FR2705895A1 - Drug tablets free of lubricating agent. - Google Patents

Abstract

Medicated tablets free from lubricating agent. These tablets are based on microcrystalline cellulose, in a content of at least 85% of the total weight of the tablet. The tablets according to the invention contain, for example, as active substances, hormones, preferably thyroid hormones.

Description

The invention relates to novel cellulose-based tablets

  microcrystalline, free from lubricating agents, which contain a pharmaceutical active substance and, where appropriate, agents which facilitate the wetting and disintegration of the mass of the tablets. The tablets according to the invention consist of at least 85% by weight of microcrystalline cellulose. In particular, the invention relates to such tablets which contain, as pharmaceutically active substances, hormones, preferably thyroid hormones or

  agents that act on the thyroid gland.

  When tabletting pharmaceutical mixtures, lubricating agents are generally used which ensure permanent lubrication of the compression tools and good mold release. They also help to give the tablets a smooth surface. Lubricants commonly used for this purpose and suitable for pharmaceutical use include, for example, magnesium stearate or mixtures of a silicone oil with high dispersion silica. These lubricating agents have disadvantages. They make most blends difficult to compress. To obtain acceptable tablets, it is necessary to

  apply relatively intense compression forces (more than 10 kN).

  Naturally, this results in faster wear of the compression tools. On the other hand, known lubricating agents often have the disadvantage of opposing a rapid and complete release of the pharmaceutical active substance. This disadvantage is particularly troublesome when the active substance used can be assayed only at

  low concentration (less than 5%) in the overall mass of tablets.

  There is therefore a need for medicinal tablets that would not have the

  known disadvantages resulting from the use of lubricating agents.

  We have precisely found that we could totally avoid the use of agents

  lubricants when microcrystalline cellulose was used as a carrier.

  According to the invention, the proportion by weight of microcrystalline cellulose

must be at least 85%.

  The subject of the invention is therefore a medicinal tablet which is characterized in that it is free of lubricating agents and is based on microcrystalline cellulose at a content of at least 85% by weight. Preferably, this content is 90 to 98% and more

  especially from 93 to 96% by weight.

  According to the invention, commercially purified microcrystalline cellulose with a grain size of from 50 to 400, preferably from 150 to 250 g, is used as a vehicle replacing conventional tablet vehicles, such as

mannitol or lactose.

  The invention also relates to tablets as defined above, which are characterized in that they contain a hydrophilizing agent, preferably at a maximum content of 5% and more especially at a content of 1 to 3%. According to the invention, hydrophilizing agents are used as auxiliaries which facilitate the wetting of the mass of the tablets. Suitable hydrophilizing agents include all water-soluble cellulose derivatives, for example hydroxypropylcellulose or hydroxyethylcellulose, sugars such as sucrose or lactose, alcohols, sugars, e.g.

  sorbitol or mannitol but also polyvinylpyrrolidone, polyethylene

  glycols or surfactants, for example sodium lauryl sulphate.

  The invention therefore also relates to a tablet as defined above but which is characterized in that it contains an agent facilitating the disintegration of the tablet (disintegrating agent) preferably at a maximum content of 5% and more especially

  at a content of 1 to 3.5% of the total weight of the tablet.

  Suitable disintegrating agents include crosslinked derivatives

  cellulose, for example sodium carboxymethylcellulose, polyvinyl

  crosslinked pyrrolidone, sodium starch glycolate or modified starches.

  Preferably, the tablets according to the invention contain both hydrophilizing agents and disintegrating agents. However, depending on the dosage and the solubility of the pharmaceutical active substance used, the hydrophilizing agent or

  even the two auxiliary products.

  The subject of the invention is in particular a tablet as defined above which contains as an active substance a thyroid hormone (thyroxine) or a

  agent acting on the thyroid gland, for example potassium iodide.

  However, new pharmaceutical active substances may be used in the new tablets, particularly those which can only be introduced at low doses and whose stability deserves special attention. In addition to the thyroxines mentioned above, mention may be made of adrenal hormones and substances with an analogous action (corticoids, for example Dexamethason, Desoxymethason or Halomethason), hormones such as sex hormones (for example ethynyloestradiol, Chlormadinon acetate), anabolic or parathyroid hormones. The concentration of the active substance in the overall mass of the tablets should not exceed 5% by weight, otherwise the release of the active substance may not be rapid and complete. Tablets are preferably prepared

  at concentrations of 0.05 to 3%, especially 0.1 to 1%.

