CAPTOPRIL TABLETS

Abstract: The invention relates to captopril tablets comprising a filler and binding agent, a disintegrating agent, a lubricant and a glidant agent wherein the filler and binding agent is a 1.5:1 - 1:1 weight ratio mixture of lactose and microcrystalline cellulose and the total amount of said mixture is 60-80 % by weight of the totalweight of the tablet. The captopril tablets of the present invention are highly stable, can be readily manufactured and the standard deviation of the active ingredient content of the individual tablets and also of the parts of tablets split into two or four parts is very low.

Description: C a p to p r i l ta b l e ts Background of the invention This invention relates to tablets containing captopril as active ingredient and a process for the preparation thereof It is known that (S)-1-(3-mercapto-2-methyl-1-oxo- propyl)-L-prolιne (International Non-propπatory Name, INN, "captopril") is a competitive ACE inhibitor, decreases arterial and venal vascular tone, the complete peπfeπal vascular resistance, the cardial pre- and post-loading and increases the minute-volume Preparation of captopril is disclosed in Hungarian patent No 181 ,965 The active ingredient content of captopril tablets used in therapeutical practice amounts to 6 25-100 mg and the daily dosage is 6 25-300 mg Captopril is highly sensitive to oxidation and captopril disulfide is formed on the thiol group in a free radical oxidation process In solid pharmaceutical compositions the velocity of decomposition is increased during the drying step of the manufacturing process and also by the moisture content of the composition In the preparation of captopril compositions particular care is to be taken to select a suitable auxiliary agent system and manufacturing process, respectively, which induces decomposition and oxidation of the active ingredient to the smallest extent It is well-known to the skilled art worker dealing with formulation that captopril is susceptible to decomposition Several patent specifications are directed to this problem According to Japanese patent Ns 86 36,127 the stability of active ingredients comprising a thio group - including captopril - may be improved by using ascorbic acid, sodium ascorbate, enthorbinic acid or the sodium salt thereof, sodium bisulfite sodium sulfite and/or sodium metabisulfite According to Japanese patent Ns 82 112,367 in injectable solutions the stability of captopril may be augmented with the aid of ammo acids and salts thereof Japanese patent Ns 94 32,776 relates to the use of antioxidants as well According to US patent Ns 5,158,777 the simultaneous use of disodium edetate and ascorbic acid is suggested However, the use of the above antioxidants - with the exception of ascorbic acid - is accompanied by sanitary risks because said substances may often cause allergic symptoms However according to the disclosure of US patent Ns 5,158,777 ascorbic acid failed to exhibit satisfactory stabilising effect when used βer se Another problem emerging in the therapeutical use of captopril compositions is that the individual dose of the compositions varies to a large extent and that in chronical treatment the applicable dose can only be adjusted by gradual increase of the dosage In order to provide flexible dosage of pharmaceutical compositions containing captopril which can be readily adjusted in view of the individual requirements of the patients, there is a strong need for tablets which have a variable active ingredient content within wide limits one the one hand and can be broken to two parts (halved) on the other Constant active ingredient delivery requires that compositions having different active ingredient content should be made available with identical percentual composition on the one hand, and that when splitting the composition the active ingredient content should be substantially the same in each part of the tablet on the other It is very important that the manufacturing process should ensure high homogenity of the active ingredient and the auxiliary agents in the composition The known processes for the manufacture of pharmaceutical compositions containing captopril fail to comply completely with the above requirements In European patent publication EPA Ns 288,732 captopril containing pellets filled into capsules and prepared by extrusion and spheronization are disclosed Such pellets contain 3-60 % of the active ingredient and 5-50 % of a carboxylic acid facilitating pellet formation The preparation of oral osmotic compositions is disclosed in PCT WO 91/01 ,130 This composition is a two- layered tablet coated with a semipermeable layer One layer contains the active ingredient and the other layer comprises a water-swellable polymer, while a bore is drilled into the layer containing the active ingredient through which the active ingredient is delivered