IE52985B1 - Pharmaceutical composition - Google Patents

Abstract

1. A pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds, is intended for oral administration to produce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound to pharmaceutical auxiliaries, wherein the calcium-antagonistic active compound is Gallopamil or Verapamil and wherein, at the sustaining dose, the ratio of the constituents with rapid release of active compound to those with sustained release of active compound is from 1 : 0.6 to 1 : 6.

Description

PATENT APPLICATION BY (71) BASF AKTIENGESELLSCHAFT, A GERMAN JOINT STOCK COMPANY OF 6700 LUDWIGSHAFEN, FEDERAL REPUBLIC OF GERMANY.

Price 90p - 2 The present invention relates to a novel pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds .

In therapy by medication, the use of oral pharmaceutical compositions with sustained release of the active constituents is conventionally practiced and is in particular necessary to lengthen the time for which a drug acts, especially in the case of drugs with relatively short biological half-lives. Compositions for oral administration which show sustained release of the active compounds substantially increase patient compliance.

The fact that these pharmaceutical forms have to be taken less frequently than conventional non-sustained release composi15 tions ensures greater therapeutic safety.

Moreover, the use of compositions for oral administration with sustained release of the active compounds . often avoids undesirable concentration peaks in the plasma.

Sustained release compositions are required to have an initial phase with rapid active compound release followed by a phase in which the concentration is sustained, so as to lengthen the period for which the plasma concentration is at the therapeutically desired level. The initial phase is absolutely essential in order to reach the requisite plasma level very rapidly. This type of sustained-release drug is described as ideal, cf. Pharmazeutische Technologie (Thieme Verlag, Stuttgart), - 3 1978, page 487. Frequently also, sustained release drugs which do not have an initial dose effect, but only release the sustaining dose, are employed - especially in therapeutic agents for long-term or continuous treatment. The sustaining dose is released uniformly, in a persistant manner.

On repeatedly taking a drug, a steady state is set up between the active compound eliminated from the plasma and the active compound taken up by the plasma, the steady state depending on the biological half-life.

To reach steady state concentrations of the therapeutically required order, frequent administration is necessary with compounds of short half-lives, and this is undesirable from the point of view of patient compliance.

A similar situation applies to compounds of longer half-life, where a major proportion is metabolized before reaching the body's principal circulatory system (as in the case of the first-pass effect in the intestine and/or the liver). Consequently, sustained release compositions of compounds exhibiting a pronounced first-pass effect are generally viewed very critically (Der Internist 19 (1978), 333, Pharm. Ind. 40 (1978), 374, especially page 381, left-hand column).

Substances exhibiting a pronounced first-pass effect include a range of β-receptor blocking agents, eg. propranolol, or of calcium antagonists, eg. verapamil and gal1opami1.

U.S. Patent 4,248,858 describes a novel sustained - 4 release composition of propranolol. In this, 160 mg of propranolol are present in a compressed core, the release of active compound being sustained because the material is embedded in gelling agents and insoluble polymers. The core is separated from an outer coating, which contains a further 20 mg of propranolol, capable of rapid release, by a film which is resistant to gastric juices and which is intended to prevent the active compound in the sustained release core from being released whilst the core is still in the stomach This composition is only suitable for substances like propranolol which, on first pass through the liver, forms 4-hydroxypropranolol, whose activity is similar to that of propranolol itself (Brit. J. Pharmacy (1971) 43, 222).

The present invention provides a novel pharmaceutical composition which contains a calcium-antagonistic active compound, with or without additional active compounds, is intended for oral, administration to p?o20 duce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound with pharmaceutical auxiliaries, in which composition the calcium-antagonistic active compound is gallopamil or verapamil and wherein, at the sustaining dose, the ratio of the constituents with rapid release of active compound to those with slow release of active compound is from 1 : 0.6 to 1 : 6.

Verapamil (X = H) and gallopamil (X = OCH^) have the formula - 5 CH_O CHjO- OCH.

’-OCnX CHIn drugs, the compounds are preferably employed as hydrochlorides.

In addition to these compounds, the novel composition may contain further active compounds, such as diuretics, psychopharmaceuticals and hypotensive agents. These additional active compounds are present in the rapid-release phase and/or the slow-release phase, depending on the order of magnitude of the biological half-life of the particular compound.

The ratio of rapidly released verapamil or gallopamil to slowly released active compound in the pharmaceutical is from 1 : 0.6 to 1 : 6, preferably from 1 : 1 to 1 : 4, especially from 1 : 1.2 to 1 : 3.

This ratio ensures, provided the right dosage is given, that substantially constant and therapeutically correct plasma levels result, the active compounds being released during the time of passage through the stomach and small intestine (as a rule from 3 to 5 hours). 2o The pharmaceuticals can be prepared in a conventional manner. Thus, coated tablets or layer tablets, in which a layer or the core consists of granules of the sustained release composition and a further layer or the coating consists of granules which rapidly release the active com25 pound, or sustained release coated pills, in which the sustained release core is coated with a sugar layer which also contains the 53985 - 6 active compound but releases it rapidly, can be prepared by conventional and widely used methods.

