IE48269B1 - A process for producing gefarnate-containing solid preparations - 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

The present invention relates to a process for producing Gefarnatecontaining solid preparations of high stability.

Gefarnate is an oily liquid and is a useful medicine and, in general, Gefarnate-containing solid preparations are produced by allowing Gefarnate to be absorbed in highly oil-absorptive solids such as inorganic silicates (referred to as carrier hereinafter). However, the Gefarnate-containing solid preparations thus obtained have no satisfactory stability, for example they produce geraniol which is a decomposite of Gefarnate.

As the result of an extensive study to overcome these problems, the inventors have previously found that Gefarnate-containing solid preparations of high stability can be produced by treating a carrier, which is selected from the group consisting of antacid aluminium compounds and magnesium compounds such as metamagnesium aluminosilicate, magnesium silicate, magnesium oxide, dry aluminium hydroxide gel or the like, with one or more of monosaccharides, disaccharides and sugar alcohols in the presence of a solvent, followed by drying and then allowing Gefarnate to be absorbed in the dried carrier (see - 2 A 8269 Japanese Patent Application No. 64218 of 1977). The inventors further have studied the problem and the producing process of the basis of this knowledge, and found that formation of decomposites such as geraniol is correlated with the pKa value of surface of the carrier used, and that said decomposition is remarkable when solids having the surface of a high pKa value, i.e. basicity, are used as a carrier.

The present invention provides a process for producing a stable Gefarnatecontaining solid preparation which comprises absorbing Gefarnate onto an oil absorptive carrier which is a solid base, the surface of the solid base having been previously adjusted to have a pKa value of 9.3 or less by treatment with a pKa adjusting agent other than a monosaccharide, disaccharide or sugar alcohol which is capable of reducing the pKa value of the surface to 9.3 or less.

The present invention is based on the use of solid bases whose surface pKa value is adjusted to 9.3 or less as carrier. The solid bases referred to herein means absorptive solids of which the surface has a relatively high pKa value. Particularly in this case, one may mention highly oil-absorptive silicates, such as magnesium silicate (pKa 9.3<), metamagnesium aluminosilicate (pKa 9.3<) and the like, and other highly oil-absorptive compounds such as magnesium oxide (pKa 9.3<), dry aluminium hydroxide gel (pKa 9.3<) and the like. As the adjusting agent, there may be used any of the acidic, neutral or weakly basic inorganic or organic substances (except for monosaccharides, disaccharides, and sugar alcohols). Particularly, organic acids such as citric acid, synthetic or natural high polymers such as polyvinyl alcohol, gum arabic and the like are effective.

Preferably, the amountof PKa adjusting agent is 15 to 25% by weight of the carrier. - 3 4 8 2 59 In the present invention, how to treat the solid bases with the adjusting agent is not particularly limited, if the pKa value of the surface of solid bases can be reduced to 9.3 or less. However, particularly an effective method is one comprising dissolving the adjusting agent in a solvent capable of dissolving the agent and adding the solution to the solid base, followed by drying, or comprising mixing the base and the agent and treating the mixture with a solvent capable of dissolving the agent, followed by drying; or comprising wetting the base with the solvent and mixing the base with the agent, followed by drying. θ The pKa value of solid surface of carrier is measured according to the wellknown method with cyclohexane as a solvent [The Archieves of Practical Pharmacy, Vol. 89, No. 7, 909-913 (1969)]. Also, the phrase the pKa value of solid surface carrier is 9.3 or less means that solid surface of carrier does not turn to red by dropwise addition of phenolphthalein.

The effect of various adjusting agents to reduce the decomposition of Gefarnate was examined using metamagnesium aluminosilicate as a solid base. The results are shown in the following Table Decomposition (%) Adjusting agent, (% by weight based on the Solid base solid base) pKa at solid surface After one At pre-week's airpa rat- tight storion age at 50°C After two weeks airtight storage at 50°C No agent Polyethylene glycol 6000 (18) Corn Starch (30) 9.3< 9.3< 9.3< 2.6 0.2 5.0 19.0 3.3 13.0 23.1 4.4 13.0 Metamagne- Glycine (18) 6.3 0 0.3 0.5 sium Citric acid (18) 3.3> 0 0.1 0.2 25 alumino- Gum arabic (18) 4.8-6.3 0 0.1 0.2 silicate Polyvinyl alcohol (18) 4.8-6.3 0 1.0 1.5 Polyvinyl pyrrolidone (18) 4.8-6.3 0 0.2 0.3 sodium carboxymethyl cellulose 4.8-6.3 0 0.6 0.9 (18) - 4 48269 As is apparent from the experimental results, the decomposition of Gefarnate depends upon the pKa value of carrier surface and is particularly remarkable when the pKa value exceeds 9.3.

Next, the same effect of various adjusting agents was examined using a dry aluminium hydroxide gel, magnesium oxide and synthetic hydrotalcite as a solid base. The results are shown in the following Table.

