The method of obtaining the dosage form of carbamazepine

 

(57) Abstract:

The method is intended for use in pharmacy. The method consists of spraying on carbamazepine aqueous solution and/or dispersion of the film former in combination with the softening agent in the granulator, fluidized bed. The foaming agent is preferably a mixture of polymethacrylates, such as poliatilenaksida and polymethyl methacrylate in a weight ratio of 2:1. Softening agent preferably glyceryltrinitrate or triethylcitrate. Covered with carbamazepine may be smashin with other excipients and compressed into scored tablets or packaged in capsules. The method allows to prevent the growth of crystals associated with the formation of the dihydrate carbamazepine in the presence of water. Due to this slows down the release of carbamazepine and it becomes possible to obtain divisible tablets that enables dosing of carbamazepine. 8 C.p. f-crystals. 2 Il.

The invention relates to a method for producing a dosage form of carbamazepine for oral dosage forms with delayed release of active substance.

Carbamazepine, 5-H-dibenz[b, f]azepin-5-carboxamid, it is mainly used as protivopar the entrances delayed action with 200-600 mg of the active substance and syrups.

It is known that carbamazepine in contact with water for a very short time forms a dihydrate. Already by granulation in an intensive mixer or granulator, fluidized bed through the water granulation liquids begins the formation of the dihydrate. The dihydrate is present in the form of needle-shaped crystals, which can grow to a particle size of 500 μm. This has a negative impact on the further processing, particularly during the formation of coatings that slow release of the active substance.

Therefore, when the well-known ways to get refused from aquatic environments and prefer the use of organic solvents.

The slow release of the active substance can be carried out in various ways. For carbamazepine in German patent N 3277520 described composition in which the active ingredient is mixed with conventional excipients for tableting and pressed into the grain or Packed in capsules. Grain or capsule covered with a mixture of methacrylic acid and methyl ester of methacrylic acid (methyl methacrylate) dissolved in isopropanol, which contains acetyltributyl as softener. Thus, thanks to the use of the Ah Germany NN 3868077 and 3725824 claimed composition carbamazepine-excipient, containing a protective colloid, which inhibits the growth of crystals of carbamazepine in the presence of water. Grain containing carbamazepine, cover the organic solution of cellulose acetate. In the film suitable way do pass in the form of holes.

Methods of obtaining these compositions have the disadvantage that it is necessary to perform the work with organic solvents, which causes environmental pollution and therefore means higher costs and expenses.

In addition, these drugs are obtained as described above (tablets or capsules), are indivisible, because dividing damaged shell, and when this is lost, and slowing down the action.

Thus the possibility of dosing is limited.

Further, the known forms of leave (tablets), which upon division or disintegration into separate parts in liquids outside or inside of the gastrointestinal tract did not lose his slow steps.

In the journal of Pharm. Ind. 55, No. 10 (1993), pp. 940-947, described solid forms of vacation for oral administration, in which individual particles cover water dispersions of copolymers of methacrylic acid and methylmethacrylate and pranie softener has the potential to greatly increase the elongation of the coating and provides mechanical stability.

We will call here the coating of the crystals of the active substance paracetamol potassium chloride and acetylsalicylic acid, of theophylline granules and pills indometacin and theophylline.

The present invention tasked to develop a suitable way of obtaining the medicinal form of carbamazepine, which, despite the use of water as a solvent or dispersion medium, the growth of crystals associated with the formation of the dihydrate carbamazepine, is prevented, and thanks to the release of carbamazepine sufficiently slowed down.

This was in accordance with the invention is solved by the fact that on carbamazepine sprayed film formers in combination with Magdalen in the form of an aqueous solution and/or dispersion. Carbamazepine coating can optionally be mixed with other excipients and compressed into tablets or packaged in capsules.

For slow release carbamazepine in use as film-forming dispersion of polymethacrylates. In this preferred:

- a mixture of politicalit and polymethyl methacrylate in a ratio of 2:1 ( EudragitNE 30D),

- a mixture of politicalit, polymethylmeth the above mixture in a ratio of 1:2:0,2 ( EudragitRL 30D).

As the water-soluble softeners can be used, for example, glyceryltrinitrate or triethylcitrate. They are used in proportions basics foaming agent to the softening agent is from 1:0.05 to 1:0,25, preferably from 1:0.15 to 1: 0,22.

The ratio between carbamazepine and foaming agent is determined depending on the desired effect of slow release and is from 1:0.03 to 1:0.5 in.

In particular, use the ratio between carbamazepine and foaming agent is from 1:0.05 to 1:0,1, however, preferably from 1:0.05 to 1:0,08.

