MXPA96005646A - Preparation of nifedipine of release prolong - Google Patents

Abstract

The present invention relates to a pressure-coated tablet, containing nifedipine, comprising a core containing nifedipine and a substance of high molecular weight forming a hydrophilic gel and an envelope that covers the core and containing nifedipine, a substance of high molecular weight forming a hydrophilic gel and a substance suppressing the disintegration, characterized in that the speed of dissolution of nifedipine from said tablet is: a) in the dissolution test using an immersion device, according to the procedure 2 of the dissolution test procedure prescribed by the Pharmacopoeia of Japan: after 2 hours 10-40%, after 4 hours 30-65%, after 6 hours at least 55%, and b) in the dissolution test according to the disintegration test method prescribed by the Pharmacopoeia of Japan: after 3 hours 20-45%, after 4 hours 30-6

Description

PREPARATION OF NIFEDIPINE FOR PROLONGED RELEASE DESCRIPTION OF THE INVENTION Field of industrial use This invention relates to a solid preparation of prolonged-release nifedipine. More specifically, the invention relates to a pressurized coated tablet containing sustained-release nifedipine and which may have a sufficiently significant antihypertensive action clinically when administered once a day. Conventional Technology and Problems In the past, a nifedipine-containing tablet containing nifedipine crystals of a specific surface area and an inert pharmaceutically acceptable adjuvant has been proposed as a solid long-acting nifedipine preparation (Japanese Patent Publication No. 14,446 / 1984 ). This tablet, however, needs to be administered twice a day to present an effect useful enough for clinical uses. In the treatment of hypertensive or similar patients, treatment that should be given over a relatively long period, the medication several times a day is not only annoying but also responsible for causing problems such as patients may forget to take the REF: 23552 medicine or they can take it at irregular intervals, thereby endangering a safe and safe therapy. For this reason, the development of a preparation of nifedipine, an agent to treat hypertension, that presents completely useful effects clinically when administered once a day ("compressed once a day") has been strongly demanded to date. ). As a preparation that meets such demands, Japanese Patent Publication No. 11,699 / 1994 discloses a solid preparation of nifedipine, composed of a core containing nifedipine in a rapid release form and a coating containing nifedipine in sustained release form. In this solid preparation, a hydrophilic gel-forming polymer is used to permit sustained release of the coating. The object of the present invention is to provide a nifedipine preparation that maintains an effective plasma concentration of nifedipine for many hours (usually 24 hours or more) and present a clinically sufficient effect when administered once a day. Another object of the present invention is to provide a nifedipine preparation that is less sensitive to mechanical agitation and stress conditions, to minimize undesired interactions dependent on food and agitation. A further object of the present invention is to provide a nifedipine preparation that also exhibits a high bioavailability despite the slow release core and which maintains a highly effective plasma concentration of nifedipine for a long period of time, preferably greater than at least 24 hours. hours.

