IE41620B1

IE41620B1 - Pharmaceutical preperations

Info

Publication number: IE41620B1
Application number: IE371/75A
Authority: IE
Original assignee: Wellcome Found
Priority date: 1974-02-22
Filing date: 1975-02-21
Publication date: 1980-02-13
Also published as: AU7844075A; AU520082B2; JPS50126822A; LU71894A1; IL46682A; ES434971A1; FR2261752B1; IE41620L; FI750489A; GB1506016A; AU501549B2; DE2507635A1; IT8349395A0; FR2261752A1; IL46682A0; SE7501967L; SE426549B; CA1096307A; IT1233251B; NL7502121A

Abstract

1506016 Encapsulated digoxin solution WELLCOME FOUNDATION Ltd 21 Feb 1975 [22 Feb 1974 19 March 1974] 7327/75 Heading A5B An orally ingestible digoxin preparation of improved properties comprises a capsule soluble in the stomach or duodenum contaming a solution of digoxin, the amount of digoxin in the capsule being less than that in a conventional tablet but nonetheless providing the same physiological effect as the conventional tablet. The capsule may contain 0.05-0.4mg. digoxin. Solvents specified include ethanol, isopropanol, propylene glycol, glycerol and polyethylene glycol of molecular weight 190-1000. The solvent may include up to 60 % water. The capsule may be a soft gelatin capsule including a plasticizer, preservative, colouring and/or opacifier.

Description

PATENT APPLICATION BY (71) THE WELLCOME FOUNDATION LIMITED, A COMPANY INCORPORATED IN ENGLAND, OF 183-193 EUSTON ROAD, LONDON NW1, ENGLAND.

Prtct The present invention relates to a new and improved method of increasing the bioavailability of digoxin in mammals including man.

The present invention enables substantially higher concentrations of digoxin in the blood to be achieved that are obtained through the use of tablets containing the same amount of digoxin.

The present invention also relates to pharmaceutical preparations comprising a solution of digoxin in a capsule which will rapidly release the digoxin for uptake in, for example and preferably, the upper gastrointestinal tract of a mammal such as a human.

The glycoside digoxin, chemically named 3g-tri-(p-D-digitoxosyl)oxy-120, 14-dihydro^y-5g-card-20(22)-enolide, has found extensive use in the treatment of human patients with cardiac insufficiency. As. used herein the term cardiac insufficiency should be understood to include congestive heart failure, atrial fibrillation, atrial flutter, supraventricular tachycardia and premature extrasystoles.

In the past, patients (i.e. adult humans) have generally been administered digoxin orally in the form of conventional tablet formulations containing 0.0625 mg, 0.125 mg, 0.25 mg, 0.375 mg, or 0,5 mg of digoxin. Of these the tablets containing respectively 0.0625 mg, 0.125 mg and 0.25 mg of digoxin have been the most commonly used with the 0.25 mg tablet finding the most general acceptance. As used herein, the term patient should be understood to mean a human patient.

In cases where rapid digitalization to treat cardiac insufficiency is desired in one day or less, the patient is normally given 0.5 mg to 1.5 mg of digoxin initially followed by 0.25 mg to 0.5 mg of digoxin every six to eight hours, as required, to complete digitalization. In elderly patients, and where there is less urgency, a smaller initial dose of 0.25 mg to 1.0 mg of digoxin may be given. In general, the average total digitalizing dose of digoxin for the patient is 2 mg to 3 mg. Thereafter maintenance doses of about 0.125 mg to 0.5 mg of » - 2 41620 digoxin are administered daily. All these doses relate to the use of digoxin tablets as described ahove.

Digoxin is known to be a drug for which the therapeutic blood levels are quite close to, and indeed sometimes overlap with, the blood levels causing toxic symptoms such as anorexia, nausea, vomiting, and various cardiac arrhythmias, etc. Although these toxic symptoms are not normally encountered in titrated patients having digoxin uptake or absorption within normal limits, patients which exhibit abnormal digoxin uptake may be at considerable risk.

