RU2345777C1 - Pharmaceutical composition of antiepileptic activity and method of production thereof - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition contains Topyramat as active substance and additives, including starch, lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and dusting agent. Preparation is produced by wet granulation technique in the form of coated tablets with 25 mg, 50 mg, 100 mg or 200 mg of Topyramat content.

EFFECT: fast decomposition, high reactant release and high durability, storage stability.

10 cl, 1 tbl, 3 ex

Description

The invention relates to medicine, specifically to a drug with antiepileptic effect.

Topiramate is an antiepileptic and belongs to the class of sulfate-substituted monosaccharides. The antiepileptic activity of the drug is due to a number of its properties. Topiramate reduces the frequency of action potentials characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking action of topiramate on Na ⁺ channels on the state of the neuron. Increases the activity of gamma-aminobutyric acid (GABA) in relation to certain subtypes of GABA receptors (including GABA receptors), and also modulates the activity of GABA receptors themselves; prevents Kainate activation of the sensitivity of Kainate / AMPK receptors (AMPK - alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) to glutamate.

In the patent application US 2006/0286163 a pharmaceutical composition is described comprising a particulate base. These particles contain topiramate and a binder, polyvinylpyrrolidone, deposited on sugar balls, with these particles having a size of 0.1 to 2.5 mm and a shell based on cellulose acetate. The known solid dosage form of topiramate is usually mixed with liquid food or drinks, or may be applied in capsule form after packaging, however, the known composition of the ingredients is unsuitable for tabletting.

It is known that topiramate easily undergoes destruction when exposed to moisture and heat, under the influence of which it is possible to change the physicochemical composition of the dosage form and the formation of unacceptable impurities in it, contributing to the loss of pharmacological activity of the active substance.

To solve this problem, WO 2004/054547 proposes a multiphase tablet comprising topiramate and a hygroscopic adhesive, preferably xanthan gum. However, the known composition has a complex manufacturing technology, and the resulting tablets have problems with disintegration.

International application WO 2006/097946 describes a pharmaceutical composition comprising topiramate, spray dried mannitol and other auxiliary ingredients — pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, aerosil and magnesium stearate. The known composition is obtained by direct compression, which avoids the use of a moisturizing agent in the manufacturing process and, thereby, reduce the destruction of the active substance. However, these tablets are characterized by poor disintegration, which reduces the release of the active substance. It should be noted that this composition requires the use of a special variety of mannitol, which imposes additional restrictions on the technology for its manufacture.

The objective of the present invention is to provide a pharmaceutical composition with antiepileptic effect, intended for oral administration in the form of a solid dosage form, with rapid disintegration, stable during storage and easy to manufacture.

To solve this problem, a pharmaceutical composition with antiepileptic action in the form of a core having a shell that contains topiramate as an active substance in a therapeutically effective amount and as auxiliary substances starch, microcrystalline cellulose and dusting agent, characterized in that it additionally contains lactose and cross-linked polyvinylpyrrolidone in the following ratio of ingredients, parts by weight 1 mph active substance:

Topiramat - 1.0,

Starch - 0.25-1.2,

Lactose - 0.5-1.0,

Microcrystalline cellulose - 0.25-0.75,

Crosslinked polyvinylpyrrolidone - 0.03-0.20,

The dusting agent is 0.04-0.295.

The proposed ranges of ratios of the ingredients obtained empirically and are optimal.

In accordance with the present invention, the claimed composition is characterized by very rapid disintegration, which leads to a high speed and degree of release of the active substance. The disintegration of tablets with the stated ratio of ingredients is 1.5-4 minutes. Rapid disintegration of the claimed composition leads to high rates of release of the active substance - after 15 minutes, almost 100% of topiramate passes into the dissolution medium, according to regulatory requirements, 75% after 30 minutes. The proposed composition is stable during storage and has increased strength compared to the prototype obtained by direct pressing.

According to the invention, as the active substance, the proposed composition contains topiramate in a therapeutically effective amount, the preferred amount of the active substance in a single dose is 25 mg, 50 mg, 100 mg or 200 mg.

As a dusting agent, it is advisable to use a combination of aerosil, crossscarmellose sodium and stearic acid salt. The preferred ratio of these ingredients is, m.h. 1 mph active substance (0.015-0.15) :( 0.015-0.11) :( 0.01-0.035).

The presence of a dusting agent in the composition in the declared amount provides excellent technological parameters, in particular flowability, of the finished tablet mixture and, as a result, good dosage uniformity (deviation by weight of tablets of different dosages by active substance does not exceed 1-2%) and stable non-stop operation of the presses (the pressure deviation of individual punches does not exceed ± 1 kN).

As the salt of stearic acid, calcium, magnesium or other metal stearates or a mixture thereof, preferably magnesium stearate, are used.

In a preferred embodiment of the invention, a combination of natural starch, for example, potato and / or corn, and / or rice, and modified starch, for example, pregelatinized starch or STARCH 1500 starch, is used as starch.

The proposed composition is in the form of a solid dosage form, preferably in the form of tablets, more preferably in the form of tablets, film-coated.

