Medicinal agent as gelatin capsule

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as a gelatin capsule. A medicinal agent as gelatin capsule consists of cycloserine and accessory additives wherein calcium phosphate dihydrate, aerosil and calcium stearate taken in the definite components are used as accessory additives. Also, gelatin capsule comprises additionally glutamic acid, gelatin and water, Invention provides rapid and complete release of agent in intake and the development of a medicinal formulation reducing toxicity of an active substance and eliciting stability in storage.

EFFECT: improved and valuable pharmaceutical and medicinal properties of agent.

1 tbl, 1 ex

 

The invention concerns a known drug cycloserine, which antibiotikum, and the drug based on it in the form of gelatin capsules.

Cycloserine - D-4-amino-3-isoxazolidinone - has a broad spectrum of antibacterial action, regarded as a “reserve” the anti-TB drug, i.e. assigned patients with chronic forms of tuberculosis, which previously used the basic preparations ceased to have effect. When treating cycloserine may experience side effects due to toxic effect of the drug on the nervous system. To prevent or reduce the toxic effects of cycloserine can appointing during treatment glutamic acid, 0,5 g 3-4 times a day (Mashkovsky PPM Drugs, 2001, Vol.2, pp. 318-319). Available in the form of tablets and capsules of 250 mg.

There is a method of reducing resistance of Mycobacterium tuberculosis to rifampicin and acebutolol cycloserine (U.S. Pat. Of the Russian Federation No. 2185162).

The closest technical solution to the claimed composition is a drug in the form of gelatin capsules filled with a filler consisting of cycloserine, and auxiliary additives (Mashkovsky PPM Drugs, 2001, Vol.2, pp. 318-319).

Lack of funds is the high toxicity of the drug, lack of sliding filler is ri filling capsules.

The purpose of this invention is the creation of the dosage form of the drug on the basis of cycloserine in the form of capsules, easily filling a filler, from which the active substance is rapidly and completely released during the reception of its patients, the creation of a dosage form that reduces the toxicity of the active substance and stable during storage.

This goal is achieved through the use of the drug in the form of gelatin capsules filled with a filler consisting of cycloserine, and auxiliary additives. At the same time as auxiliary additives used calcium phosphate dihydrate, Aerosil, calcium stearate in the following ratio of ingredients, wt.%:

cycloserine 64-66

Aerosil 0,8-1,2

calcium stearate 0.8 to 1.2

calcium phosphate dehydrate the rest,

while gelatin capsule further comprises a glutamic acid in the following ratio of ingredients, wt.%:

gelatin - 15-20

glutamic acid - 2-5

water - the rest

The technical result is obtained when implementing the present invention is that the resulting dosage form, firstly, it satisfies all the requirements of Gosfarmakapei pharmaceutical agent, namely: it is stable during storage, provides a high clinical effect by reducing toxic what about the actions of cycloserine, a convenient form and high bioavailability of its components.

Used pharmaceutically acceptable additives target - calcium phosphate dihydrate, Aerosil and calcium stearate. To give the best technological properties, namely, flowability, as diluent used calcium phosphate dihydrate. Gelatin capsule provides strength pharmaceutical form and due to the additional introduction of glutamic acid capsule reducing the toxic effect of cycloserine. With the purpose of improving the fluidity of the mass, prevent sticking it on the mechanical parts of the equipment as lubricating and sliding substances used Aerosil and calcium stearate.

The composition and quantity of excipients was determined experimentally and is optimal, providing the flowability of the filler. The result is a mixture of substances having good processing properties in the process of filling gelatin capsules. Selected excipients allowed to eliminate the effect of electrolyzation cycloserine.

The proposed composition of the filler capsules has the following technological features: the flowability of the composition is 3.0 to 3.6 g/s, bulk density - of 0.61 to 0.63 g/cm3, bulk density is 0.84-0.88 g/cm3. Thus, the proposed structure has sufficient flowability, not electrified, h is about makes it easy to measure with great precision.

The mass of the proposed filler completely fills the capsule, thereby eliminating the phenomenon of “flotation”, resulting from the free air space capsules. This is quite an important factor, since otherwise there is a reduction in contact area of the medicinal substance in the gastrointestinal tract, which, in turn, slows down the dissolution rate of a drug and, consequently, reducing the bioavailability of the dosage form.

Clinical testing of the proposed drug in the form of gelatin capsules containing glutamic acid were carried out in 20 patients with pulmonary tuberculosis. All the patients were allocated to the office, and eight - drug-resistant (rifampicin and isoniazid) office. All patients were determined by the cavity decay. Of clinical forms prevailed infiltrative tuberculosis of the lungs. In 85% of patients were expressed symptoms of tuberculosis intoxication. The treatment was performed within 3 months. Patients received rifampicin and cycloserine declare forms in normal doses. The control group received rifampicin and streptomycin in normal dosages.

The symptoms of tuberculosis intoxication disappeared in most patients (94%) after 2 months, the control group by the end of 3 months.

