NZ192442A - Pharmaceutical preparations: cardiac glycoside in combination with polymer - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 92442 1 ] Priority I Compacts S^scrifoatscn Ftfsd: Class: S FiibSica'^cn Deto: ... 31.M.W4. < Je:™!, Ko: NEW ZEALAND THE PATENTS ACT 1953 COMPLETE SPECIFICATION " A PHARMACEUTICAL PREPARATION COMPRISING A CARDIAC GLYCOSIDE IN COMBINATION WITH A POLYMER" We, AKTIEBOLAGET HASSLE, a Swedish Company, of Fack, S-4 3J 20 Molndal 1, Sweden, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: 192442 Field of Invention; The present invention provides a novel pharmaceutical preparation comprising a digitalis glycoside or similar cardiac compound effective in the treatment of cardiac disorders; a 5 process for producing such preparation; and a method of treat ment using such preparation.

An object of the invention is to provide a pharmaceutical preparation in which a cardiac glycoside present therein is protected against substantial decomposition in the acid 10 environment of the stomach of a mammal (including man), without loss of bioavailability upon release and intestinal absorption.

A further object is to provide a pharmaceutical preparation which gives a sustained or controlled release of a -... cardiac glycoside present therein, without loss of bioavailability. 15 Background of invention: Digitalis glycosides or other cardiac glycosides constitute a class of drugs among which are a few of the oldest drugs in current use. Their main utility is in the treatment of cardiac disorders such as cardiac insufficiency and cardiac arrythmias. 20 Persons skilled in the art will appreciate that the term "cardiac glycosides" as used herein means a glycoside which has a stimulating effect on the heart, vide: Butterworth1s Medical Dictionary, 2nd Edition, page 739, and includes therapeutically effective naturally occurring digitalis glycosides and similar compounds of 25 different origin, including compounds prepared as semisynthetic derivatives of naturally occurring compounds, irrespective of the source or manner of production thereof. Hereinafter, the cardiac glycosides are occassionally referred to as "the active ingredient".

Cardiac glycosides are substantially decomposed in an acid environment. This effect is^j&eeji^especially with 192442 digoxin, lanatoside C, digitoxin and proscillaridin. Thus, digoxin is hydrolysed very rapidly in a buffer solution of pH 1, leaving only 10% thereof after exposure for 1 hour.. Such decomposition also takes place in vivo. Thus, it is described, that 40% of a given dose may be decomposed. As some of the products of hydrolysis have a substantially lower biological activity than has the parent substance, this- means that the therapeutical response of a given dose of .cardiac glycosides may vary between individuals and between the time of administration, depending upon the period that the preparation stays in the stomach and the pH prevailing at the time of passage.

Gastric juice resistant preparations of digitalis glycosides such as tablets provided with a conventional enteric coating are known, however, it is also known in the literature that such preparations give an impaired bioavailability of the glycoside. The fact that digitalis glycosides are sparingly soluble in aqueous media, make them further difficult to include in pharmaceutical preparations, while obtaining satisfactory bioavailability.

Digitalis glycosides in general .have a narrow therapeutical index, that is, the dose thereof producing toxic or other undesirable side effects is not much greater than the therapeutically effective dose. Several side effects, for example, nausea and arrythmias, encountered in treatment with cardiac glycosides, are related to a peak in plasma concentration often occurring a few hours after administration of a dose. For these reason, it is strongly desirable to prepare compositions giving a sustained release of the cardiac glycosides. Bio-pharmaceutical studies have shown, however. 192442 ; ; .that hitherto known sustained release preparations have the drawback of giving an impaired bioavailability of the digitalis glycoside.