Curves of release for these different ratios between carbamazepine and foaming agent is shown in Fig. 1. As testing methods were used dissolution test USP XXII for carbamazepine (medium: water with addition of 1% nitrilotriacetate).

Unexpectedly failed due to the composition of the dosage form of carbamazepine in accordance with the invention to prevent spontaneous, as is known, when the contact of carbamazepine with water education dihydrate, which entails the growth of needle-shaped crystals and, as a consequence, limited suitability for processing.

The foaming agent in doriginal layer.

To prevent bonding of coated particles can additionally be introduced into the dispersion of the separation means and/or to spray them later in the fluidized bed in the form of separate suspensions.

For example, put talcum powder at the ratio of concentrations of the basics of film-forming and separating agent is from 1:0.4 to 1:1, preferably from 1: 0.45 to 1:0,55.

The crystals of carbamazepine floor can in a known manner to admix other glenavy excipients. Thus obtained mixture or crystals coated can then be packaged in capsules of hard gelatin or extruding in scored tablets. Mechanical loading of individual particles associated with the specified further processing of carbamazepine with the floor, especially when pelletizing, does not cause damage to the film coating.

The final dosage form finds the same speed slow release, which was determined by the method of USP XXII to carbamazepine and carbamazepine coated (Fig. 2).

The method in accordance with the invention will be further clarified by examples of its implementation.

Example 1. Get the suspension out of 2.23 kg Eudragit RS 30D, 135 g of the granulator fluidized bed WSG 15 (Glatt) per 10 kg of carbamazepine. After that sprayed suspension 625 g of talc in 2 l of water. The granules obtained in this way is mixed with 914 g of microcrystalline cellulose, 653 g of insoluble polyvidone, 70 g of highly dispersed silicon dioxide and 35 g of magnesium stearate. The mixture is pressed into tablets containing the active substance 200, 400 or 600 mg of carbamazepine, or the appropriate number of granules Packed in capsules of size 1.

Example 2. Receive a suspension of 340 g of Eudragit RS 30D, 20,4 g triethylcitrate dissolved in 0.3 l of water, and 40 g of talc suspended in 0.1 l of water. The suspension is sprayed into the granulator, fluidized bed GPCG 1 (Glatt) when the product temperature 27-30oC for 1 kg of carbamazepine. The granules obtained in this way is mixed with 65 g of microcrystalline cellulose, 65 g of insoluble polyvidone, 7 g of highly dispersed silicon dioxide and 3.5 g of magnesium stearate. The mixture is pressed into tablets containing the active substance 200, 400 or 600 mg of carbamazepine, or the appropriate number of granules Packed in capsules of size 1.

Example 3. Receive a suspension of 29 g of Eudragit NE 30D, 1.3 g of glyceryltrinitrate dissolved in 0,03 l of water and 9 g of talc suspended in 0,03 l of water. The suspension is sprayed into the granulator with pseudowire is a procedure, mixed with 16 g of microcrystalline cellulose, 16 g of insoluble polyvidone, 2 g of highly dispersed silicon dioxide and 1 g of magnesium stearate. The mixture is pressed into tablets containing the active substance 200, 400 or 600 mg of carbamazepine, or the appropriate number of granules Packed in capsules of size 1.1

1. The method of obtaining the dosage form of carbamazepine delayed release of the active substance, characterized in that the binders in combination with softeners in the form of an aqueous solution and/or dispersion sprayed on carbamazepine in the granulator, fluidized bed.

2. The method according to p. 1, characterized in that as the film is a mixture of polymethacrylates, such as politicalit and polymethyl methacrylate in a ratio of 2:1, politicalit, polymethylmethacrylate and chloride polytrimethylterephtalate in a ratio of 1:2:0.1 or 1:2:0,2.

3. The method according to p. 1, characterized in that the ratio of carbamazepine and the foaming agent is 1:0.03 to 1:0.5 in.

4. The method according to p. 1, characterized in that the binders used in combination with a softener in a ratio of 1:0.05 to 1:0.25 in.

5. The method according to PP.1-4, characterized in that the ratio of plancom, that as a softener used glyceryltrinitrate or triethylcitrate.

7. The method according to p. 1, wherein optionally the dispersion of the foaming agent injected separating agent, such as talc, in a ratio of 1:0.4 to 1:1 and/or sprayed them later in the fluidized bed in the form of separate suspensions.

8. The method according to PP.1-7, characterized in that the covered carbamazepine mixed with other excipients, pressed into scored tablets or Packed in capsules.

9. The method according to PP.1-7, characterized in that carbamazepine coated Packed in capsules without other auxiliary substances.

 

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