Patients with abnormal uptake due to conditions such as greatly increased gastrointestinal mobility often require larger than normal doses of digoxin to evoke appropriate digitalization. Clearly, in such patients receiving larger than normal doses, the greater the variation and the quantity of digoxin available for uptake the greater is the risk that the therapeutic to toxic threshold will be crossed. All oral diogoxin preparations investigated to date and known to us have been less than completely absorbed and hence have the potential for variable absorption. The present invention enables a reduction in the risk of variable uptake because it enables a significant reduction in the incompleteness of absorption.

The present invention relates to a new and improved method and pharmaceutical preparation for increasing the bioavailabll1ty of digoxin in mammals including man. According to one aspect of this invention, digoxin is administered to a patient in an amount which is approximately 80% of the dosage administered as conventional digoxin tablets to achieve substantially the same blood level of digoxin in the patient. The aforementioned increase in bioavailability is accomplished by the utilization of a solution of digoxin in a soluble capsule shell, for example, soluble in the upper gastrointestinal tract of the patient. The capsule thus preferably comprises a soft gelatin shell which will substantially - 3 416S0 completely dissolve within the upper gastrointestinal tract in a short period of time to release a solution containing digoxin in an effective cardiac insufficiency treatment amount. The dissolution rate of the capsule shell in the upper gastrointestinal tract is desirably 100% in not more than one hour, preferably 100% in not more than 30 minutes and optimally 100% in not more than 15 minutes.

It should be clearly understood that wherever reference is made herein to the administration of conventional digoxin tablets or of capsules of the present invention the said administration is by the oral route with the tablets or capsules being swallowed by the patient while Still in an essentially intact condition. Further, the capsules of the present invention as herein described should be understood to permit of administration in this manner.

As used herein the following terms should be understood to have the definitions respectively indicated therefor: (i) the upper gastrointestinal tract means the stomach and the duodenum; (ii) a solution of digoxin means a pharmaceutically and medicinally acceptable solution of digoxin; (iii) a solution means a pharmaceutically and medicinally acceptable solution; and (iv) pharmaceutically and medicinally acceptable means acceptable to the gastrointestinal tract of the patient. Further, as the term is used herein, a solution of digoxin should be understood to include those mixtures in which at least a portion of the digoxin is in solution, and pharmaceutical preparations comprising a solution of digoxin in a soluble capsule shell should accordingly be understood to include those preparations wherein at least a portion of the digoxin held within the capsule shell is in solution.

The capsule shell when preferably made of gelatin may include I plasticizers such as glycerin or sorbitol; water; preservative(s); colouring agent(s); and opacifying agent(s). Reference may be had to the standard work Remington's Practice of Pharmacy, Martin and Cook - 4 41620 (eds.), 14th Edition, published by The Mack Publishing Company, Easton, Pennsylvania, page 1675 under the heading Elastic Capsules to page 1677, for a description of gelatin capsules rapidly dissolvable in the gastrointestinal 'tract and the manufacture of such capsules, all of which is incorporated herein by reference hereto. Reference may also be had to U.S. Patents 1,970,396, 2,899,361 and 2,928,128 for a description of soft gelatin capsules and their manufacture, said descriptions being incorporated herein by reference hereto. In addition reference may be had to the standard work The Theory and Practice of Industrial Pharmacy by Lackman, Lieberman and Kanig, published by Lea and Febiger, Philadelphia, Pennsylvania (1970) at pages 359 to 384 for a discussion of soft gelatin capsule technology, said text pages 359 to 384 being incorporated herein by reference hereto.

Thus conventionally a gelatin mass is first prepared comprising gelatin, water, and the other ingredients of the capsule shell (as detailed hereinabove) by milling together the ingredients in a suitable mixer. The mixture is then transferred to a melter where it is kept under a more or less complete vacuum and heated until a smooth, fluid mass is obtained. The filled capsules of the present invention may be prepared from this plastic mass by in general forming the mass into two plastic sheets and marginally welding two such sheets together around a unit dose of the solution of digoxin which will form the content of the resulting capsule. Advantageously, to enable uniformity of quality of the capsule shells, the gelatin mass is completely and constantly agitated until the step of fonning into sheets.

