The pharmaceutical composition, its use and method for producing

 

(57) Abstract:

The invention relates to the field of pharmaceutical industry, namely pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions. The invention lies in the fact that the pharmaceutical composition contains microcapsules of medicinal substances, grease and water, and each microcapsule includes 96,0-of 99.2 wt.% drug and 0.8 to 4 wt.% film-forming substance. The composition also introduce the Ripper. The method of obtaining the pharmaceutical composition comprises the production of microcapsules by coating on whether the particles of drug substance of the shell and the film-forming substance, adding lubricants and Ripper. 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 of 0.1 to 3 wt.%. After introduction of the mixture of the lubricant add a Ripper in the form of a fine fraction of the specified drug. The invention provides for the creation of K. the crystals, 12 PL.

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 No. 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 active early, 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 the regulation of the length raspadaemosti dosage forms. Adjusting the duration raspadaemosti possible only due to a change in p # 3873713, CL 424/184, 1975; U.S. patent No. 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 pharmaceutical composition comprising microcapsules, to the open polymer shell of the film-forming substance, Ripper (crystals medicinal substances), grease and water.

In accordance with the invention mentioned pharmaceutical composition is prepared in the following ratio, wt.%:

Microcapsules 96,0-99,8

Lubricating substance 0,1-1

Water Is 0.1-3

when the content of the Ripper in an amount of 0.1-10 wt.% from the mixture, and the content of the microcapsule medicinal substance and a film-forming substance, respectively 96,0-of 99.2 wt.% and 0.8 to 4 wt.%.

In accordance with the invention for coating a film take not agglomerated particles of water-soluble medicinal substance with sizes ranging from 200 to 700 μm.

The use of large particle size can slow the process of dissolution, as well as to reduce the concentration of excipients required for pressing tablets. Changing the size of the particles, it is possible to vary the speed raspadaemosti and dissolution of tablets. According to the invention the number of particles with a size of 200 microns and below in the total mass of matter typically should not exceed 10%.

In the preparation of compositions previously get microcapsules by applying a sheath of natural the and. 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 to 3 wt.%. The hydration is carried out before the swelling of the polymer shell microcapsules. After that enter the lubricating component, and then the Ripper in the form of a fine fraction of the medicinal substance.

Drying and subsequent hydration of the microcapsules during cooking tabletas mixture give the shell of the microcapsules is more correct shape and positively influence the homogeneity of the manufactured dosage forms, which makes it possible to stabilize the performance raspadaemosti tablets.

The moisture content in the range of 0.1-3 wt.% provides the swelling of the polymer membrane and leads to the fact that the structure of the polymer shell, which after the application of the apparatus with fluidized bed was a scaly structure, it becomes unbreakable. This structure of the polymer shell is stored in the obtained tablet the shell.

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 drug substances allow without adding 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 the medicinal substance. Thus, a substance which is an active early tablets, and Ripper have the same physical parameters. Due to this (in particular, due to the same solubility Ripper and medicinal substances in the composition of the microcapsules) is not a rapid erosion of the tablet on its constituent particles, 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 of drug substance pacity used stearic acid or its salts, acceptable from a pharmaceutical point of view, as well as a mixture of stearic acid and its salts.

As a medicinal substance can be used aminouksusnoy acid or xylitol, or other water-soluble crystalline substance.

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 film-forming substance, which is, for example, methylcellulose, according to the following:

provide training materials for the production of microcapsules, with 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;

make ptx2">translate aminouksusnoy acid in a state of fluidization, then the apparatus with fluidized bed at a temperature of 35-42°C submit 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.

Collected in this way the finished product is loaded into containers for temporary storage prior to further processing. The content of the methyl cellulose in the finished product is 1±0.1%), moisture - 0.5% of the total mass.

Then, on the basis of the obtained microcapsules form a mixture for pressing tablets (tabletow mixture). 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%.

After moistening implementing listello 1 kg), 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 pills tablets weight is entered Ripper in an amount of 0.1-10%, a 1 kg mass can be introduced from 10 to 100 g of the Ripper. As the cultivator is used fine fraction of drug substance which is an active early.

Prepared in this manner are then screened. 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 tablets weight pressed on automatic tablet press with a punch diameter of 6 mm, providing tablets with weight 0,102±7,5%.

In the process of pressing at least once per hour controlled cracklenen from the given 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) of 0.001,

The average mass of the obtained tablets is is 0.102 g±7.5%, the tablet has a face height of 2.6±0.3 mm in diameter, 6±0,2 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 with elements of marbling.

