SK286119B6 - Drug form containing zaleplon - Google Patents

Abstract

Drug form containing zaleplon for the treatment of serious insomnia in the tablet form or coating tablet containing zaleplon in an amount of 0.005 to 0.02 g and further containing microcrystalline cellulose having a middle particle size 10 to 1000 um in an amount of 60 to 90 % by weight, dry binder in an amount of 2 to 20 % by weight, disintegrant in an amount of 1.5 to 10 % by weight, agent regulating flow features in an amount of 0.1 to 2 % by weight, antiadhesive agent in an amount of 0.5 to 4 % by weight, colouring agent prohibiting misusing of the drug form in an amount of 0.5 to 5 % by weight and eventually film forming agents in an amount of 2 to 5 % by weight.

Description

The invention is in the field of pharmacy, solves the formulation of a zaleplon-containing dosage form in the form of tablets and film-coated tablets. The preparation is used for the treatment of severe insomnia which causes ex5 thyroid stress to patients.

BACKGROUND OF THE INVENTION

Currently, the dose of zaleplon in the world's fast-acting oral formulations is in the range of 5 mg to 10 mg. Hard gelatin capsules are used as the dosage form.

The following excipients are used in the preparation of the capsule filler: microcrystalline cellulose, lactose monohydrate, pregelatinised corn starch, sodium lauryl sulfate, colloidal anhydrous silica, indigo carmine E 132 and magnesium stearate.

The powder mixtures are filled into hard gelatin capsules. The production of hard gelatine capsules is more expensive and the performance of the filling machines is less than that of the coated tablet manufacturing machines.

WO / 0178725 describes the preparation of modified release pellets containing zaleplon. The pellets are prepared by wetting a mixture of the active ingredient and microcrystalline cellulose with water, which is evaporated from the mixture under elevated temperature and vacuum.

EP 1005863 discloses capsules, tablets, multilayer tablets, zaleplon-containing, controlled-release tablets which release about 40 to 70% of the active ingredient within 30 minutes, and about 90% of the active ingredient after 2 to 6 hours. The release control is ensured by coating the granules, pellets, resp. tablets with hydrophilic or hydrophilic polymers.

The two cited applications have not yet been put into practice, or are not in use to date.

The disadvantages of the prior art, i. j. produced hard gelatin capsules include:

- From the perspective of healthcare professionals and patients, the inability to accurately titrate the dose, the capsule can only be spilled, but it is impossible to divide it into exact halves after spilling.

Dose titration is particularly important at the start of therapy, in elderly and ill patients, as well as in patients with malnutrition or obesity.

- Technology requiring the use of hard gelatine capsules, which are more expensive and generally time-consuming to produce, and at the same time the use of gelatine, i.e. j. material of animal origin.

The use of excipients of animal origin is also the reason why patients do not like this formulation in some countries.

According to the current state of the art, the capsules used are not weight equivalent, so that each batch must be earned separately to the degree before the capsule.

The essence of you finding

The present invention provides a dosage form comprising zaleplon, in the form of a tablet or film-coated tablet, comprising zaleplon in an amount of 0.005 to 0.02 g, and further comprising at least one excipient or mixture of excipients containing microcrystalline cellulose, regulating the flow properties of the pulp, anti-adhesive agents, tablet disintegrating agents, and coloring agents 45 to prevent abuse of the dosage form or film-forming agent. The structural formula of zaleplon is

The dosage form in the form of a tablet or film-coated tablet contains zaleplon in an amount of 0.005 to 50 0.02 g, and further microcrystalline cellulose of a mean particle size of 10 to 1000 µm in an amount of 60 to 90 wt.

%, dry binder in an amount of 2 to 20 wt. % disintegrant in an amount of 1.5 to 10 wt. %, a flow modifier in an amount of 0.1 to 2 wt. %, anti-adhesive in an amount of 0.5 to 4 wt. % dye to prevent abuse of the dosage form in an amount of 0.5 to 5 wt. % and optionally film-forming agents in an amount of 2 to 5 wt. %.