SummarY_of_Invention: The present invention provides a pharmaceutical preparation in dosage unit form suitable for oral administration/ said pharmaceutical preparation comprising a cardiac glycoside ■ (hereinbefore specified) in combination with a polymer and characterized in beihg in the form of a plurality of small bodies, each body comprising a fraction of a therapeutically effective dosage of the cardiac glycoside, each body having a core of pharmaceutically-indifferent material (hereinafter •' specified), and on said core a layer of a composition comprising the cardiac glycoside and an anionic carboxylic polymer which is sparingly soluble or insoluble below a selected pH value within the range-of pH 4-7.5 but soluble at a pH above said selected value.

Normally each dosage unit contains about 10 to 10^ I bodies. Preferably the number of bodies is about 200 to 1000. i Thus, each body of the preparation contains a fraction of a j therapeutically effective dosage of the cardiac glycoside.

The fraction is normally 1.10 ® to 1.10 ^ times such dosage, j -3 -3 ' and preferably 1.10 to 5.10 times such dosage. Suitable ! dosage units include tablets and capsules. Pharmaceutically acceptable additives may be included in the dosage units, together with the preparation of the invention. Preparations wherein the solid bodies are in admixture with a liquid medium are also within the scope of the invention. 192442 The pharmaceutically-indifferent material forming the cores of the preparation bodies may be in granular or pulverulent form of the type normally used in pharmaceutical preparations, such as sugar, microcrystalline cellulose, starch and waxes. The term "pharmaceutically-indifferent" means that the materials are indifferent with regard both to the organism treated and the active substance employed. The size of the cores may be sieve fractions between 0.1 and 3.0 mm, preferably between 0.5 and 1.5 mm.

Among active ingredients which may be employed according to the present invention are therapeutically effective compounds containing the ring system of digitoxigenin: CH.

HO or scillaridin A: CH Q or derivatives thereof. Digoxin, digitoxin, lanatoside C, acetyldigoxin, methyldigoxin, proscillaridin, methylproscillari-din, pentaacetylgitoxin, 16-epigitoxin and actodigin are specifically mentioned as such active ingredients.

The polymer substance may be selected from the group of anionic carboxylic polymers useful for pharmaceutical purposes and difficultly soluble at a low pH but soluble at a I* ^ 1914 4 2 higher pH, the pH limit for solubility being within the range of pH 4 to 7.5. Said group comprises cellulose acetate phthalate (CAP)(5.0-5.5); hydroxypropylmethylcellulose phthalate, for example, a quality sold under the name HP 55 (5.0-5.5); polyvinyl acetate phthalate (PVAP) (4.5-5.0); and acrylic acid polymers, for example, partly esterified methyl methacrylic acid polymers such as Eudragit L (6.0) and Eudragit S (7.0); and methylacrylate - methacrylic acid copolymers such as MPM-05 (5.0). The numbers in brackets above are approximate pH limits. These polymers may be used alone or in combination with each other.

The polymers may be admixed with plasticizers such as diethyl or dibutyl phthalates, citric acid esters, for example, acetyl tributyl citrate (Citroflex A-4), stearic acid and fatty alcohols such as cetanol. Suitably, a polymer is selected which is insoluble or difficultly soluble in gastric juice but soluble in intestinal juice. A preferred polymer is hydroxypropylmethylcellulose phthalate. Further preferred polymers are Eudragit S in combination with hydroxypropylmethylcellulose phthalate or MPM-05.

The relative amounts of core material and material constituting the layer applied thereon may be varied depending inter alia on the properties of the components employed. Preferably, the weight of the core relative to the weight of the layer thereon is 1 to between 0.01 and 0.5, most preferably between 0.01 and 0.30.

The bodies prepared preferably have a size of 0.1 to 3 mm. Their shape, partly dependent on the shape of the cores, is preferably spherical or nearly spherical. 19 2442 According to the present invention, it has surprisingly been found possible to obtain protection of the active ingredient by including the active ingredient in admixture with the acid resistant polymer. Among the advantages of the preparations of the present invention further to be mentioned are that they have an improved biological availability as compared to conventional tablets having an enteric coating. The release of the active component in vitro, at a pH over the pH limit selected, for example, the pH of intestinal juice, is rapid with the preparations of the present invention.