Means for solving the problems In order to achieve the aforementioned object, we have carried out extensive studies on a sustained-release pressure-coated tablet, such as that described in the aforementioned patent publication number 11,699 / 1994, whose core and envelope covering the cited nucleus contains nifedipine, and we have found that this object can be achieved by giving the nucleus an erosive matrix structure containing nifedipine and a high molecular weight substance forming a hydrophilic gel, and giving the envelope an erodible matrix structure containing, in addition to nifedipine and a substance of high molecular weight forming a hydrophilic gel, a substance suppressing the disintegration. With which the present invention is completed. Therefore, the invention provides a pressure coated tablet, containing nifedipine, and comprises a nucleus containing nifedipine and a substance of high molecular weight forming a hydrophilic gel and an envelope that covers the nucleus and contains nifedipine, a substance of high molecular weight forming a hydrophilic gel and a substance suppressing the disintegration, characterized in that the rate of dissolution of nifedipine from said tablet is: (a) in the dissolution test using an immersion device , according to procedure 2 of the dissolution test procedure prescribed by the Pharmacopoeia of Japan: after 2 hours 10-40% after 4 hours 30-65% after 6 hours at least 55%, and (b) in the dissolution test according to the disintegration test procedure prescribed by the Pharmacopoeia of Japan: after 3 hours 20-25% after 4 hours 30-65%. Compared to the aforementioned preparation, described in Japanese Patent Publication No. 11,699 / 1994, the main features of the tablet of the present invention are that the coating contains a substance suppressing the disintegration and that the core shows a slower release of nifedipine. The tablet of the present invention is explained in more detail below. The tablet of the present invention is a pressurized compressed tablet, composed of a core and a sheath that covers said core. The core contains nifedipine and a substance of high molecular weight that forms a hydrophilic gel. Said high molecular weight substance forming a hydrophilic gel which is mixed in the core swells on contact with water and forms a gel, examples of which include cellulose derivatives such as methylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) , sodium carboxymethylcellulose; and poly (vinyl alcohol). Of these, lower hydroxyalkyl ethers of cellulose, particularly hydroxypropylcellulose (HPC), are preferred. Here, the term "lower" means that the number of carbons is not more than 6. As HPC, various HPC of different viscosity levels can be used, for example, low viscosity HPC (HPC-L) having a viscosity of about 6 to about 10 cp, medium viscosity HPC (HPC-M) having a viscosity of about 150-400 cp, and high viscosity HPC having a viscosity of about 1,000 to about 4,000 cp, the said values being determined viscosity in Aqueous solutions of 2% HPC and at 20 ° C. Generally, trends are observed that the use of high viscosity HPC reduces the rate of release of the active ingredient from the preparation, while the use of low viscosity HPC increases the rate of release. Accordingly, by selecting and appropriately combining HPC of different viscosity levels, the release profile of nifedipine can be adjusted from the core. In general terms, the core can contain said high molecular weight substance forming a hydrophilic gel in an amount of 5-90%, preferably 10-80%, inter alia. 10-70%, based on percentages by weight in the total weight of the core. In addition to the high molecular weight substance forming a hydrophilic gel, the core can additionally contain, if the individual occasion demands, for example, excipients such as starch, for example, corn starch, potato starch, α-starch, dextrin, carboxymethylstarch, etc .; sugars such as lactose, sucrose, glucose, mannitol, sorbitol, etc .; inorganic salts such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate-aluminate, calcium phosphate, calcium carbonate, etc .; oils and fats such as paraffins, waxes, higher fatty acids, etc .; and cellulosic substances: disintegrating agents such as starch, sodium crosscarmellose, sodium carboxymethyl-sodium, carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, crystalline cellulose, crosslinked polyvinylpyrrolidone, etc .; lubri-cantes such as magnesium stearate, talc, synthetic aluminum silicate, etc .; coloring agents such as various food colorants; and dissolution promoters such as various surfactants. In order to meet the objective of the once-a-day tablet described in the present invention, it is desirable to adjust the final core composition so that the dissolution rate of nifedipine from a tablet of identical composition to that of the core, tested according to procedure 2 of the dissolution test procedure which does not use an immersion device, prescribed in the Pharmacopoeia of Japan [hereinafter referred to as "procedure 2 of the dissolution test of the Pharmacopoeia (which does not use immersion device. ) "] is, in general terms: after 45 minutes: 20-70%, preferably 25-65%, more preferably 30-60%; after 2 hours: at least 65%, preferably at least 70%, more preferably at least Here the procedure 2 of the dissolution test of the Pharmacopoeia (which does not use immersion device) is carried out under the following conditions: Test liquid: 900 ml of phosphoric acid buffer of pH 6, 8, containing 1% sodium lauryl sulfate Temperature: 37 ° C Rotation speed: 75 rpm. The tablet having composition identical to that of the core, which is to be used in the aforementioned dissolution test, is compressed under the same conditions used to compress the core of the pressurized tablet of the present invention. The outstanding feature characterizing the envelope according to the present invention is that it contains, in addition to nifedipine and a substance of high molecular weight forming a hydrophilic gel, a substance suppressing the disintegration. The disintegration-suppressing substance is a pharmaceutically acceptable and pharmacologically inactive substance that can form a pH-independent matrix together with said nifedipine and said high molecular weight substance forming a hydrophilic gel, and gives robustness to the envelope so that the envelope disintegrates gradually and stable under a mechanically stressed atmosphere, such as that of the digestive tract. As examples of said disintegration-suppressing substance, specific, water-insoluble and pH-independent polymers can be given, which are commonly used as bases or films for sustained release formulations. Preferably, water insoluble methacrylate copolymers and water insoluble cellulose derivatives such as ethyl cellulose and cellulose acetate can be used. Of these, the most preferred is a polymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (hereinafter referred to as "aminoalkyl methacrylate copolymer"), composed of the three recurring units indicated in the following formulas (I ), (II) and (III): As mentioned aminoalkyl methacrylate copolymer, one is preferred in which the weight ratio of the recurring units of the above formulas (I), (II), and (III), that is, (I) / (II) / (III) is within the range 1/2 / 0.1-0.2 and also preferably has a viscosity from about 1 to about 4 centistokes. Said aminoalkyl methacrylate copolymer has been marketed and can be purchased under the trade names of Eudragit RS or RL (manufactured by Roehm Pharma G.m.b.H., Germany). The wrapping contains the said substance suppressing the disintegration, in an amount of normally 5-50% by weight, preferably 7.5-40% by weight, more preferably 10-30% by weight, based on the weight of the envelope. As a high molecular weight substance which forms a hydrophilic gel to be mixed in the envelope, those mentioned can be cited as examples of substance forming a hydrophilic gel to be mixed in the core, which can be appropriately selected taking into account, for example, the Desired release capacity of the wrap medicine. The shell may normally contain said high molecular weight substance forming a hydrophilic gel in a range of 30-90% by weight, preferably 35-85% by weight, more preferably 40-80% by weight, based on the weight