CS207784B2 - Method of making the solid substances with the phepharnate contents - Google Patents

Abstract

A storage stable Gefarnate-containing solid preparation in which Gefarnate is absorbed on a basic solid carrier such as magnesium silicate, metamagnesium aluminosilicate, magnesium oxide, aluminium hydroxide gel or synthetic hydrotalcite, is obtained by treating the surface of the base with a pKa adjusting agent (other than a mono- or di- saccharide or sugar alcohol) such as citric acid, sodium citrate, polyvinyl alcohol or gum arabic, to bring its surface pKa to 9.3 or less (e.g. 3-8), and then absorbing the Gefarnate onto the treated carrier.

Description

(54) A process for producing solids containing gefarnate

The present invention relates to a process for the production of very stable solid formulations containing gefarnatate.

Gefarnatate is an oily liquid that is useful in medicine. Solid formulations containing gefarnatate are generally made by adsorbing gefarnatate to solids capable of substantially adsorbing oils, such as inorganic silicates (hereinafter referred to as "carriers"). However, the solid formulations containing gefarnatate do not have sufficient stability, for example, to provide geraniol, which is the product of the decomposition of gefarnate.

As a result of extensive study to overcome these problems, it has previously been discovered that very stable solid formulations of gefarnatate can be produced by treating a carrier selected from the group of antacid aluminum and magnesium compounds such as magnesium metasilicate, magnesium silicate, magnesium oxide, a dry aluminum hydroxide gel of a similar compound, with one or more monosaccharides, disaccharides or sugar alcohols in the presence of a solvent. This is followed by drying and adsorption of the gefarnatate on a dry support. Furthermore, the problem of production method was studied. It has been found that the formation of decomposition products such as geo-raniol depends on pKa. and that said decomposition is noticeable if the surface of the solids used as the carrier has a high pK _a , i.e. basicity.

Results of studies in which they obtain solid compositions containing gefarnátu in which such a carrier are used solid surface having a high _pK, is the discovery of preparing a stable solid compositions containing gefarnátu, characterized in that the supports are treated with "the adjusting an agent, including acidic substances such as citric acid or acacia, which reduce the pKa of the surface to 9.3 or less, after which the gefarnatate is allowed to adsorb to the carriers.

The present invention is based on the foregoing knowledge. Its principle is that a solid support is used as a carrier, the surface of which has a pK a of 9.3 or less with an "adjusting agent.""A solid carrier" here means a solid whose surface has a relatively high pK a. Especially in this case, these may be silicates capable of adsorbing extensively such as magnesium silicate (pKa 9.3 <), magnesium aluminum metasilicate (pKa 9.3 <) and the like, and other oil-absorbing compounds such as magnesium oxide (pKa). _and 9.3%, dry aluminum hydroxide gel (pK _and 9.3%) and the like. Any acidic, neutral or weakly basic inorganic or organic substance (except monosaccharides, diasaccharides, polysaccharides and sugar alcohols) can be used as the "adjusting agent" herein. Particularly preferred are organic acids such as citric acid, synthetic or natural high polymeric materials such as polyvinyl alcohol, acacia and the like.

The processing of the "solid support" with the adjusting agents is not particularly limited according to the present invention, provided that the pK _{and the} surface of the solid support are reduced to 9.3 or less. However, there is a particularly advantageous method, characterized in that the adjusting agent is dissolved in a solvent in which the agent is soluble, this solution is added to the solid support and the mixture is dried. Alternatively, the carrier and the agent are combined and the mixture is treated with a solvent in which the agent is soluble and then dried. Alternatively, the base is moistened with a solvent, the base is mixed with the reagent and dried.

The pK _{and the} surface area of the carrier are measured by a well-known method with cyclohexane as the solvent [The Archives ΐ Practical Pharmacy 89 (7), 909 (1969) ..]; The yield of pK _and the carrier surface area is 9.3 or less, so that the surface of the carrier does not turn red upon the addition of phenolphthalein.

The effect of various adjusting agents on reducing the degradation of the gefarnatate was studied on magnesium aluminum metasilicate as a solid support. The results are shown in the following table.