Granules which release the active compound rapidly are obtained by granulating the latter with sugar, cellulose, starch and binders, and adding mold lubricants and flow regulators to the granules.

The content of active compound in the granules can vary within wide proportions but is preferably from 40 to 80%. If these granules are used as the coating material for coated tablets, or are used in twolayer tablets, it is found that the rate of release of active compound is substantially independent of the pressure used when pressing the tablets.

If gelling agents are used, granules with sus15 tained release of active compound can be obtained, which do not dissolve in the digestive tract but form swollen particles from which the active compound slowly diffuses into the digestive juices.

Particularly suitable gelling agents are algin20 ates, eg. sodium alginate, especially those which, as a 10% strength aqueous solution, have a viscosity of from 100 to 3,000 cp at 20°C. If low-viscosity alginates are used, it is advisable to add water-insoluble natural materials, such as celluloses or starches, whilst when high-viscosity alginates are employed,the addition of soluble substances, such as lactose or low molecular weight polyethylene glycols, is useful. Suitable rates of - 7 release can also be achieved by employing polyacrylic acid derivatives and polymethacrylic acid derivatives. The pressure employed for tableting can, in the case of the granules with sustained release of the active compound, also influence the rate of release.

It is also possible to introduce the active compound in the form of sustained release granules or compressed cores conjointly with the free or non-sustained release active compound into one therapeutic unit, for example a hard gelatin capsule.

The invention makes it possible to provide pharmaceuticals which contain verapamil or gallopamil and give a constant and effective level of action over a long period.

The novel sustained release drugs are exceptionally useful as therapeutic agents for prolonged administration a therapeutically active plasma level with relatively little variation being achieved over the entire period of therapy. A drop in the plasma level into the subtherapeutic range will not occur if the drug is taken regularly. Moreover, the novel sustained release form allows the frequency of administration to be reduced to once or twice daily, thereby substantially improving patient compliance. The safety of the drug is also improved.

Finally, the novel composition has the advantage that it can be prepared very simply, by means of conventional processes. - 8 EXAMPLE 1 A. Preparation of the starting granules a) Granules with rapid release of active compound .6 kg of verapamil, 4 kg of cellulose powder, (r) 0.6 kg of Kollidon VA 64 and 4 kg of lactose were very thoroughly mixed and then moistened by adding 6 liters of water, with stirring. The mixture was then mechanically stirred vigorously and kneaded to give a crumbly moist mass which was converted to granules by forcing it through a sieve. The granules were dried and then again sieved. 0.7 kg of cellulose powder and 0.1 kg of magnesium stearate were added, giving granules suitable for pressing. b) Granules with sustained release of active compound kg of verapamil, 25 kg of sodium alginate, kg of Kollidon 30 (linear polyvinylpyrrolidone, molecular weight 30,000) and 5 kg of cellulose powder were very thoroughly mixed and moistened with 17 kg of water, while stirring. The mixture was then mechanically stirred vigorously and kneaded to give a crumbly moist mass which was converted to granules by forcing it through a sieve. The granules were dried and then again sieved. 1.75 kg of cellulose powder and 0.25 kg of magnesium stearate were added, giving granules suitable for pressing.

B. Preparation of the finished tablets Tablets of the following composition were formed on a press for the production of two-layer tablets: lower layer: 190 mg of granules Aa (100 mg of verapamil) 53385 - 9 upper layer: 500 mg of granules Ab (140 mg of verapamil). To mask the flavor, the tablets obtained were coated with a film-forming lacquer of cellulose derivatives, conventional plasticizers and dyes.

