DK144261B - - Google Patents

Description

(19) DENMARK

© (12) PUBLICATION <n> 11 + 4261 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 2801/74 (51) IntCI.3 A 61 K 31/505 (22) Filing Day 22 May 1974 (24) Running Day 22 May 1974 (41) Aim. available Nov. 24; 1974 (44) Presented 1. February 1982 (86) International application # - (86) International filing day - (85) Continuation day - (62) Master application no -

(30) Priority 23 May 1973 * 24628/73 * GB

(71) Applicant THE WELLCOME FOUNDATION LIMITED * London N.W.l GB.

(72) Inventor David Harden, GB: Allan John Torode, GB.

(74) Clerk of the International Patent Office.

(54) Medical tablet containing allopurinol and its method of preparation.

The invention relates to a medical tablet containing allopurinol as an active ingredient as well as a disintegrant, a granulating agent and other tablet adjuvants, and the invention further relates to a process for the preparation of such a tablet.

Allopurinol, 4-hydroxypyrazolo (3,4-d) pyrimidine, is a potent in-OQ hibitor for the enzyme xanthine oxidase in vivo. It interferes with a patient's metabolic pathway and prevents the formation of uric acid from hypoxanthine and xanthine by inhibiting the action of the enzyme xanthine oxidase. It is itself metabolized in vivo to the 4,6-dihydroxy analog (oxipurinol) which inhibits the same system. In addition, allopurinol may act as a substrate for the aforementioned enzyme, thereby contributing to its overall efficiency as an inhibitor of this system. Thus, q has been obtained very favorable results when administered to patients suffering from arthritis urica and other hyperuricaemic conditions.

Although daily doses of up to or even above 1 g have occasionally been recommended for administration to adult patients under special circumstances, the usual dose of 100 mg allopurinol is administered two to four times per day. today, see U.S. Patent Nos. 3,497,307 and 3,624,205. Such amounts of the drug are usually administered in the form of a tablet containing usual excipients such as fillers, granulating agents, lubricants and disintegrants, in addition to the 100 mg allopurinol which represents 22-30% of the weight of the tablet. Tablets provided in this way are now recognized in medical practice and have been taken by hundreds of thousands of patients several times a day, sometimes for a number of years.

In practice, it was previously strongly recommended that daily doses should be divided into smaller doses taken at intervals due to the short half-life of less than 2 hours for allopurinol and an alleged risk of gastric hypersensitivity. However, it has later been shown that oxipurinol has a longer half-life than allopurinol, namely between 18 and 40 hours, and it has further been clinically established that a single dose of 300 mg allopurinol taken at any time during the day can be as effective as 100 g allopurinol taken three times daily at intervals throughout the day. Thus, the same uric acid concentrations can be obtained in patients, and both the excretion of oxipurinol and oxipurines through the urine and the serum concentration of oxipurinol are essentially the same if one or the other administration plan is used. Furthermore, the LD LD value for a single dose of 300 mg allopurinol in mice is not significantly different from the value for the same amount taken in multiple doses during the day.

Also, there appears to be no adverse clinical effect due to the presence right from the beginning of the larger amount of drug in the body, despite the fact that allopurinol and its metabolites work in a complex manner, and consequently the previous administration schedule with shared doses, which have always been recommended for their reliable and smooth effect, are advantageously replaced by a single dose administration plan.

As the clinical requirements for "once-a-day therapy" can be met, the replacement of multiple single-dose tablets, introduced as the recommended treatment plan, will be beneficial to the majority of patients. Such an administration schedule will significantly help to make it convenient for the patient who only needs to take one tablet during the day, e.g. after breakfast. This will increase the likelihood of the patient taking the required amount of medication per day. day.

The single-dose schedule additionally allows the use of a tablet dispensing device, such as a "bubble wrap". Eg. For example, a month's consumption of tablets may be placed on a piece of cardboard with an imprint on each tablet indicating the day on which the tablet is to be taken. The patient's task of usually remembering to take the daily tablet will be greatly simplified. The provision of an increased dose tablet to meet the newly created needs poses many problems. Eg. attention must be given to the size of the tablet to a large extent, so as to avoid the patient's reluctance to take the tablet which could occur if the tablet was too large. Therefore, when increasing the amount of allopurinol, the size of the tablet must be kept sufficiently small without jeopardizing the efficacy of the tablet as a whole.

