CH637827A5 - PROCESS FOR THE MANUFACTURE OF SOLID PREPARATIONS CONTAINING GEFARNATE. - Google Patents

Description

The present invention relates to a method for manufacturing solid preparations containing gefarnate having high stability.

Gefarnate is an oily liquid and is a useful drug and, in general, solid preparations containing gefarnate are made by having gefarnate absorbed by strongly oil-absorbing solids, for example mineral silicates (hereinafter called carriers) . However, the solid preparations containing gefarnate which are thus obtained do not have satisfactory stability; they form, for example, geraniol which is a decomposition product of gefarnate.

Following extensive research to solve these problems, the authors of the present invention had discovered that it was possible to manufacture solid preparations containing gefarnate, of great stability, by treating a carrier, chosen from the group comprising the compounds d antacid aluminum and magnesium compounds such as metamagnesium aluminosilicate, magnesium silicate, magnesium oxide, dry aluminum hydroxide gel, etc., by monosaccharides, disaccharides and / or sugar alcohols, in the presence of a solvent, then drying and allowing the gefarnate to be absorbed by the dried carrier (see Japanese patent application No. 64218/1977). The authors of the present invention have further studied the problem and the manufacturing process on the basis of this acquired knowledge, and have discovered that the formation of decomposition products such as geraniol is linked to the pKa of the surface of the carrier. used, and that said decomposition is

2

remarkable when using as carriers solids whose surface has a high pKa, that is to say a high basicity.

As a result of researches aimed at obtaining solid preparations containing gefarnate which are stable, in which solids whose surface has a high pKa are used as carriers, the authors of the present invention have succeeded in obtaining stable solid preparations containing of gefarnate by treating the carriers with an adjusting agent comprising acidic substances such as citric acid or gum arabic, so as to lower the pKa of the solid surface to 9.3 or less, and by absorbing the gefarnate by carriers.

The present invention is based on previous knowledge, and its essential point is that solid bases whose pKa of the solid surface is adjusted to 9.3 or less, with the aid of the adjusting agent, are used as carriers. The solid bases in question are solids whose surface has a relatively high pKa. It is especially in this case that it is possible to use highly oil-absorbing silicates, for example magnesium silicate (pKa 9.3 <), metamagnesium aluminosilicate (pKa 9.3 <), etc. ., and other highly oil absorbing compounds, e.g. magnesium oxide (pKa 9.3 <), dry aluminum hydroxide gel (pKa 9.3 <), etc. As the adjusting agent, any of the acidic, neutral or weakly basic mineral or organic substances can be used (except monosaccharides, disaccharides and sugar alcohols). In particular, organic acids such as citric acid, high synthetic or natural polymers such as polyvinyl alcohol, gum arabic, etc., are effective.

According to the present invention, the mode of treatment of the solid bases with the adjusting agent is not precisely limited if the pKa of the surface of the solid bases can be reduced to 9.3 or less. However, a particularly effective method is to either dissolve the adjusting agent in a solvent capable of dissolving the agent, add the solution to the solid base and then dry, or mix the base and the agent and treating the mixture with a solvent capable of dissolving the agent, then drying, or wetting the base with the solvent and mixing the base with the agent, then drying.

The pKa of the solid surface of the carrier is measured according to the well-known method using cyclohexane as solvent 40 ["The Archives of Practical Pharmacy", vol. 89, No. 7, 909-913 (1969)]. On the other hand, the phrase "the pKa of the solid surface of the carrier is 9.3 or less" means that the solid surface of the carrier does not turn red by the dropwise addition of phenolphta-lein.

45 The effect of various adjusting agents to reduce the breakdown of gefarnate was examined, using the metamagnesium aluminosilicate as a solid base. The results are given in Table I.

Solid base

Adjustment agent (% by weight relative to the solid base)

pKade the solid surface

Decomposition (%)

Ala preparation

After one week of airtight storage at 50 ° C

After two weeks of storage in air-protected at 50 ° C

No agent

9.3 <

2.6

19.0

23.1

Polyethylene glycol 6000

(18)

9.3 <

0.2

3.3

4.4

Corn starch

(30)

9.3 <

5.0

13.0

13.0

Aluminosi-

Wisteria

(18)

6.3

0

0.3

0.5

meta licate

Citric acid

(18)

3.3>

0

0.1

0.2

magnesium

Gum arabic

(18)

4.8-6.3

0

0.1

0.2

Polyvinyl alcohol

(18)

4.8-6.3

0

1.0

1.5

Polyvinylpyrrolidone

(18)

4.8-6.3

0

0.2

0.3

Carboxymethylcellulose sodium

(18)

4.8-6.3

0

0.6

0.9

Table I

3

637,827

As these experimental results prove, the decomposition of gefarnate depends on the pKa of the surface of the carrier and is particularly remarkable when the pKa exceeds 9.3.

Next, the same effect of different adjusting agents was examined using an aluminum hydroxide gel, magnesium oxide and synthetic hydrotalcite as the solid base. The results are given in Table II.