Thus, the advantage claimed is army drug cycloserine is a scientifically-based selection of effective and well-tolerated composition gelatin capsules with the addition of glutamic acid in the claimed amounts.

In addition, the introduction into the composition of the calcium phosphate dihydrate having lubricating properties, can reduce the content of other anti-friction additives - Aerosil to values not exceeding the allowed Pharmacopoeia GF XI.

Comparison of the effect of different binding agents on the manufacturability of the process, as well as on the quality of the dosage form identified the need to include calcium phosphate dihydrate in the composition.

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

The proposed medication is in the form of powder filling, which are filled in gelatin capsules, which allows for maximum adaptability subsequent packaging.

Received the drug meets the requirements of the global Fund XI (in appearance, raspadaemosti, dissolution, uniformity of dosage and other requirements), stable during storage and has a shelf life of over 5 years.

The invention is illustrated by the following example (see table).

Example. In the sifted mixture of powders of cycloserine, Aerosil, taken in the estimated quantities, add calcium phosphate dihydrate, mix to a uniform distribution of components, optivault calcium stearate. P the obtained composition has a flowability 3.6 g/s, bulk mass 0,63 g/cm3, bulk density 0,86 g/cm3. The obtained filler fill gelatin capsules on a machine for packaging (Capsulator Globex Mark-2, Nethelands) is usually adopted in pharmacy technology, which meets the requirements.

Technology of preparation of the proposed gelatin capsules is simple and is as follows: pour the gelatin with water and leave to swell for 1.5-2 h, then the mass when heated, melted and stirred into it glutamic acid in the claimed amounts. Then, the resulting gelatinous mass is formed into a gelatinous membrane by immersion, vacuum and thermostatic.

In most known gelatin capsules the main difficulties are connected with the provision of stability during storage, the absorption or bioavailability of a drug to obtain the desired therapeutic effect. In the world practice is widely used dosage forms based on natural polymers, in particular gelatin. Due to the physico-chemical properties of gelatin, his indifference to the body, on the basis of the developed sufficient amount of dosage forms. A significant advantage of this framework is the easy absorption of drugs from it and light absorption of all components. Due to the slipperiness of the new, when the moisture in the oral cavity drug products based on it are easily ingested. The presence of gelatin glutamic acid reduces the toxicity of cycloserine.

Improving the lubricating properties of gelatin capsules and bioavailability controlled using such physical factors as the melting temperature and the time of dissolution. The melting point was determined by method 3 GF XI edition. The time of dissolution was determined by valuation method raspadaemosti dosage forms. The base is a jelly-like homogeneous mass, without odor, melting point varies 37,2-41,2°With the time of dissolution of 11.4-24,3 minutes

All components included in the capsule allowed to be used in medical practice and are issued by enterprises in accordance with the requirements of the relevant pharmacopoeial articles:

gelatin - article 309 of the State Pharmacopoeia X edition, glycerin - FS 42-2202-84, purified water - FS 42-261989, glutamic acid - Mashkovsky PPM, 2001, Vol.2, page 122.

Physical stability of gelatin capsules filled with tested while keeping thermostat (5°S-40° (C) with the temperature conditions change every 24 hours, and then tested the samples for 1 day, 1 week and 4 weeks. Samples which showed minimal or not observed is icacy changes of physical properties, analyzed for the stability of their chemical properties.

Chemical stability of gelatin capsules filled with tested during storage of the sample at 70°C for 4 weeks.

The results of physico-chemical studies have attested to the fact that the relative humidity of the capsules remained almost without changes: 1 week - 0,84, 4 week - 0,81, noticeable degradation was observed only when stored for 7 weeks at 70°C.

Studies have shown that the cycloserine of the proposed structure in gelatin capsules are well tolerated and due to the low toxicity practically harmless to the human body.

Table
No. compositionThe composition of the filler, %Gelatin capsule, %
  GelatinGlutamic acidwater
1Cycloserine - 6415283
 Calcium phosphate dihydrate and 34.4   
 Aerosil - 0,8   
 Calcium stearate - 0,8    
2Cycloserine - 6520575
 Calcium phosphate dihydrate - 33,0   
 Aerosil - 1,0   
 Calcium stearate - 1,0   
3Cycloserine - 6617380
 Calcium phosphate dihydrate of 31.6   
 Aerosil - 1,2   
 Calcium stearate - 1,2   

Drug, have antibacterial properties, consisting of cycloserine, and auxiliary additives, characterized in that it is made in the form of gelatin capsules and as an auxiliary additives include calcium phosphate dihydrate, Aerosil, calcium stearate in the following ratio, wt.%:

Cycloserine 64-66

Aerosil 0,8-1,2

Calcium stearate 0,8-1,2

Calcium phosphate dehydrate the Rest

while gelatin capsule contains glutamic acid, gelatin, water in the following ratio, wt.%:

Gelatin 15-20

Glutamic acid 2-5

Water the Rest



 

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