of the envelope. The casing, in addition to nifedipine, the high molecular weight substance forming a hydrophilic gel and the substance suppressing the disintegration, may contain, if necessary, excipients such as starch, for example, starch d '. corn, potato starch, a-starch, dextrin, carboxyethyl starch, etc .; sugars such as lactose, sucrose, glucose, mannitol, sorbitol, etc .; inorganic salts such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate-aluminate, calcium phosphate, calcium carbonate, etc .; oils and fats such as paraffins, waxes, higher fatty acids, etc .; and cellulosic substances: disintegrating agents such as starch, sodium croscarmellose, sodium carboxymethyl-sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxymethyl cellulose, crystalline cellulose, cross-linked polyvinyl pyrrolidone, etc .; lubricants such as magnesium stearate, talc, synthetic aluminum silicate, etc .; coloring agents such as various food colorants; and dissolution promoters such as various surfactants. Desirably, the final composition of the envelope is adjusted so that the dissolution rate of nifedipine from a tablet of identical composition to that of the envelope is: (a) in the dissolution test using a dipping device, in accordance with procedure 2 of the dissolution test procedure prescribed in the Pharmacopoeia of Japan [hereinafter "procedure 2 of the dissolution test of the Pharmacopoeia (using immersion device)"]: after 2 hours: 20-50%, preferably 25-45%, more preferably 30-40%, after 4 hours: 40-90%, preferably 45-85%, more preferably 50-80%, after 6 hours : at least 75%, preferably at least 80%, more preferably at least 85%, and (b) in the dissolution test according to the disintegration test procedure prescribed in the Pharmacopoeia of Japan [hereinafter "test device procedure"]. of disintegration of the Pharmacopoeia "]: after 3 hours: 30-60%, preferably 35-55%, more preferably 40-50%, after 4 hours: 40-90%, preferably 45-85%, more preferably 50 -80%. In the present specification, the procedure 2 of the dissolution test of the Pharmacopoeia (using immersion device) is carried out under the following conditions: Test liquid: 900 ml of phosphoric acid buffer of pH 6.8, containing lauryl sulfate sodium at 1% Temperature: 37 ° C Rotation speed: 100 rpm Fixed position of the immersion device: fixed to a position in the center between the level of the test liquid and the upper edge of the stirring blade, and separated 10 mm from the wall of the vessel, with wire resistant to acids with a diameter not exceeding 1.0 mm. Also, the procedure of the disintegration test device of the Pharmacopoeia is carried out under the following conditions: Test liquid: 900 ml of phosphoric acid buffer of pH 6.8, containing 1% sodium lauryl sulphate Temperature: 37 ° C An auxiliary disk is used. The tablet having the same composition as the wrapper, to be used in the aforementioned dissolution tests, is compressed under the same conditions as those used to compress the pressurized tablet of the present invention, but without using the core. The pressurized compressed tablet of the present invention, composed of a core and a shell, each having the composition and the components before described, can be prepared, for example, by forming by per se known means a core tablet serving as a core, and then coating said core tablet with the envelope having the composition described above, using a dry coating machine ( pressure coating). The compression conditions are not limited strictly here but are variable, depending on the desired dissolution characteristics, etc., of the final tablets. Thus, the compression pressure normally suitable for the core (core) tablet is in the range of approximately 0.1-1 t, and that of the pressurized tablets is approximately 0.5-2 t. The diameter of the core (the core tablet) is generally within the range of 3-7 mm, and it is desirable that the diameter of the final tablet coated under pressure (uncoated) is usually in the range of 7-12 mm. The inner core (core) tablet can be coated with a thin film that precedes the wrapping. As the basis for said coating of a film there may be mentioned, for example, water-soluble cellulose coating bases such as HPC, HPMC, hydroxyethylcellulose, tnethylhydroxyethylcellulose. slab, etc .; enteric-coated cellulose bases such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate-to-acetate, carboxymethylethylcellulose, cellulose acetate phthalate, etc.; and bases of enteric coating films such as copolymers of methacrylic acid, shellac and the like. In addition, the final tablet can be integrated with at least one coating layer of a lightweight protection film. As such a coating of a light protection film there may be mentioned, for example, a water soluble cellulose coating mixed with a suitable amount of a light protection agent, for example, iron sesquioxide and / or titanium dioxide. As a water-soluble cellulosic coating, HPMC is particularly preferred because of its good property of forming a film, with HPMC being especially preferred whose 2% aqueous solution has a viscosity, at 20 ° C, not exceeding 100 cp, in particular not higher than 15 cp. If necessary, these foundations for coating a film can be added with a plasticizing agent, such as polyethylene glycol or similar agents. The pressure-coated tablets of the present invention, prepared in this way, have the following dissolution characteristics of nifedipine. Namely, the speed of dissolution of the nifedipine from the tablet The pressure coated mido shows a dissolution model (profile) of: (a) according to the procedure 2 of the dissolution test of the Pharmacopoeia (using immersion device); after 2 hours: 10-40%, preferably 15-35%, more preferably 20-29%, after 4 hours: 30-65%, preferably 35-60%, more preferably 39-56%, after 6 hours: at least 55%, preferably at least 35-60%, more preferably at least 65 %, and (b) according to the procedure of the disintegration test device of the Pharmacopoeia, after 3 hours: 20-45%, preferably 25-40%, more preferably 28-35%, after 4 hours: 30 -65%, preferably 35-60%, more preferably 40-55%. The pressurized compressed tablet of the present invention may generally contain 10-120 mg, preferably 20-90 mg of nifedipine per tablet. The relative proportion of nifedipine content in the core and in the envelope is not strictly limited, although in general terms the content weight ratio of Nifedipine in the nucleus at nifedipine content in the envelope may be within the range 1 / 7-3 / 1, in particular 1 / 5-2 / 1. The properties of the nifedipine to be mixed and dispersed in the tablets of the present invention are not particularly limited. Normally, however, nifedipine crystals which are micropulverized are conveniently used at a level such that their average diameter, as measured by a settling procedure or by a particle size distribution method of the laser diffraction scattering type, is approximately 1-30 μm; or the specific surface measured by a gas adsorption process is approximately 0.5-10 m2 / g. Nifedipine which has been made amorphous may also be used together with polvinylpyrrolidone or similar components, or nifedipine once dissolved in an organic solvent and then adsorbed on a porous substance such as light silicic anhydride or similar substances. As the pressurized tablet of the present invention has the structure described above, when administered orally it absorbs digestive fluid or water in the upper part of the digestive tract and its envelope forms an erodible matrix, but due to its resistance Mechanical does not break easily under the peristaltic movement of the digestive tract and is transformed into a gel from outside in a safe and slow manner. Thus, as time passes, the envelope releases nifedipine stably and continuously from its surface. Accordingly, in the approximate time that the release of the drug from the matrix layer of the envelope has been completed, the preparation reaches the lower digestive tract of low water content, and the core begins to release the drug. Accordingly, the tablet of the present invention improves the stability against peristaltic / mechanical agitation of the digestive tract and achieves the excellent effect of maintaining the effective plasma concentration of nifedipine when administered once a day.

