The method of obtaining a combined drug in hard gelatin capsules

 

(57) Abstract:

The invention relates to chemical-pharmaceutical industry, in particular to a method of obtaining a combined drug analyticheskogo, antipyretic, anti-inflammatory action in hard gelatin capsules. The method of obtaining a stable and non-toxic dosage form of a combined preparation "Chitrapur" containing acetylsalicylic acid, paracetamol, caffeine, citric acid, is to use powders of active substances. Powders of active ingredients were sifted, mixed with auxiliary substances and they dosaged in hard gelatin capsules. As auxiliary substances used talc in the amount of 2.5-3.0%, polyvinylpyrrolidone and Aerosil in the amount of 0.65-0.7%, which gave an opportunity to get a lot of capsule filling, providing the necessary linkage and uniformity of dosage. With a less toxic form of drug in the drug entered the paracetamol in the number of 33-41% instead fenatsetina. The proposed method for obtaining a medicinal product "Chitrapur" hard gelatin capsules eliminates the contact of the composite mixture with moisture, the second drug is initially containing a lower percentage of free salicylic acid. The resulting preparation "Chitrapur" in the form of powder dosage form has a high bioavailability and stability during storage.

The invention relates to pharmaceutical industry, and in particular to methods for obtaining a combined drug analgesic, antipyretic, anti-inflammatory action in hard gelatin capsules.

A method of obtaining tableted drugs analgesic actions: "Aspen", "Kofitsil", "Novomigrofen", "Pirkofen", "Sedalgin" etc.

The prototype of the present invention is preformed drug "Aspirin", which includes, g: acetylsalicylic acid (ASA) 0,24; phenacetin 0,18; caffeine 0,03; cocoa 0,03; citric acid 0,02; starch 0,05.

The method of obtaining the "Aspirin" is the mixing of the ASC fenatsetina, caffeine, cocoa; wet weight solution of citric acid and starch paste, wet granulation mass and drying; mixing with the starch and the formation of the tablets.

The disadvantage of this method is that included in the preparation of substances subjected to moisture, heat drying of the granulate and davleniya decomposition ASC to free salicylic acid in the finished tablets.

Currently using phenacetin limited by its high toxicity, high doses can cause methemoglobinemia and anemia, to have a nephrotoxic effect, to promote the formation of tumors in the urinary tract.

The purpose of this invention to provide a non-toxic stability of the dosage form combined drug with analgesic, antipyretic, anti-inflammatory action with high bioavailability.

The essence of the invention lies in the fact that to obtain stability and non-toxic dosage forms with high bioavailability combined drug "Aspirin" use powders of active substances, which are sieved, mixed with auxiliary substances and dosed in hard gelatin capsules in the following ratio, wt.%: acetylsalicylic acid 44 - 45; paracetamol 33 - 41; caffeine 5 - 7; citric acid 3 - 5; talc 2 - 3; Aerosil 0,6 - 0,75; polyvinylpyrrolidone (PVP) 0,6 - 0,75.

Technological properties of the composition of the mixture depends on the number of auxiliary substances. Overdose last leads to the fact that is introduced into the body many nutrients that do not have t paly, not kept hanging.

The dependence of the technological properties of the composition on the number and type of auxiliary substances. As auxiliary substances were selected: talc, Aerosil, PVP. To the powder mixture of active substances (ASA, acetaminophen, caffeine, citric acid), was added to the talc in the amount of 2 - 3%; Aerosil 0,60 - 0,75%, polyvinylpyrrolidone 0,60 - 0,75%. The dependence of the technological properties of powders on the number of excipients was determined by the following indicators: flowability, bulk density, compaction factor.

As a result of researches it is established that the addition of talc is less than 2.5% does not cause a significant improvement in the flowability of the composition, and the content of talc in the composition above 3% is unacceptable in accordance with the State Pharmacopoeia XI. Optimal is the addition of 2.5 - 3% talc. However, only the addition of talc in optimal quantities in the composition of the mixture does not provide the required level of flowability to achieve this figure, as the uniformity of caffeine.

To improve the flowability was injected into the mixture of Aerosil in the amount of 0.60 - 0.76 per cent. The addition of Aerosil in quantities of 0.60 - 0,7% provides led is the reduction of the bulk mass of the mixture. To increase the bulk weight in the composite mixture was added PVP, the optimal number of which is found experimentally.

Thus, proper amounts of auxiliary substances gives the opportunity to get a lot of capsule filling, providing the necessary equipment and uniform dispensing of the components of the proposed method.

