Pharmaceutical composition and method of reception

 

The invention relates to medicine, namely to pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions. The pharmaceutical composition contains 98,1-and 99.8 wt.% microcapsules of medicinal substance, 0.1 to 10.0 wt.% lubricants and 0.1 to 0.9 wt. % of water, and each microcapsule includes 97,6 to 99.9 wt.% medicinal substance and 0.1-2.4 wt. % film-forming substance. The song also introduces the Ripper in an amount of 0.1-10 wt.% by weight of the mixture. As the cultivator is used fine fraction of drug substances. The method of obtaining the pharmaceutical composition comprises the production of microcapsules by coating on whether the particles of drug substance of the shell of the film-forming substance, adding lubricants and Ripper. Upon receipt of the microcapsules and/or their intermediate storage the moisture content in the shell is brought to a concentration of not more than 0.5 wt.%, and before adding lubricants and Ripper microcapsules hydrate to water content in the membrane of 0.1-0.9 wt.%. After introduction of the mixture of lubricating videosome receipt of such compositions, help to produce slow release tablets with time raspadaemosti up to 30 minutes 2 C. and 12 C.p. f-crystals, 12 tab.

The invention relates to the field of pharmaceutical industry, namely pharmaceutical compositions intended for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such pharmaceutical compositions.

Known pharmaceutical form prolonged action (U.S. patent 4036207, CL 128-26, 1984), which is a capsule filled with microcapsules with an active ingredient (drug substance). Microcapsules formed deposited on the insoluble core of medicinal substance, coated with a polymer shell. This dosage form intended for oral use and is designed for a duration raspadaemosti for 15 hours. The structure of the dosage form and duration raspadaemosti not allow you to use this solution for formulations used sublingually. A method of manufacturing microcapsules does not provide any features to ensure regulation prodoljitel the odd change settings microcapsules and its shell.

Known compositions for making tablets (U.S. patent 3873713, CL 424/184, 1975; U.S. patent 4016254, CL 424/497, 1977), which include microcapsules consisting of crystals of medicinal substance, coated polymer material. The microcapsules, mixed with auxiliary substances (excipients), pressed tablets. Methods of preparing the compositions include coating the crystals medicinal substance membranes of the film-forming substance, adding lubricating components and subsequent pressing of tablets. In these decisions is not the role of the speed control raspadaemosti dosage forms. Duration raspadaemosti is determined by the structure of the resulting dosage form and add a standard auxiliary substances.

The task of the invention is to provide pharmaceutical compositions for the manufacture of tablets and prolonged action with time raspadaemosti up to 30 min and method of producing such a composition that allows the specified range to control the time raspadaemosti tablets, in particular when they are sublingual application, with the use of medicinal substances and water.

To solve this problem is proposed fare the shell of the film-forming substance not agglomerated particle water-soluble substances, being proactive, grease, Ripper, representing the fine fraction of the substance, which is an active early, and water.

In accordance with the invention mentioned pharmaceutical composition is prepared in the following ratio, wt.%: Microcapsules - 98,1 - 99,8 grease - 0,1 - 1,0 Water - 0.1 - 0.9 at the content of the Ripper in an amount of 0.1-10 wt.% from the resulting mixture. Moreover, the microcapsules contain, wt.%: Active start - 97,6 - 99,9 film-forming substance is 0.1 to 2.4 Water To 0.5 In the preparation of compositions previously get microcapsules by applying a sheath made of natural or synthetic polymers on whether the particles of water-soluble substances that are active early. In the process of production of microcapsules, the moisture content in the shell is brought to a concentration of not more than 0.5 wt.%. May reduce the moisture content of the microcapsules during interim storage.

To prepare the pharmaceutical compositions according to the invention microcapsules with humidity not higher than 0.5 wt.% hydrate to water content of 0.1-0.9 wt. %. The hydration is carried out before the swelling of the polymer shell microcapsules. After that enter the lubricating company and subsequent hydration of the microcapsules during cooking tabletas mixture gives the shell of the microcapsules is more correct form and has a positive effect on the homogeneity of the manufactured dosage forms, that provides the ability to stabilize the indicators raspadaemosti tablets.

The content in the polymeric shell of the moisture in the range of 0.1-0.9 wt.% provides the swelling of the polymer shell, its continuity and permeability reduction. This, ultimately, is crucial for increasing the duration raspadaemosti finished dosage forms (tablets), in which the structure of the polymer shell is preserved.

Introduction to composition Ripper gives made tablets porosity and reduces the time of their raspadaemosti. At the same time, changes in the concentration of the Ripper and use as a Ripper fine fraction of the substance, which is an active early, allows without the addition of conventional auxiliary substances to regulate the time raspadaemosti dosage forms and to maintain a high content of drug substance in the drug.

According to the invention the function of the Ripper performs a substance which is an active early. Thus, a substance which is an active early tablets, and Ripper have the same physical parameters. Due to this (in particular, due to the similar solubility of the Ripper and lekarstvami, and its gradual dissolution - drug release - without increasing the total surface dissolution.