EXAMPLES The invention will be explained more specifically below, with reference to the working examples, in which "Eudragit RSPOL" is the commercial name of a product of Roehm Pharma G.m.b.H. from Germany, a polymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride. As HPC-L and HPC-M, hydroxypropylcellulose products manufactured by Nippon Soda K.K. were used, which have respectively a viscosity of 6.0-10.0 cp (in 2% aqueous solution and at 20 ° C) and 150-400 cp (in 2% aqueous solution and at 20 ° C). As HPMP, hydroxypropylmethylcellulose 2910 manufactured by Shinetsu Kagaku Kogyo K.K. was used, which has a viscosity of 15 cp (in 2% aqueous solution and at 20 ° C).

Example 1 Nifedipine (micropulverized crystals) 7.0 g Lactose 16.4 g HPC-L 21.4 g The above starting materials were homogeneously mixed, granulated, dried and sieved, to which 0.2 g of magnesium stearate was added and mixed. The mixture was pressed under a pressure of 0.5 t with a simple punch press machine (Korsch EKO) to form the core tablets weighing 45 mg per tablet (diameter = 5 mm, thickness = 2 mm). Nifedipine (micropulverized crystals) 33.0 g HPC-L 116.7 g HPC-M 49.0 g Eudragit RSPOL 50.0 g The above starting materials were homogeneously mixed, granulated, dried and sieved. Then 1.3 g of magnesium stearate were added and mixed with them. co. The resulting composition with which the wrap was made, together with the previously prepared core tablet, was compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide pressurized tablets containing 40 mg of nifedipine and weighing 295 mg per tablet (diameter = 9 mm, thickness = 5 mm). In addition, a coating of a film composed of: HPMC (15 cp) 3.0 mg polyethylene glycol 4000 1.0 mg iron sesquioxide 1.0 mg was applied on the tablet, to produce the total weight of the final tablet of 300 mg. .

