Antiviral agent and method thereof

 

(57) Abstract:

The invention relates to medicine, in particular to pharmacology relates to antiviral agents in the form of solid dosage forms containing acyclovir, microcrystalline cellulose, salt of stearic acid, low molecular weight polyvinylpyrrolidone, and, optionally, a dye in a certain ratio, and method of its production. Antiviral agent is obtained by mixing the active substance with filler, wetting the mixture, wet granulation, drying, dry granulation, the introduction of a salt of stearic acid and subsequent formation of granules. 2 S. and 4 C.p. f-crystals, 2 tab.

The invention relates to the field of medicine and is suitable for the treatment of viral diseases of the skin and mucous membranes caused by a simple virus or herpes zoster, and prevention of these diseases in patients with immune system disorders.

Creating drugs for the treatment of viral lesions of the skin and mucous membranes is particularly relevant in the current period, not only due to significant growth in the number of patients, but the lack of adequate therapeutic agents. Acyclovir (or 9-(2-hydroxyethoxymethyl)g is tirovannyh cells, exhibits highly selective therapeutic effect.

In medical practice acyclovir is used in the form of various dosage forms. However, when the drug is designed for oral ingestion, one of the most convenient for manufacture, storage and use is a solid dosage form.

Acyclovir, like most substances, medicines, has no ability to direct pelletizing. Therefore, to obtain solid dosage forms of acyclovir must be entered in the composition of the excipients in amounts determined pharmaceutical and therapeutic usefulness.

There are various pharmaceutical compositions on the basis of acyclovir made in the form of tablets (Register of medicines of Russia. M: Remake, 1997). However, the specific qualitative and quantitative composition of auxiliary ingredients are not listed.

In the patent of Russian Federation N 2106861, publ. 1998, described composition, which contains, wt%:

Active connection - 5,0-95,0

Pharmaceutically acceptable swellable clay - 0,25-60,0

Targeted supplements - Rest

As an active connection, it can steevie supplements such as binders and adhesives, fillers (e.g., microcrystalline cellulose), lubricant additives (for example, salt of stearic acid, and other excipients (dezintegriruetsja, wetting (surface-active), flavorings and other) in the following concentration, wt.%: filler 0% to 95%, preferably 5-15, disintegrity agent 0-20, preferably 0-5, binders and adhesives 0-25, preferably 0.5 to 2, the lubricating additive of 0.1 to 5, preferably 0.25 to 2, other excipients 0-15.

Because of swelling clay (marialusitana1 connection) has a binding effect, the introduction of the separate binder component is not compulsory and has the objective to enhance the strength of the produced tablets. As a binder component, it is proposed to apply a wide range of substances, such as sucrose, starch paste, starch mucilage, starch, swelling in cold water, gelatin and others. In the specific examples of carrying out the invention as a binder used povidone K30 (polyvinylpyrrolidone with an average molecular weight of 40,000).

The presence in the composition of the swelling clay (manuallyselected zoedisbelief tablet, i.e., in the form of an aqueous dispersion, which is not always acceptable, and the use of this composition as a normal tablet involves the application of a film coating. In addition, the active substance must be pre-translated in fine condition, and tablets with a high dose of active compound is necessary significantly increase the relative content manuallyselected connection, which complicates the process.

The set of essential characteristics closest to the claimed represented a pharmaceutical composition in the form of solid dosage forms described in the above patent (patent RF N 2106861), which contains the following ingredients, wt.%:

Acyclovir - 72,6

Microcrystalline cellulose - 8,7

Corn starch is 4.3

Nitroglycerin starch ("Explotab") - 4,3

Cross-linked polymer of sodium carboxymethyl cellulose (Ac-Di-Sol) - 2,0

Sodium dodecyl sulfate - 0,2

Polyvinylpyrrolidone with an average molecular weight of 40,000 (Povidone K30) - 1,9

Kollidon CL (insoluble polyvinylpyrrolidone) - 5,2

Magnesium stearate - 0,8

However, the quality indicators specified composition unstable during storage, which significantly grater, as swelling clay, significantly increases the time raspadaemosti tablets, resulting in decreasing the rate of absorption of active compounds in the body, its concentration in the blood and, therefore, therapeutic effect.