Furthermore, difficulties are often encountered in the manufacture of a tablet which has a high content of active ingredient, but which retains a sufficiently long disintegration time combined with a satisfactory degree of hardness.

Since allopurinol is a drug usually administered to patients with chronic disease over a long period of time, the above factors are of considerable importance.

It has now been found that a tablet with excellent properties and with a greater amount of allopurinol can be prepared than has hitherto been obtained. These tablets, containing e.g. ca. 95 weight Z allopurinol, are particularly suitable for use as the above-mentioned increased dose tablets.

Such a high content of active ingredient in a tablet has been made possible by the use of allopurinol having a particle size, as defined below, of from 2-40pm and further by reducing the content of the inert filler component which, in addition to the disintegrant and the granulating agent, is usually present in relatively large quantities in conventional tablets, to a minimum or, more preferably and unexpectedly, upon complete omission of this component. When this method is used in the preparation of the increased dose tablet, ie. a tablet containing 300 mg allopurinol, the preparation obtained not only has great similarity in size and physical properties to the conventional 100 mg tablets, but it also has a pharmacological effect in mammals which is practically identical to the same effect of an equivalent majority of conventional tablets when administered over a given period of time, such as 24 hours.

The medical tablet according to the invention is characterized in that it contains 80-98 wt% allopurinol with a particle size of 2-40 µm, 1-19 wt% of a disintegrant and 1-19 wt% of a granulating agent.

In particular, the tablet contains at least 85% by weight, preferably at least 90% by weight, e.g. 95% by weight of allopurinol. Furthermore, tablets containing less than 5% by weight, e.g. ca. 2% by weight of a granulating agent and less than 5% by weight, e.g. ca. 2% by weight of a disintegrant.

A preferred tablet of the invention contains either from 250-350 mg, e.g. 300 mg, or from 50 to 150 mg, e.g. 100 mg, of allopurinol.

144261 4

Particles of allopurinol form elongated, tetragonal prisms, but after grinding, these prisms exist as rounded rods and irregular spheres, and in this specification the particle size is expressed in "average diameter by weight", hereinafter referred to as .i.D. Thus, each particle is considered as a sphere of the same volume as the particular particle, and M.D.V · is the "diameter" relative to whose numerical value 50% of the equivalent spheres have a larger diameter and 50% a smaller diameter. The M.D. value can be determined using a Coulter counter, wherein the allopurinol powder previously dispersed in an electrolyte comprising an aqueous solution of e.g. sodium chloride saturated with allopurinol is passed through a small opening in a tube on either side of which is immersed an electrode. ' The changes of resistance as particles pass through the orifice produce voltage pulses whose amplitudes are proportional to the volume of the particles. The pulses are amplified and the numbers are counted at different threshold values. From this data, the size distribution of the suspended particles and thus the M.D.V. value can be determined.

The particle size of allopurinol can be readily reduced by crystallization methods or by grinding the particles by any known apparatus or in any other known manner suitable for this purpose. In particular, a hammer mill which may be either of the rigid hammer type or of the swing hammer type is preferred and is suitably combined with a fan and a cyclone to collect the material.

The actual particle size of allopurinol to be used depends on the intended content of allopurinol in the tablet. For example, if If 80% by weight of allopurinol is required, the average particle size, e.g. lie between 28 and 38pm. On the other hand, if an active ingredient content of 95% by weight is required, it is advisable to keep the particle size below 28pm, preferably below 15pm, e.g. of approx. 10pm.

Disintegrants which can be used in the tablet of the invention include alginic acid, a sodium starch glycolate, on guar based vegetable gum species, such as "Supercol U" (trade name) or "Supercol F" (trade name), calcium carboxymethyl cellulose such as "ECG 505" , and most preferably "Primojel" (trade name for carboxymethyl starch).

Granulating agents which may be used in the tablet of the invention include starch in the form of mucus and starch derivatives such as starch "Snow Flake" (marketed by Corn Products (Sales) Ltd.), cellulose derivatives such as methyl cellulose, polyvinylpyrrolidone and most preferred gelatin .