To get the shell can be used cellulose ethers soluble in water or in a mixture of water and an organic solvent.

Not agglomerated particles covered with a shell in the apparatus with fluidized bed.

As the lubricating component can be used stearic acid or its salts that are acceptable from a pharmaceutical point of view, as well as a mixture of stearic acid and its salts.

As substances which are active early (drug substances), can be used aminouksusnoy acid or xylitol, as well as other amino acids, sugar or other water-soluble crystalline substances (e.g. vitamins).

To obtain in accordance with the invention, pharmaceutical compositions for making dosage forms of the drug, containing a medicinal substance, in particular, aminouksusnoy acid (crystalline water soluble substance), first obtained microcapsules, each of which represents not agglomerated particle aminouksusnoy acid coated captured the effect the preparation of raw materials for the production of microcapsules, at 100 kg aminouksusnoy acid take 1,24 kg of methylcellulose;
in a reactor equipped with a heating jacket and a stirrer, or in tanks with manual stirring to prepare a 1.2% aqueous solution of methyl cellulose, the resulting solution was incubated until complete swelling of methylcellulose, and then cooled and filtered from lumps;
provide training aminouksusnoy acid by sieving the raw material with the separation of particles of a given size, while it is preferable to use not agglomerated particles with sizes ranging from 200 to 700 μm, and the number of particles with a size of 200 μm or below in the total mass of the substance, as a rule, should not exceed 10%;
translate aminouksusnoy acid in a state of fluidization, then the apparatus with fluidized bed at 35-42oServed with a solution of methylcellulose, spraying it with the help of pneumatic nozzles and providing the application shell of methylcellulose on whether the particles aminouksusnoy acid;
at the end of the feed solution of methyl cellulose mass is dried to a residual moisture content of 0.5%;
the product is discharged and separated from the agglomerates and lumps, this can be separated fraction of the specified size.

Retrieved described Spaceballs in the finished product is 1of 0.1%, moisture up to 0.5% of the total mass.

Then, on the basis of the obtained microcapsules form a mixture for pressing tablets (tabletow mass). The formation of this mixture conducting portions 10 kg. For this purpose, sifted microcapsules with sizes 200-700 μm hydrate water in the mixer, and then placed in a closed container for a sufficient time to swell the polymer shell and receiving the intermediate product with residual moisture from 0.2 to 0.8 wt.%.

After moistening are preparing tabletas mass for tableting. To do this, the moist mass of the microcapsules taken part (approximately 1 kg), which is in a separate container mix with the lubricating component, which can be used magnesium stearinovokisly introduced in small portions with thorough stirring. The total mass of the lubricating component is usually 0,097 kg. Then the mixture containing microcapsules, a lubricating component is mixed with the remaining part (about 9 kg) wetted microcapsules.

The purpose of regulation time raspadaemosti tablets in tabletwo mass introduces the Ripper in an amount of 0.1-10%, a 1 kg mass can be introduced from 10 to 100 g of the Ripper. As realitivley thus the mass is then sieved. Screening can be carried out also after the introduction of the lubricating component, prior to the introduction of the Ripper. Both components can also be entered after sifting.

Prepared tabletow mass is pressed on automatic tablet press with a punch diameter of 6 mm, providing tablets with weight is 0.102 g7,5%.

In the process of pressing at least once per hour monitored the average weight of tablets, the geometric dimensions of the tablets, their appearance, as well as time raspadaemosti. When the deviation from the set parameters regulate the press pressure and weight.

Manufactured in the described manner tablet includes aminouksusnoy acid 0.1 g of water-soluble methylcellulose - 0.001 g and magnesium stearinovokisly (magnesium stearate) is 0.001,

The average mass of the obtained tablets is is 0.102 g7.5%, the tablet has a face height of 2.60.3 mm in diameter 60,2 mm Tablets obtained by the method in accordance with the invention, in appearance meets the standard requirements. Characteristic of the obtained tablet is the color white color up to 30 minutes

The technological scheme is common for different water-soluble crystalline drug substances, and in specific cases may vary individual parameters, such as temperature, fluidization, the concentration of the hydrating liquid, the processing time for the coating of the crystal shell. The obtained tablets are effective for sublingual application.

The possibility of implementation of the present invention the following examples.

Example 1.

100 kg aminouksusnoy acid with the size of the crystals mainly from 200 to 700 μm, but not more than 10% of the crystals up to 200 microns is placed in the apparatus with a fluidized bed for coating shell. The substance is treated with a 1.2% solution of methyl cellulose (grade M-100) for 4-5 hours at a temperature of 42oC. After the end of the process the product is dried to a moisture content of 0.1 wt.%, optivault the stearate and mixed with Ripper, representing the fine fraction aminouksusnoy acid, in an amount of 5 wt.%.