Example 2 Nifedipine (micropulverized crystals) 15,0 g Lactose 24.1 g HPC-L 5.7 g The above starting materials were homogeneously mixed, granulated, dried and sieved, to which 0.2 g of magnesium stearate was added and mixed. The mixture was compressed under a pressure of 0.5 t with a single-punch tablet machine (Korsch EKO) to form core tablets weighing 45 mg per tablet (diameter = 5 mm, thickness = 2 mm).

Nifedipine (micropulverized crystals) 25.0 g HPC-L 124, 7 g HPC-M 49, 0 g Eudragit RSPOL 50.0 g The above starting materials were homogeneously mixed, granulated, dried and sieved, to which 1.3 g of magnesium stearate were added and mixed. The resulting composition with which the wrap was made, together with the previously prepared core tablet, was compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide pressurized tablets containing 40 mg of nifedipine and weighing 295 mg per tablet (diameter = 9 mm, thickness = 5 mm). The tablets were also coated with the same film used in Example 1.

Example 3 Nifedipine (micropulverized crystals) 7.5 g Lactose 20.3 g HPC-L 17.0 g The above starting materials were homogeneously mixed, granulated, dried, sieved and then mixed with 0.2 g of magnesium stearate. The mixture was compressed under a pressure of 0.5 t with a machine manufacture single-punch tablets (Korsch EKO) to form core tablets weighing 45 mg per tablet (diameter = 5 mm, thickness 2 mm). Nifedipine (micropulverized crystals) 12.5 g HPC-L 141, 2 g HPC-M 45, 0 g Eudragit RSPOL 50.0 g The above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 1.3 g of magnesium stearate. The resulting mixture with which the wrap was made, together with the previously prepared core tablet, was compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide pressurized coated tablets containing 20 mg of nifedipine and weighing 295 mg per tablet (diameter = 9 mm, thickness = mm). The same film coating used in Example 1 was applied to the tablets in addition.

