefovir dipivoxil and a pharmaceutically acceptable carrier. The invention also relates to a preparation method for the preparation. The invention further relates to the application of the clinorhomboidal adefovir dipivoxil preparation to preparation of a medicine for relieving hepatitis symptoms which are caused by hepatitis B virus. The high-dose clinorhomboidal adefovir dipivoxil preparation has the advantages of high safety, quick hepatitis B virus resistance response, high curative effect, ideal comprehensive treatment effect, and the like.

Description

technical field [0001] The invention relates to a fast-acting, high-efficiency and safe high-dose preparation of triclinic adefovir dipivoxil, its preparation method and its application. Background technique [0002] The chemical structural formula of Adefovir Dipivoxil (AD for short) is 9-[2-[[[[bis(trimethylacetoxy)methyl]oxophosphoryl]methoxy]ethyl]adenine. It has strong in vitro antiviral activity against HIV, HBV, human CMV, HSV-1 and HSV-2. Clinical studies have found that adefovir dipivoxil is effective in treating chronic hepatitis B with relatively low adverse reactions. [0003] US Patents 4,724,233 and 4,808,716, EP 481,214, etc. disclose adefovir dipivoxil, its preparation and application. The prepared adefovir dipivoxil is in an amorphous form, and its physical properties are not conducive to subsequent clinical use. [0004] Chinese patent 00137059.6 discloses a composition containing monoclinic adefovir dipivoxil crystals, its application and a method for sy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/675A61K9/20A61K9/48A61P1/16A61P31/20C07F9/6561
Inventor 李科汪元璋张峥范国萍李淑君周剑竑牛春娟陆慧丽
Owner CHF SHANGHAI PHARMA
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