into the organism The preparation of zero order sustained release coated tablets is disclosed in US patent specification Ns 4 756 911 The tablet core contains at least 70 % of active ingredient and 5-15 % of a hydrocolloidal gel forming auxiliary agent particularly hydroxypropyl methyl cellulose, and the coating of the tablet consists of a 4 1 - 1 4 mixture of at least one hydrophlic polymer and at least one hydrophobic polymer The preparation of compositions comprising gel forming auxiliary agents (e g a polymer comprising a lactame group and a polymer comprising a carboxy group) and a gas forming auxiliary agent (e g sodium hydrogen carbonate) is disclosed in European patent publication Ns EPA 669,129 Sustained release capsules comprising a semisolid filling, which consists of at least one fatty acid glyceπde and/or polyethylene glycol ester, are disclosed in US patent Ns 5,433,951 Summary of the invention It is the object of the present invention to provide captopril tablets which are highly stable and show a high homogenity of the active ingredient and the auxiliary agents The above object is achieved by selecting a special filler/binding agent combination and a specific ratio of filler and binding agent According to the present invention there are provided captopril tablets comprising a filler and binding agent, a disintegrating agent, a lubricant and a glidant agent wherein the filler and binding agent is a 1 5 1 - 1 1 weight ratio mixture of lactose and microcrystalline cellulose and the total amount of said mixture is 60-80 % by weight of the total weight of the tablet According to the present invention there is also provided a process for the preparation of captopril tablets containing a filler and binding agent, a disintegrating agent, a lubricant and a glidant agent which comprises using as filler and binding agent a 1 5 1 - 1 1 mixture of lactose and microcrystalline cellulose, the amount of said mixture being 60-80% by weight related to the total weight of the tablets. Detailed description of the invention The present invention is based on the recognition that captopril tablets having high stability can be prepared by adjusting the ratio of lactose and microcrystalline cellulose in the tablets to a value between 1.5:1 and 1 :1. The above recognition is so much the more surprising as on the basis of the state of the art it could have been expected that high stability of captopril can be achieved by using a system of auxiliary agents which has the lowest moisture content and the smallest moisture-uptake. It can be seen from the comparative experiments disclosed in the present patent specification that on increasing the amount of the microcrystalline cellulose having a high moisture-uptake, also the moisture-uptake of the tablets increases. It has been found, however, in an unforeseen manner, that when using a relatively narrow interval of lactose/microcrystalline cellulose ratio, the amount of the captopril disulfide formed in the captopril tablets shows a minimum and tablets of high stability are obtained. The total lactose and microcrystalline cellulose content of the captopril tablets of the present invention is 60-80 % by weight, preferably 65-75 % by weight, particularly 70 % by weight, related to the total weight of the composition. The active ingredient content of the tablets according to the present invention is preferably 5-150 mg. The particle size of 90 % of the active ingredient is preferably 3-80 μm and the starting captopril disulfide content is preferably below 0 3 % by weight Lactose is used preferably in the form of lactose monohydrate The amounts and % values used in the present patent specification are expressed in lactose monohydrate It is preferred to use lactose monohydrate prepared by spray-drying and having an average particle size of 50-200 μm, particularly 80-160 μm The particle size of 90 % the microcrystalline cellulose used in the compositions of the present invention is 20-150 μm particularly 50-100 μm The compositions of the present invention may contain as disintegrating agent preferably corn starch, carboxymethyl starch, partially hydrolized starch, carbomethyl cellulose or cross-linked polyvinyl pyrrolidone The amount of said disintegrating agent is preferably 1-20 % by weight, particularly 5-15 % by weight, related to the total weight of the composition The compositions of the present invention contain as lubricant preferably steaπne, magnesium stearate, calcium stearate, sodium steanne fumarate or hydrogenated castor oil The amount of the glidant agent is 0 2-3 % by weight, preferably 0 5-2 % by weight, related to the total weight of the composition The compositions of the present invention contain preferably silica as glidant agent The amount of this auxiliary agent is 0 2-1 % by weight, preferably 0 4-0 6 % by weight The auxiliary agents - disintegrating