Apparatus suitable for the continuous production of soft elastic capsules is well known in the art. In one form such apparatus comprises a pair of smoothfaced drums on each of which a gelatin ribbon or film is cast, a pair of cooperating die rolls containing complementary die cavities in which the ribbon is shaped to form the capsules, and a - 5 41620 feeder head disposed in the bight of the die rolls for introducing the liquid content (in the present invention, the solution of digoxin) into the capsule as it is formed. The ribbons are stripped from the drums and simultaneously fed over the rotating rolls into justaposition where5 upon the liquid content is ejected, at precisely the correct time, from the feeder head into the ribbons to stretch them into opposed die cavities to shape and fill the capsule. As the die rolls rotate, ridges surrounding each of the cooperating opposed cavities serve progressively to seal the ribbon together about the entire periphery of the distended portion of the ribbon which comprises the capsule and sever the formed capsule from the ribbon. In this process the content of each capsule is measured individually by the single stroke of a pump.

Immediately after a capsule of conventional construction as-described above has been formed, the shell thereof still contains the water content of the gelatin mass from which the shell has been made. For this reason the capsules are characteristically relatively weak when first made. To make the capsules stronger they are therefore, in general, dehydrated by exposure to dry warm air, to acetone, or to some other agent capable of extracting water from the capsule shell.

The shell thickness of. conventional soft gelatin capsules ranges typically from 0.018 inch to 0.030 inch and may average about 0.025 inch. The capsules are generally circular in transverse cross-section. The capsules provided by the present invention are preferably elongated such as ellipsoidal, oval, or cylindrical with rounded ends.

The digoxin is placed in solution prior to the encapsulation step.

A suitable solution may be prepared by conventionally mixing digoxin with a solvent such as ethanol, glycerine, propylene glycol, isopropanol, and polyethylene glycols such as polyethylene glycol 400, or a mixture of two or more of these solvents. Heating may optionally be employed to speed solution of the digoxin. It will be appreciated that a suitable - 6 41620 mixture of solvents will vary with the desired concentration and composition of the solvent system. As used herein the term solvent should be understood to mean a solvent which is pharmaceutically and medicinally acceptable to the gastrointestinal tract of a mammal, which will dissolve digoxin to form a solution, and which is not substantially destructive of the capsule shell. A cosolvent which may be used together with the abovementioned solvents is polyvinyl-pyrrolidone.

Polyethylene glycols having an average molecular weight of 190 to 6000 and containing 2 to 136 ethylene glycol monomer units (—CH2CH2O—) may advantageously be used as a cosolvent, and polyethylene glycols having an average molecular weight of 190 to 1000 and containing about 2 to 25 ethylene glycol monomer units as above may advantageously be used as a solvent or cosolvent. Other solvents or cosolvents which are suitable include 1,2-propylene glycol, hexamethylene glycol, 1,3butylene glycol, dimethylsulfoxide, polyethylene glycol ethers of tetrahydrofurfuryl alcohol, and di-(l ,2-propylene glycol). In addition, water may be used as a cosolvent in an amount not more than 60% (by weight) of the solvent mixture, preferably up to 5% (by weight) of the solvent mixture.

Preferred capsules of the present invention are those which each contain a digoxin solution in an amount which contains digoxin in the range 0.05 mg to 0.4 mg, more preferably 0.05 mg to 0.2 mg. Specifically preferred capsules of the present invention contain digoxin in an amount per capsule selected from 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg and 0.4 mg; of these, capsules each containing 0.05 mg, 0.1 mg or 0.2 mg are more preferred and a capsule containing 0.2 mg of digoxin the most preferred. For general convenience capsules containing a lesser amount of digoxin are preferably physically smaller than those capsules containing a greater amount of digoxin.

The concentration of the digoxin solution within the capsules of - 7 41620 the present invention may be in the range 0.1 to 2.0 mg digoxin/ml, in but/capsules of the present invention is preferably in the range 0.25 to 0.95 mg digoxin/ml, more preferably 0.35 to 0.6 mg digoxin/ml, and optimally 0.4 to 0.5 mg digoxin/ml. As the term is used herein, concentration should be understood to mean mg of digoxin/ml of solution.

The capsule shells may be chosen from those that are commercially available, the size (capacity) thereof and the concentration of the digoxin solution filled therein being balanced the one against the other such that each capsule contains the desired unit dose of digoxin.