This is advantageous and accounts in part for the improved.bioavailability, however, in vivo a sustained release will oacur as the several bodies of the preparation are emptied from the stomach into the small intestine during an extended period of time. The preparation of the invention thereby gives less variation in plasma concentration in patients under continuous treatment, than can be obtained with conventional tablets. A further advantage is the improved economy of production that is obtainable, as a batch of the preparation can be prepared in short time, typically 15-20 minutes, while meeting the special demands of cardiac glycoside preparations.

Another aspect of the present invention is a process for preparing a pharmaceutical preparation in dosage unit form suitable for oral administration. Thus, the invention provides a process for preparing a pharmaceutical preparation comprising a cardiac glycoside (hereinbefore specified) in combination with a polymer, said pharmaceutical preparation being in the form of a plurality of small bodies, each body comprising a fraction of a therapeutically effective dosage of the cardiac glycoside, 192442 Which process comprises providing a large number of cores of pharmaceutically-indifferent material (hereinbefore specified) , with a layer of a composition comprising the cardiac glycoside and an anionic carboxylic polymer which is sparingly soluble or insoluble below a selected pH value within the range of pH 4-7.5 but soluble at a pH above said selected value, for the formation of such bodies. The layer, which is unitary, preferably is applied by spraying a solution containing the components thereof.

All components of the preparation employed in the process of the invention are as further defined above.

% * Solvents employed to prepare said solutions for use in the process of the invention are solvents having a sufficient volatility to evaporate under the conditions of application, leaving a layer of the solute on the surface of the core or body so prepared. Preferably, organic solvents such as alcohols, hydrocarbons and esters are used, as well as derivatives thereof, such as chlorinated hydrocarbons. The process of applying the layers may be carried out in an apparatus normally used in the pharmaceutical industry for coating of solid pharmaceutical preparations, such as a coating pan or a fluid bed apparatus. The process is normally carried out at ambient conditions, however, temperature and pressure conditions may be varied within broad limits. In a fluid bed spraying process, the temperature of the inlet air is suitably 15 to 60°C.

A method of treatment of cardiac disorders employing the pharmaceutical preparation defined above constitutes a 19 2442 . further aspect of the invention. The therapeutically effective doses of the cardiac glycosides of the preparations are not greater than those normally prescribed, that is, about 0.0 5 to 1.5 mg/day for compounds specified herein, subject to variations 5 between different patients. However, it is in many instance possible to employ doses lower than those normally prescribed.

Practical_Examgles: The invention is illustrated by the following example*3 in which Example 6 is considered to represent the bed mode known 10 at present.

Examples 1 - 9: On 500 g of core material, 0 0.6-0.7 mm, consisting of 30% starch and 70% sugar, a layer was applied by spraying a solution having a composition as shown in Table 1 below, in 15 a fluid bed apparatus.

The coated granules were analysed according to the so-called beaker method (Levy et al, New England Journal of Medicine, Vol. 262, p. 1053-1058 (I960)). The release of the active ingredient was studied in artificial gastric juice of 20 pH 1.0 and phosphate buffer of pH 6.5 at 37- 0.1°C. The results are set out in Table 2 below.

Table 1 Example 1 2 3 Active ingredient Digitoxin (g) 2.5 Proscillaridin A (g) Digoxin (g) 2.5 2.5 Polymer HP-55 (g) 36 36 36 Vinnapas B 100 (g) Eudragit L 100 (g) Eudragit S 100 (g) CAP (g) PVAP (g) Plasticizer Cetylalcohol (g) 2.5 2.5 2.5 Stearic acid (g) Solvent Methylenechloride Isopropanol (g) 500 500 500 (g) 300 500 300 4 5 6 7 8 9 1.25 1.25 1.25 1.25 1.25 1.25 20 20 17.5 17. 5 13 4.5 2.5 20 500 300 500 300 500 300 250 150 500 300 500 300 1 'Table 2 Example % Active ingredient released in pH 1.0 after 4 h % Active ingredient released in phosphate buffer pH 6.5 after 10 min 30 min 60 min 1 < 1 74 95 100 2 12 79 102 3 4 99 104 4 7 102 < 1 88 102 6 < 1 64 95 103 7 1 36 78 94 8 94 100 9 < 1 52 96 100 Amounts of coated granules prepared according to Examples 6 and 7, corresponding to a dose of 0.38 rng digoxin, were filled into hard gelatin capsules size No. 4.