agents, glidant agents and lubricants meet the criteria disclosed in the Pharmacopoeia (e.g USP 23 or VII Hungarian Pharmacopoeia) The tablets according to the present invention may be prepared preferably by the so-called direct compression technology which has the advantage that the drying step is eliminated According to this process prior to the tabletting step the powder of the active ingredient is homogenized in solid state with auxiliary agents which ensure suitable compressibility of the composition. The stability of the captopril tablets of the present invention is very good If broken one into two or four parts, the standard deviation of the active ingredient content of the parts thus obtained is better than the corresponding values of known compositions . Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the Examples In comparative Example 1 the effect of the ratio of lactose monohydrate and microcrystalline cellulose on the compressibility of the powder blends is examined The measured data are in conformity with the teaching of the state of the art and show that on increasing the amount of microcrystalline cellulose used as dry binder, the powder mixture can be more easily pressed i.e on using identical pressing force the breaking strength of the tablets becomes higher and the friability gets lower. In comparative Example 2 the effect of the ratio of lactose and microcrystalline cellulose on the moisture-uptake of the tablets is examined The results are in conformity with the teaching of prior art and show that when stored under a relative humidity of 75 % the increase of the amount of the microcrystalline cellulose having a higher moisture-uptake (higher equilibrum moisture content) results in an increase of the moisture-uptake of the tablets In comparative Examples 3 and 4 the effect of the ratio of lactose and microcrystalline cellulose on the stability of the active ingredient content of the tablets is examined In view of the state of the art the results are surprising and show in an unforeseen manner that when storing the tablets under 75 % relative humidity, oxidation of captopril - i e the captopril disulfide content of the tablets - shows a minimum at a lactose monohydrate microcrystalline cellulose ratio interval of 1 5-1 1-1 On the basis of prior art it could have been expected that tablets containing the lowest amount of microcrystalline cellulose would be the most stable The series of experiments show, however, that if the ratio of lactose monohydrate and microcrystalline cellulose is adjusted to a relatively narrow interval, the amount of captopril disulfide formed in the tablets is reduced to a minimum and this value is below the captopril disulfide content of captopril tablets allowed by Pharmacopoeia (e g USP 23) In Examples 5-8 the preparation of captopril tablets of varying composition according to the present invention is described In comparative Example 9 the standard deviation of the individual active ingredient content of tablets manufactured on industrial scale and the standard deviation of the individual active ingredient content of parts of tablets split in two or four parts, respectively is disclosed The experimental results show that if the captopril tablets of the invention are split in two or four parts, respectively, the standard deviation of the active ingredient content of said tablet parts is very favourable Accordingly the pharmaceutical composition of the present invention can be preferably used because such compositions meet the special requirements of captopril therapy i e when on adjusting the individual dosage required by a patient the dose is to be increased, the tablets according to the present invention can be reliably split in two or four parts due to the low standard deviation of the active ingredient content of the tablet parts In comparative Example 10 the disulfide content of samples subjected to loaded stability test is determined Tablets containing 12 5 mg of captopril are packed into blisters formed from a PVC/PVDC plastic foil and closed by an aluminium foil The tablets of the present invention are compared to tablets which have a lactose/microcrystalline cellulose ratio outside the scope of the present invention but are otherwise of identical composition The blistered tablets are stored at 40°C under a relative humidity of 75 % for 3 months After this storing period the captopril disulfide content of the invention tablets increases from the initial value of 0 31 % to 3 32 %, while in the reference tablets the captopril disulfide content augments from 0 30 % to 5 04 % Example 11 shows that captopril tablets of the present invention have a very high stability in moisture-proof "cold blister" packaging Example 1 (comparative Example) (Effect of the ratio of lactose monohydrate and microcrystalline cellulose on the compressibility of the powder