Pharmaceutical composition having hypnotic, sedative and tranquilizing activity, its preparation

 

(57) Abstract:

The invention relates to chemical-pharmaceutical industry, namely, creating a potent tranquilizer. The proposed structure includes phenazepam, milk sugar, potato starch, calcium stearate, gelatin or PVP weight and tal. Method for obtaining a pharmaceutical composition, which is prepared trituration mixture phenazepam with milk sugar to the mixture add the potato starch, the remaining milk sugar, moistened with a solution of gelatin or polyvinylpyrrolidone weight, dry, re-passed through the granulator, dry granulate is mixed with talc, calcium stearate, and starch potato, tabletirujut. The method provides uniform mixing of the components and optimal bioavailability of the active substance. Compared with other drugs of the proposed pharmaceutical composition has a high hypnotic and sedative and tranquilizing activity, meets the requirements of the global Fund X1. 2 S. p. f-crystals.

The invention relates to chemical-pharmaceutical industry, namely the creation of high-level trunk is, Tsatsa derivative of benzodiazepine. According to current data, the range of application of benzodiazepines includes a number of conditions, ranging from preclinical to psychopathologies completed. The first includes: somatotropine disorders - neurotic or constitutional (nervousness, neuropathy, and other); conversion (various pathological bodily sensations); hypochondriacal symptoms of neuropathy (phobias and anxiety); psychosomatic condition (mental disorder, somatovegetative disorders; sleep disorders and adaptation (in these cases, benzodiazepines can be considered as an adaptogen). Among psychopathologies completed disorders, where used benzodiazepines include anxiety and phobic disorders (panic attacks, posttraumatic stress, sleep disorders, and others).

One of the high level of domestic tranquilizers (1,4-benzodiazepines) is phenazepam (Mashkovsky, M. D. , Medicines, Moscow, 2000, volume 1, page 79). Strength sedative and anxiolytic action than other trancvillizator; has also expressed an anticonvulsant, miorelaksantnoe and widespread effects; increases effective is their and psychopathic States, accompanied by anxiety, fear, increased irritability, emotional lability. Strength sedative and mainly anti-anxiety actions phenazepam is not inferior to some of the brain. Phenazepam is also used to relieve alcohol withdrawal symptoms.

Phenazepam, like most substances, medicines, has no ability to direct pelletizing. Therefore, to create stable for quite a long time meet pharmacopoeial requirements of the dosage form is necessary to introduce auxiliary substances in quantities defined pharmaceutical and therapeutic usefulness.

In European patent (EP 0139460, 02.05.85, decision Upjohn CO., A 61 K 31/55) presents a pharmaceutical composition containing (1,4)benzodiazepine, in the following ratio of ingredients, wt.%:

8-Chloro-6-phenyl-4H-S-triazolo (1,4)benzodiazepine - 0,2355

Calcium phosphate - 0,3533

Methylcellulose - 14,1343

Talc - 35,3356

Corn starch - 47,1144

Calcium stearate - 2,8269

The drug is in the form of solid dosage forms.

The method thereof is as follows:

8-chloro-6-phenyl-4H-S-triaz is icellulse, wipe through a sieve 8 and dried. Dry granules are forced through a sieve 12, mixed with talc, starch and calcium stearate. Pressed into tablets. The drug used in the treatment of schizophrenia.

The disadvantages of this structure should include a high content of talc - 35, 3356% and starch - 47,1144%, which does not meet the requirements of the global Fund. Thus, an excessive increase in starch content (above 5%) causes a sharp decrease in strength of the tablets and the main reduction raspadaemosti. The talc content more than 3% (in the proposed version 35,3356%) may adversely affect the gastric mucosa. Does not meet the requirements of the global Fund and the high content of calcium stearate is more than 1% (2,8269%), which can also cause irritation of the mucous membrane (Ant I. A. Technology of drugs. M.: Medicine, 1971, page 612; State Pharmacopoeia of the USSR XI, 1998, pp. 154-156).

In U.S. patent (US 4229447, 21.10.1980, American Home Products Corporation, A 61 K 31/33) proposed a pharmaceutical composition containing a highly effective sedative lorazepam, in the following ratio, wt.%:

Lorazepam - 2,7778

Lactose - 30

Potato starch - 8,3333

Magnesium stearate - 0,2778

Microcrystalline cellulose - 58,6111

The drug is orazepam, lactose, potato starch, cellulose and magnesium stearate are blended, wipe through the appropriate sieve, granularit. Add magnesium stearate and pressed. The drug has a high tranquilizing, sedative and miorelaksantnoe action, however, has a sufficiently high hypnotic and anticonvulsant action. (A. C. Bogatsky, Phenazepam, 1982, pp. 142-145).

The objective of the invention is to develop a pharmaceutical composition having high hypnotic, sedative and anxiolytic activity which conforms to pharmacopoeial requirements and is stable during storage, and method of producing such pharmaceutical compositions with optimal bioavailability of the active component.