In the present tablet, from 0.09 to 0.4% by weight of a surfactant suitable for promoting rapid disintegration, such as dioctyl sodium sulfosuccinate, may be incorporated. However, it is further preferred to use 0.05-0.6% by weight of a surfactant, such as dioctyl sodium sulfosuccinate, in combination with 0.1-1.0% by weight of finely divided silida such as "Aerosil". This combination, in particular when used in a ratio of 3: 1 to 1: 5 (surfactant: finely divided silica), has been shown to contribute even more to accelerate rapid disintegration while still contributing to the achievement of a very satisfactory hardness of a tablet according to the invention.

It is convenient to incorporate a small amount, e.g. ca. 1% by weight, of a suitable lubricant, such as magnesium stearate, in the tablet of the invention, thereby preventing the tablet from adhering to the pistons and molds of the automatic tableting apparatus. If desired, dyes such as "Certolake Sunset Yellow" or "Sunset Yellow F.C.F." can also be added. Lake 1971 Color βΓ)

Index 15985, and preservatives such as "Nipagiir® M" (methyl p-hydroxybenzoate).

Of course, it will have a relatively low content of allopurinol, e.g. 80-90% by weight, it is necessary either to increase the amounts of the other components, such as the disintegrant and the granulating agent, or also to incorporate some inert filler in such amount as to reach 100% by weight.

Fillers which may be used in the tablet of the invention include di-calcium phosphate, microcrystalline cellulose such as "Avicel", mannitol and preferably lactose. Although it is preferred that the inert filler be used over one of the other components to constitute the residual amount up to 100%, it is more preferred, and is actually one of the advantages of the invention, to have a high content of allopurinol. eg. 90-95% by weight, thereby avoiding the problem of adding or further adding a component to be included as the remaining amount up to 100%.

Of course, since a short disintegration time is associated with a low hardness for the type of drug that has allopurinol's physical properties, the various claims must of course be carefully matched, and it has been very difficult, or even proved impossible, to provide. a tablet of a similar size to the conventional tablet, but with a higher allopurinol content, e.g. 300 mg, without applying the conditions of the invention.

Apart from the component amounts listed above and the property requirements listed, the tableting process can be conveniently carried out according to the usual methods of preparing pharmaceutical products. Thus, the ingredients are mixed in the dry state and usually at low speed, e.g. ca. 15 rpm, in a planetary agitator, then mixing wet for up to approx. 30 minutes with an aqueous alcohol granulation solution and a granulating agent and, if necessary, with additional solvent to maintain the consistency of the pulp. The material is then ground and dried on trays at approx. 50 ° C for several hours or alternatively dried in a fluidized bed at approx. 60 ° C for approx. 30 minutes. The dry material is sieved and the lubricant is added to the granules thus obtained. By compressing the granular granules in usual apparatus to the specified hardness, tablets of the desired size and shape are then obtained and the product is then tested to verify that it meets the standard requirements of British Pharmacopoeia or United States Pharmacopoeia.

According to the invention there is also provided a process for the preparation of a tablet comprising, containing allopurinol as an active ingredient as well as a disintegrant, a granulating agent and other tablet excipients, characterized in that 80-98% by weight of allopurinol having a particle size of 2- 40 µm are mixed with 1-19 wt Z disintegrant, 1-19 wt Z granulating agent and other tablet adjuvants, after which the mixture is granulated, dried and pressed into tablets.

The disintegration time can be determined by the method described in British Pharmacopoeia 1968, which involves rapid movement of the tablet in water under standard conditions until no fragments are left over a supporting wire mesh (see pages 1366-1367).

British Pharmacopoeia 1968 also states that the disintegration time of any tablet should not exceed 15 minutes, but this time should conveniently be less than 10 minutes, especially less than 5 minutes, for safety reasons, taking into account inevitable tablet-to-tablet variations. In United States Pharmacopoeia XVIII (1970), a specific maximum disintegration time for allopurinol of 45 minutes is specified. In addition to this essential requirement, it is generally recommended that the moisture content of the granules from which the tablet is made should be less than 1%, since? additional moisture is inevitably absorbed by subsequent exposure to air before or after pressing. Significantly higher moisture content, e.g. 3%, gives the risk of mold growth.

A tablet "thawed" is the force required to crush it, or more properly, the crushing strength, and although it can be accurately measured by various standard methods, the Monsanto method is convenient and suitable for testing the tablet of the present invention. The method requires the use of a Monsanto tablet hardness tester, which is a spring loaded device capable of exerting a radial pressure on one edge of the tablet, and the crushing force is read on a scale on the device housing.