The way to obtain this composition includes the following steps. The mixture of the active substance with microcrystalline cellulose, nitroglicerina starch, structured sodium carboxymethyl cellulose (Ac-Di-Sol) and lauryl sulfate hydrate 50% aqueous-alcoholic solution of povidone K 30, the wet granules are dried at a temperature of 50-80oC to a residual moisture content of not more than 4%, after sifting mixed with Calligonum CL and stearate and tabletirujut. However, the application of the composition of a large number of auxiliary substances complicates the process.

Therefore, still relevant is the problem of creating an antiviral drug on the basis of acyclovir intended for oral administration in the form of solid dosage forms, quick release of the active principle, which, of course, necessary to replenish the register of medicines.

The technical result to be obtained by the implementation of astenia in the form of solid dosage forms, stable for a sufficiently long period (at least 3 years) and it quickly dissolves, thereby easily releasing the active substance that provides a high speed of absorption of acyclovir in the gastrointestinal tract, as well as the sequence of operations and their technological options that allow you to produce a dosage form of the required quality, in particular with satisfactory strength.

This technical result is achieved by the fact that the proposed drug with antiviral activity, containing as the active ingredients of acyclovir and as excipients microcrystalline cellulose and a salt of stearic acid, further comprises polyvinylpyrrolidone with an average molecular weight of 2600 - 16000 and, optionally, the dye in the following ratio of ingredients, wt.%:

Acyclovir - 65,0 to 96.5

Microcrystalline cellulose - 3,0-28,8

Polyvinylpyrrolidone with an average molecular weight of 2600 - 16000 - 0,2-5,0

Salt of stearic acid is from 0.2 to 1.0

Dye - 0-1,0

The claimed ratio of ingredients found experimentally and ensures compliance of the composition requirements of the global Fund XI.

The introduction of the dosage forms of the dye greatly improves its appearance by adding a uniform and pleasing colors. The optimum concentration of dye in the dosage form is 0.01 to 1.0 wt.%. The lower limit of the content of the dye is determined by the presence or absence of the effect and the upper and economic expediency. As the dye can be applied Indigo Carmine, tropeolin About or any other pharmaceutically acceptable dye.

Noncompliance found ratios of ingredients is not possible to obtain the necessary quality and stability of the composition during storage.

The proposed pharmaceutical composition is in the form of solid dosage forms, preferably in tablet form that provides maximum adaptability subsequent packaging and precision dosing of the active substance.

The method of obtaining the claimed medicinal product containing acyclovir and pharmaceutically acceptable excipients, includes the specified mixing the active substance with filler, wetting the mixture with a solution of neskovic substance 1:(of 1.2-3.5), respectively, wet granulation, drying to a residual moisture content of 4-7%, dry granulation, the introduction of a salt of stearic acid and the subsequent formation of granules. Use in obtaining granules of the claimed ratio of acyclovir and the humidifier provides a significant increase in the strength of the tablets. The ratio is calculated on the dry active substance, taking into account existing in the acyclovir moisture. As a moisturizer, you can apply the solution of low-molecular polyvinylpyrrolidone in water, alcohols or mixtures thereof, in which, if necessary, add dye.

The wet granules are dried to a residual moisture content of 4-7%. Higher humidity causes caking of the granules, making it difficult to obtain a homogeneous mixture and conducting tabletting, while lower moisture deteriorates the strength and increases the rejection of tablets (spalls, delamination). It is preferable to conduct the drying at a temperature not exceeding 40oC.

Conduct after drying, the dry granulation improves the adhesion between the ingredients, which further increases the strength of the core tablets (up to 17 kg, the abrasion resistance of not less than 99.4 per cent).

The obtained pharmaceutical composition complies with the requirements of the global Fund XI (externally the years.

Pharmacokinetic studies of the proposed drug was carried out on rabbits male breed chinchilla after a single injection of drugs per os at a dose of 40 mg/kg was Found that the bioavailability of the new composition did not differ significantly from the substance of acyclovir, the concentration of acyclovir in blood within 1 hour after administration of equivalent doses of the active substances was proposed composition is 13% more than in substance.