As used herein the term an effective cardiac insufficiency treatment amount of digoxin should be understood to mean one or more capsules of the present invention as described herein, each capsule preferably containing digoxin in the range 0.05 mg to 0.4 mg as detailed hereinabove. The capsules of the present invention, by virtue of their providing as herein described an increased bioavailability of digoxin as compared with digoxin tablets, enable the dosing schedule detailed below to be utilized in the treatment of cardiac insufficiency. Each individual dose and the cumulative dosage of digoxin thereby administered is but 80% of that required with the equivalent schedule as set out hereinabove utilizing digoxin tablets.

Thus where rapid digitalization is desired in one day or less the patient may be given 0.4 mg to 1.2 mg of digoxin initially followed by 0.2 mg to 0.4 mg of digoxin every six to eight hours, as required, to complete digitalization. In elderly patients, and Where there is less urgency, a smaller initial dose of 0.2 mg to 0.8 mg of digoxin is suitable. Thereafter maintenance doses of 0.1 mg to 0.4 mg of digoxin per day may be given, depending of course upon the patient and the discretion of the physician.

The applicants are aware of the specification of granted Belgian Patent No. 817,757 in the name of R.P. Scherer Limited which relates to - 8 41620 cardiotonic unit dosage forms comprising a soft gelatin capsule containing a liquid cardiotonic composition comprising a cardiac glycoside in a 4- or 5-component solvent system. There is no teaching in this Belgian specification of less complex solvent systems for the glycoside such as those contemplated by the present invention, nor is there any suggestion that the capsule dosage forms disclosed therein enable any reduction in the incompleteness of absorption of the glycoside as compared with conventional tablet formulations. In particular there is no teaching in the Belgian specification that the capsule dosage forms therein disclosed enable substantially the same blood level of glycoside to be achieved in a patient by administration of only 80% of the dosage of glycoside required when formulated and administered as conventional tablets.

In various aspects there are provided by the present invention the following. (a) An orally ingestible pharmaceutical preparation comprising a solution of digoxin in a capsule shell which is soluble in the upper gastrointestinal tract of a mammal, the amount of digoxin in the capsule being an amount which is less than the digoxin content of a conventional tablet and which provides upon oral administration of the capsule to man substantially the same therapeutic effect as is provided by oral administration to man of the conventional tablet. (b) The preparation of paragraph (a) comprising an amount of digoxin which is 80% of that of a conventional tablet formulation. (c) A method of preparing a pharmaceutical preparation according to (a) or (b) above which comprises marginally welding two sheets of the material comprising the capsule shell together around a unit dose of the solution of digoxin comprising the content of the capsule. (d) A method for the treatment of cardiac insufficiency in a mammal including man which comprises the administration to the mammal of a - 9 41620 pharmaceutical preparation according to (a) or (b) above containing an effective cardiac insufficiency treatment amount of digoxin. (e) A method for increasing the bioavailability of digoxin in a mammal including man suffering from cardiac insufficiency which comprises administering to the mammal a pharmaceutical preparation according to (a) or (b) above containing an effective cardiac insufficiency treatment amount of digoxin.

The following Examples are provided by way of illustration of the present invention and should not be construed as in any way providing a limitation thereof.

Example (I).

The following comparative example illustrates the unexpected properties of a capsule containing digoxin in solution in comparison with t tablets containing digoxin in dry form at the same dose or in a greater dose than in the capsule. All capsules and tablets used in this example were subjected to quality control testing to ensure content uniformity.

The procedure used for obtaining the results was as follows.

Eight normal human subjects were given each of the four following digoxin preparations with rest periods in between to permit digoxin clearance.

(A) 0.2 mg digoxin in solution in soft gelatin capsule shell— dissolution rate 100% at 1 hour (6th Interim revision, U.S.3. XVIII (November 15, 1973)).

(B) 0.2 mg digoxin in tablet—dissolution rate 97% at 1 hour.

(C) 0.25 mg digoxin in tablet—dissolution rate 97% at 1 hour.

(D) 0.25 mg digoxin in tablet (standard Lanoxin (Trade Name) brand digoxin)—dissolution rate 78% at 1 hour.