A tablet's brittleness is a measure of the weight loss that a tablet undergoes during wear or shock, and it can be measured by a "Roche Friabilitor" whereby a weighted sample of tablets in the apparatus is subjected to wear under a corresponding upheaval, that the tablets rub against each other or shake against the walls of their container in ordinary use, and are subjected to a shock resulting from a free fall of 15 cm, which the tablets may experience during various stages of packaging, handling and transport.

144261 7

For example, the dissolution time of a tablet can be determined according to U, S, P, XVIII using an apparatus comprising a cylindrical basket of stainless steel mesh of mesh size 1680µπι, a covered 1000 ml glass container, a constant temperature water bath and a motor with variable speed. The dissolution medium, which for example may be 0.6% hydrochloric acid, pH 1.2, is poured into the container which is pre-immersed in the constant temperature bath and allowed to adjust to a temperature of 37 ° C. A tablet is placed in the basket and the apparatus is assembled so that the basket is completely submerged in the medium. The curve is rotated with e.g. 120 rpm and at intervals samples are taken with a syringe, which samples are tested, e.g. using ultraviolet absorption.

The invention and the advantages thus obtained are further elucidated by means of the following examples.

Example 1

Allopurinol is grinded to a particle size with an M.D.V. at 10pm using a "Micropul mill" connected to an air filter system in a "No. 2 Pallman mill".

5.0 kg allopurinol and 100 g of Primojel were mixed in a planetary stirrer for 10 minutes at 14 rpm. A granulation solution containing 100 g of gelatin, 2.5 g of Bunset Yellow, Lake Dispersed, 10.0 was prepared. g of dioctyl sodium sulfosuccinate, 520 g of purified water and 400 g of alcohol. The solution was wet mixed with the powder for 15 minutes at low speed. The granulation was carried out in a grinding mill fitted with a 0.6 cm sieve and operated at a medium speed. The granulate was then dried in a fluidized bed at 60 ° C for 20 minutes to a moisture content of 0.4 l, then sieved through a 100 µm sieve. The granules were mixed with 50 g of magnesium stearate and 31.7 g of "Aerosil 200". The granulate was pressed into a "ManestyB.B.3 Rotary Machine" to provide tablets containing 300 mg allopurinol and with a hardness value of 12.0 kg (Monsanto), a des integration time of 6 min. 54 sec. and a brittleness value of less than 0.5%. By compressing to a hardness value of 7.0 kg, the integration time was reduced to 3 minutes. 14 seconds, and the brittleness value increased to 3 7 '. The time it took for 50% of the tablet to dissolve in 0.6% HCl (pH 1.2), hereinafter referred to as T in 0.6% HCl (pH 1.2), hereinafter referred to as T, were 2.5 and 10 minutes, respectively. Each of the tablets weighed 317.65 mg and 80 contained 300 mg allopurinol.

144261 8

Example 2 5.0 kg of allopurinol, prepared as in Example 1, 105 g of Primojel and 16.6 g of Sun Yellow, Lake Dispersed were mixed in a planetary stirrer for 10 minutes at 14 rpm. A granulation solution containing 83 , 3 g of gelatin, 416 g of purified water and 300 g of alcohol. The solution was wet mixed with the powder for 15 minutes at low speed.

The granulation was carried out in a grinding mill fitted with a 0.6 cm sieve and operated at a medium speed. The granulate was then dried in an oven on trays at 60 ° C for 12 hours to a moisture content of 0.35% and then sieved through a 100 µg sieve. The granulate was mixed with 50 g of magnesium stearate sieved through a 250 µm sieve. The granulate was pressed into a "Manes Ty ^ BB3 Rotary Machine" to provide tablets containing 300 mg allopurinol and a hardness value of 9.5 kg (Monsanto) , a disintegration time of 5 min. 06 sec. and a brittleness value of less than 0.5 7 ". The T1 and TgQ values were 3 and 10 min, respectively. Each of the tablets weighed 315.5 mg and contained 300 mg allopurinol.