blends) Composition (mg/tablet) (g/5000 tablets) N° of experiment 1/1 1/2 1/3 (mg) (g) (mg) (g) (mg) (g) Captopril 25.0 125.0 25.0 125.0 25.0 125.0 Lactose monohydrate 85.0 425.0 70.0 350.0 60.0 300.0 Microcrystalline cellulose 25.0 125.0 40.0 200.0 50.0 250.0 Corn starch 22.0 110.0 22.0 110.0 22.0 110.0 Stearine 3.0 15.0 3.0 15.0 3.0 15.0 Sum of weights 160.0 800.0 160.0 800.0 160.0 800.0 Lactose:microcrystalline 3.4:1 1.75:1 1.2: 1 cellulose ratio The components are sieved through a 0.5 mm sieve and thereafter homogenized in a Lόdige 5M type high speed mixer under stirring for 5 minutes. The homogenized powder mixture is pressed to tablets on a Fette E XI type eccentric tabletting machine by using flat rimmed tabletting punches under a pressing force of 5 kN, 10 kN and 15 kN, respectively. The breaking strength (Schleuniger 4M measuring apparatus), friability (Roche-type friability measuring device, 100 r.p. 4 minutes) and the disintegration time at 37°C in distilled water (Erweka disintegration measuring apparatus) of the tablets is determined The results are summarized in Table 1 Table 1 Results of tests carried out on the tablets N° of experiment 1/1 1/2 1/3 Pressing force 5 10 15 5 10 15 5 10 15 Breaking 1 1 35 48 15 41 51 19 46 59 strength (average of 10 tablets N) Friability 14 1 2 0 9 8 4 0 9 0 6 6 3 0 8 0 4 (average of 10 tablets %) Disintegration 5 15 35 5 20 30 5 20 45 (average of 6 tablets s) The above data show that on changing the ratio of lactose and microcrystalline cellulose in favour of microcrystalline cellulose the pressability of the powder mixture improves (the breaking strength values corresponding to identical pressing force increase and the friability decrease) and the disintegration time of the tablets is very good (shorter than 1 minute) If the mixture contains lactose and microcrystalline cellulose in approximately identical amounts (Experiment Ns 1/3) the friability is below 0 5 % and this is a characteristic feature of tablets having excellent mechanical strength In the above Experiment Ns 1/3 corresponds to the composition of the present invention. Example 2 (comparative Example) (Effect of the ratio of lactose monohydrate and microcrystalline cellulose on the moisture-uptake of tablets) Composition (mg/tablet) (g/1000 tablets) N° of composition 2/1 2/2 2/3 2/4 2/5 Captopril 100 0 100 0 100 0 100 0 100 0 Lactose monohydrate 330 0 270 0 210 0 150 0 90 0 Microcrystalline cellulose 60 0 120 0 180 0 240 0 300 0 Corn starch 60 0 60 0 60 0 60 0 60 0 Cutina H * 5 60 5 60 5 60 5 60 5 60 Aerosil 200 ** 2 80 2 80 2 80 2 80 2 80 Magnesium-stearate 1 60 1 60 1 60 1 60 1 60 Sum of weights 560 0 560 0 560 0 560 0 560 0 Remarks = hydrogenated castor oil = colloidal silica The tablets are prepared by using the method and equipment disclosed in Example 1 , batch size 1000 tablets The tablets are pressed by using tabletting punches and dye having a diameter of 12 mm and under a pressing force of 20 kN Moisture-uptake is determined by storing the tablets in an air-conditioner (LABORMIM, LP-23) at 40°C and a relative humidity content of 75 % (The relative humidity content of 75 % is provided by a saturated solution of ammonium sulfate the fluctuation of temperature and humidity is controlled by a thermometer-hygrometer - "LOMBIK HOMERO es UVEGIPARI MUSZERGYARTO SZOVETKEZET" type 06912) During the storing period of two weeks the temperature fluctuated between 39 7°C and 40 4°C, while the humidity varied between 73 % and 88 % Moisture-uptake of the tablets is measured after a storing period of 1 , 2, 4, 8 and 14 days, respectively Moisture-uptake is determined on the basis of the weight increase of the tablets (SARTORIUS A 200 S analytic balance) and calculated with the aid of the following equation Moisture-uptake w/w % = x 100 wherein mi = weight of the sample before storage m 2 = weight of the sample after storage Not only the tablets, but also the components used for the preparation thereof were placed in the air conditioner and moisture-uptake of the captopril (active ingredient) and the auxiliary agents was measured at the points of time indicated The results are summarized in Tables 2 and 3 Table 2 Moisture-uptake of tablets, w/w % Ns of Lactose compomicrocrysStoring period (days) sition talline cellulose 0 1 2 4 8 14 nabo 2/1 551 00 027 037 031 027 035 2/2 2251 00 033 045 037 034 036 2/3 1171 00 043 056 048 045 043 2/4 06251 00 051 066 054 053 050 2/5 031 00 066 082 068 067 063 Table 3 Moisture-uptake of the active ingredient and the auxiliary agents (w/w %) Storing time (days) Component 0 1 2 4 8 14 Captopril 00 00 00 00 00 00 Lactose monohydrate 00 <001 <001 001 002 002 Microcrystalline 00 094 128 115 107 124 cellulose Corn starch 00 144 182 158 149 158 Cutma H 00 00 00 00 00 00 Aerosil 200 00 045 068 060 080 092 Magnesium-stearate 00 012 021 019 020 022 The above data show that