IE45448B1

IE45448B1 - Enterally highly-absorbable preparations of cardiac glycosides which by themselves are absorbable with difficulty and process for the production of such preparations

Info

Publication number: IE45448B1
Application number: IE137977A
Authority: IE
Original assignee: Kali Chemie Pharma Gmbh
Priority date: 1976-07-12
Filing date: 1977-07-04
Publication date: 1982-08-25
Also published as: CA1087985A; NZ184612A; IE45448L; GB1544576A; IL52472A

Abstract

A readily enterally absorbable pharmaceutical composition of cardiac glycosides is disclosed which comprises a therapeutically-effective amount of at least one cardiac glycoside distributed in a vehicle comprising an absorptionenhancing amount of at least one partial glyceride of a fatty acid of medium chain length. The preparation is suited for formulating cardiac glycosides which per se are poorly enterally absorbable,in particular, k-strophanthin, gstrophanthin, and proscillaridin.

Description

This invention relates fco enterally absorbable preparations of cardiac glycosides which by themselves are absorbable with difficulty, and to a process for the production of such preparations.

Cardiac glycosides, by reason of their effect on the contraction of the heart muscle, are used therapeutically in the treatment of the insufficient heart. It has, however, proved disadvantageous that v/hen the cardiac glycosides are administered enterally they are absorbed to only a low degree, so that, frequently , only intravenous injection can be used for sure therapy, i.e. with controllable bioavailability of the active substance.

There has therefore been no lack of attempts to render cardiac glycosides amenable to enteral administration.

Chemical modifications of the glycosides have » met with some success as for example in the case of completely, or acceptably, enterally absorbable digitoxin or digoxin. Other cardiac glycosides, such as for j example g- and k-strophanthin or proscillaridin must, however! continue to be administered parenterally, i.e. intravenously, because they are insufficiently absorbable v/hen administered enterally. 1 The invention therefore seeks to provide enterally i absorbable preparations of cardiac glycosides which by I themselves are absorbable with difficulty, and to provide a process for the production of such preparations. ! The term cardiac glycosides which by themselves are absorbable with difficulty is used in this specification to mean not only £- and k-strophanthin and proscillaridin which are the preferred cardiac glycosides, but also -2those in which are improved enteral absorbability is desirable.

Accordingly one aspect of the present invention provides an enterally absorbable preparation comprising at least one cardiac glycoside which by itself is absorbable with difficulty, wherein the preparation comprises a solution or micro-crystalline suspension of the cardiac glycoside (s) in one or more partial glycerides of a fatty acid having 6 to 12 carbon atoms or a mixture of such partial glycerides.

According to another aspect of the present invention there is provided a process for the production of an enterally absorbable preparation comprising at least one cardiac glycoside which by itself is absorbable with difficulty, wherein the cardiac glycoside is dissolved in one or more partial glycerides of a fatty acid having 6 to 12 carbon atoms, or a mixture of such partial glycerides.

It has already been proposed to dissolve or suspend medicaments in glycerides of medium-chain fatty acids for the purpose of improving absorption. Thus, e.g. according to German Patent Specification No. 1,282,853,. chloramphenicol has been suspended in triglycerides of medium-chain fatty acids. Belgian Patent Specification No. 567,598 describes the suspension of antibiotics in triglycerides. British Patent Specification No. 1,432,784 describes solutions or suspensions of various medicaments in monoglycerides and German Offenlegungsschrift No. 2,357,389 describes solutions or suspensions of the same medicaments in mixtures of triglycerides and partial glycerides. -3> However, in so far as any concrete figures on the absorption improvement are stated at all in the said Specifications, this improvement is so slight that it could not be expected that the dissolving or suspending of cardiac glycosides in partial glycerides of medium-chain fatty acids would lead to usable results. In the case of cardiac glycosides, the small therapeutic breadth of these active substances in conjunction with large individual variations in the absorption quota has to he taken into account. By small therapeutic breadth- is to be understood the property of such active substances to have no effect at all in the case where a slight under-dosage is administered and, where a slight over-dosage is administered, to lead to cardiac arrest, i.e. a dose which in one individual has no effect at all may suffice to lead to death in another individual. Thus, e.g. for ^-strophanthin, individual variations of from 0.46% to 4.4%, i.e. absorption quotas differing by the factor 10, have been observed, which has caused various authors to take the view that enteral administration cannot he used. With such large individual variations in the absorption of cardiac glycosides which by themselves are absorbable with difficulty, and with the slight improvements in absorption obtainable with other medicaments by means of glycerides, the improvement in absorption of cardiac glycosides which by themselves are absorbable with difficulty in the present preparations was very surprising and not suggested by the prior art.