Time raspadaemosti obtained tablets aminouksusnoy acid 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 use of particles of drug substance with dimensions of 200-700 μm causes sublingual application manufactured as described tablets.

The possibility of implementation of the present invention podtverzdeniye layer for deposition of the shell. The humidified substance 1,2% solution of methyl cellulose (grade M-100) for 4-5 hours at a temperature of 42°C. After the end of the process, the product is dried to a residual moisture of 0.1 wt.%, outrivals the stearate and mixed with Ripper, which is a fine fraction of the active agent, in an amount of 5 wt.%.

The composition of the intermediate mixture for tabletting (tabletas mixture) are presented in table 1. Relevant physicochemical properties of the tablets (6 mm; is 0.102 g) are shown in table 2.

Example 2. Microcapsules obtained similarly specified in example 1 is humidified to a moisture content of 0.7 wt.%, optivault a stearate, and then impose the fine fraction of the active agent 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 fluidized bed. For film coating substance moistened 3,0% solution of methyl cellulose (grade M-16) similar to that described in example 1. After completing the fast Ripper similar to that described in example 1. The composition of the obtained composition are presented in table 5, physico-chemical properties of their 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 moistened 3% solution of methyl cellulose (grade Ml6) similar to that described in example 1.

After the process is finished, the product is dried to a moisture content of 3 wt.%, optivault of magnesium stearate 1 wt.% and mixed with the Ripper 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 table 10.

Example 6

100 kg aminouksusnoy acid is placed in the apparatus with a fluidized bed for coating film. The humidified substance of 0.8% solution of methyl cellulose (grade 100) for 4-5 hours at the I-stearate in an amount of 0.1 wt.% and add the Ripper - aminouksusnoy acid fine fraction 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 table 12.

1. Pharmaceutical composition for the preparation of tablets and prolonged action, including microcapsules containing not agglomerated particles of water-soluble medicinal substance, coated from a film-forming agent, and a lubricating substance and Ripper, characterized in that it further comprises a water content of drug substance and a film-forming substance in the microcapsules, respectively 96,0-of 99.2 wt.% and 0.8 to 4 wt.%, and as Ripper uses the specified medicinal substance in the following ratio, wt.%:

microcapsules 96,0-99,8

lubrication of 0.1-1

water is 0.1-3

adding Ripper in an amount of 0.1-10 wt.% from the resulting mixture.

2. The pharmaceutical composition under item 1, characterized in that the dimensions are not agglomerated particles of drug substance are 200-700 μm.

3. The pharmaceutical composition according to p. 1 Il"ptx2">4. The pharmaceutical composition under item 1 or 2, characterized in that as a film-forming substance used pharmaceutically acceptable substance capable of swelling.

5. The pharmaceutical composition under item 1 or 2, characterized in that, as a medicinal substance used aminouksusnoy acid.

6. The pharmaceutical composition under item 1 or 2, characterized in that, as a medicinal substance used xylitol.

7. The pharmaceutical composition under item 1 or 2, 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.

8. The pharmaceutical composition under item 1 or 2, characterized in that the lubricant used stearic acid, or its pharmaceutically acceptable salt, or a mixture.

9. The pharmaceutical composition under item 1, characterized in that it is made in the form of tablets for sublingual use.

10. A method of obtaining a pharmaceutical composition for the manufacture of mixtures for pressing tablets prolonged action, including the production of microcapsules by applying a shell from the group of 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 moisturize with water to 0.1-3 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 specified drug.

11. The method according to p. 10, characterized in that use not agglomerated particles of the drug by the size of 200-700 μm.

12. The method according to p. 10 or 11, characterized in that the amount used to cover the shell neopolitana particles of the drug by the size of 200 μm is not more than 10 wt.%.

13. The method according to p. 10 or 11, characterized in that the application of a polymer coating on whether the particles of drug substance is carried out in an apparatus with a fluidized bed.

14. The method according to p. 10 or 11, characterized in that as a film-forming substance use pharmaceutically acceptable substance capable of swelling.

15. The method according to p. 10 or 11, characterized in that as a film-forming substance use dissolve trichosis fact, as a lubricating substance use stearic acid, or its pharmaceutically acceptable salt, or salt.

17. The method according to p. 10 or 11, characterized in that, as a medicinal substance use aminouksusnoy acid.

18. The method according to p. 10 or 11, characterized in that, as a medicinal substance use xylitol.

Priority points

20.08.2001 on PP.1, 2, 6, 9 and 18.

28.11.2000 on PP.3-5, 7, 8, 10-17.



 

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