on augmenting the amount of microcrystalline cellulose in the tablets the moisture-uptake of the tablet increases and this is in conformity with the finding that during storage lactose monohydrate does not take up moisture while the moisture-uptake of microcrystalline cellulose is above 1 w/w % Since the high moisture-uptake of microcrystalline cellulose is known from prior art, the moisture-uptake of the tablets is in conformity with the expected results In the above Experiment composition Ns 2/3 corresponds to the present invention Example 3 (comparative Example) (Effect of the ratio of lactose monohydrate and microcrystalline cellulose on the stability of captopril) In this experiment the captopril active ingredient content of the tablets is characterized by determining the captopril disulfide content of the tablets before and after storing (the conditions of storing are those disclosed in Example 2) The amount of captopril disulfide in the tablets is determined according to the HPLC methods described in USP 23 To the measurement VARIAN MODEL 5000 Liquid Chromatograph type apparatus, PYE UNICAM LC-3 UV detector and HEWLETT-PACKARD HP 3394A integrator is used The disulfide content of the tablets is expressed in the % by weight of the nominal captopril content of the tablets The results are summarized in Table 4 Table 4 Amount of captopril disulfide in the tablets, expressed in % by weight of the nominal captopril content of the tablets (w/w %) Ns of Lactose compormcroαys- Storing time (days) sition talline cellulose 0 1 2 4 8 14 rabo 2/1 5 5 1 0 28 0 46 0 73 0 95 2 13 5 15 2/2 2 25 1 0 30 0 45 0 62 0 91 1 39 3 47 2/3 1 17 1 0 28 0 46 0 56 0 91 1 39 2 69 2/4 0 625 1 0 34 0 56 0 78 1 05 1 55 3 25 2/5 0 3 1 0 34 0 62 0 73 1 02 1 96 3 60 It appears from the above data that on increasing the microcrystalline cellulose content of the tablets (i e decreasing the lactose content) the amount of captopril disulfide formed in the tablets passes a minimum value i e decomposition of the composition (disulfide formation) is the lowest at a well-defined ratio of lactose monohydrate and microcrystalline cellulose This experimental result is surprising because according to the teaching of prior art a greater rate of oxidation of captopril - i e the formation of a higher amount of captopril disulfide - could have been expected in a system having higher moisture content, i e at a higher microcrystalline cellulose content Example 4 (comparative Example) (Effect of the ratio of lactose monohydrate and microcrystalline cellulose on the stability of captopril) In order to determine more precisely the optimal ratio, in this series of experiments the stability of the captopril content of the tablets is determined by using lactose/microcrystalline ratios near to those found to be advantageous according to Examples 2 and 3 The composition of the tablets is adjusted to values between the compositions 2/2 and 2/4 The compositions used are disclosed in Table 5 Stability is determined before and after a storing period of 2 weeks and 4 weeks, respectively, by measuring the captopril disulfide content of the tablets according to the HPLC method disclosed in Chapter "Captopril Tablets" of USP 23 To the measurements a VARIAN MODEL 5000 Liquid Chromatograph type apparatus, a PYE UNICAM LC-3 UV detector and a HEWLETT PACKARD HP 3394A integrator is used The amount of disulfide measured in the tablets is expressed as % weight of the nominal captopril content of the tablets The results are summarized in Table 5 Table 5 Composition (mg/tablet) (g/1000 tablets) Ns of composition 4/1 4/2 4/3 4/4 4/5 Lactose microcrystalline 2 1 1 6 1 1 25 1 1 1 0 7 1 cellulose ratio Captopril 100 0 100 0 100 0 100 0 100 0 Lactose monohydrate 260 0 234 0 217 0 195 0 160 0 Microcrystalline cellulose 130 0 146 0 173 0 195 0 230 0 Corn starch 60 0 60 0 60 0 60 0 60 0 Cutina H * 5 60 5 60 5 60 5 60 5 60 Aerosil 200* * 2 80 2 80 2 80 2 80 2 80 Magnesium-stearate 1 60 1 60 1 60 1 60 1 60 Average weight 560 0 560 0 560 0 560 0 560 0 Remarks = hydrogenated castor oil = colloidal silica The tablets are prepared by using the method and apparatus described in Example 1 , batch size 1000 tablets On pressing the tablets with tabletting punches and dye having a diameter of 12 mm and a pressing force of 12 kN is used Moisture uptake is carried out by storing the tablets in an air conditioner (LABORMIM, LP-23) at 40°C and a relative humidity of 75 % (The relative humidity content of 75 % is provided by a saturated solution of ammonium sulfate the fluctuation of temperature and humidity is controlled by a thermometer-hygrometer - "LOMBIK HOMERO es UVEG- IPARI MUSZERGYARTO SZOVETKEZET" type 06912) During the storing period of two weeks the temperature fluctuated between 39 6°C and 40 5°C, while the humidity varied between 72 % and 78 % Moisture-uptake is determined after a storing