Said microcrystalline cellulose preferably has an average particle size of 50 to 180 μm. Alternatively, the dosage form, based on the total weight of the formulation, comprises 10-15 wt. % microcrystalline cellulose with an average particle size of 50 µm and 60 to 71 wt. % microcrystalline cellulose with a mean particle size of 180 μπι.

According to another preferred embodiment, the dosage form, based on the total weight of the formulation, comprises 15 to 23 wt. % microcrystalline cellulose with an average particle size of 100 µm and 60 to 70 wt. % microcrystalline cellulose with a mean particle size of 180 µm.

In the case of a film-coated tablet, it contains film-forming substances preferably in an amount of 3 to 4 wt. %.

The dry binder content is preferably 4 to 6 wt. %, the preferred representative is pregelatinized corn starch. The disintegrant content is preferably 1 to 5 wt. %, preferably croscarmellose sodium.

A preferred representative of the flow properties of the tablet is anhydrous colloidal silica, preferably in an amount of 0.2 to 0.5 wt. % substances.

Magnesium stearate is preferably used as the anti-adhesive and its content is preferably 0.7 to 1.5% by weight. % antiadhesive.

A preferred representative of the dye to prevent abuse of the dosage form is Indigocarmine 85 E 132, preferably used in an amount of 0.7 to 1.5 wt. %.

The essence of the method of manufacture of the dosage form consists in preparing the tablet by dry mixing, compressing the tablet and optionally coating the tablets with a film coating.

The preparation of the pulp is technologically simple, it is limited to energy and time-saving technological steps. The preparation of the tablet does not involve stressful procedures such as the introduction of a humectant into the mixture of the active ingredient and the excipients for the preparation of the tablet.

Dry blending of the tablet allows the preparation of cores of suitable parameters.

Film coating of the tablets is performed with an aqueous suspension of the finished film-forming concentrate, plasticizer, filler and color pigments without the use of organic solvents.

Film forming agents are the commonly used film forming agents available under the commercial name Sepifilm.

Microcrystalline cellulose is a pharmaceutical excipient known as Avicel which is used as a direct compression filler. It is produced e.g. Avicel PH 101 powder (mean particle size 50 µm); Avicel PH 102 in the form of granules (mean particle size 100 µm) and Avicel PH 200 in the form of granules (mean particle size 180 µm). It has good flow properties. Tablets have satisfactory strength and disintegration because microcrystalline cellulose in the compact ensures the maintenance of capillary holes through which water penetrates to inhibit the binding force efficiency. They provide the product with very good stability. According to the present invention, these properties have been repeatedly achieved by using combinations of microcrystalline cellulose with different mean particle sizes.

The essence of the technological process is the preparation of a tablet by mixing the active substance zaleplon with a corresponding amount:

- microcrystalline cellulose having a particle size of 10 to 1000 µm of said composition,

- compressing the tablet of that composition,

- coating the tablets with an aqueous suspension of the finished concentrates Sepifilm 752 White and Sepifilm 1015 Blue in a total amount of 2 to 5 wt. %;

Sepifilm 752 White and Sepifilm 1015 Blue are commercially available film coating compositions for cores. They are applied in the form of a 16% aqueous suspension in a total amount of 2 to 5 wt. %.

Sepifilm 752 White (from Seppic, France) is a granulated powder composed of hydroxypropylmethylcellulose - Methocel E5 (film forming agent), polyoxyl 40 stearate plasticizer) and titanium dioxide (white pigment).

Sepifilm 1015 Blue (from Seppic, France) is a granulated powder composed of hydroxypropyl methylcellulose - Methocel E5 (film-forming substance), microcrystalline cellulose (filler), polyoxyl-40 stearate (plasticizer), titanium dioxide (white pigment) and indigotine aluminum paint pigment,

and polishing the coated tablets with an aqueous solution of polyethylene glycol in an amount of 0.05 to 0.25 wt. %, preferably 0.1 to 0.15 wt. %.

The film-coated tablets thus prepared according to the invention guarantee the reproducibility of the manufacturing process. The preparation of the tablets is carried out in the same manner, omitting the coating and polishing of the tablets in the final phase.

The advantage of the process according to the invention is lower energy and time consumption, especially preparation of tablet, simple technology, reduction of capsule use - use of materials of animal origin, possibility of dose titration.