Example 4 Nifedipine (micropulverized crystals) 3.75 g Lactose 26.05 g HPC-L 20.0 g the above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 0.2 g of magnesium stearate. The mixture was compressed under a pressure of 0.5 t with a simple die making machine (Korsch EKO) to provide the core tablets weighing 50 mg per tablet (diameter = 5 mm, thickness = 2 mm). Nifedipine (micropulverized crystals) 6.25 g HPC-L 147.45 g HPC-M 45.0 g Eudragit RSPOL 50.0 g The above starting materials were homogeneously mixed, granulated, dried and sieved. The mixture was further mixed with 1.3 g of magnesium stearate. This composition with which the wrap was made, together with the previously prepared core tablets, was compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide pressurized tablets containing 20 mg of Nifedipine and weighing 300 mg per tablet (diameter = 9 mm, thickness = 5 mm). The same coating of a film used in Example 1 was applied to the tablets in addition.

Comparative Example 1 Nifedipine (micropulverized crystals) 7.0 g Lactose 15.0 g Corn starch 17.85 g Polyvinyl pyrrolidone 5.0 g Crystalline cellulose 5.0 g The above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 0.15 g of magnesium stearate. The mixture was compressed under a pressure of 0.5 t with a simple die making machine (Korsch EKO) to provide core tablets weighing 50 mg per tablet (diameter = 5 mm, thickness = 2 mm). Nifedipine (micropulverized crystals) 33.0 g HPC-L 110.0 g HPC-M 70.0 g Lactose 35.3 g The above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 1.7 g of magnesium stearate. This composition was used as a coating (sheath) which, together with the pre-prepared core tablets, was compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide pressurized compressed tablets containing 40% of the surface. mg of nifedipine and weighing 300 mg per tablet (diameter 9 mm, thickness = 5 mm). The same film coating used in Example 1 was applied to the tablets.

Comparative Example 2 Nifedipine (micropulverized crystals) 15,0 g Lactose 10,0 g Cross-linked polyvinyl pyrrolidone 5.0 g Crystalline cellulose 17.2 g Polyvinylpyrrolidone 1.8 g Polysorbate 80 0.8 g The above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 0.2 g of magnesium stearate. This mixture was compressed into tablets under a pressure of 0.5 t with a single punch tablet machine (Korsch EKO) to provide core tablets weighing 50 mg per tablet (diameter = 5 mm, thickness = 2 mm). Nifedipine (micropulverized crystals) 25.0 g HPC-L 25.0 g HPC-M 155.0 g Lactose 44.0 g The above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 1.0 g of magnesium stearate. This composition was used as a coating (core) which, together with the previously prepared core tablets, were compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide coated dry tablets containing 40 mg of nifedipine and weighing 300 mg per tablet (diameter = 9 mm, thickness = 5 mm). The same film coating used in Example 1 was applied to the tablets in addition.

Comparative Example 3 Nifedipine (micropulverized crystals) 33.0 g HPC-L 2.7 g HPC-M 163.0 g Eudragit RSPOL 50.0 g The above starting materials were homogeneously mixed, granulated, dried, sieved and mixed with 1.3 g of magnesium stearate. This composition was used as a wrap which, together with the core tablets prepared as in Example 1, was compressed under a pressure of 1 t with a pressure coating machine (Kikusui Cleanpress Correct 18DC) to provide pressurized coated tablets containing 40 mg of nifedipine and weighing 295 mg per tablet (diameter = 9 mm, thickness = 5 mm). The same film coating used in Example 1 was applied to the tablets in addition.

Test example Each of the tablets formed in Examples 1-2 and comparative examples 1-3 and a commercial sustained-release nifedipine tablet and twice-daily administration type (trade name: 20 mg Adalat L tablet; containing 20 mg of nifedipine) were orally administered to 12 healthy adult men, once, on an empty stomach, and the dynamics of nifedipine in the blood of the patients was compared. The results are indicated in table 1.