period of 4 weeks Moisture-uptake is determined on the basis of the weight increase of the tablets (SARTORIUS A 200 S analytical balance) and calculated with the aid of the following equation Moisture-uptake w/w % = x 100 ITh wherein mi = weight of the sample before storage m 2 = weight of the sample after storage The results are summarized in Table 6 Table 6 Ns of composition 4/1 4/2 4/3 4/4 4/5 Ratio of lactose and microcrystalline cellulose 2 0 1 1 6 1 1 25 1 1 0 1 0 7 1 Storing for 2 weeks captopril disulfide (%) 2 5 2 4 2 2 1 7 2 1 Storing for 4 weeks captopril disulfide (%) 5 3 5 3 4 4 4 1 4 9 Moisture uptake (%) 0 4 0 5 0 6 0 6 0 9 The results of this experiment fully confirm the data obtained according to Example 3 Thus on increasing the microcrystalline cellulose content of the tablets (i e decreasing the lactose content) the amount of captopril disulfide formed in the tablets on storing reaches a minimum value and at a specified lactose monohydrate microcrystalline cellulose ratio the decomposition of the tablet (disulfide formation) shows a minimum The results of these two series of experiments are surprising and unforeseen because on the basis of prior art one could expect an oxidation of higher extent of captopril (i e the formation of a larger amount of captopril disulfide) in a system of higher moisture content One could expect that the higher the microcrystalline cellulose content, the larger degree of captopril decomposition would take place and the higher amount of captopril disulfide would be formed However if the ratio of lactose and microcrystalline cellulose is between 1 5 1 and 1 1 a surprising surplus effect takes place Example 5 Tablets having an active ingredient content of 12 5 mg Batch size 2 million tablets (140 kg) Substances used Component Amount, kq Captopril (particle size 90 % between 3 5 2500 and 46 9 μm) Lactose monohydrate 5250 Microcrystalline cellulose 4500 Corn starch 1500 Hydrogenated castor oil 140 Colloidal silica 070 Magnesium stearate 040 The above substances - with the exception of magnesium stearate - are stirred in a 450 I mixer for 20 minutes, whereupon the magnesium stearate is added and stirring is continued for further 2 minutes Tabletting is carried out with a Fette Perfecta 2000 type tabletting machine (43 pressing sites) by using flat rimmed split punches at 40 r p m The breaking strength of the tablets is 35-45 N, the disintegration time amounts to 2-3 minutes, the active ingredient is dissolved within 5 minutes at a rate of 100 % and the relative standard deviation (RSD) of the individual active ingredient content is 3 7 % On storing the tablets for 3 months at 40°C in a glass container closed with a polyethylene cap the amount of captopril disulfide formed is 1 6 %, while the breaking strength, disintegration time and the velocity of active ingredient dissolution remained substantially unchanged On the basis of the above data the captopril containing tablets prepared according to this Example fully meet the requirements of the Pharmacopoeia (USP 23, Captopril Tablets) In the tablets the ratio of lactose and microcrystalline cellulose amounts to 1 16 1 Example 6 Tablets having an active ingredient content of 25 mg Batch size 100,000 tablets (14 kg) Substances used Component Amount, kg Captopril (particle size 90 % between 5 5 2 50 and 69 6 μm) Lactose monohydrate 4 90 Microcrystalline cellulose 4 90 Corn starch 1 50 Hydrogenated castor oil 0 10 Colloidal silica 0 06 Magnesium stearate 0 04 The above substances - with the exception of magnesium stearate - are stirred in a 50 I mixer for 20 minutes, whereupon the magnesium stearate is added and stirring is continued Tabletting is carried out on a Manesty B3B type tabletting machine having 16 pressing sites, by using flat rimmed twice split press punches at 30 r p m The breaking strength of the tablets amounts to 40-55 N, the disintegration time amounts to 2-3 minutes, the dissolution of the active ingredient is 100 % within 10 minutes The relative standard deviation (RSD) of the individual tablets is 1 9 % On storing the tablets in a glass container closed with a polyethylene cap at 40°C for 3 months the amount of the captopril disulfide is 1 5 % while the breaking strength, disintegration time of the tablets and the dissolution speed of the active ingredient remain substantially unchanged On the basis of the above data the captopril containing tablets prepared according to this Example fully meet the requirements of the Pharmacopoeia (USP 23, Captopril Tablets) Example 7 Tablets having an active ingredient content of 50 mg Batch size 50,000 (14 kg) Substances used Component Amount, kg Captopril (particle size 90 % between 2 3 2 50 and 36 5 μm) Lactose monohydrate 5 85 Microcrystalline cellulose 3 90 Corn starch 1 50 Hydrogenated castor oil 0 14 Colloidal silica 0 07 Magnesium stearate 0 04 The