DK144261C - Medical tablet containing allopurinol - Google Patents

Description

144261

The invention relates to a medical tablet containing allopurinol as an active ingredient as well as a disintegrant, a granulating agent and other tablet auxiliaries.

Allopurinol, 4-hydroxypyrazolo (3,4-d) pyrimidine, is a potent inhibitor of the enzyme xanthine oxidase in vivo. It interferes with a metabolic pathway in the patient 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, very favorable results have been obtained by administering it to patients, 2 144261 suffering from arthritis urica and other hyperuricaemic conditions.

Although daily doses of up to or even over 1 g are occasionally recommended for administration to adult patients under special circumstances, a usual dose of 100 mg allopurinol is administered two to four times per day. today, see 3A 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,

Isom fillers, granulating agents, lubricants and disintegrants, are the 100 mg allopurinol, which represents 22-30% of the weight of the tablet. Losses obtained in this way are now recognized in medical practice and are ble-it taken by hundreds of thousands of patients several times a day, sometimes in a nasty year.

In practice, it was previously strongly recommended that daily doses should be> divided into smaller doses 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 been later shown that oxipurinol has a longer throat ring time than allopurinol, namely between 18 and 40 hours, and it has also been clinically established that a single dose of 300 mg allopurinol taken at a random time during the day can be as effective as 100 g allo-irinol taken three times daily at intervals during the day. Thus, the same uric acid concentrations can be reached in patients, and both the excretion of oxy-srinol 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 ^ 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 throughout the day.

Also, no adverse clinical effect appears to occur as a result: the presence right from the beginning of the larger amount of drug at play, despite the fact that allopurinol and its metabolites interact in a complex manner, and thus the previous administration schedule may be shared. doses that have always been recommended for its 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 multiple dose single-dose tablets introduced as the recommended course of action will be beneficial to the majority of patients. Such administration will significantly help to make it convenient for the patient who only has to take one tablet during the day, e.g. after breakfast. It 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 that 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. the attention must be paid to the size of the tablet, so as to avoid the patient's reluctance to take the tablet that 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% by weight allopurinol is 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 µπι, 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.

4 144261

Allopurinol particles 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 M.D.V. Each particle is thus considered as a sphere of the same volume as that 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.V. value can be determined using a 3oulter counter, wherein the allopurinol powder previously dispersed in an electrolyte comprising an aqueous solution of e.g. sodium chloride saturated with allopurinol, pas s, erg_s through a small aperture in a .r «ear, on each side of which an electrode is immersed. 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 blower and a cyclone: collection of 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. between 28 and 38pm. On the other hand, if an active ingredient content of 5% by weight is required, it is advisable to keep the particle size below 28pm, preferably below 15pm, e.g. of approx. 10pm.

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

Granulating agents which can 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 preferably gelatin.

In the present tablet, from 0.09 to 0.4% by weight can be incorporated into a surfactant suitable for promoting rapid disintegration, such as dioctyl sodium sulfosuccinate. 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 comminuted cilia, such as "Aerosil". especially 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 high degree of 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 Index 15985, and preservatives such as "NipagiiT ^ M" (methyl p-hydroxybenzoate).

Of course, it will have a relatively low content of allopurinol, e.g. 80-90% by weight, it is necessary to either 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 Avicel1, mannitol and preferably lactose. Although it is preferred that the inert filler be used over one of the other components to form the residual up to 100%, it is more preferred, and is actually one of the advantages of the invention, to have a high content of allopurinol, e.g., 90-95% by weight, avoiding the problem of adding or further adding a component to 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 virtually 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 tabletting process can be conveniently carried out according to the usual methods of preparing pharmaceutical products. Thus, the ingredients are mixed in a dry state and usually at a low rate, e.g. 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 pressing the granulate grains in conventional apparatus to the prescribed hard, tablets of the desired size and shape are then obtained, and the product is then tested for compliance with the standard requirements of British Pharoe or United States Pharmacopoeia.

The tablet can be prepared by mixing 80-98 wt.% Allopuride a 2-40 µm particle size with 1-19 wt. Disintegrating-3.1, 1-19 wt. Granulating agent and other tablet adjuvants, then granulating, drying and pressing tablets.

The disintegration time can be determined by the method described in Bri-3harmacopoeia 1968, which involves rapid movement of the tablet under standard conditions until no fragments are left over an unsightly wire mesh (see pages 1366-1367).

British Pharmacopoeia 1968 also states that the disintegration time of each tablet should not exceed 15 minutes, which time should conveniently be less than 10 minutes, especially below 5, for safety reasons, taking into account inevitable variations from the tablet: the tablet. In United States Pharmacopoeia XVIII (1970), a specific 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 granulate if the tablet is prepared should be less than 1? Ό since additional moisture is absorbed unavoidably upon subsequent exposure to air before or after pressing, i.e., higher moisture content, e.g. .g. 3%, gives the risk of mold

The hardness of a tablet is the force required to crush it, or more accurately, its strength, and although it can be accurately measured by various welding methods, the Monsanto method is convenient and suitable for testing the tablet of the present invention. The method requires the use of a net tablet hardness tester, which is a spring-loaded apparatus capable of exerting a slight pressure on one edge of the tablet, and the crushing force is read on a scale on the body of the ate.