The partial glycerides of medium-chain fatty acids which may be used in the present preparations and -4process are, as indicated, mono- and/or diglycerides of fatty acids with chain lengths of 6 to 12, preferably 8 to 10, carbon atoms and/or mixtures of such partial glycerides.

Depending upon the nature of the administration, whether oral or rectal, it is advantageous to bring the preparation into a suitable form for the intended administration. For such forms as e.g. tablets, gelatin capsules or suppositories, viscosity-changing or structuregiving additives such as e.g. finely-divided silica, such as that sold under the registered Trade Mark Aerosil, modified montorillonite, such as that sold under the Trade Mark Betone, oleic acid monoglyceride, stearic acid monoglyceride, palmitic and stearic acid, cetyl and stearyl alcohol, beeswax, spermaceti and the material sold under the Trade Mark Softigen 701 which is a mixture of partial glycerides of an unsaturated fatty acid which contains hydroxyl groups, including the unsaturated fatty acid ricinoleic acid, may be added to the preparation. Since many cardiac glycosides are sensitive to acid, it may be advantageous that forms intended for oral administration such as gelatin capsules, be provided with a coating which is resistant to gastric juice.

The production of the present preparations can be effected by dissolving the cardiac glycoside in the partial glyceride. Depending upon the solubility and/or speed of dissolution of the cardiac glycoside in the partial glyceride on the melting point of the partial glyceride, the dissolution may also take place with heating. If the cardiac glycoside crystallises out during the cooling of such a preparation produced with heating, or if the partial glyceride should solidify a microcrystalline suspension or solid solution is formed which, as regards absorption, behaves like a true solution.

In order to improve the ability of the preparation to be filled into gelatin capsules or to improve the shaping of the preparation into suppositories or tablets, the aforesaid viscosity-changing or structure-giving additives may.be added to the preparation.

The high enteral absorption of the present preparations was determined by means of toxicity investigations, s blood-level measurements and the modified Hatcher process (Lenke and Schneider, Arzneimittelforschung (Medicament Research'''), 19 (1969), pp. 687-693; 20 (1970), pp. 1199-1206; (1970), pp. 1765-1770).

In the toxicity investigations, g-strophanthin and proscillaridin dissolved in water and in a mono-diglyceride mixture of capric and caprylic acid (obtainable under the Trade Mark Witafrol 7420 from Dynamit-Nobel) were administered orally by means of a tubular probe to female guinea-pigs of 250 - 300 g. weight.

The following lethal doses were observed; LD50 in water mg./kg.

LD50 in Witafrol 7420 mg./kg. g-strophanthin 34.8 5.2 proscillaridin 12.3 6.8 In the blood-level measurements, tritium-marked gstrophanthin in a dose of 50 /ig./kg. dissolved in water and in a mono-diglyceride mixture of capric acid and caprylic acid (obtainable under the designation WL 2391 from -64 3 4 4 8 Gattefosse) was administered intraduodenally to cats. The blood-level values measured were recorded graphically and the areas under the blood-level curves were compared. From the comparison of the areas, the following absorption rates result: £-strophanthin in water: 19 % g-strophanthin in WL 2391:61 % In the modified Hatcher process Filling-up method, 100 jug./kg. of £-strophanthin dissolved in Witfrol 7420 were administered intraduodenally to cats of both sexes while under chloralose-urethane anaesthesia (with such a dose, which otherwise is not lethal, 2 out of 34 cats died). 4 hours later, filling-up was effected by means of intravenous infusion until cardiac arrest. Depending upon the survival time, average statistical absorption quotas of 60 - 80 % resulted.