Dosage was 4 doses at 8-hour intervals each of 2 tablets or capsules, then 1 tablet or capsule twice a day on days 3—9. Serum digoxin levels - 10 41620 after the first dose and in the steady state (days 8—10), and 24-hour urine digoxin excretion on day 1 were measured by radioimmuno-assay.

The results (mean and standard errors) are as below.

Area under curve Preparation Serum peak (ng/ml) (serum) 0—6 hr. (ng/ml x min.) 24 hr Urine (ug) Steady State serum(ng/ml) (A) 3.34+0.53 451+30 273±21 1.08+0.06 (B) 2.08+0.21 311±16 206±12 0.91±0.07 (C) 2.58+0.30 448+26 248±13 1,02±0.06 (D) 2.12+0.18 376+14 260+26 1.17+0.12 Mean digoxin serum levels 1,0 hr. after the first dose were as follows (ng/ml): (A) : 2.74+0.38 (B) : 1.20±0.33 (C) : 2.05±0.51 (D) : 1.55+0.34 Preparation (A) was better absorbed than (B), as indicated by 1 hr. (p<.05) serum levels, 24 hr. urine levels (p<.01), areas under curve (p=.001), and steady state serum levels (p<.02). Despite the smaller digoxin dosage, absorption of (A) was similar to that of (C) and (D). There were also no significant differences between (C) and (D). (B)-to(D) differences were significant, consistent with different digoxin content. Coefficient of variation of steady state serum values did not differ significantly among the four preparations. ECG (electrocardiogram) changes (8 hr. monitoring) were similar with all four preparations.

It was concluded that (1) digoxin tablets having a dissolution rate of 97% at 1 hr. are no better absorbed by normal human subjects than currently available tablets (preparation (D)); and (2) a switch from tablet to solution filled capsules would require a reduction in digoxin dosage. - 11 41620 The soft gelatin capsules (preparation (A)) contained 0.2 mg digoxin in a fill volume of 6.65 minims, a fill weight of 448 mg. The digoxin was dissolved in a solvent comprising ethanol (absolute), water, propylene glycol, and polyethylene glycol 400. With the above fill weight the concentration of the digoxin was calculated to be about 0.45 mg/ml by dividing the weight of digoxin by the fill volume in ml, assuming the solution to have a density of 1.0 g/ml. The percentage amounts of the various ingredients of the solvent were as set forth in Example (Π).

Example (II).

A suitable solvent system for use in preparing capsules each containing 0.2 mg of digoxin includes the following ingredients (percentages by weight): Polyethylene glycol 400 —90% Ethanol (absolute) — 6% Propylene glycol — 3% Water — 1% A solution of digoxin in the aforementioned solvent system was packaged in a conventional soft gelatin capsule shell using conventional soft gelatin capsule packaging machinery to provide soft gelatin capsules, each containing 0.2 mg of digoxin. The solution ingredients are conventionally stirred together and may be heated if desired to speed solution of the digoxin.

For a solution having a concentration of 0.35 mg of digoxin/ml, a capsule containing 0.2 mg of digoxin would require about 0,57 ml of solvent. This is conventionally determined by dividing the weight of the digoxin to be incorporated in the capsule by the concentration of the solution, assuming the weight of digoxin in the solution to be negligible. For the capsules of Example (I), the amount of solvent of Example (II) - 12 41620 used would weigh about 447.8 mg and may be determined by subtracting the weight of digoxin from the fill weight. The concentration would be calculated as detailed in Example (I).

Example (III).

A soft gelatin, capsule shell was filled with a solution containing 0.1 mg of digoxin in polyethylene glycol 400, 100% by weight. For a solution having a concentration of 0.25 mg/ml, a capsule containing 0.1 mg of digoxin was calculated to require about 0.4 ml of polyethylene glycol 400.

Examples (IV) to (X).

By methods analogous to that described in Example (II), the following solutions of digoxin were prepared and packaged in soft gelatin capsule shells to provide capsules each containing digoxin in the respective amounts shown.