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

7 144261

For example, the dissolution time of a tablet can be best quenched using an apparatus comprising a cylindrical basket of stainless steel mesh with mesh width 1680µπι, a covered 1000 ml glass container, a constant temperature water bath and a variable speed motor. 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 was ground down 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 Sun Yellow, Lake Dispersed was prepared, 10.0 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 7o, after which it was sieved through a ιμιη sieve. The granulate was mixed with 50 g of magnesium stearate and 32.7 g of "Aerosil 200". The granulate was pressed into a "Manesty ^ .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 crispness value increased to 3%. The time it took for 50 ° K of the tablet to dissolve in 0.6% HG1 (pH 1.2), hereinafter referred to as T og, and the time it took for 80% of the tablet to dissolve in 0.6% HCl (pH 1.2), hereinafter referred to as T, was 2.5 and 10 minutes, respectively. Each of the tablets weighed 317.65 mg and 80 'contained 300 mg allopurinol.

8 144261

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

The granulation was carried out in a grinding mill fitted with a 0.6 in sight 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%, after which it was sieved through a 100 µm sieve. The granulate was mixed with 50 g of magnesium stearate sieved through a 250μιη sieve. The granulate was pressed into a "Manesty1 iB.3 Rotary Machine" to provide tablets containing 300 mg allo-irinol and a hardness value of 9.5 kg (Monsanto ), a de-integration time of 5 In. 06 sec. and a brittleness value of less than 0.5%. The T ^ q and Tg ^ values were 3 and 10 minutes, respectively. Each of the tablets weighed 315.5 mg and contained 300 mg of Llopurinol.

Example 3 5.0 kg of allopurinol, prepared as in Example 1, 100 g of Primojel and 16.6 g of Mset Yellow, Lake Dispersed were mixed in a planetary stirrer for 10 minutes at 14 rpm. A granulation solution containing 83.3 g of gelatin, L6 g of purified water, 10 g of dioctyl sodium sulfosuccinate and 300 g of alcohol The solution was mixed with the powder for 15 minutes at low speed. The granulation was carried out using a 0.6 cm sieve grinding mill and operated with 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 (00μιη) sieve. The granulate was mixed with 50 g of magnesium stearate which was sieved through a 250μπι The granulate was pressed into a "Manest ^ JB3 Rotary Machine" to provide tablets containing 300 mg allopurinol and having a hardness value of 7 kg (Monsanto), a disintegration time of 3 min 10 sec and a crisp time value of less each of the tablets weighed 315.6 mg and contained 30 mg allopurinol.

Example 4 5.0 kg allopurinol, prepared as in Example 1, and 108 g of "Primojel" blend 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.P. was prepared. Lake 71 Color Index 15985, B.S.S. (British Standard Specification), 458 g of 9 144261 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% and then sieved through a 100pm 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 MManest ^^ B.3 Rotary Machine "to provide tablets containing 300 mg allopurinol and having a hardness value of 10 kg (Monsanto), a disintegration time of 5 minutes 40 seconds and a brittleness value of less than 0.5% and ΤΟΛ were 8 and 28 minutes, respectively. Each of the tablets 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 100 ° B B.S. (British Standard Specification), 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 µl screen and mixed with 10.0 g of magnesium stearate and 6.7 g of Aerosil® P

The granulate was pressed under "Manestj 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%. The ΤΕΛ and Tor. values were 5 min. and 11 min.

50 oU

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

The mixture was then granulated and pressed as in Example 5, drying the granulate to a moisture content of 0.58%. 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 TgQ 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 screened as in Example 5, dried to a moisture content of 1.25% and pressed as in Example 5.

10 144261

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

Example 8 1.0 kg of allopurinol, prepared as in Example 1, 200 g of pregelatinized 3ritish Pharmacopoeia starch and 33.3 g of Primojel were mixed for 10 minutes.

> 0 g of purified water was mixed with the powder for 10 minutes.

The obtained wet mixture was then sieved as in Example 5, dried to an accuracy 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%. T5Q and TgQ were 29 min, respectively. g> 60 min.

Example 9 1.0 kg of allopurinol having a particle size of 34μιη and 66.7 g of "Primojel" landed for 10 minutes. A granulation solution containing 0 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 in Example 5. The wet granulate was dried to a moisture content of 0.51% g 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 TgQ values were 4 min and 9 min respectively.

Example 10 5.0 kg of 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 was prepared. 416 g of purified duck and 300 g of alcohol. The solution was wet mixed with the powder for 15 minutes at high speed (14 rpm).

The granulation was carried out in a grinding mill equipped with a 0.6 m sieve and operated at medium speed. The granulate was then dried in a furnace on trays at 60 ° C for 12 hours to a moisture content of 0.32%, which was then sieved through a ΙΟΟΟμιη sieve. The granulate was mixed with 50 g of magnesium tearate sieved through a 250μπι sieve and 31.7 g of Aerosil 00 sieved through a 300μπι sieve. The granulate was pressed into a "ManestyTJ3 Rotary Ma-hine" 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

Claims (18)

144261 min. and 22 min. Each of the tablets weighed 315.05 mg and contained 300 mg of allopurinol. The same granule was also pressed into a "Manestyatoe Rotary Machine" to provide tablets containing 100 mg allopurinol and having a hardness value of 4.0 kg (Monsanto), a dfes integration time of 1 min 47 sec and a brittleness value of less than 0, The 5% Τ, -q and Tgg values were 6 min and 14 min, respectively. 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, a granulating agent and other tablet excipients, characterized in that it contains 80-98 wt.% Allopurinol having a particle size of 2-40 µm, 1-19 wt.% 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. 1U 261 Tablet according to any one of claims 1-12, characterized in that it contains allopurinol having a particle size of less than 28 microns. Tablet according to claim 14, characterized in that it contains allopurinol having a particle size of less than 15 µm. Tablet according to claim 15, characterized in that it contains allopurinol having a particle size of approx. 10ym. Tablet according to any one of the preceding claims, characterized in that the disintegrant is carboxymethyl starch. Tablet according to any one of the preceding claims, characterized in that the granulating agent is gelatin.