Intraduodenal application Survival time (Min.) Calculated (average) strophanthin fill-up dose intravenous (ug./kg,) Enternal effectiveness (%) g- s trophanthin 50 63.9 80.8 in Witafrol 100 jig./kg. 100 49.7 60.7 Witafrol 50 144.7 - 0.1 ml/kg. 100 110.4 - With the absorption quota of up to 80% which is achievable with the present preparation, a hitherto unobtainable oral or rectal therapy by means of cardiac glycosides, which by themselves are absorbable with difficulty, becomes possible with a high degree of reliability. -710 The following Examples serve further to illustrate the invention. Where parts are mentioned in the Examples, j these are to he understood to be parts by weight unless anythingI different is stated. In the Examples, the amount stated | of the specific cardiac glycoside may be replaced by an equal amount of one of the other two cardiac glycosides mentioned in the Examples.

Example 1.

Gelatin capsules A mixture to be filled into gelatin capsules has the following composition: g-strophanthin 0.125 parts caprylic acid/capric acid mono- and diglyceride 99.875 parts (obtainable under the designation WL 2391 from Gattefoss4) _ TOTAL 100 parts The mixture is prepared by dissolving the £-strophanthin in caprylic acid/capric acid mono- and di-glyceride at a temperature of 35 to 40°C. with stirring. The resulting solution is filled into gelatin capsules in such a manner that each capsule contains 200 mg. of the mixture, 0.25 mg. of active substance being contained in each capsule. Example 2.

Gelatin capsules A mixture to be filled into gelatin capsules has the following composition: ^-strophanthin 0.125 parts Aerosil R 972 7.500 parts caprylic acid/capric acid mono- and diglyceride 92.375 parts (obtainable under the designation WL 2391 from Gattefosse) TOTAL 100 parts -8; ...ί The mixture is prepared by dissolving the gstrophanthin in caprylic acid/capric acid mono- and di-glyceride at a temperature of 35 to 40°C. with stirring.

The Aerosil is then added, likewise with stirring. The mixture may then be finally homogenised using e.g. a colloid mill or a high-pressure homogeniser. This mixture is filled into gelatin capsules in such a manner that each capsule contains 200 mg. of the mixture, 0.25 mg. of active substance being contained in each capsule.

Example 3.

Gelatin capsules A mixture to be rilled into gelatin capsules has the following composition k-strophanthin 0.125 parts Bentone 27 4.5 parts ethanol 2.25 parts caprylic acid/capric acid mono- and di-glyceride 93.125 parts (obtainable under the designation WL 2391 from Gattefosst) TOTAL 100 parts The mixture is prepared by dispersing the Bentone in about half the stated amount of the partial glyceride mixture with the aid of a high-speed stirring device of the rotor/stator type and, following the addition of the ethanol, a viscous gel is formed. The k-strophanthin is dissolved in the remaining amount of the partial glyceride mixture and this solution is added portionwise, with stirring, to the previously produced gel, stirring being continued until a uniform consistency is achieved. In each case 200 mg. of this mixture are filled into a gelatin capsule, 0.25 mg. of -919 active substance being contained in each capsule.

Example 4.

Gelatin capsules A mixture to be filled into gelatin capsules has the following composition: proscillaridin ' 0.1 parts Softigen 7Q1 · 50.0 parts caprylic acid/capric acid mono- and diglyceride 49,9 parts (obtainable under the designation WL 2391 from Gattefossb) __ TOTAL 100 parts The mixture is prepared by dissolving the proscillaridin in the mono- and di-glyceride mixture at a temperature of 35 to 40°C, with stirring. The Softigen o liquefied at 40 C,, is added and cooling to room temperature is allowed to take place, with stirring. In each case 200 mg. of this mixture are filled into gelatin capsules, Q.2 mg. of active substance being contained in each capsule.

Example 5.

Gelatin capsules A mixture tc be filled info gelatin capsules has the following composition:jg-strophanthin 0.125 parts oleic acid monoglyceride 40 parts' caprylic acid/capric acid mono- and di-glyceride 59.875 parts (obtainable under the designation WL 2391 from Gattefosse) -, ' TOTAL· 100 parts The mixture is prepared by dissolving the £strophanthin in the caprylic acid/capric acid mono- and di-glyceride at a temperature of 35 to 40°C. with stirring.

