CA2026384C - A solid drug form with a high verapamil content - Google Patents

Abstract

A solid drug form containing net less than 90 % by weight verapamil is produced by granulating at from 30 to 55°C with a little water, drying and, where appropriate, conventional tableting or by pelleting, in which case the granules obtained as described are, after cooling, moistened once again and compacted in a granulating mixer at from 30 to 55°C and are dried.

Description

O.Z. 0480/01074 A solid drug form with a hicxh verapamil content The present invention relates to solid drug forms with a distinctly higher verapamil hydrochloride content than previously possible, and to processes for the production thereof.
"Verapamil" in the title and hereinafter always means verapamil hydrochloride. It is, of course, equally possible to use other pharmacologically accceptable salts in amounts appropriately modified from those in the claims.
The maximum content of verapamil in commercial verapamil tablets and cores of film-coated tablets is 70 %. The highest concentration reported is just about 80 % (EP-A 217 778). Higher concentrations cannot be attained because, in the granulating stage necessary before tableting, verapamil tends to become gummy in the granulating equipment and, even after drying, is diffi- .
cult to form into tablets because this tendency also results in adhesion to the die of the tablet press.
Direct tableting of commercial verapamil in high concen-tration (more than 70 %) without previous granulation fails because of, the poor flowability of the commercial raw material, the deficient binding ability despite the addition of readily deformable auxiliaries such as microcrystalline cellulose, and the tendency to become gummy and adhere under high compressive forces.
Because of the relatively large amounts of active compound and added auxiliaries required, verapamil tablets, especially tablets with a coating to delay release, are relatively large and thus unpleasant to swallow.
Hence it was an object of the present invention to develop smaller verapamil tablets, especially smaller delayed release verapamil tablets, or else smaller capsules filled with pellets, each of which contain the same amount of active compound. Fox this it was necessary to find a process for producing granules which have 2~2~~~4 - 2 - O.Z. 0480/01074 satisfactory flowability and a uniform small particle size and are readily formed into tablets, and pellets, each of which have a high veragamil concentration.
We have found that this object is achieved by solid drug forms with a verapamil content of not less than 90, preferably not less than 95 and, in particular, not less than 98, % by weight and processes for the production thereof. Solid drug forms within the meaning of the present invention are granules, pellets, tablets and film-coated tablets. In the latter case, the above-mentioned concentrations relate to the core of the tablets (without coating).
We have found, surprisingly, that verapamil granules which are outstandingly suitable tar forming into tablets and have excellent flowability can be produced with little or no added auxiliaries and thus high content of active compounds, of up to 100 %, in a .
straightforward manner by carrying out the granulation at from 30 to 55, preferably 40 to 50 °C, only with water (from 2 to 10, preferably 3 to 7, % by weight) or with water and small amounts of added release-delaying agent and/or binder, and that repetition of the procedure results in pellets of low porosity with a smooth surface and a diameter of from 0.3 to 1.5 mm, with the mean diameter and at least 70 % by weight being in the range from 0.5 to 1 mm.
The maximum temperature is limited by the start of softening of the mixture. The effect according to the invention is gradually lost at below 30 to 40°C. The necessary energy input should preferably be provided entirely mechanically, but assistance from heating or introduction of warm (in place of cold) water is also possible.
It has emerged, unexpectedly to those skilled in the art, that granulation of commercial verapamil powder at elevated temperature results in a considerably smaller consumption of aqueous granulating medium (water or 20~~~~

- 3 - O.Z. 0480/01074 aqueous suspension or solution of auxiliary) than at normal temperature. Moreover, compaction in a conven-t:ional granulating mixer, preferably a high-efficiency granulator (high-speed mixing element, with or without a cutter, eg. a Ltidige vertical or horizontal granulator or Diosna, Colette, Henschel or Fielder granulator) takes place considerably more ~tltensively than at room tempera-ture and without the substance becoming gummy; the granules have a homogeneous particle size distribution so that not less than 70 % by weight are within a 430 ~cm band within a particle size range of from O.I to I mm, preferably 0.2 to 1 mm. The granules which have been dried to a residual moisture content of 0.5 % or less at from 30 to 50°C in a conventional manner (cf. Handbooks of Pharmaceutical Technology) are equalized by screening without difficulty and without a tendency to become gummy. The process according to the invention can be used .
to produce even fine granules (not less than 80 % by weight below 500 gym) without a large dust content (not more than 10 % below 100 gym) very straightforwardly. In addition, the granules have exceptional flowability so that not less than 250, preferably not less than 300, grams flow through a DIN No. 8 cup in one minute. It is thus possible to use the granules according to the invention to produce microtablets, ie. compressed pellets with a diameter of less than 2.5 mm, which are suitable for filling capsules (multi-unit dose).
The straightforward granulating and compaction process takes from 5 to 30, usually 10 to 15, minutes.
Durinq this time, the temperature of the product should rise into the range indicated above. Repetition of this process with the resulting granules which have been cooled, again adding from 2 to 10 % water, until from 30 to 55°C is again reached, results in the formation of the abovementioned pellets which are of low porosity compared with conventional pellets and have a smooth surface and a bulk density of from 0.5 to 0.7, preferably 0.55 to ~~z~~~~