EXAMPLE 2 Aa) Following a procedure similar to Example 1 Aa, granules with rapid release of active compound were prepared by granulating sugars, celluloses or starches with the active compound and a binder. Mold lubricants and flow regulators were then added, giving granules of the following compositions: - ίο o GO m in in o in o KT o (O in in o co id J CQ en ft CD a φ ft a (!) o a ε o o co tn CO in co CM in O CO CO CM o O CM o o CM o o CM co in O CO CO CM o o CM in o CM i i co in i in ^r O CM •μ ε co a co ft o > CO CO ft cO < r-i QJ > o 4J £ CO r-i O c £ •ri ft 0 0 O ε ε cO ca Ό 3 CO +3 0 •ri •H •K Q. tn i—i r-i r-i ca O 3 r-i r-i r-I c i-Ί O 0 c r-i ft r4 bO o o o © © o 4J O <0 - 11 Ab) Using a method similar to Example 1 Ab, granules with sustained release of active compound were prepared with the following compositions: - 12 TABLE ς. Ο. to *Ρ (0 CL c •H c •H -P •H Ώ O CL ε o o cm CM l I t o I 1 co 10 CM co 00 I I o 1 1 co rH in (O in co ’T (O | I o I co co T in in co CM r- o I 1 o I co in in m CM co • • • • c*- o !>· I o I I co in in - in CM co • • • • o r» 1 o 1 1 co m in in co CM c^ o I I o 1 co in o © CO lO CO CO > l Φ Ο I I I I I co W CD O 00 I CO O I ! I I I CM ΙΛ rH •p nJ c •H to <—1 nJ O CO ΰ o Ό Sh TJ O o. Ό) 4-3 OJ u (0 -μ to ε Ή ο Ο •H <0 ε rH co rH W Or □ rH ο 3 0 nJ Ή Ο 4J rH C q Ό bi Ο rH to 0 Ο © nJ 0 nJ > CO •J o £ x: o &4 (0 P Polyethylene glycol TABLE 3 Substances Composition in parts per 100 Gallopamil 20 22.5 Sodium alginate 50 44.4 ©Kollidon 30 7.5 6.6 Cellulose powder 4.5 5.5 Magnesium stearate 0.5 0.4 Lactose 17.5 10.6 B. Tablets were prepared, by a method similar to that of Example 1 B, from the granules listed in Tables 1 to 3. The amounts of free active compound were from 60 to 150 mg, and the amounts of bound active compound from 80 to 190 mg in the case of verapamil; for gallopamil, the corresponding values were from 30 to 80 and from 40 to 100 mg, respectively.

EXAMPLE 3 Compressed cores containing 140 mg of verapamil were prepared from the granules obtained as described in Example 1 Ab. The compressed cores were then coated in a press coater with a layer of the granules of Example 1 Aa (active compound content 120 mg of verapamil), and were subsequently coated with a film lacquer, by a method similar to Example 1 B, EXAMPLE 4 The granules obtained as described in Example 1 Ab were pressed to form compressed cores containing 150 mg of verapamil or 75 mg of gallopamil. The compressed cores were then provided with coatings of the composition - 145 shown in Table 4, in such a way that the coatings contained 90 mg of verapamil or 45 mg of gallopamil.

TABLE 4 Substances Composition in parts per 100 Verapamil 26.3 - 69.5 - 35.4 45.7 Gallopamil - 26.3 - 69.5 - - Water 26.3 26.3 5.2 5.2 25.8 20 Sugar 26.4 26.4 - - 24.6 15.1 Talc 10.5 10.5 17.4 17.4 8.9 12 Methylcellulose 10.5 10.5 - - 2.2 3 Gum arabic - - 3.5 3.5 0.9 1.2 ®Aerosil - - - - 2.2 3 Polyethylene glycol 400 However, this process is involved, since the water must be removed. Moreover it is very difficult to achieve good content uniformity in the coating. The best results were obtained with coatings having a low content of active compound. The cores were given a smooth coating with a 70% strength aqueous sugar solution (from about 20 to 40 g of the solution being required per 10 kg batch of the cores), and a film coating was then applied, on top as described above.

In the Examples the registered trademarks stand for the following materials: ©Kollidon V 64: Copolymer of ' vinylpyrrolidone and vinyl acetate in the ration of 6 : 4 - 15 - ® Kollidon 30: Linear polyvinylpyrrolidone, molecular ©Kollidon 90: weight 49,000 Linear polyvinylpyrrolidone, molecular 5 ®Eudragit RL: weight 1,100,000 Polyacrylic acid and polymethacrylic ®Aerosil: acid derivatives Highly disperse silica 2985

Claims (6)

1. Λ pli.-irni.ii nut. i en 1 compos j tjuri which contains a calcium-antagonistic active-compound, with or without one or more additional active compounds, is intended for oral administration to produce a sustained action for continuous therapy and contains only the sustaining dose of active compound, bound with one or more pharmaceutical auxiliaries, wherein the calcium-antagonistic active compound is gallopamil or verapamil and wherein, at the sustaining dose, the ratio of the constituent(s) with rapid release of active compound to the eonstituent(s) with sustained (slow) release of active compound is from 1:0.6 to 1:6.

2. A composition as claimed in claim 1, wherein the ratio of the constituent(s) with rapid release of gallopamil or verapamil to the constituent(s) with sustained (slow) release of gallopamil or verapamil is from 1:1.2 to 1:3.

3. A composition as claimed in claim 1 or 2, wherein gallopamil hydrochloride or verapamil hydrochloride is employed as sole active compound or in conjunction with a diuretic, psychopharmaceutical or hypotensive agent.

4. A process for the preparation of a pharmaceutical composition as claimed in claim 1, wherein the active compound in rapid release form and the active compoundin slow release form are incorporated into the composition in a ratio of from 1:0.6 to 1:6.

5. A process as claimed in claim 4 carried out substantially as hereinbefore described or as illustrated in any of the foregoing Examples.

6. A pharmaceutical composition as claimed in claim 1 when prepared by a process as claimed in claim 4 or 5.