  The novel tablet compositions provide a rapid and almost quantitative release of the active substances, in particular thyroid hormones. For example, the thyroxines are released in proportions of 95 to% of the mass of the tablets free of lubricating agents according to the invention in minutes. By cons, in the same period, thyroxines introduced at the same dose (about 0.1%) in a mass of mannitol-based tablets, in the presence of a lubricant essential for this purpose (for example the couple oil of siliconelSiO2) are only released in proportions of 30 to 50%. This poor release of thyroxines, known from the prior art, is allowed in official monographs whose requirements in this respect are very limited (cf USP XXI: "Levothyroxine Sodium Tablets": 55% in 90 minutes). The improvement of the

  speed of release is also observed with the other drugs mentioned above.

  above. This is an entirely surprising phenomenon because microcrystalline cellulose is insoluble and it can not be excluded, in general, from

  losses due to adsorption effects.

  In the case of drugs with limited stability, for example thyroxines, and with the prior art tablet formulations (with lubricating agent), there are in some cases considerable initial decomposition rates (during manufacturing operations). ) that could not be

  to remedy until now by compensating by additions to production.

  For example, for levothyroxine, there are losses of 5 to 15% depending on the vehicle and the lubricant used. With the tablet formulation according to the invention, on the other hand, the decomposition losses that have been observed are at most 1%. We can therefore avoid additions to production. Also with regard to storage stability, the tablets according to the invention have improved properties. Thus, after 6 months, losses are only 1 to 3%, against more than 5% for tablet formulations containing

lubricating agents.

  The suppression of the lubricating agent in the manufacture of tablets according to the invention generally leads to a simpler and less expensive preparation process, by suppressing an operation. In addition, the compressive forces necessary to obtain high quality tablets are lower (3 to 6 kN vs. 12 to 16 kN in the presence of a lubricating agent and with prior art vehicles). These lower compressive forces allow for gentle operation and, therefore, longer service life.

compression tools.

  The invention finally relates to a process for the preparation of medicinal tablets free from lubricating agents, this process being characterized in that the microcrystalline cellulose is mixed with the active substance in the form of a powder or a solution. if necessary with the auxiliary products, and if appropriate after drying, the tablets are immediately put into microcrystalline cellulose content of at least 85% by weight and the compression forces are applied.

  preferably between 3 and 6 kN.

  The process according to the invention also makes it possible to manufacture a much larger number of tablets per unit of time. Thus, the speed of manufacture of the tablets is about two to three times higher than with the conventional methods described above. The method according to the invention is particularly effective when the pharmaceutical active substance is added in the dissolved state, preferably in methanolic solution, to the mass of the tablets. In addition to methanol and ethanol, it is also possible to use ketonic solvents (for example acetone) or mixtures of

  these solvents when the solubility of the drug in these mixtures is sufficient.

  The following examples illustrate the invention without limiting its scope.

EXAMPLE 1

  141.4 kg of microcrystalline cellulose (180 to 200 gm), 3 kg of hydroxypropyl methylcellulose and 5.3 kg of sodium carboxymethylcellulose (crosslinked) are introduced into a high speed mixer and are subjected to intensive mixing for approximately 20 minutes. On the other hand, 0.18 kg of levothyroxine sodium and 0.2 kg of potassium iodide are dissolved in 201 ml of methanol and the mixture is mixed with the methanolic solution. The tablet mass is then dried for about 90 minutes in the high speed mixer at a maximum temperature of 28 to 30 ° C and compressed onto a commercially available tableting machine at a compression force of 3 to 4 kN at a compression speed of 200,000 to 300,000 tablets / hour. Approximately 1,500,000 tablets are obtained at a

active drug of about 0.12%.

EXAMPLE 2

  By operating as described in Example 1, tablets containing thyroxine are prepared. Instead of hydroxypropylcellulose, it is used as an agent

  hydrophilizing, in the same amount, polyvinylpyrrolidone.

EXAMPLE 3

  By operating as described in Example 1, tablets containing thyroxine are prepared; instead of the cross-linked carboxymethylcellulose, sodium glycolate is used as the disintegrating agent in the same amount.

EXAMPLE 4

  By operating as described in Example 1, tablets are prepared which

  contain 0.3% levothyroxine-sodium but no potassium iodide.

EXAMPLE 5

  By operating as described in Example 1, tablets are prepared which

  contain only potassium iodide (0.1%) as the active substance.