The purpose of clinical testing of the proposed tool was to study the clinical effectiveness, tolerability and identification of possible side effects in the treatment of patients with simple recurrent cold sores (Herpes simplex) or shingles (Herpes zoster). Clinical trials were conducted on 30 patients (19 women and 11 men) aged from 16 to 75 years of age with clinical manifestations of herpes infections on the skin and mucous membranes, of which Herpes simplex was in 17 patients, genital herpes in 4 patients and Herpes zoster - 9 patients. Disease duration ranged from 6 months to 12 years.

The proposed tool was administered in monotherapy. Simple and recurrent genital herpes 200 mg (active ingredient) 5 times a day every 4 hours tx2">

Therapeutic activity was assessed by the duration of the acute period (until the formation of crusts), complete healing with rejection crusts, severity of subjective symptoms (itching, pain, burning).

In the treatment of herpes simplex effect of the drug was evident in the short term. Already on the first day of treatment was a decrease, and sometimes the complete disappearance of itching and burning sensation on the skin area rashes, and on the 3rd - 4th day was celebrated complete clinical resolution process. In patients with recurrent herpes clinical manifestations were allowed approximately the same time frame as herpes simplex. Initially (2-3 day) was filmed acute inflammatory phenomena, and the full resolution process occurred on 5-6 day. In genital herpes first observed the disappearance of the discomfort (burning, itching), and then 4-5 days of treatment, the disappearance of clinical manifestations. In patients with Herpes zoster were also observed pronounced therapeutic effect. To 8-10 days of treatment decreased pain, burning, redness lost bright color, dried vesicles.

During treatment there were complications or side effects. Analysis of laboratory studies, provocative side or toxic effects on the blood-forming apparatus and renal function.

Thus, the data of clinical trials of a new composition for the treatment of herpetic infection allow to conclude that the proposed tool has a pronounced antiviral activity, and is useful for all the above forms of herpes, especially in his appointment at the early stage of the disease, and can be recommended for widespread medical use.

The invention is illustrated by the following examples (see tables 1 and 2).

Example 1. Pre-prepare a solution of 4.83 g (2.0 wt.%) polyvinylpyrrolidone with an average molecular weight of 12600 and 0,242 g (0.1 wt.%) of Indigo Carmine in a mixture of distilled water and ethanol (1:1) and moisturize them with a mixture of powders of acyclovir (204,5 g, the moisture of 5.5%; 80 wt.%) and microcrystalline cellulose (40,8 g; to 16.9 wt.%), mix to a uniform distribution of moisture and uniformity of coloration mass and granularit. The wet granules are dried to a residual moisture content of 5% at a temperature of 35-40oC. After dry granulation crushed to the granulate is added 2.4 g (1.0 wt.%) the magnesium stearate and the mixture tabletirujut. The obtained tablets with an average weight of 0.25 g satisfy the requirements of the pharmaceutical agent.

Examples 2, 3 perform anal is for drinking, preparing tablets are presented in tables 1 and 2.

1. Antiviral agent in the form of a solid dosage form containing as the active ingredients of acyclovir and as excipients microcrystalline cellulose, salt of stearic acid and polyvinylpyrrolidone, characterized in that it contains as polyvinylpyrrolidone polyvinylpyrrolidone with an average molecular weight of 2600 - 16000 and, optionally, the dye in the following ratio of ingredients, wt.%:

Acyclovir - 65,0 to 96.5

Microcrystalline cellulose - 3,0 - 28,8

Polyvinylpyrrolidone with an average molecular weight of 2600 - 16000 - 0,2 - 5,0

Salt of stearic acid is from 0.2 to 1.0

Dye - 0 - 1,0

2. Antiviral agent under item 1, characterized in that it contains polyvinylpyrrolidone with an average molecular weight 9900 - 15300.

3. Antiviral agent under item 1 or 2, characterized in that it contains as the dye Indigo Carmine.

4. Antiviral agent according to any one of paragraphs.1, 2 or 3, characterized in that it is made in the form of tablets.

5. The method of obtaining antiviral agents, characterized in PP. 1 to 4, which includes the specified mixing the active substance with the filler is microcrystalline cellulose, uveitis when the mass ratio of the humidifier and the active substance 1 : (1,2 - 3,5), respectively, wet granulation, drying to a residual moisture content of 4 to 7%, dry granulation, the introduction of a salt of stearic acid and the subsequent formation of granules.

6. The method according to p. 5, characterized in that the drying of the wet granulate is carried out at a temperature not exceeding 40oC.

 

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