This object is achieved in that a pharmaceutical composition containing as an active ingredient phenazepam. Phenazepam is extremely hypnotic activity and this manifestation of the action, as well as tranquilizing effect, occupies a dominant position among the famous drugs benzodiazepine series, surpassing lorazepam and nitrazepam, but also has a high sedative activity.

earth, food gelatin or polyvinylpyrrolidone weight, talc. The stated proportion of ingredients is optimal and fully complies with the requirements of the global Fund XI. The proposed composition comprises,in wt.%:

Phenazepam - 0,4259-1,3753

Milk sugar 67,6788-72,9145

Potato starch - 25,6543-27,7944

Calcium stearate - 0,8077-0,9503

Food gelatin or polyvinylpyrrolidone weight - 1,0801-1,32264

Talc - 0,8552-1,0452

The use of milk sugar (lactose) can increase the release of the active substance from the dosage form is released over 80% phenazepam for 45 min), and also improves organoleptically properties of the composition.

Introduction starch having lubricating properties, can reduce the content of other anti-friction additives, talc and calcium stearate to values not exceeding the allowed Pharmacopoeia GF XI (3 and 1%, respectively). Comparison of the effect of different binding agents on the manufacturability of the process of granulation and drying, as well as on the quality of the dosage form identified the need to include polyvinylpyrrolidone or gelatin in the composition.

The combination of all excipients of the fil release phenazepam.

The obtained pharmaceutical composition is in the form of solid dosage forms, preferably in the form of tablets that allows for maximum adaptability subsequent packaging and precision dosing of the active substance.

The obtained pharmaceutical composition complies with the requirements of the global Fund XI, stable during storage and has a shelf life of 3 years.

The peculiarity of the method of producing a tablet form of the claimed composition is a preparation trituration mixture that provides uniform mixing of the components. In addition, it was found that for the most uniform distribution of the binding agent (gelatin or PVP) it is appropriate to introduce it in the form of a 5% solution. These differences are the advantages of the claimed method in comparison with the considered analogues and ensure optimal bioavailability of the active substance. In more detail, the method of obtaining the drug discussed in example 2. The invention is illustrated by the following examples.

Example 1. An example of a song with hypnotic, sedative and tranquilizing activity,wt.%:

Phenazepam - 0,6668

Milk sugar 69,4392

Starch BR>
Talc - 0,9501

Example 2. The method of obtaining funds with hypnotic, sedative and tranquilizing activity

1. Obtain a dry granulate

A) preparation trituration mixture phenazepam

To ensure uniform mixing of a small amount of phenazepam with other ingredients to prepare mix it with milk sugar, then gradually add the next portion of sugar of milk and mix thoroughly.

B) obtaining a wet granulate

In the mixer download milk sugar, pre-cooked mixture of phenazepam and sugar milk (stage A), the potato starch in an amount of about 95% of its total mass, the mixture is stirred for 10-15 minutes and humidified 5% solution of gelatin (or PVP) in several portions until evenly moistened mass is stirred for another 10 minutes.

The wetted mass is discharged from the mixer and passed through a granulator with a hole diameter of the drum 1.5 mm and is passed to the drying operation.

C) drying and dry granulating

Wet GRANULAT dried in a dryer at a temperature of (555)oC for 50-60 minutes until a residual moisture content (3,00,5)%. Drying the product is made by the Assu is passed through the pellet mill with the diameter of the drum of 1.50 mm and collected in containers. The dry granulate is passed through the receiving tablemats and tableting.

2. Preparation of tablet mass

In the boiler to get tablemats load dry granular, calcium stearate, talc, and the remaining quantity of starch and blended in the granulator substandard tablet, everything is stirred for 15 min and discharged into the tank.

The tabletting mixture is passed through tableting.

3. Tableting and rejection

Tableting is performed on a rotary press.

Filling mix 2 kg produced periodically every 5-8 minutes During tabletting every 15-20 min check the average weight of the tablets appearance.

The obtained tablets are discarded under the pull of the fume hood through a metal sieve from dust, rejected substandard tablets, conforming tablets direct to the stage of packing. Get tablets 0.0005; 0,001; 0,0025,

1. Pharmaceutical composition having hypnotic, sedative and anxiolytic activity in the form of tablets containing phenazepam and excipients, characterized in that the quality of excipients contains lactose, starch CT the attachment of components, wt.%:

Phenazepam - 0,4259-1,3753

Milk sugar 67,6788-72,9145

Potato starch - 25,6543-27,7944

Calcium stearate - 0,8077-0,9503

Food gelatin or polyvinylpyrrolidone weight - 1,0801-1,32264

Talc - 0,8552-1,0452

2. A method of obtaining a pharmaceutical composition having hypnotic, sedative and tranquilizing activity, wherein the pre-prepared trituration mixture phenazepam part of milk sugar to the mixture add the starch in an amount of about 95% of its total mass, the remaining milk sugar, is humidified 5% solution of gelatin or polyvinylpyrrolidone weight, granularit, dried, re-passed through the granulator, dry granulate is mixed with talc, calcium stearate, the remaining quantity of potato starch, tabletirujut.

 

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