Solution Weight of Solvent Digoxin concn. digoxin per Example No. (% by weight)(mg/ml) capsule (mg) (IV) Polyethylene glycol 400 (90%) Glycerin (10%) 0.50 0.05 (V) Propylene glycol (100%) 0,40 0.05 (VI) Propylene glycol (100%) 0.50 0.2 (VII) Ethanol (absolute) (50%) Propylene olycol (50%)' 0.45 O.l (VIII) Ethanol (absolute) 0.50 0.2 (5%) Glycerin (5%) Propylene glycol (90%) - 13 41620 Solution Example No. Solvent (% by weight) Digoxin concn. (mg/ml) Weight of digoxin per capsule (mg) (IX) Ethanol (absolute) (10%) Propylene glycol (89%) Water (1%) 0.43 0.1 10 (X) Propylene glycol (99%) Water (1%) 0.35 0.1 Example (XI).

Seven normal human subjects were each given (i) two of the capsules 15 (preparation (A)) of Example (I), and (ii) an equivalent (as regards digoxin content) dose of a digoxin solution corresponding to the contents of the said capsules, with a rest period between the administration of (i) and (ii) to permit digoxin clearance.

The mean results obtained are as shown below: all data refer to 20 digoxin.

Capsules Solution Peak serum concn. (ng/ml) : 3.63 2.53 Area under curve (serum), 0—6 hrs. : 471 314 (ng/ml x min.) Area under curve eliminating subject: : 409 303 with double peak (ng/ml x min.) Mean 6 hr. serum concn. (ng/ml) : 0.42 0.39 24 hr. Urine excretion (yg) : 102 85 Examples (XII) to (XVI).

By methods analogous to that described in Example (II), soft gelatin capsules were prepared each containing digoxin in the respective amounts shown. - 14 41620 Example No.

Fill vol. Fill weight (minims) (mg) Weight of digoxin per capsule (mg) (XII) 0.90 59 0.05 (XIII) 1.80 118 0.10 (XIV) 3.60 235 0.20 (XV) 5.40 353 0.30 (XVI) 7.20 470 0.40 The digoxin solution filled into the capsule shells had the same lo composition in each instance, as below (all percentages by weight).

Solvent: Polyethylene glycol 400 : 89.5% Ethanol (absolute) : 6% Propylene glycol : 3.5% Water : 1% Concentration of digoxin : 0.94 rag/ml Examples (XVII) to (XXXII).

By methods analogous to that described in Example (II) solutions of digoxin in the following solvent systems were prepared and packaged in soft gelatin capsule shells to provide capsules each containing 0.05 mg of digoxin, the concentration of digoxin (mg/ml) in the solution and the size (capacity) of the capsule shells being chosen appropriately in each case. All references are to percentages by weight: the ethanol was in each case absolute.

Example No, (XVII) (XVIII) (XIX) (XX) Solvent Glycerin (100%) Ethanol (40%). water (6β%) Ethanol (50%), water (50%) Ethanol (80%), water (20%) Example No. Solvent (XXI) (XXII) (XXIII) (XXIV) (XXV) (XXVI) (XXVII) (XXVIII) (XXIX) (XXX) (XXXI) (XXXII) Propylene glycol (100%) Propylene glycol (75%), Propylene glycol (50%), Propylene glycol (40%), Polyethylene glycol 200 Polyethylene glycol 400 Isopropanol (100%) Propylene glycol (40%), Propylene glycol (50%), Propylene glycol (30%), Propylene glycol (40%), Propylene glycol (50%), water (25%) water (50%) water (60%) (100%) (100%) ethanol (5%), water (55%) ethanol (5%), water (45%) ethanol (10%), water (60%) ethanol (10%), water (50%) ethanol (10%), water (40%)

Claims

1. WHAT WE CLAIM IS:1. An orally ingestible pharmaceutical preparation comprising a solution of digoxin in a capsule shell which is soluble in the upper gastrointestinal tract of a mammal, the amount of digoxin in the capsule being an amount which is less than the digoxin content of a conventional tablet and which provides upon oral administration of the capsule to man substantially the same therapeutic effect as is provided by oral administration to man of the conventional tablet.

2. A preparation as claimed in claim 1 comprising an amount of digoxin which is 80% of that of a conventional tablet formulation as herein before defined.

3. A preparation as claimed in claim 1 or 2 wherein the capsule shell comprises soft gelatin.

4. A preparation as claimed in claim 3 wherein the capsule shell includes at least ohe ingredient selected from a plasticizer, a preservative, a colouring agent and an opacifying agent.