The oleic acid monoglyceride, liquefied at 50°C., is added ------and cooling to room temperature is allowed to take place, with stirring. In each case 200 mg. of this mixture are filled into gelatin capsules, 0.25 mg. of active substance being contained in each capsule.

Example 6.

Gelatin capsules A mixture to be filled into gelatin capsules has the following composition:g-strophanthin 0.125 parts oleic acid monoglyceride 40 parts Witafrol 7420 59.875 parts TOTAL 100 parts The mixture is prepared by dissolving the £strophanthin in the Witafrol 7420 at a temperature of 30 to 40°C. with stirring. The oleic acid monoglyceride, liquefied at 50°G., is added and cooling to room temperature is allowed to take place, with stirring. In each case 200 mg. of this mixture are filled into gelatin capsules which subsequently are rendered resistant to gastric juices, 0.25 mg. of active substance being contained in each capsule. Example 7.

Gelatin capsules A mixture to be filled into gelatin capsules has the following composition tiki-strophanthin 0.125 parts capric acid monoglyceride 17.5 parts Witafrol 7420 82.375 parts TOTAL 100 parts The mixture is prepared by dissolving the k-strophan -11thin in the Witafrol 7420 at a temperature of 35 to 40°C. with stirring. The capric acid monoglyceride, molten at 60°G., is added and cooling to room temperature is allowed to take place, with stirring. In each case 200 mg. of this mixture are filled into gelatin capsules which are subsequently rendered resistant to gastric juices, 0.25 mg. of active substance being contained in .each capsule.

= Example 8.

Gelatin capsules A mixture to be filled into gelatin capsules has the following composition:proscillaridin 0.1 parts glycerol monostearate 5 parts Witafrol 7420 94.9 parts TOTAL 100 parts The mixture is prepared by dissolving the , proscillaridin in the Witafrol 7420 at a temperature of 35 to 40°C. with stirring. The glycerol monostearate, .molten at 70°C. is added and cooling to room temperature is allowed to take place, with stirring. In each case 200 mg. of the mixture are filled into gelatin capsules, 0.2 mg. of active substance being contained in each capsule.

Example 9.

Rectal capsules A mixture to be filled into gelatin capsules for rectal administration has the following composition:proscillaridin 0.02 parts Softigen 701 50 parts Witafrol 7420 49.98 parts TOTAL 100 parts -12The mixture is prepared by dissolving the procillaridin in the Witafrol 7420 at a temperature of 35 to 40°C. with stirring. The Softigen 701, liquefied at 40°C., is added and cooling to room temperature is allowed to take place, with stirring. In each case 1 g. of the mixture is filled into gelatin capsules for rectal administration of 0.2 mg. of active substance being contained in each rectal capsule.

Example 10.

Rectal capsules A mixture to be filled into gelatin capsules for rectal administration has the following composition:jg-strophanthin , 0.025 parts Aerosil R 972 7.5 parts caprylic acid/capric acid mono- and diglyceride92.475 parts (obtainable under the designation WL 2391 from Gattefosse) _ TOTAL 100 parts The mixture is prepared by dissolving the gstrophanthin in the caprylic acid/capric acid, mono and diglyceride at a temperature of 35 to 40°C. with stirring.

The Aerosil is then added, likewise with stirring. The mixture may then be finally homogenised, e.g. a colloid mill or a high-pressure homogeniser. In each case 1 g. of this mixture is filled into gelatin capsules for rectal administration, 0.25 mg. of active substance being contained in each rectal capsule.

Example 11.

Suppositories A mixture to be formed into suppositories has the - 13 «3448 following composition:k-strophanthin 0.01 parts caprylic acid monoglyceride 99,99 parts TOTAL 100 parts The caprylic acid monoglyceride (m.p. 35-37°C., purity 90%, remainder caprylic acid di- and tri-glyceride, glycerol) is liquefied at 45°C. and the k-strophanthin is dissolved in. this melt, with stirring. The mass is poured out into suppository moulds in which it solidifies. Each suppository weighs 2.5 g. and contains 0.25 mg. of kstrophanthin.

Example 12.