Tablet dosage forms and coated tablets are accepted by virtually the entire population.

SK 286119-6

DETAILED DESCRIPTION OF THE INVENTION

The subject matter of the invention is illustrated in the examples without being limited thereto.

Example 1

(a) Pharmaceutical preparation containing in the composition of tablets:

Ingredients: core Weight in g Weight% zaleplon 0.00500 g 6,03% Avicel PH 101 0.00100 g 12.06% Avicel PH 200 0.05680 g 68.43% Pregelatinised maize starch 0.00400 g 4.82% Croscarmellose sodium 0.00240 g 2.89% Anhydrous colloidal silica 0.00020 g 0.24% Indigo carmine 85 E132 0.00080 g 0,96% Magnesium stearate 0.00080 g 0,96% Composition: packaging Sepifilm 752 White 0.00210 g 2.53% Sepifilm 1015 Blue 0.00080 g 0,96% Makrogol 6000 0.00010 g 0,12% Together: 0,08300 g 100.00%

(b) Method for its preparation

The active ingredient and Avicel PH 101 are placed in a homogenizer. The mixture is stirred for 15 minutes (Mixing I). The mixed premix is drained into a container and then sieved through a sieve with a mesh side length of 1.0 mm. The homogenizer was charged with Avicel PH 200, pregelatinised corn starch, croscarmellose sodium, anhydrous colloidal silica and indigo carmine 85 E 132. The mixture was stirred for 15 minutes (Mixing II).

The mixed mixture is discharged into a container and then sieved through a sieve with a mesh side length of 0.80 mm.

Mixed and sieved mixtures I and II are placed in a homogenizer. and stirred for 30 minutes. Magnesium stearate is added to the mixture in the homogenizer. The mixture was stirred for 15 minutes (Finish). Lentil-shaped tablets are compressed from the finished tablet to a tablet weight of 0.080 g. The tablets are coated on a horizontal or other suitable coating machine at a drying air temperature of 60 ° C with an aqueous suspension of Sepifilm 752 White and Sepifilm 1015 Blue. The coated tablets are polished with an aqueous solution of polyethylene glycol.

Example 2

(a) Pharmaceutical preparation containing in the composition of tablets:

Ingredients: core Weight in g Weight% zaleplon 0.00500 g 6,03% Avicel PH 102 0.01600 g 19.28% Avicel PH 200 0.05080 g 61,21% Pregelatinised maize starch 0.00400 g 4.82% Croscarmellose sodium 0.00240 g 2.89% Anhydrous colloidal silica 0.00020 g 0.24% Indigocarmine 85 El32 0.00080 g 0,96% Magnesium stearate 0.00080 g 0,96% Composition: packaging Sepifilm 752 White 0.00210 g 2.53% Sepifilm 1015 Blue 0.00080 g 0,96% Makrogol 6000 0.00010 g 0,12% Together: 0,08300 g 100.00%

(b) Method for its preparation

The active ingredient and Avicel PH 102 are placed in a homogenizer. The mixture is stirred for 15 minutes (Mixing I). The mixed premix is drained into a container and then sieved through a sieve with a mesh side length of 1.0 mm. The homogenizer was charged with Avicel PH 200, pregelatinised corn starch, croscarmellose sodium, anhydrous colloidal silica and indigo carmine 85 E 132. The mixture was stirred for 15 minutes (Mixing II). The mixed mixture is discharged into a container and then sieved through a sieve with a mesh side length

SK 286119-6

0,80 mm. Mixed and sieved mixtures I and II are placed in a homogenizer. and stirred for 30 minutes. Magnesia stearas is added to the mixture in the homogenizer. The mixture was stirred for 15 minutes (Finish). Lentil-shaped tablets are compressed from the finished tablet to a tablet weight of 0.080 g. The tablets are coated on a horizontal or other suitable coating machine at a drying air temperature of 60 ° C with an aqueous suspension of Sepifilm 752 White and Sepifilm 1015 Blue. The coated tablets are polished with an aqueous solution of polyethylene glycol.