Table solid support adjusting agent pK _and on the surface decomposition (%) (weight%, based on solids in production after one week after two weeks solid base) storage without access storage without air at 50 ° C air at 50 ° C + OO QOO rH OO CM tH ocúooohhomco σ> oo oo ooo т-Γ cd cd cd o tn ooo cd oo

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It is apparent from the experimental results that the decomposition of gefarnatate depends on the pK _{and the} surface of the support. This degradation is particularly noticeable if the pKa exceeds 9.3.

The same effect of various adjusting agents was followed using dry aluminum hydroxide gel, magnesium oxide and synthetic hydrotalcite as solid carriers. The results are shown in the following table.

Table solid support adjusting agent pK _and on the surface decomposition (%) (weight%, based on solids in production after one week to two weeks to solid base) storage without storage without

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From experimental results, it is apparent that the reduction of the degradation of the formate is low or there is no reduction in the degradation of the formate when the pKa of the surface of the carrier exceeds 9.3 after treatment of the basic with an adjusting agent such as polyethylene glycol 6000. the adjusting agent uses citric acid or acacia;

According to the method of the present invention, as described above, it is possible to use many solid carriers which have so far been difficult to use, despite having a high oil-adsorbing capacity by decomposing gefarnatate. Furthermore, it is possible to produce very stable compositions according to the invention.

When the gefarnatate is adsorbed on carriers having a pKa surface area of 9.3 or less, solid formulations are produced in various forms such as powders, granules, tablets and solid capsules. For this purpose, excipients, lubricants, disintegrators or binders such as magnesium stearate, talc, starch, lactose, hydroxypropylcellulose, calcium carboxymethylcellulose, fine crystalline cellulose and the like may be added, if necessary. These additives may be added before or after the gefarnatate has been adsorbed onto the supports.

The solid formulations containing gefarnatate thus obtained contain very few decomposition products, such as geraniol, have excellent stability and good ability to release the active ingredient.

The following examples illustrate the invention in more detail, but the invention is not limited thereto.

Example 1

Composition (for 250 mg):

gefarnatate 50mg magnesium magnesium metasilicate 110mg arabic gum 40mg

Production:

g Arabic gum is dissolved in 300 g pure water at 00 ° C. The aqueous gum arabic solution is added to 320 g of magnesium magnesium metasilicate and mixed uniformly. This mixture was dried at 00 ° C on a plate for 17 hours. After drying, 00 g of gefarnate is added to 200 g of the powder thus obtained, and the mixture is uniformly mixed to obtain a powder.

Example 2

Composition (for 330 mg):

gefarat 00mg dry aluminum hydroxide gel 100mg sodium citrate 30mg lactose 90mg

Production:

080 g of dry aluminum hydroxide gel and 90 g of sodium citrate are mixed well for 10 minutes in a blender. The mixture was further stirred in the mixer for 10 minutes with 000 ml of pure water, then dried on a dish at 00 ° C for 17 hours. The 070 g of powder thus obtained are mixed uniformly with 100 g of gefarnatate and then with 270 g of lactose after drying. The produced powder is filled into solid capsules to obtain capsules containing about 330 mg / capsule.

Example 3

Composition (for 200 mg): gefarnát 60 mg magnesium silicate . 100 mg polyvinyl alcohol 30 mg

Production:

Sixty grams of polyvinyl alcohol are dissolved in 300 g of pure water at 00 ° C, 320 g of magnesium silicate are added and mixed uniformly. The mixture was dried on a dish at 00 ° C for 17 hours. After drying, the mixture is ground in a 20 mesh Fitz mill. The powder composition is then prepared by uniformly mixing 190 g of the powder thus obtained with 00 g of gefarnatate.

Claims (3)

SUBJECT 1. A process for the preparation of solid formulations containing gefarnate, comprising mixing the carrier and gefarnate, characterized in that the surface of the solid carrier is pretreated with an adjusting agent consisting of an acidic, neutral or weakly basic inorganic or organic substance, except monosaccharides, disaccharides and sugar alcohols, to a pKa of the carrier surface of up to 9.3. vynalezu 2. The method of claim 1 wherein the solid support is selected from the group consisting of magnesium silicate, magnesium aluminum metasilicate, magnesium oxide, dry aluminum hydroxide gel, and synthetic hydrotalcite. 3. The method of claim 1 wherein said adjuvant is selected from the group consisting of citric acid, sodium citrate, and acacia.