above components - with the exception of magnesium stearate - are stirred in a 50 I mixer for 20 minutes, whereupon the magnesium stearate is added and stirring is continued for a further 2 minutes Tabletting is performed on a Manesty BB3B type tabletting machine having 27 press sites, by using flat rimmed twice split press punches, at 30 r p m The breaking strength of the tablets amounts to 45-65 N, the disintegration time is 2-3 minutes, the dissolution of the active ingredient within 10 minutes is 100 % and the relative standard deviation of the individual active ingredient content of the tablets (RSD) amounts to 3 7 % On storing the tablets in a glass container closed with a polyethylene cap at 40°C for 3 months the amount of the captopril disulfide formed in the tablets is 1 7 %, while the breaking strength and disintegration time of.the tablets and the speed of dissolution of the active ingredient remain substantially unchanged On the basis of the above data the captopril containing tablets prepared according to this Example fully meet the requirements of the Pharmacopoeia (USP 23, Captopril Tablets) In the tablets the ratio of the lactose and microcrystalline cellulose is 1.5 1 Example 8 Tablets having an active ingredient content of 100 mg Batch size 500,000 tablets (140 kg) Substances used Component Amount, kq Captopril (particle size 90 % between 4 3 2500 and 65 3μm) Lactose monohydrate 5250 Microcrystalline cellulose 4500 Corn starch 1500 Hydrogenated castor oil 140 Colloidal silica 070 Magnesium stearate 040 The above substances - with the exception of magnesium stearate - are stirred in a 450 I mixer for 20 minutes whereupon the magnesium stearate is added and stirring is continued for further 2 minutes Tabletting is carried out on a Manesty BB3B type tabletting machine having 35 pressing sites, by using flat rimmed split punches having a diameter of 12 mm at 30 r p m The breaking strength of the tablets is 70-90 N, the disintegration time is 1 5-3 minutes, the dissolution of the active ingredient within 10 minutes is above 90 % and the relative standard deviation of the individual active ingredient content of the tablets (RSD) is 3 7 % On storing the tablets in a glass container closed with a polyethylene cap at a temperature of 40°C for 3 months the amount of captopril disulfide formed is 1 7 % while the breaking strength and dissolution time of the tablets and the dissolution speed of the active ingredient remains substantially unchanged On the basis of the above data the captopril containing tablets prepared according to this Example fully meet the requirements of the Pharmacopoeia (USP 23, Captopril Tablets) In the tablets the ratio of lactose and microcrystalline cellulose is 1 16 1 Example 9 Determination of the standard deviation of the active ingredient content of tablets according to the present invention on halving and dividing the tablets into quarters The test is carried out by using cross-split tablets having an active ingredient content of 25 mg In order to administer a dose of 12 5 mg and 6 25 mg, respectively, the patients have to cut the tablets into two or four parts respectively, during the treatment In the course of the test the standard deviation of the active ingredient content of the whole tablets is determined by measuring the individual active ingredient content of 10 tablets each and the relative standard deviation of the active ingredient content (RSD) is calculated Thereafter 10 tablets from both compositions each are broken in two parts by hand and the relative standard deviation of the weight and active ingredient content of the halved tablets is determined by measuring alternately the weight and captopril content of the half-tablets remaining in the right and left hand, respectively The remaining half tablets are then broken by hand in two parts and the relative standard deviation of the tablets broken into four parts is determined by measuring alternately the weight and captopril content of the quarter tablets remaining in the right and left hand, respectively The captopril content of the whole, halved and quarter tablets is determined according to the Chapter "Captopril Tablets" of USP 23 by measuring the individual active ingredient content of the captopril tablets by HPLC The results are summarized in Table 7 Table 7 Tested Weight Active ingredient tablet RSD % content RSD % Whole 2.5 2 0 Half 8 4 8 2 Quarter 13 4 12 9 The above data show that on halving and breaking the tablets in four parts, respectively, the standard deviation of the weight and active ingredient content of the half and quarter tablet parts is lower than the 15 % limit allowed for the standard deviation of the active ingredient content Accordingly the tablets of the present invention can be preferably used in therapeutical practice if tablets are to be broken to two or four parts in order