The presence of a shell improves the appearance of the dosage form, masks the unpleasant taste of the active substance, and also further increases the stability of the drug during storage. Preferably, the shell is made on the basis of a cellulose derivative — hydroxyalkyl methyl cellulose, more preferably hydroxypropyl methyl cellulose. Additionally, the shell may include a filler, such as titanium dioxide, lactose and talc, a plasticizer, such as polyethylene glycol and glycerin, a dye, for example, iron (III) oxide red, or a combination of these compounds.

A preferred method for preparing the inventive pharmaceutical composition comprises wet granulating a mixture of topiramate with lactose, starch, microcrystalline cellulose and cross-linked polyvinylpyrrolidone, then adding a dusting agent to the dry granulate, molding the finished mixture into cores and coating the resulting cores.

As a dusting agent, it is advisable to use a combination of aerosil, crossscarmellose sodium and stearic acid salt.

It is preferable to use a suspension of starch in water as a wetting agent, more preferably a suspension of pregelatinized starch in water.

The following examples illustrate the invention (see Table).

Example 1. Pre-prepare a suspension of pregelatinized starch (0.5 parts by weight - hereinafter, 1 part by weight of the active substance) in water and wet granulation of a mixture of powders of topiramate (1 part by weight), corn starch (total the amount of starch in the composition is 0.8 mph), lactose (0.6 mph), microcrystalline cellulose (0.6 mph) and Kollidon CL M cross-linked polyvinylpyrrolidone (0.15 mph) .). A combined dusting agent is added to the dry granulate - a mixture of aerosil, crosscarmellose sodium and magnesium stearate. Everything is thoroughly mixed until a homogeneous mass is obtained, after which it is tabletted. A film-forming composition containing 4.0 wt.% Hydroxypropylmethylcellulose, 1.2 wt.% Glycerol, 0.8 wt.% Polyethylene glycol 6000 1.2 wt.% Titanium dioxide, 0.8 wt.% Talc, 1.0 wt.% Lactose and 0.05 wt.% Red iron oxide (III). Layering is carried out until a film of satisfactory thickness is obtained. The resulting tablets with an average weight of 0.084 g satisfy the regulatory requirements for a pharmaceutical agent. The content of topiramate in one tablet is 25 mg, the deviation from the average weight,% is +0.6, -0.8; dissolution, after 15 minutes, 100% topiramate, impurities (% by weight of the active substance, HPLC method) are absent. The resulting tablets have a shelf life of more than 2 years. Examples 2, 3 are performed similarly, with the difference that instead of magnesium stearate, calcium stearate is used and the content of topiramate in one tablet is 100 mg, and in example 3, the content of topiramate in one tablet is 200 mg and potato starch is used instead of corn starch . For the obtained tablets, dissolution (15 min) - 100% topiramate, impurities - are absent and the shelf life is more than 2 years.

Table. Ingredients Content, parts by weight / 1 parts by weight topiramata Examples one 2 3 Topiramat 1,0 1,0 1,0 Starch 0.8 1,2 0.25 Lactose 0.6 0.5 1,0 Microcrystalline cellulose 0.6 0.25 0.75 Polyvinylpyrrolidone crosslinked 0.15 0.20 0,03 Dusting agent, incl. 0.2 0.04 0.295 - aerosil 0.08 0.015 0.15 - crossscarmellose sodium 0.02 0.01 0,035 - stearic acid salt 0.1 0.015 0.11

Claims (10)

1. The pharmaceutical composition with an antiepileptic action in the form of a core having a shell that contains topiramate as an active substance in a therapeutically effective amount and as excipients, starch, microcrystalline cellulose and dusting agent, characterized in that it additionally contains lactose and cross-linked polyvinylpyrrolidone when the following ratio of ingredients, mh 1 mph active substance:
Topiramat 1,0 Starch 0.25-1.2 Lactose 0.5-1.0 Microcrystalline cellulose 0.25-0.75 Crosslinked Polyvinylpyrrolidone 0.03-0.20 Dusting agent 0.04-0.295 2. The composition according to claim 1, characterized in that it contains, as a dusting agent, a combination of aerosil, sodium crosscarmellose and stearic acid salt in the following ratio, m.h. 1 mph active substance: (0.015-0.15) :( 0.015-0.11) :( 0.01-0.035). 3. The composition according to claim 2, characterized in that it contains magnesium stearate as a salt of stearic acid. 4. The composition according to claim 3, characterized in that it contains as a starch a combination of natural starch and modified starch. 5. The composition according to claim 4, characterized in that it contains potato and / or corn starch as natural starch. 6. The composition according to claim 5, characterized in that it contains pregelatinized starch as modified starch. 7. The composition according to p. B, characterized in that it is made in the form of a tablet, coated with a shell based on hydroxypropyl methylcellulose. 8. The method of obtaining the composition described in claim 1, including wet granulation of a mixture of topiramate with lactose, starch, microcrystalline cellulose and cross-linked polyvinylpyrrolidone, the subsequent addition of dusting agent to the dry granulate, molding the finished mixture into cores and coating the resulting cores. 9. The method of claim 8, wherein a combination of aerosil, sodium crosscarmellose and stearic acid salt is used as a dusting agent. 10. The method of claim 8, in which an aqueous suspension of pregelatinized starch is used as a humidifier.