Table II

Decomposition (%)

Solid base

Adjustment agent (% by weight relative to the solid base)

pKa of solid surface

At the preparation

After one week of storage sheltered from air at 50 ° C

After two weeks of storage in air-protected at 50 ° C

Dry aluminum hydroxide gel

No agent

Polyethylene glycol 6000 Sodium citrate Citric acid

(18) (18) (18)

9.3 <9.3 <6.7-8.3 3.3-4.8

1.6 0.8 0.2 0.1

10.9 4.8 2.0 1.6

12.5

6.2 2.9

2.3

Magnesium oxide

No agent

Polyethylene glycol 6000 Sodium citrate Gum arabic

(18) (18) (18)

9.3 <9.3 <

6.7-8.3

4.8-6.3

0.3 0.3 0 0

3.2 2.6 1.2 0.4

3.6 3.3 1.8 0.7

Synthetic hydrotalcite

No agent

Polyethylene glycol 6000 Sodium citrate Gum arabic

(18) (18) (18)

9.3 <9.3 <6.7-8.3 6.7-8.3

1.5 0.4 0.1 0

7.9 3.9 1.2 0.7

8.4 5.2

2.1

1.2

As these experimental results prove, the effect of reducing decomposition is weak or zero when the pKa of the surface of the carrier exceeds 9.3, by treatment with a basic substance such as polyethylene glycol 6000 serving as an adjusting agent. , while the stability of gefarnate is improved when the critical acid or gum arabic is used as the adjusting agent.

According to the process of the present invention as described above, it becomes possible to use many solid bases which it was very difficult to use despite their high absorbency vis-à-vis the oil , since they break down gefarnate, and it also becomes possible to obtain very stable preparations.

It is possible to produce solid preparations in various forms, for example powder, granules, tablets and capsules of hard gelatin, by having gefarnate absorbed by the carriers, whose pKa of the solid surface is adjusted to 9.3 or less. For this, it is optionally possible to add excipients, lubricants, disintegrators or binders such as magnesium stearate, talc, starch, lactose, hydroxypropylcellulose, carboxymethyl cellulose calcium, finely cellulose. crystallized, etc. These additives can be added before or after the absorption of gefarnate by the 55 carriers.

The solid preparations containing gefarnate which are thus obtained contain very few decomposition products such as geraniol and have excellent stability and good release property. 60

The present invention will be illustrated in more detail by the following examples, but it is not limited by them.

Example 1:

Formula (for 250 mg): 65

gefarnate 50 mg metamagnesium aluminosilicate 160 mg gum arabic 40 mg

Preparation:

80 g of gum arabic were dissolved in 300 g of pure water at 50 ° C. This aqueous solution of gum arabic was added to 320 g of metamagnesium aluminosilicate and mixed uniformly. This mixture was dried at 60 ° C for 17 h in a tray dryer. After drying was completed, 50 g of gefarnate was added to 200 g of the powder thus obtained and mixed uniformly to obtain a powder.

Example 2:

Formula (for 330 mg):

gefarnate 50 mg dry gel aluminum hydroxide 160 mg sodium citrate 30 mg lactose 90 mg

Preparation:

480 g of dry aluminum hydroxide gel and 90 g of sodium citrate were thoroughly mixed for 10 min in a mixer. Mixing was continued for another 15 min with 400 ml of pure water in the mixer and the resulting mixture was dried at 60 ° C for 17 h in a tray dryer. When the drying was complete, 570 g of the powder thus obtained were uniformly mixed with 150 g of gefarnate, then with 270 g of lactose. The powder obtained was loaded into hard capsules to obtain a hard capsule containing about 330 mg per capsule.

Example 3:

formula (for 240 mg):

gefarnate 50 mg magnesium silicate 160 mg polyvinyl alcohol 30 mg

40

637,827

Preparation:

60 g of polyvinyl alcohol were dissolved in 300 g of pure water at 60 ° C., 320 g of magnesium silicate were added to this solution, then mixed uniformly. The resulting mixture was dried at 60 ° C for 17 h in a tray dryer. After drying was completed, the mixture was pulverized using a Fitz mill equipped with a 700 µm mesh screen. Then, 50 g of gefarnate were uniformly mixed with 190 g of the powder thus obtained to obtain a powder preparation.

R

Claims (3)

637,827 CLAIMS 1. A method of manufacturing solid preparations containing gefarnate, characterized in that the surface of a solid base, which serves as a carrier, is treated with an adjusting agent capable of adjusting the surface to a pKa of 9, 3 or less, provided that this adjusting agent is neither a monosaccharide, nor a disaccharide, nor a sugar alcohol, and that the gefarnate is made to be absorbed by the carrier thus treated. 2. Method according to claim 1, characterized in that said solid base is magnesium silicate, meta-magnesium aluminosilicate, magnesium oxide, a dry gel of aluminum hydroxide or synthetic hydrotalcite . 3. Method according to claim 1, characterized in that said adjusting agent is citric acid, sodium citrate or gum arabic.