Example 3 5.0 kg allopurinol, prepared as in Example 1, 100 g of Primojel and 16.6 g of Sunset Yellow, Lake Dispersed were mixed in a planetary stirrer for 10 minutes at 14 rpm. A granulation solution containing 83 , 3 g of gelatin, 416 g of purified water, 10 g of dioctyl sodium sulfosuccinate and 300 g of alcohol. The solution was wet mixed with the powder for 15 minutes at low speed. The granulation was carried out in a grinding mill fitted with a 0.6 cm sieve and operated at medium speed. The granulate was then dried in a fluidized bed at 60 ° C for 20 minutes to a moisture content of 0.4% and then sieved through a ΙΟΟΟμπι sieve. The granulate was mixed with 50 g of magnesium stearate which sieved through a 250 µm sieve. The granulate was pressed into a "Manest ^^ B.3 Rotary Machine" to provide tablets containing 300 mg allopurinol and with a hardness value of 7 kg (Monsanto), a disintegration time of 3 min. 10 sec. and a brittleness value of less than 0.5%. Each of the tablets weighed 315.6 mg and contained 300 mg allopurinol.

Example 4 5.0 kg allopurinol, prepared as in Example 1, and 108 g of "Primojel" are mixed in a planetary stirrer for 10 minutes at 14 rpm. A granulation solution containing 91.7 g of gelatin, 2.5 g of Sunset Yellow F.C.F. was prepared. Lake 1971 Color Index 15985, B.S.S. (British Standard Specification), 458 g of U4261 9 purified water and 300 g of alcohol. The mixture was wet mixed with the powder for 15 minutes at low speed. The granulate was then dried in a fluidized bed at 60 ° C for 20 minutes to a moisture content of 0.25 µm, after which it was sieved through a 100 µm sieve. The granulate was mixed with 50 g of magnesium stearate which was sieved through a 250 µm sieve. The granulate was pressed into a "Manest ^^ B.3 Rotary Machine" to provide tablets containing 300 mg allopurinol and with a hardness value of 10 kg (Monsanto), a des integration time of 5 min. 40 sec, and a brittleness value of less than 0.5%. T and T were 8 and 28 min, respectively. Each of the loss-

-) You oU

the digits weighed 315.15 mg and contained 300 mg allopurinol.

Example 5 1.0 kg of allopurinol, prepared as in Example 1, and 50.0 g of "Primojel" were mixed for 10 minutes. A granulation solution containing 33.4 g of gelatin, 2.0 g of dioctyl sodium sulfosuccinate, 83.0 g of purified water and 40.0 g of alcohol was prepared. The solution was wet mixed with the powder for 10 minutes.

After sifting through a 1000pm B.S.S. (British Standard Specification) sieve, the granulate was dried in a fluidized bed at 60 ° C for 20 minutes to a moisture content of 0.63%.

The dried granules were sieved through a 100 µm sieve and mixed with 10.0

/ gS

g of magnesium stearate and 6.7 g of Aerosil

The granulate was pressed into "ManestyTJ. 3 Rotary Machine" to provide tablets containing 300 mg allopurinol and with a hardness value of 12.0 kg (Monsanto), a disintegration time of 5 min. 57 sec. and a crispness value of 0.5 7 ». The T ^ q and Tg0 values were 5 min, respectively. and 11 min.

Example 6 1.0 kg allopurinol with an M.D.V. of 38μιη, 84.3 g of Primojel and 66.7 g of lactose were mixed for 10 minutes.

The mixture was then granulated and pressed as in Example 5, the granulate being dried to a moisture content of 0.58 7 The tablets had a hardness value of 10 kg (Monsanto), a disintegration time of 6 min. 40 sec. and a brittleness of 0.32 7o. and the Tg0 values were 6 min, respectively. and 10 min.

Example 7 1.0 kg of allopurinol, prepared as in Example 1, and 200 g of corn starch were mixed for 10 minutes. A granulation solution was prepared containing 33.3 g of polyvinylpyrrolidone K. 30, 150 g of purified water and 120 g of alcohol. The solution was wet mixed with the powder for 10 minutes.

The obtained wet mixture was then sieved as in Example 5, dried to a moisture content of 1.25% and pressed as in Example 5.

14426 1 ίο

The tablets had a hardness value of 10 kg (Monsanto), a disintegration time of 2 min. 10 sec. and a brittleness of 0.49%. The T ^ Q and ^ values were 2 min, respectively. and 4 min.