Example 3

(a) Pharmaceutical preparation containing in the composition of tablets:

Ingredients: core Weight in g Weight% zaleplon 0.01000 g 6,03% Avicel PH 101 0,02000 g 12.06% Avicel PH 200 0.11360 g 68.43% Pregelatinised maize starch 0.00800 g 4.82% Croscarmellose sodium 0.00480 g 2.89% Anhydrous colloidal silica 0.00040 g 0.24% Indigocarmin 85 E132 0.00160 g 0,96% Magnesium stearate 0.00160 g 0,96% Composition: packaging Sepifilm 752 White 0.00420 g 2.53% Sepifilm 1015 Blue 0.00160 g 0,96% Makrogol 6000 0.00020 g 0,12% Together: 0.16600 g 100.00%

(b) Method for its preparation

The active ingredient and Avicel PH 101 are placed in a homogenizer. The mixture is stirred for 15 minutes (Mixing I). The mixed premix is drained into a container and then sieved through a sieve with a mesh side length of 1.0 mm. The homogenizer was charged with Avicel PH 200, pregelatinised corn starch, croscarmellose sodium, anhydrous colloidal silica and indigo carmine 85 E 132. The mixture was stirred for 15 minutes (Mixing II). The mixed mixture is discharged into a container and then sieved through a sieve with a mesh side length of 0.80 mm. Mixed and sieved mixtures I and II are placed in a homogenizer. and stirred for 30 minutes. Magnesium stearate is added to the mixture in the homogenizer. The mixture was stirred for 15 minutes (Finish). Lentil-shaped tablets are compressed from the finished tablet to a tablet weight of 0.160 g. The tablets are coated on a horizontal or other suitable coating machine at a drying air temperature of 60 ° C with an aqueous suspension of Sepifilm 752 White and Sepifilm 1015 Blue. The coated tablets are polished with an aqueous solution of polyethylene glycol.

Example 4

(a) Pharmaceutical preparation containing in the composition of tablets:

Ingredients: core Weight in g Weight% zaleplon 0.01000 g 6,03% Avicel PH 102 0,03200 g 19.28% Avicel PH 200 0.10160 g 61,21% Pregelatinised maize starch 0.00800 g 4.82% Croscarmellose sodium 0.00480 g 2.89% Anhydrous colloidal silica 0.00040 g 0.24% Indigocarmin 85 E132 0.00160 g 0,96% Magnesium stearate 0.00160 g 0,96% Composition: packaging Sepifilm 752 White 0.00420 g 2.53% Sepifilm 1015 Blue 0.00160 g 0,96% Makrogol 6000 0.00020 g 0,12% Together: 0.16600 g 100.00%

(b) Method for its preparation

The active ingredient and Avicel PH 102 are placed in a homogenizer. The mixture is stirred for 15 minutes (Mixing I). The mixed premix is drained into a container and then sieved through a sieve with a mesh side length of 1.0 mm. The homogenizer was charged with Avicel PH 200, pregelatinised corn starch, croscarmellose sodium, anhydrous colloidal silica and indigo carmine 85 E 132. The mixture was stirred for 15 minutes (Mixing II). The mixed mixture is discharged into a container and then sieved through a sieve with a mesh side length of 0.80 mm. Mixed and sieved mixtures I and II are placed in a homogenizer. and stirred for 30 minutes. Magnesium stearate is added to the mixture in the homogenizer. The mixture was stirred for 15 minutes (Finish). Lentil-shaped tablets are compressed from the finished tablet to a tablet weight of 0.160 g. The tablets are coated on a horizontal or other suitable coating machine at a drying air temperature of 60 ° C with an aqueous suspension of Sepifilm 752 White and Sepifilm 1015 Blue. The coated tablets are polished with an aqueous solution of polyethylene glycol.