Suppositories A mixture to be formed into suppositories has the following composition:^-strophanthin 0.01 parts caprylic acid monoglyceride (40%) (Drewmulse GMC - 8) 33 parts Novata G 66.99 parts TOTAL · · 100 parts The strophanthin is dissolved at 50°C., with stirring, in the caprylic acid monoglyceride (manufacturer: PVO International Inc.). The suppository composition Novata C (manufacturer: Henkel) is likewise melted and added to the mixture, with stirring. The composition is poured out. into suppository moulds in which it solidifies. Each suppository weighs 2.5 g. and contains 0.25 mg. of g-strophanthin. -14A 3 4 4 8

Claims

1. CLAIMS:1. An enterally absorbable preparation comprising at least one cardiac glycoside which by itself is absorbable with difficulty, wherein the preparation comprises a solution or micro-crystalline suspension of the cardiac glycoside(s) in one or more partial glycerides of a fatty acid having 6 to 12 carbon atoms or a mixture of such partial glycerides.

2. A preparation as claimed in claim 1,·'wherein the fatty acid of the partial glyceride(s) has 8 to 10 carbon atoms.

3. A preparation as claimed in claim 1 or 2, wherein the partial glyceride(s) is (are) mono- or di-glycerides or mixtures of such mono- and di-glycerides.

4. A preparation as claimed in any one of claims 1 to 3, wherein the preparation contains one or more viscositychanging or structure-giving additives.

5. A preparation as claimed in claim 4, wherein the additive is selected from finely-divided silica, a modified montmorillonite, oleic acid monoglyceride, stearic acid monoglyceride, palmitic and stearic acid, cetyl and stearyl alcohol, beeswax, spermaceti and a mixture of partial glycerides of an unsaturated fatty acid which contains hydroxyl groups.

6. A preparation as claimed in any one of Claims 1 to 5, wherein the preparation is filled into gelatin capsules.

7. A preparation as claimed in Claim 6, wherein the gelatin capsules have a coating which is resistant to gastric juices.

8. A preparation as claimed in any one of Claims 1 -15I . A S448 to 5, wherein the preparation is in the form of suppositories.

9. A preparation as claimed in any one of Claims 1 to 8, wherein the cardiac glycoside is g- or k-strophanthin or proscillaridin. 5 10. A process for the production of an enterally absorbable preparation comprising at least one cardiac glycoside which by itself is absorbable with difficulty, wherein • the cardiac glycoside is dissolved in one or more partial glycerides of a fatty acid having 6 to 12 carbon atoms, or a

10. Mixture of such partial glycerides.

11. A process as claimed in claim 10, wherein the cardiac glycoside is dissolved, with heating, in the partial glyceride(s) of said fatty acid.

12. A process as claimed in claim 10 or ll, wherein 15 the fatty acid of the partial glyceride(s) has 8 to 10 carbon atoms.

13. A process as claimed in any one of claims 10 co ' ι 12, wherein the partial glyceride is a mono- or di-glyceride or a mixture of mono- and di-glycerides. 2o Ϊ4. A process as claimed in any one of claims 10 to 13, wherein one or more viscosity-changing or structure-giving additives is or are added to the solution.

14. 15. A process as claimed in claim 14, wherein the additive is selected from finely-divided silica, modified 25 montmorillonite, oleic acid monoglyceride, stearic acid monoglyceride, palmitic and stearic acid, cetyl and stearyl alcohol, beeswax, spermaceti and a mixture of partial glycerides of an unsaturated, fatty acid which contains hydroxyl groups.

15. 16. A process as claimed in any one of claims 10 to 15, 3o wherein the solution is filled into gelatin capsules. -1617. A process as claimed in claim 16, wherein the gelatin capsules have a coating which is resistant to gastric juices.

16. 18. A process as claimed in any one of claims 10 to 15, 5 wherein the solution is formed into suppositories.

17. 19. A process as claimed in any one of claims 10 to 18, wherein the cardiac glycoside is g- or k-strophanthin or proscillaridin.

18. 20. A process for the production of an enterally 10 absorbable preparation substantially as hereinbefore described in any one of the foregoing Examples.

19. 21. An enterally absorbable preparation substantially as..hereinbefore described in any one of the foregoing Examples. Dated this the 4th day of July, 1977.