Example 8 1.0 kg of allopurinol, prepared as in Example 1, 200 g of pregelatinized (British Pharmacopoeia) starch and 33.3 g of Primojel were mixed for 10 minutes.

550 g of purified water were mixed with the powder for 10 minutes.

The obtained wet mixture was then sieved as in Example 5, dried to a moisture content of 1.33% and pressed as in Example 5.

The tablets had a hardness value of 10 kg (Monsanto), a disintegration time of 5 min. 30 sec. and a brittleness of 0.33%. T ^ Q and TgQ were 29 min, respectively. and> 60 min.

Example 9 1.0 kg of allopurinol with a particle size of 34μπι and 66.7 g of "Primojel" were mixed for 10 minutes. A granulation solution containing 60 g of polyethylene glycol 6000 and 110 g of purified water was prepared.

The solution was wet mixed with the powder for 10 minutes and then sieved as in Example 5. The wet granulate was dried to a moisture content of 0.51% and then pressed as in Example 5.

The tablets had a hardness value of 5 kg (Monsanto), a disintegration time of 3 min. 15 sec. and a brittleness of 0.48%. The T ^ q and Tg ^ values were 4 min and 9 min, respectively.

Example 10 5.0 kg allopurinol prepared as in Example 1 and 83.4 g of Primojel were mixed in a planetary stirrer as in Example 2. A granulation solution containing 83.3 g of gelatin, 2.5 g of methyl hydroxybenzoate, 416 g of purified water was prepared. and 300 g of alcohol. The solution was wet mixed with the powder for 15 minutes at low speed (14 rpm).

The granulation was carried out in a grinding mill fitted with a 0.6 cm sieve and operated at medium speed. The granulate was then dried in an oven on trays at 60 ° C for 12 hours to a moisture content of 0.32%, then sieved through a 100 µm sieve. The granules were mixed with JO g of magnesium stearate sieved through a 250 µm sieve and 31.7 g of "AerosiflOO" sieved through a 300 µm sieve. The granulate was pressed into a "ManestyTJ3 Rotary Machine" to provide tablets containing 300 mg allopurinol and with a hardness value of 8.8 kg (Monsanto), a disintegration time of 4 min. 55 sec. and a brittleness value of less than 0.5%. The T ^ Q and Tg ^ values were 11, respectively

Claims (13)

144261 11 min. and 22 min. Each of the tablets weighed 315.05 mg and contained 300 mg allopurino1 '. The same granulate was also pressed into a "Manestyu3 Rotary Machine" to provide tablets containing 100 mg allopurinol and with a hardness value of 4.0 kg (Monsanto), a disintegration time of 1 min. 47 sec. and a brittleness value of less than 0.5%. and the TgQ values were 6 min, respectively. and 14 min. Each of the tablets weighed 105 mg and contained 100 mg allopurinol. A medical tablet containing allopurinol as an active ingredient as well as a disintegrant, granulating agent and other tablet excipients, characterized in that it contains 80-98% by weight allopurinol having a particle size of 2-40pm, 1-19% by weight of a disintegrant and 1 -19% by weight of a granulating agent. Tablet according to claim 1, characterized in that it contains at least 85% by weight of allopurinol. Tablet according to claim 2, characterized in that it contains at least 90% by weight of allopurinol. The tablet according to claim 3, characterized in that it contains approx. 95% by weight allopurinol. Tablet according to any one of the preceding claims, characterized in that it contains less than 5% by weight of the granulating agent. Tablet according to claim 5, characterized in that it contains approx. 2% by weight of the granulating agent. Tablet according to any one of the preceding claims, characterized in that it contains less than 5% by weight of the disintegrant. Tablet according to claim 7, characterized in that it contains approx. 2% by weight of the disintegrant. Tablet according to any one of the preceding claims, characterized in that it contains 250-350 mg allopurinol. Tablet according to claim 9, characterized in that it contains approx. 300 mg allopurinol. Tablet according to any one of claims 1-8, characterized in that it contains from 50-150 mg allopurinol. Tablet according to claim 11, characterized in that it contains approx. 100 mg allopurinol. Tablet according to any one of the preceding claims, characterized in that it contains allopurinol having a particle size of from 28 to 38 µm.