5. A preparation as claimed in any preceding claim wherein the dissolution rate of the capsule shell in the upper gastrointestinal tract is 100% in not more than one hour.

6. A preparation as claimed in any of claims 1 to 5 comprising 0.05 mg of digoxin.

7. A preparation as claimed in any of claims 1 to 5 comprising 0.1 mg of digoxin.

8. A preparation as claimed in any of claims 1 to 5 comprising 0.2 mg of digoxin.

9. A preparation as claimed in any of claims 1 to 5 comprising 0.3 mg of digoxin.

10. A preparation as claimed in any of claims 1 to 5 comprising 0.4 mg of digoxin.

11. A preparation as claimed in any of the preceding claims wherein the solution of digoxin comprises digoxin and at least one solvent sel30 - 17 41620 ected from glycerin, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 1000.

12. A preparation as claimed in any of the preceding claims wherein the solution of digoxin comprises digoxin and a solvent mixture comprising not more than 60% (by weight) of water.

13. A preparation as claimed in any of claims 1 to 11 wherein the solution of digoxin comprises digoxin and at least one solvent selected from ethanol and isopropanol.

14. A preparation as claimed in any of claims 1 to 10 wherein the solution of digoxin comprises digoxin and at least two solvents selected from glycerin, propylene glycol, ethanol and water, the water being present in an amount of not more than 60% (by weight) of the solvent mixture.

15. A preparation as claimed in any of claims 1 to 11 and 14 wherein the solution of digoxin comprises digoxin and a solvent mixture comprising up to 5% (by weight) of water.

16. A preparation as claimed in any of claims 1 to 10 wherein the solution of digoxin comprises digoxin and at least two solvents selected from glycerin, ethanol, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 6000,

17. A preparation as claimed in any of claims 1 to 10 wherein the solution of digoxin comprises digoxin, ethanol, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 6000.

18. A preparation as claimed in either of claims 16 and 17 wherein the polyethylene glycol has an average molecular weight of 190 to 1000.

19. A preparation as claimed in any of claims 1 to 10 wherein the solution of digoxin comprises digoxin and at least one solvent selected from ethanol, isopropanol, propylene glycol and polyethylene glycol 400.

20. A preparation as claimed in any of claims 1 to 5 wherein the - 18 41620 digoxin is present in an amount selected from 0.1 mg, 0.2 mg and 0.4 mg and wherein the solution thereof comprises digoxin and a solvent mixture comprising a polyethylene glycol having an average molecular weight of 190 to 6000, ethanol, propylene glycol and water, the water being present in an amount of not more than 60% (by weight) of the solvent mixture.

21. A preparation as claimed in any of claims 1 to 5 wherein the digoxin is present in an amount selected from 0.1 mg and 0.2 mg and wherein the solution thereof comprises digoxin and a solvent mixture comprising a polyethylene glycol having an average molecular weight of 190 to 1000, ethanol, propylene glycol and water, the water being present in an amount of up to 5% (by weight) of the solvent mixture.

22. A preparation as claimed in any of the preceding claims wherein the concentration of the solution of digoxin is in the range 0.25 to 0.95 mg digoxin/ml.

23. A preparation as claimed in any of claims 1 to 21 wherein the concentration of the solution of digoxin is in the range 0.4 to 0.5 mg digoxin/ml.

24. A method of preparing a pharmaceutical preparation as claimed in any of the preceding claims which comprises marginally welding two sheets of the material comprising the capsule shell together around a unit dose of the solution of digoxin comprising the content of the capsule.

25. A method as claimed in claim 24 wherein the capsule shell 1s subsequently dehydrated by exposuee to an agent capable of extracting water therefrom.

26. A method as claimed in claim 25 wherein the agent is dry warm air or acetone.

27. A pharmaceutical preparation as claimed in any of claims 1 to 23 when prepared by a method as claimed in any of claims 24 to 26. - 19 41620

28. A pharmaceutical preparation as defined in any of claims 1 to 23 and 27, substantially as hereinbefore described with particular reference to Examples (I) to (XI), (XIII), (XIV) and (XVI) to (XXXII)