to adjust the optimal dose of treatment Example 10 (comparative Example) In comparative Example 10 tablets according to the present invention (Example 2, Ns 2/3) are compared with those having a lactose/microcrystalline cellulose ratio outside the scope of the invention, otherwise the active ingredient content (12 5 mg) and the other components of the tablets are identical The tablets are packed into blister (bed formed from a PVC/PVDC plastic foil and closed with an aluminium foil) The samples are subjected to loaded stability testing and the disulfide content is measured The tablets packed into blister are stored at 40°C and a relative humidity content of 75 % for 3 months The captopril disulfide content of the tablets is determined before and after storing The results are summarized in Table 8 Table 8 Sample Captopril disulfide content before storing after storing Present invention, Example 2, Ns 2/3 0 31 % 3 32 % Reference sample 0.30 % 5 04 % Example 11 Testing of the stability of the tablets of the present invention (active ingredient content 12.5 mg) packed in moisture proof "cold blister" The tablets of the present invention (Example 2, Ns 2/3 active ingredient content 12 5 mg) are filled into beds formed from aluminium foil combined with plastic (AI/PE/PVC) by using a deep-drawing packaging machine The beds are closed by welding with an aluminium foil The tablets are stored at 40°C (± 2°C) and a relative humidity content of 75 % for 3 months whereupon the captopril disulfide content of the tablets is determined by HPLC method in accordance with USP 23 The results obtained are summarized in Table 9 Table 9 Sample Captopril disulfide content before storing after storing Example 2, Ns 2/3 0 19 % 0 62 % It can be seen that the captopril disulfide content of the tablets increases only to small extent, well below the allowed limit, even if stored under agressive conditions

Claims: What we claim is, 1 ) Captopril tablets comprising a filler and binding agent, disintegrating agent, a lubricant and a glidant agent whe rei n the filler and binding agent is a 151 - 11 weight ratio mixture of lactose and microcrystalline cellulose and the total amount of said mixture is 60-80 % by weight of the total weight of the tablet 2 ) Tablets according to Claim 1 whe re i n the total amount of the mixture of lactose and microcrystalline cellulose is 67-75 % by weight of the total weight of the tablets 3 ) Tablets according to Claim 2 whe re i n the total amount of the mixture of lactose and microcrystalline cellulose is 69-70 % by weight of the total weight of the tablets 4 ) Tablets according to any of Claims 1-3 where i n the disintegrating agent is corn starch, carboxymethyl starch, partially hydrolized starch, carboxymethyl cellulose or cross-linked polyvinyl pyrrolidone, the amount thereof being 1-20 % by weight related to the total weight of the tablets 5 ) Tablets according to any of Claims 1-3 wherein the lubricant is steaπne, magnesium stearate, calcium stearate, sodium stearyl fumarate or hydrogenated castor oil, in an amount of 02-3 % by weight related to the total weight of the tablets 6) Tablets according to any of Claims 1-3 whe rein the glidant agent is colloidal silica in an amount of 02-1 % by weight related to the total weight of the tablets 7) Tablets according to any of Claims 1-3 whe rei n the lactose is lactose monohydrate having an average particle size of 50-200 μm 8 ) Tablets according to Claim 7 wherei n the lactose is lactose monohydrate having an average particle size of 80-160 μm 9) Tablets according to any of Claims 1-3 whe rei n 90 % of the microcrystalline cellulose has an average particle size of 20-150 μm 10 ) Tablets according to Claim 9 wherei n 90 % of the microcrystalline cellulose has an average particle size of 50-100 μm 11 ) Process for the preparation of captopril tablets containing a filler and binding agent, a disintegrating agent, a lubricant and a glidant agent which comprises using as filler and binding agent a 151 - 11 mixture of lactose and microcrystalline cellulose, the amount of said mixture being 60-80% by weight related to the total weight of the tablets 12) Process according to Claim 11 wh ich com prises using lactose, microcrystalline cellulose, disintegrating agents, lubricant and/or glidant agents defined in any of Claims 2-10

Inventors: FEKETE PAL, GORA LASZLONE, KRISZTIAN MARIA, LADY BLANKA, PALFI ZOLTANNE, SZENTGROTI PALNE, FEKETE, PAL, GORA, LASZLONE, KRISZTIAN, MARIA, LADY, BLANKA, PALFI, ZOLTANNE, SZENTGROTI, PALNE
Applicants: EGYT GYOGYSZERVEGYESZETI GYAR, FEKETE PAL, GORA LASZLONE, KRISZTIAN MARIA, LADY BLANKA, PALFI ZOLTANNE, SZENTGROTI PALNE, EGIS GYOGYSZERGYAR RT., FEKETE, PAL, GORA, LASZLONE, KRISZTIAN, MARIA, LADY, BLANKA, PALFI, ZOLTANNE, SZENTGROTI, PALNE
Application year: 1997
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47, A61P5