EXAMPLE 6

  By operating as described in Example 1, the micro cellulose is dry-blended.

  crystalline, sodium starch glycolate and Fludrocortisone and tableted as described above. The active substance content of the tablets is

0.2%.

EXAMPLE 7

  By operating as described in Example 5, tablets containing

  as active substance of Dexamethason in a proportion of 1%.

EXAMPLE 8

  By operating as described in Example 6, tablets containing

  as the active substance of prednisolone (3%).

EXAMPLE 9

  By operating as described in Example 1, tablets containing

  as the active substance of ethynyl estradiol (0.05%).

  EXAMPLE 10 (comparative example, state of the art) 127.5 kg of mannitol is introduced into the high speed mixer. 0.2 kg of potassium iodide and 0.18 kg of levothyroxine-sodium are dissolved in 20 l of methanol and this solution is added with stirring. After drying for about 90 minutes at 26-28 ° C., 1.5 kg of high-dispersion silica (17.6 kg of microcrystalline cellulose (about 10%) and 3 kg of a 50% high dispersion in silicone oil (commercial lubricant Silicon-AerosilR). The mass is subjected to intensive mixing for about 20 minutes. After determination of levothyroxine-sodium, a methanolic solution of this substance in proportion corresponding to the loss is added, mixed and dried. The mass is then tableted at a force of 14 to 16 kN and at the maximum possible manufacturing speed under these conditions of 100,000 tablets / hour. Approximately 1,500,000 tablets are obtained at a

drug of about 0.12%.

  EXAMPLE 11 (release of the active substance) A determined amount of the tablets prepared in Example 1 and in Test Example 5 are put into the Deutsche Arzneibuch's delivery apparatus and after a few minutes the dissolved drug is dosed with known procedures. We

  proceeds in the same manner with the tablets prepared in Example 10.

  process of the ex-process of ex. 10.

  release of active substance,% levothyroxine / KI (0.05%) 1) 100 51

98 43

Levothyroxine (0.1%) 1) 101 55

98 49

100 39

  Dexamethason (0.3%) 98 Ethynyl estradiol (0.05%) EXAMPLE 12 (stability) The active substance is measured by known procedures in the finished tablets immediately after compression (initial stability) and after 6 months (storage stability). The values given for dosages taken at six months are based on the initial values determined after tabletting.

  (after deducting the initial decomposition).

  process of the ex. 1/5 process of ex. 10 months immediately after 6 months decomposition of the active substance, levothyroxine / KI (0.05%) 1) 2.3 1.0 16.8 5.0

1.9 1.5 15.3 3.5

  Dexamethason (0.3%) 1.2 1.0 12.3 3, 0 1) Several values depending on the hydrophilizing and / or disintegrating agents

  used or different loads.

Claims (14)

  1. Drug-free, cellulose-based drug tablet   microcrystalline at a content of at least 85% by weight.   2. Tablet according to claim 1, characterized in that it contains a hydrophilizing agent. 3. Tablet according to claim 2, characterized in that the agent content   hydrophilizing is at most 5% by weight.   4. Tablet according to claims 2 or 3, characterized in that the agent   Hydrophilizing is a water soluble cellulose derivative.   5. Tablet according to one of claims 1 to 4, characterized in that it contains   an agent facilitating the disintegration of the tablet (disintegrating agent).   6. Tablet according to claim 5, characterized in that the content of disintegrant   gregnant is at most 5% by weight.   7. Tablet according to claim 5 or 6, characterized in that the agent   Disintegrating is a cross-linked cellulose derivative.   8. Tablet according to one of claims 1 to 7, characterized in that the content   in active drug substance is at most 5% by weight.   9. Tablet according to claim 8, characterized in that the active substance is   a thyroid hormone or an agent acting on the thyroid gland.   Process for the preparation of medicinal tablets free from lubricating agents, characterized in that microcrystalline cellulose is mixed with the active substance in the form of powder or solution, optionally with auxiliary products, and optionally after drying, it is put directly into the form of tablets,   the microcrystalline cellulose content being at least 85% by weight.   11. Method according to claim 10, characterized in that the added auxiliary product is a hydrophilizing agent and / or an agent facilitating the disintegration of the tablet (disintegrating agent).   12. Process according to claim 10 or 11, characterized in that the constituents   of the mixture are compressed under a compressive force of 3 to 6 kN.   13. Method according to one of claims 10 to 12, characterized in that the   active substance used is a thyroid hormone.   14. Process according to claim 13, characterized in that the active substance is   introduced in the state of methanolic solution in the mixture.