Example 10 On 460 g of core material, f6 0.2-0.5 mm, consisting of anhydrous lactosej a layer was applied by spraying a solution having the following composition, in a fluid bed apparatus: Digoxin 2.5 g Hydroxypropylmethylcellulose phthalate (HP-55) 8 g Eudragit S 100 32 g Methylene chloride 500 g Isopropanol 300 g

Claims (11)

Release of digoxin in vitro in per cent according to the method referred to in Examples 1-7: Gastric juice Buffer pH 6.5 10 min - 60 5 0.5 hours 1 .90 1 1 95 1.5 " - 97 2 2 9 7 4 2 10 Example 11 Example 8 was repeated using 460 g of polyvinyl acetate (Vinac ASB 576), jzS < 0.5 mm, as the core material. Release of digoxin: Gastric Juice Buffer pH 6.5 15 10 min - 32 0.5 hours <1 6 9 1 <1 96 1.5 " - 102 2 <1 102 20 4 < 1 The matter contained in each of the following claims is to be read as part of the general description of the present invention. - 12 - 192442 What we claim is:

1. A pharmaceutical preparation comprising a cardiac glycoside (hereinbefore defined) in combination with a polymer, said pharmaceutical preparation characterized in being in the form of a plurality of small particles, each particle comprising 5 a fraction of a therapeutically effective dosage of the cardiac glycoside, each particle having a core of pharmaceutically-indifferent material (hereinbefore defined), and on said core a layer of a composition comprising the cardiac glycoside and an anionic carboxylic polymer which is sparingly soluble or 10 insoluble below a selected pH value within the range of pH 4-7.5 but soluble at a pH above said selected value.

2. A pharmaceutical preparation according to claim 1 characterized in that the layer is applied by spraying a solution of the components thereof.

3. A pharmaceutical preparation according to claim 1 or 2 characterized in that the cardiac glycoside is a digitalis glycoside.

4. A pharmaceutical preparation according to claim 1 substantially as described in any one of Examples 1-11 herein.

5. A process for preparing a pharmaceutical preparation comprising a cardiac glycoside (hereinbefore defined) in combination with a polymer, said pharmaceutical preparation being in the form of a plurality of small particles, each ■ >. 5 particle comprising a fraction of a therapeutically effective dosage of the cardiac glycoside, which process comprises providing a large number of cores of pharmaceutically-indifferent YV 2. material thereinbefore defined), with a layer of a composition comprising the cardiac glycoside and an anionic carboxylic polymer which is sparingly soluble or insoluble below a selected pH value within the range of pH 4-7.5 but soluble at a pH above said selected value.

6. A process according to claim 5 characterized in that said layer is formed by applying a solution of the components thereof.

7. A process according to claim 6 characterized in that the solution is applied by spraying.

8. A process according to claim 6 characterized in that said layer is applied in a fluid bed apparatus.

9. A process according to any one of claims 5 to 8 characterized in that the cardiac glycoside is a digitalis glycoside.

10. A process according to claim 5 substantially as described in any one of Examples 1-11 herein.

11. A pharmaceutical preparation obtained by the process according to any one of claims 6 to 10. AKTIEBOLAGET HASSLE By Their Attorneys N.2. PATEN HENRY HUGHES LIMITED 16 JAN 1984 RECEIVED 14 -