The composition of the obtained composition (tabletas mixture) are presented in table 1 (hereinafter, the content of active principle stated cumulatively for microcapsules and Ripper). Sootvetstvuyushiye similarly indicated in example 1, humidified to a moisture content of 0.7 wt.%, optivault the stearate and mixed with the fine fraction aminouksusnoy acid in an amount of 5 wt.%. The composition of the obtained composition are presented in table.3. Physico-chemical properties of their tablets (6 mm; is 0.102 g) are presented in table.4.

Example 3.

100 kg of xylitol is placed in the apparatus with a fluidized bed followed. For film coating substance is treated with a 3.0% solution of methyl cellulose (grade M-16) similar to that described in example 1. After the process is finished, the product is dried to a moisture content of not more than 0.1 wt.% and optivault a stearate. Then mixed with the Ripper in the form of a fine fraction of xylitol in an amount of 5 wt.%. The composition of the obtained composition are presented in table.5, physico-chemical properties of the respective tablets - in table.6.

Example 4.

The intermediate obtained as described in example 3, moistened to a moisture content of 0.3 wt.% and optivault a stearate. The composition of the obtained composition are presented in table.7, the relevant physico-chemical properties - in table.8.

Example 5.

100 kg aminouksusnoy acid is placed in the apparatus with a fluidized bed for coating film. Substance C is otessa the product is dried to a moisture content of 0.6 wt.%, optivault of magnesium stearate and mix with the Ripper in the amount of 10 wt.%. The composition of the obtained composition (tabletas mixture) are presented in table.9, the physicochemical properties of the tablets (6 mm, is 0.102 g) in the table.10.

Example 6.

100 kg aminouksusnoy acid is placed in the apparatus with a fluidized bed for coating shell. The humidified substance of 0.8% solution of methyl cellulose (grade 100) for 4-5 hours at a temperature in the layer 420oC. After the end of the process the product is dried to a moisture content of 0.1 wt.%, optivault of magnesium stearate in an amount of 0.1 wt.% and add the fine fraction aminouksusnoy acid, in an amount of 0.1 wt.%.

The composition of the obtained composition (tabletas mixture) are presented in table.11, the physicochemical properties of the tablets (6 mm, is 0.102 g) in the table.12.


Claims

1. Pharmaceutical composition for the preparation of tablets and prolonged action, including microcapsules, representing a coated film-forming substance not agglomerated particles of water-soluble substances that are active early, grease and Ripper, characterized in that it further contains water, Ripper is the quality of the mixture, in the following ratio, wt.%:
Microcapsules - 98,1 - 99,8
Lubricating - 0,1 - 1,0
Water - 0,1 - 0,9
moreover, the microcapsules contain, wt.%:
Active start - 97,6 to 99.9
Film-forming substance is 0.1 to 2.4
Water - 0.5
2. The pharmaceutical composition under item 1, characterized in that as a film-forming substance used pharmaceutically acceptable substance capable of swelling.

3. The pharmaceutical composition under item 1 or 2, characterized in that the substance which is an active early, used aminouksusnoy acid.

4. The pharmaceutical composition according to p. 3, characterized in that the size not agglomerated particles, which is an active early, is 200-700 μm.

5. The pharmaceutical composition according to paragraphs.1 or 2, or 3, or 4, characterized in that, as film-forming substances are soluble in water or in a mixture of water and an organic solvent, the cellulose ethers.

6. The pharmaceutical composition according to paragraphs.1 or 2 or 3 or 4 or 5, characterized in that the lubricant is used stearic acid or its pharmaceutically acceptable salt, or a mixture thereof.

7. A method of obtaining a pharmaceutical composition d is l by applying a sheath of film-forming substance on whether the particles of water-soluble substances, being proactive, adding lubricants and Ripper, characterized in that during the production of microcapsules and/or interim storage, the moisture content in the shell is brought to a concentration of not more than 0.5 wt.%, before adding lubricants and Ripper microcapsules hydrate water content in the membrane of 0.1-0.9 wt.% to the swelling of the membrane, and after the introduction of lubricant to the mixture entering the Ripper in the form of a fine fraction of the substance, which is an active early.

8. The method according to p. 7, characterized in that the substance which is an active early, use aminouksusnoy acid.

9. The method according to p. 8, characterized in that use not agglomerated particles of matter, which is an active early, with dimensions of 200-700 μm.

10. The method according to p. 9, characterized in that the number not agglomerated particles, which is the active beginning, the size of 200 μm is not more than 10 wt.%.

11. The method according to p. 7, or 8, or 9, or 10, characterized in that the application of a polymer coating on whether particles of matter, which is the active beginning, is carried out in an apparatus with a fluidized bed.

12. The method according to p. 7, or 8, or 9, or 10, or 11, distinguish the Noah to swelling.

13. The method according to p. 7, or 8, or 9, or 10, or 11, or 12, characterized in that as a film-forming substance use are soluble in water or in a mixture of water and an organic solvent, the cellulose ethers.

14. The method according to p. 7, or 8, or 9, or 10, or 11, or 12, or 13, characterized in that the lubricant used stearic acid or its pharmaceutically acceptable salt, or a mixture.

 

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