Tecovirimat dry suspension and preparation method thereof

A technology of Tevirima and dry suspension, which is applied in the field of Tevirima dry suspension and its preparation, can solve the problems of unreported preparation bioavailability and pharmacokinetic parameters, and achieve anti-mousepox virus activity Strong, easy to take, slow sedimentation effect

Active Publication Date: 2012-04-11
INST OF BIOENG ACAD OF MILITARY MEDICAL SCI OF THE CHINESE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

U.S. Patent US20080004452 reports the capsule formulation of Tavirim (Chinese patent of the same name CN101702904), and Chinese patent (CN101912389) reports the tablet f

Method used

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  • Tecovirimat dry suspension and preparation method thereof
  • Tecovirimat dry suspension and preparation method thereof
  • Tecovirimat dry suspension and preparation method thereof

Examples

Experimental program
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Example Embodiment

[0033] Example 1. Investigating the method to improve the monoclinic crystal solubility of Tevirima monohydrate

[0034] The effective dose of Tevirima is large, the solubility in water is low (the measured value is 1.52 μg / ml), and the addition of acid cannot increase the solubility, and the addition of alkali causes degradation, which poses many challenges to the preparation of Tevirima.

[0035] In order to improve the bioavailability of tevirima monohydrate crystals, the inventors explored methods such as particle size reduction, solubilization, cyclodextrin inclusion, and solid dispersion to increase the monoclinic crystals of tevirima monohydrate. Solubility in water.

[0036] 1) Tevir is immediately micronized

[0037] The micronization of the drug can significantly reduce the particle size, increase the surface area of ​​the drug in contact with the solvent, increase the solubility, and improve absorption. The monoclinic crystals of Tevirima monohydrate are micronized, and th...

Example Embodiment

[0053] Example 2. Preliminary Screening of Prescription for Tevirima Dry Suspension

[0054] The bioavailability of Tevirima in different suspending agents and solubilizer formulations was investigated. CL-611 (FMC, USA) is a product made by special mixing of microcrystalline cellulose and sodium carboxymethyl cellulose. The effect is good, so try to apply. In addition, in order to improve the wettability of Tavirima, surfactants such as SDS, Tween 80 poloxamer 407 and 188 were added to the prescription respectively; while the micronized silica gel has the ability to resist caking and glid, which can make The preparation has good powder properties. Hydroxypropyl beta cyclodextrin can increase the solubility of the drug immediately after the inclusion of Tevir, and is also included in the formulation screening. The prescription design is shown in Table 2. Each prescription complies with the requirements of Appendix IO of the 2010 edition of the Chinese Pharmacopoeia.

[0055] Tab...

Example Embodiment

[0062] Example 3 Optimization of the prescription of Tevirima dry suspension

[0063] (1) Screening of wetting agents

[0064] Add 500mg of Tevirima to 50mL of water, and add the wetting agent according to a 5mg gradient to observe whether Tevirima is completely wetted and sinks below the liquid surface, and produces less foam.

[0065] By investigating the wetting effect of Tween 80, sodium lauryl sulfate, poloxamer 407 and 188 on tevirima, it was found that when the amount of poloxamer 407 added was 20-25mg, there was significant Good wetting effect.

[0066] (2) Screening of defoamers

[0067] In the suspended state, the wetting agent will generate a lot of bubbles. In order to ensure the wetting of Teviron, only defoamers can be added to reduce the generation of bubbles. Dimethicone is odorless, non-toxic, physiologically inert, and has good chemical stability. Because dimethicone has low surface tension and is insoluble in water, it has been widely used as a defoamer in petroleum...

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Abstract

The invention discloses a tecovirimat dry suspension and a preparation method thereof. The tecovirimat dry suspension provided by the invention comprises the following components in parts by mass: 20 to 30 parts of monoclinic crystal micro-powder of tecovirimat monohydrate, 40 to 80 parts of filler, 5 to 10 parts of suspending aid, and 1 to 5 parts of wetting agent, wherein, in the monoclinic crystal micro-powder of tecovirimat monohydrate, the space group of a monoclinic system is C2/c, cell parameters are as follows: a is 28.724 (2), b is 10.533 (1), c is 12.902 (1) tenthmeter and beta is 112.18 (1) degrees, the cell volume V is 3614.7 (6) cubic tenthmeter, and the number Z of molecules in unit cell is 8. The dry suspension solid powder has good liquidity, can be quickly transformed into a uniform and stable suspension after being mixed with water, has less foam, low deposition speed and excellent redispersibility, and is convenient for administration of patients. Animal experimentsprove that: the preparation has long half-life period, high blood concentration and strong mousepox virus resisting activity.

Description

technical field [0001] The invention relates to a tevir immediate dry suspension and a preparation method thereof. Background technique [0002] Tecovirimat is a small molecular compound (also known as ST-246, Tecovirimat), which can effectively resist various orthopoxviruses such as vaccinia, monkeypox, camelpox, ratpox and smallpox, and has selectivity (J . Virol, 2005(20): 13139-13149; Antimicrob. Agents. Chemother, 2007(51): 689-695). Threatened by bioterrorism, as an oral anti-smallpox virus drug, Tevirima was approved by the US FDA in May 2006 for clinical trial research, and is currently in phase I clinical research. U.S. Patent US20080004452 reports the capsule formulation of Tavirim (Chinese patent of the same name CN101702904), and Chinese patent (CN101912389) reports the tablet formulation of Tavirim, but the bioavailability and pharmacokinetic parameters of the preparation are not reported. and the in vivo antiviral activity of the preparations. [0003] Dry s...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K31/403A61P31/20
Inventor 戴秋云董铭心余硕彭博王毅飞朱梅
Owner INST OF BIOENG ACAD OF MILITARY MEDICAL SCI OF THE CHINESE
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