Replacement fenatsetina in the composition on paracetamol provides the ability to get less toxic dosage form. Introduction paracetamol eliminates the negative effect of phenacetin, and the presence of citric acid reduces the nephrotoxicity of paracetamol. For pain management, anti-inflammatory and cough activity of paracetamol is not inferior to phenacetin.

The ACU, which is part of a tablet form of "Aspirin", under the influence of moisture and temperature in the process of obtaining the drug decomposes to form free of salicylic acid, which is a toxic substance that adversely affects the properties of the drug.

The proposed method for the preparation of a powder dosage form, which eliminates the contact compositionwise drug, originally containing a lower percentage of free salicylic acid, stable in storage, with higher bioavailability. Thus, the percentage of free salicylic acid in tablets "Aspirin" after making four times more than the drug, "Chitrapur" hard gelatin capsules (0.4 and 0.01%, respectively).

Comparative evaluation of the content of free salicylic acid in tablets "Aspirin" in preparation "Chitrapur" showed that in the last 2 years of storage it is much less than in the "Aspirin" after 6 months of storage. The data given in the table.

Thus, obtaining dosage forms combined drug in powder form in capsules and the introduction of the paracetamol instead fenatsetina allows to stabilize the ASC and get a non-toxic drug, stable during storage.

An important advantage of the method of producing drug "Chitrapur" in the form of powder dosage form of hard gelatin capsules is found in the region of its clinical effectiveness, in particular bioavailability.

The increase in bioavailability was assessed by the content of acetylsalicylic acid and paracetamol Board in determining the contents of ASA and paracetamol in the blood, is shown in Fig. 1,2.

The concentration of ASA was determined in the dynamics spectrophotometrically at 540 nm, using the reaction of formation of the colored complex of salicylic acid with ferric salts. Paracetamol - spectrophotometrically at 540 nm, using the reaction of hydrochloric acid hydrolysis of paracetamol to p-aminophenol, which reacts with the phenol with the formation of colored indophenol.

Receiving the drug, "Chitrapur" on the proposed method causes a significant increase in blood concentrations of ASA and paracetamol, leads to an increase in the relative bioavailability of ASA by 27.8% and paracetamol by 21.3% compared to the tablets, which were selected for comparison.

The increase in bioavailability leads to an increase in analgesic and anti-inflammatory effect. To increase pain threshold requires a smaller effective dose "of Chitrapur" compared to tablets: 66,5 mg/kg instead of 272,1 mg/kg (analgesic effect) and instead of 129.6 236,8 mg/kg (anti-inflammatory effect).

The invention is illustrated by the following examples.

Example 1. Acetylsalicylic acid, paracetamol, citric acid, caffeine, Aerosil sieved through a sieve with time>/P>Sifted the components are mixed in the mixer for 30 min at 18 - 22oC and dispense into hard gelatin capsules.

The resulting preparation in their properties meet the requirements of normative-technical documentation.

Example 2. All raw materials, in addition to paracetamol, sieved as described in example 1. The sifted raw materials and paracetamol are mixed in the mixer 30 minutes the Obtained composite mixture is sieved through a sieve with a mesh size of 0.3 - 0.5 mm and dosed in hard gelatin capsules.

The resulting preparation in their properties meet the requirements of normative-technical documentation.

The list of references.

1. Bernstein, I. J. Kaminsky Y. A. spectrophotometric analysis in organic chemistry. L.: Chemistry, 1975, 230 S.

2. Grisou A. I., Levin M,, George B. N. Modified method of Pirotta. //Journal of analytical chemistry, 1984, T. 3 - 11, C. 1987 - 1990.

3. Production schedule the production of tablets "Aspirin" JSC "Darnitsa".

4. Delacoux E., Pagniez M., Gousson T., Cesbron N. Etude biologique sur I interet de trois formes galeniques d'administration de I aspirin. //Therapie, 1970, Vol 25, p. 553 - 569/

5. Von Engelhardt G. Tierexperimentelle Untersuchunger Question sur des Zusammenwirkens von und Paracetamol Acetylsalicylsaure. //Arzneim.-Forsch, 1984, Bd. 34 (II), 9. S. 992-ptx2">

The method of obtaining a combined drug analgesic, antipyretic, anti-inflammatory action, containing acetylsalicylic acid, caffeine, citric acid, characterized in that the powders of active ingredients are screened, mixed with paracetamol taken in the amount of 33 to 41% of the total mass of the mixture, and excipients, which are used talc, Aerosil and polyvinylpyrrolidone in an amount of 2 to 3 %, and 0.6 - 0.75 % and 0.6 to 0.75 % of the total mass of the mixture is metered into hard gelatin capsules.

 

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