Solid base Adjusting agent, (% by weight based on the solid base) pKa at solid surface At preparation After one After two weeks' air-weeks' airtight stor-tight stor- age at 50°C age at 50°C No agent 9.3< 1.6 10.9 12.5 Dry Polyethylene 9.3< 0.8 4.8 6.2 aluminium hydroxide gel glycol 6000 (18) Sodium citrate (18) 6.7-8.3 0.2 2.0 2.9 Citric acid (18) 3.3-4.8 0.1 1.6 2.3 No agent 9.3< 0.3 3.2 3.6 Magnesium Polyethylene glycol 6000 (18) 9.3< 0.3 2.6 3.3 oxide Sodium citrate (18) 6.7-8.3 0 1.2 1.8 Gum arabic (18) 4.8-6.3 0 0.4 0.7 No agent 9.3< 1.5 7.9 8.4 Synthetic Polyethylene glycol 6000 (18) 9.3< 0.4 3.9 5.2 hydrotalcite Sodium citrate (18) 6.7-8.3 0.1 1.2 2.1 Gum arabic (18) 6.7-8.3 0 0.7 1.2 As is apparent from the experimental results, there is little or no effect to reduce the decomposition when the pKa value of carrier surface exceeds 9.3 by treatment with a basic substance such as polyethylene glycol 6000 as the adjusting agent, whereas the stability of Gefarnate is improved when citric acid or gum arabic is used as the adjusting agent. - 5 48269 According to the method of the present invention as described above, it becomes possible to use many solid bases which have been substantially difficult to use irrespective of their high oil-absorptivity since they decompose Gefarnate, and further to produce very stable preparations.

Solid preparations of various forms such as powder, granule, tablet and hard capsule can be produced by allowing Gefarnate to be absorbed in the carriers, of which the pKa value at solid surface is adjusted to 9.3 or less. For this purpose, there may be added, if necessary, excipients, lubricants, disintegrators or binders such as magnesium stearate, talc, starch, lactose, hydroxypropyl cellulose, calcium earboxymethyl cellulose, finely crystalline cellulose and the like. These additives may be added before or after Gefarnate is absorbed in the carriers.

The Gefarnate-containing solid preparations thus obtained contain very little decomposites such as geraniol and have an excellent stability and a good release property.

The present invention will be illustrated in more detail with reference to the following Examples, but the present invention is not limited to these Examples.

EXAMPLE 1.

Formulation (per 250 mg): Gefarnate 50 mg Metamagnesium aluminosilicate 160 mg Gum arabic 40 mg Preparation: Eighty grams of gum arabic was dissolved in 300 g of pure water at 50°C.

This aqueous gum arabic solution was added to 320 g of metamagnesium aluminosilicate and uniformly mixed. This mixture was dried at 60° for 17 hours in a tray drier. After drying was finished, 50 g of Gefarnate was added to - 6 48269 200 g of the powder thus obtained and uniformly mixed to obtain a powder.

EXAMPLE 2.

Formulation (per 330 mg): Gefarnate 50 mg Dry aluminium hydroxide gel 160 mg Sodium citrate 30 mg Lactose 90 mg Preparation: 480 g of dry aluminium hydroxide gel and 90 g of sodium citrate were well mixed for 10 minutes in a mixer. The mixture was further mixed for minutes with 400 ml of pure water in the mixer and dried at 60°C for 17 hours in a tray drier. After drying was finished, 570 g of the powder thus obtained was uniformly mixed with 150 g of Gefarnate and then with 270 g of lactose. The powder obtained was filled in hard capsules to obtain a hard capsule containing about 330 mg/capsule.

EXAMPLE 3.

Formulation (per 240 mg): Gefarnate 50 mg Magnesium silicate 160 mg Polyvinyl alcohol 30 mg Preparation: Sixty grams of polyvinyl alcohol was dissolved in 300 g of pure water at 60°C, and 320 g of magnesium silicate was added thereto, followed by uniform mixing. The mixture was dried at 60°C for 17 hours in a tray drier. After drying was finished, the mixture was powdered by means of the Fitz mill equipped with a 24-mesh screen. Thereafter, to 190 g of the powder thus obtained was uniformly mixed 50 g of Gefarnate to obtain a powder preparation.

Claims (8)

1. A process for producing a stable Gefarnate-containing solid preparation which comprises absorbing Gefarnate onto an oil absorptive carrier which is a solid base, the surface of the solid base having been previously adjusted 5 to have a pKa value of 9.3 or less by treatment with a pKa adjusting agent other than a monosaccharide, disaccharide or sugar alcohol which is capable of reducing the pKa value of the surface to 9.3 or less.

2. A process according to Claim 1, wherein the solid base is magnesium silicate, metamagnesium aluminosilicate, magnesium oxide, dry aluminium 10 hydroxide gel or synthetic hydrotalcite.

3. A process according to Claim 1 or 2 wherein the pKa adjusting agent is citric acid, sodium citrate or gum arabic.

4. A process according to any one of the preceding claims wherein the pKa value at the surface of the carrier is adjusted to 3-8. 15

5. , A process according to any one of the preceding claims wherein the amount of pKa adjusting agent is 15-25% by weight of the carrier.

6. A process according to Claim 1 substantially as hereinbefore described with reference to any one of the Examples.

7. A stable Gefarnate containing solid preparation obtained by a process 20 according to any one of the preceding claims.

8. A preparation according to Claim 7 in the form of a powder, granule, tablet or hard capsule.