- 4 - O.Z. 0480/01074 0.65, g/ml and, above all, a verapamil content of previously unattained magnitude.
The pellets produced in this way contain about 3 % water. This water can be substantially removed (ie.
down to about s 0.5 % residual moisture) by conventional drying processes as are described in all handbooks of pharmaceutical technology.
The nature of the binder is not critical, it being possible to emplojj.ill conventional pharmaceutical binders such as gelatin, starch, casein, cellulose derivatives (eg. methylcellulose, hydroxypropylmethyl-cellulose), shellac, polyglycols and polyvinylpyrrolidone in amounts of less than 10, preferably less than 5, in particular less than 2, % by weight based on verapamil.
It is also possible to employ a release-delaying agent in place of a binder or in addition thereto (up to a total amount of auxiliaries not exceeding 10 % by:
weight).
If added auxiliaries, besides a binder and/or release-delaying agent, are required for the tablet core, small amounts of conventional pharmaceutical lubricants and release agents such as magnesium stearate, stearic acid, glycerol tribehenate, Aerosil and talc suffice.
To delay release, the pellets or tablets are Z5 preferably coated with a release-delaying film. However, it ie also possible to introduce small amounts (not exceeding 10 9t by weight) of release-delaying agent during the granulation. Suitable release-delaying materials for the film coatings or for incorporation into the tablet are the conventional ones described in pharma cological textbooks, for example cellulose derivatives and copolymers of acrylic esters and their cationic and anionic derivatives (~Eudragit E, R and S). They are applied dry, as organic solution or, preferably, as aqueous dispersion.
The essential advantages of the granules and pellets according to the invention may be summarized once 2~2~~~~

- 5 - O.Z. 0480/01074 again as follows:
1. They have a substantially uniform particle size.
2. They have a high strength so that they can undergo conventional processes for producing pharmaceutical forms without friability losses.
3. The low content or absence of auxiliaries and additives means that they can be used to produce small and compact and thus easy for patients to take) tablets, whi~.:~ may be film- or sugar-coated, or capsule fillings.
4. The pellets are substantially spherical with a smooth and low-porosity surface so that delay of release can be brought about very reproducibly with a very small amount of coating.

Production of granules 2 kg of powdered verapamil were heated to 40°C in a small, jacketed high-efficiency granulator (UMC 12 mixer, Stephan & StShne, Hameln, FRG) . With maximum energy input, 100 g of water at 40°C was added within 30 sec, and granulation was continued until the temperature had risen to 50°C (for about 5 min). After cooling, the initial granules had the following particle size distri-bution:
< 100 pm < 5 %
< 200 ~m < 13 %
< 430 ~m > 70 %
< 630 Wn > 85 %
< 750 ~m > 99 %.
They were passed without difficulty through an oscillating screener (Frewitt S.A., Fribourg, Switzerland) with a 1.0 mm screen. The granules were dried to a 0.4 % residual moisture in a circulating air oven at 40°C and then passed without difficulty through an oscillating screener with a 0.63 man screen; no clog-ging of the screen occurred. The flowability, measured in a DIN No. 8 cup, was 305 g/min.