Example 5

(a) Pharmaceutical preparation containing in the composition of tablets:

Tablet composition Weight in g Weight% zaleplon 0.01000 g 6.25 Avicel PH 102 0,03200 g 20.00 Avicel PH 200 0.10160 g 63.50 Pregelatinised maize starch 0.00800 g 5.00 Croscarmellose sodium 0.00480 g 3.00 Anhydrous colloidal silica 0.00040 g 0.25 Indigo carmine 85 E132 0.00160 g 1.00 Magnesium stearate 0.00160 g 1.00 Together: 0.16000 g 100.00%

(b) Method for its preparation

The active ingredient and Avicel PH 102 are placed in a homogenizer. The mixture is stirred for 15 minutes (Mixing I). The mixed premix is drained into a container and then sieved through a sieve with a mesh side length of 1.0 mm. The homogenizer was charged with Avicel PH 200, pregelatinised corn starch, croscarmellose sodium, anhydrous colloidal silica and indigo carmine 85 E 132. The mixture was stirred for 15 minutes (Mixing II). The mixed mixture is discharged into a container and then sieved through a sieve with a mesh side length of 0.80 mm. Mixed and sieved mixtures I and II are placed in a homogenizer. and stirred for 30 minutes. Magnesium stearate is added to the mixture in the homogenizer. The mixture was stirred for 15 minutes (Finish). Lentil-shaped tablets are compressed from the finished tablet to a tablet weight of 0.160 g.

Dissolution results of the active substance

The in vitro dissolution of zaleplon is monitored for:

Used equipment: Dissolution device according to Ph.Eur., Paddle, 100rpm medium: 0.1 HCl, 900 mL temperature: 37 ° C ± 0.5 ° C Time: 30 minutes

Determination of drug dissolution: HPLC at 230 nm

The dissolution of the active compound is illustrated in the embodiment no. 4 which was used for the clinical trial and the dissolution results are shown in the table.

table

Dissolution of the active substance

Time Amount of active substance released (%) 5 minutes 10 minutes 20 minutes 30 minutes 45 minutes 81.88 88.63 92.04 93,35 93.74

The results of the dissolution of the active substance show that more than 80% of the active substance is released within 10 minutes.

Industrial usability

The invention is useful in the pharmaceutical manufacture of tablets and film-coated tablets. The film-coated tablets can be used therapeutically in the treatment of severe insomnia.

Claims (10)

A dosage form comprising zaleplon, characterized in that it is in the form of a tablet or film-coated tablet comprising zaleplon in an amount of 0.005 to 0.02 g, and further comprising microcrystalline cellulose with an average particle size of 10 to 1000 μπι in an amount of 60 to 90% by weight. . %, dry binder in an amount of 2 to 20 wt. % disintegrant in an amount of 1.5 to 10 wt. %, a flow modifier in an amount of 0.1 to 2 wt. %, anti-adhesive in an amount of 0.5 to 4 wt. % dye to prevent abuse of the dosage form in an amount of 0.5 to 5 wt. % and optionally film-forming agents in an amount of 2 to 5 wt. %. Dosage form according to claim 1, characterized in that the microcrystalline cellulose has a mean particle size of 50 to 180 µm. The dosage form according to claim 1 and 2, characterized in that it contains, based on the total weight of the preparation, 10 to 15 wt. % microcrystalline cellulose with an average particle size of 50 µm and 60 to 71 wt. % microcrystalline cellulose with a mean particle size of 180 µm. The dosage form according to claim 1 and 2, comprising, based on the total weight of the preparation, 15 to 23 wt. % microcrystalline cellulose with an average particle size of 100 µm and 60 to 70 wt. % microcrystalline cellulose with a mean particle size of 180 µm. A dosage form according to claim 1, characterized in that it comprises 4 to 6 wt. % dry binder, preferably pregelatinized corn starch. A dosage form according to claim 1, characterized in that it contains 2 to 5% by weight. % disintegrant, preferably croscarmellose sodium. A dosage form according to claim 1, characterized in that it comprises 0.2 to 0.5 wt. % of the flow control agent of the tablet, preferably anhydrous colloidal silica. Pharmaceutical form according to claim 1, characterized in that it contains 0.7 to 1.5 wt. % antiadhesive, preferably magnesium stearate. The dosage form according to claim 1 and 2, characterized in that it contains 0.7 to 1.5 wt. % dye to prevent abuse of the dosage form, preferably Indigo carmine 85 E 132. Pharmaceutical form according to any one of claims 1 to 9, characterized in that it contains film-forming substances in an amount of 3 to 4% by weight. %.