FI63670C - REFERENCE DETAILS FRAMSTAELLNING AV DIGOXIN INNEHAOLLANDE DOSERINGSENHETER - Google Patents

Description

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Patents and rights issued on 29.04.83 (32) (33) (31) Pyydetty etuoikeus —Begird prloritet 20.07.73

England-England (GB) 34804 (71) R * P. Scherer Limited, 216-222 Bath Road, Slough, Buckinghamshire, England-England (GB) (72) Norman Grainger, London, England-England (GB) (74) Oy Kolster Ab (54) Method for preparing dosage units containing digoxin -Förfarande The present invention relates to a new process for the preparation of a dosage unit capsule containing digoxin. Digoxin is a cardiac glycoside obtained from Digitalis species purpura or lanata.

Digoxin is a widely used cardiac drug, which is usually administered in the form of oral tablets. Each tablet should contain only a very small amount of active substance, (e.g. 250 μg or less) because digoxin is administered in very small doses, almost always less than 0.5 mg. The fact that each tablet may contain only so little active ingredient causes formulation difficulties and makes it very difficult to mix the tablet mixture with sufficient certainty so that each tablet receives the same amount of active ingredient within tolerances, (see, e.g., Thomas et al., The Lancet, December 1 , 1073, pp. 1267-8; Fraser et al., 5, Pharm. Pharmac., 1973, 25, pp. 263-973; 63670 2 and Shaw et al., British Medical Journal, 1973, 4, pp. 763-766. ).

With the method according to the invention, the amount of digoxin contained in the dosage unit can be determined very accurately.

The process according to the invention is characterized in that the digoxin is dissolved in a water / ethanol mixture, the solution obtained is mixed with a mixture of polyethylene glycol and propylene glycol and / or glycerol, and the resulting composition is filled into capsules.

In the process according to the invention, the digoxin is dissolved in a mixture of ethanol and water, in which case it is recommended that the amount of water is as small as possible but still sufficient to dissolve the active substance. The amount of water in the mixture is generally less than ethanol by weight, preferably the amount of water is less than 25% by weight of the total amount of water / ethanol mixture. A suitable weight ratio of water / ethanol to digoxin is on the order of about 80: 1 or even higher.

In a second step, the digoxin solution is mixed with polyethylene glycol, propylene glycol and / or glycerol, of which polyethylene glycol is the main component of the mixture, generally present in an amount of at least 75% by weight, preferably 80-95% by weight, based on the total finished drug mixture.

As a third step, the composition is filled into a capsule made of gelatin with a plasticizer, for example glycerol, propylene glycol, diethylene glycol or hexanetriol. Furthermore, the plasticizers may be one of the above in combination with sorbitol to improve the properties of the capsules so that they can withstand the moisture contained in the air. The amount of sorbitol mainly corresponds approximately to the amount of glycerol or other plasticizer.

The gelatin capsules prepared according to the invention suitably contain about 100 to 300 mg of the pharmaceutical composition, the amount of digoxin contained in each capsule corresponding to a dosage unit, for example 50 to 300.

The method according to the invention makes the digoxin evenly distributed throughout the liquid phase, so that it can be ensured that each capsule contains a sufficiently precise amount of the active substance.

Experiments carried out have shown that the capsules prepared according to the invention release the active substance better and faster (demonstrated in artificial gastric fluids).

II

3,63670 release trials) than the corresponding tablets.

The dissolution rate of the capsules (A, B and C) prepared according to the invention (A and B in Example 3 and the capsule prepared in Example 1 of C) in 0.6% HCl was studied according to Beckett et al. The Pharmaceutical Journal, August, 11, 1973, pp. 111 and 112) and the results are shown in the following table, which also shows, for comparison, the results obtained from similar experiments using commercial tablets containing the observed 0.25 mg digoxin. Tablets A, B, C, and D were the same commercial tablet formulation, and Tablets E, F, and G were each tablet samples of different formulations.

Table

Time Dissolved digoxin percentage (minutes) Capsules Tablets

ABC A B C D E F G

5 86 25 - - - - 10 12 14 68 ------ - 15 31 40 100 19 29 29 76 - - 69 20 - 72 - - - - - 30 91 95 - 28 35 29 80 25 30 79 45 93 - - - - - 60 - - - 37 45 53 96 - - 100 120 --------- 103 240 - 93 - - - - - - -

In order that the invention may be better understood, the following are examples of prescription mixtures of 140 mg and 280 mg capsules prepared by the method of the invention.

Example 1 140 mg capsule containing 62.50 μg digoxin

Digoxin 0.0625 mg

Ethanols, abs. 8.5 mg

Water 1.5 mg 4,63670

Propylene glycol 4.74 mg

Polyethylene glycol (m.p. about 400) 125.1875 mg

Example 2 140 mg capsule containing 150 micrograms of digoxin

Digoxin 0.125 mg

Ethanols, abs. 8.5 mg

Water 1.5 mg

Propylene glycol 4.75 mg

Polyethylene glycol (m.p. about 400) 125.125 mg

Example 3 280 mg capsule containing 250 micrograms of digoxin

Digoxin 0.250 mg

Ethanol 17.0 mg

Water 3.0 mg

Propylene glycol 9.5 mg

Polyethylene glycol (m.p. about 400) 250.25 mg