2~~~ ~~~~

- 6 - O.Z. 0480/01074 The granules were mixed with 2 % by weight talc and 1 % by weight magnesium stearate and compressed to mechanically stable tablets which were easy to coat, and there Haas no tendency of the tablets to adhere to the sides of the die or faces of the punches.
The granules which had been passed through a 500 ~m screen were compressed to microtablets which had a height of 2 mm and a diameter of 2 mm, with almost spherical convexities, wis . ch had high mechanical strength and low friability and ;~hich could be given a very effective release.-delaying coating with relatively little diffusion-controlling lacquer in a fluidized bed or else in a perforated drum coater.
COMPARATIVE EXAMPLE
When 2 kg of verapamil are granulated in the small high-efficiency granulator of Example 1 under conventional conditions, ie. at room temperature, using .:
pure water, about 300 g are required for uniforms wetting.
The resulting granules cannot be passed through a 1.0 mm screen because an attempt leads to clogging and blockage.
Even after wet screening through a 3 mm screen and conventional drying it is difficult to pass the granules through a 1 mm screen because even the dry granules tend to gum up the screen. Fine granules cannot be produced.
An attempt to compress granules of this type with the addition of small amounts of tableting auxiliaries (2 % talc, 1 % magnesium stearate) fails because pressure on the composition leads to immediate adhesion to the sides of the die and' to the punches. Moreover, the resulting tablets are not bound together; they can be crushed between thumb and forefinger. It was possible to produce satisfactory tablets by including 20 % lactose and 5 % polyvinylpyrrolidone as binders in the granulat-ing fluid, in each case proportions by mass of the dry granules. Furthermore, it was necessary to mix 5 %
microcrystalline cellulose with the composition before compression in order to reduce the tendency to adhesion.

- 7 - O.Z. 0480!01074 However, these conventional granules could not be used to produce microtablets 2 mm in diameter because the particle size could not be reduced sufficiently and the granules tended to adhere to the small punches after a short compression time so that some of the tablets were torn apart when the punches Were retracted.
EXAMPhE 2 Production of pellets kg of verapamil hydrochloride were weighed 10 into a 50 1 mixer with a horizontal propeller and cutter (manufactured by Diosna, Osnabriick). With the mixer running, 0.5 kg of water at 27°C was added. The process protocol is as follows:
Process Time Mixer Cutter Final [min] setting setting temp.[°C]
Start 0 - - 21.5 Addition of Water 1 2 1 22.2 Mixing 20 2 2 45.0 Cooling 60 - - 23.0 Repetition of the moistening and mixing process The moisture content of the pellets at the end of the process was 3.0 %. They were dried on trays in a circulating air oven with the inlet air at 40°C until the residual moisture content was 0.3 %.
The flowability of the pellets was measured after drying. The pellets flowed out of a DIN No. 8 cup in 14-15 sec, which corresponds to 235-250 glmin.
80 % of the pellets had a particle size of from 0.5 to 0.8 mm. The bulk density of the pellets was 0.58-0.60 g/ml.

Claims (10)

1. A solid drug form containing not less than 90 %
by weight verapamil hydrochloride.

2. A solid drug form containing not less than 95 %
by weight verapamil hydrochloride.

3. A solid drug form containing not less than 98 %
by weight verapamil hydrochloride.

4. A solid drug form wherein said verapamil hydrochloride is in the form of granules of which not less than 70% by weight are within a 430 µm band within a particle size range of from 0.1 to 1 mm, and with flowability such that not less than 250 grams flow through a DIN No. 8 cup in one minute.

5. A solid drug form wherein said verapamil hydrochloride is in the form of pellets with a particle size in the range from 0,3 to 1.5 mm, not less than 70% by weight being in the range from 0.5 to 1 mm, and a bulk density of from 0.5 to 0.7 g/ml.

6. A process for producing verapamil hydrochloride granules as claimed in claim 4 by mixing verapamil hydrochloride powder with water or an aqueous solution or suspension of a binder or release-delaying agent, which comprises verapamil hydrochloride powder being vigorously mixed with from 0 to 10% by weight of conventional pharmaceutical auxiliaries and from 2 to 10% by weight of water or the said aqueous solution or suspension and compacted so that the product temperature rises to from 30 to 55°C, and dried.

7. A process as claimed in claim 6, with such vigorous mixing and compaction that the product tempera-ture rises to from 40 to 50°C.

8. A process for producing verapamil hydrochloride pellets as claimed in claim 5, which comprises granules being initially produced by the process of claim 6 or 7 and, after cooling, being once again moistened with from 2 or 10% by weight of water and treated as claimed in claim 6 or 7.

9. A tablet, with or without delayed release, compressed from granules as claimed in claim 4 or pellets as claimed in claim 5.

10. A capsule which is filled with pellets, with or without delayed release, produced as claimed in claim 8.