TABLE 1 Dynamics of nifedipine in blood (Mean values ± standard deviation) Test tablet C ^ (ng / ml) AUC (na.h / ml) Example 1 12.4 ± 6.0 815.2 ± 424.0 Example 2 12.6 ± 7.2 793.7 ± 382.8 Comparative Example 1 7.9 ± 4.7 858.7 + 391.4 Comparative Example 2 7.1 ± 5.1 647.7 + 452.5 Comparative Example 3 5.6 ± 4.3 506.6 ± 286.2 Tablet Adalat L 3.1 ± 2.0 391.5 ± 156.0 C24: concentration of nifedipine in the plasma 24 hours after its administration ABC: area under the curve "drug concentration / time" The plasma concentration of nifedipine 24 hours after administering the tablets of the examples it was greater than 12 hours after administering the said sustained release nifedipine tablet and administration twice a day. So, it is assumed that the tablets of the examples continuously present the pharmacological effect - for at least 24 hours per administration. Furthermore, it can be seen that, when the tablets of the invention were administered, the maximum plasma concentration of nifedipine was approximately the same as that of the commercial nifedipine sustained-release tablet and the type of administration twice daily. In addition, the area under the curve of the plasma concentration of the tablets in the examples was approximately double the area under the curve of the commercial nifedipine sustained-release tablet and the type of administration twice a day, confirming its excellent bioavailability Compared with the comparative examples, the tablets of the invention show a higher plasma concentration of nifenipine 24 hours after its administration. The dissolution models of the pressure-coated tablets prepared in examples 1-2 and comparative examples 1-3 and that of a composite tablet identical to the wrapping of example 2 are shown in table 2 and in figures 1 and 2.

TABLE 2 Dissolution speed of nifedipine from the tablet (%) (mean values ± standard deviation) Procedure 2 of the Pharmacopoeia Procedure of the device Tablet (using immersion device) of the test of test preparation 2 h 4 h 6 h 3 h 4 h Example 1 27, 9 ± 0.8 54.9 ± 1.1 80, 6 ± 4.5 37, 3 ± 2.3 49.5 ± 3.8 Example 2 26.4 ± 0.2 48.7 ± 0.4 90.5 ± 10.8 31, 2 ± 1.6 43.3 ± 4.8 Ex. comp. 1 30.7 ± 0.1 78.2 ± 2.8 103, 5 ± 1.0 95, l ± 3.0 102.8 ± 1.1 Ex. comp. 2 12, l ± 0, 9 26, 8 + 1.1 46.9 + 11.5 53.4 ± 17.46.6 ± 9.1 Ex. comp. 3 12.8 ± 0.3 28.7 ± 0.6 43, 6 ± 1.0 18, 6 ± 1.1 25.2 ± 1.2 Compound composed of the wrapping of the Ejemp. 2 36.8 ± 0.8 67, 9 ± 1, 1 89, 5 ± 1, 0 43, 5 + 1.4 55.9 ± 1.9 The nifedipine dissolution models from pressurized tablets having identical compositions to those of the core tablets used in examples 1 and 2 and in comparative examples 1 and 2, respectively, were those indicated in table 3.

TABLE 3 Speed of dissolution of nifedipine from the core (%) Dissolution test according to procedure 2 of the Pharmacopoeia (not using immersion device) (mean values ± standard deviation) 45 min 120 min Example 1 44.2 ± 4.7 99.6 ± 3.3 Example 2 49.8 ± 9.8 96.4 ± 0.8 Comparative Example 1 > 75 Comparative Example 2 > 75 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the dissolution models of nifedipine from the tablets of the examples and the comparative examples, according to the dissolution test according to the procedure 2 of the Pharmacopoeia (using immersion device). Figure 2 shows the dissolution models of nifedipine from the tablets of the examples and from the comparative examples, according to the procedure of the device according to the disintegration test of the Pharmacopoeia. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following

Claims (9)

1. CLAIMS 1. A pressurized coated tablet, containing nifedipine, comprising a core containing nifedipine and a substance of high molecular weight forming a hydrophilic gel and an envelope that covers the core and containing nifedipine, a substance of high molecular weight forming a hydrophilic gel and a substance suppressing the disintegration, characterized in that the rate of dissolution of nifedipine from said tablet is: (a) in the dissolution test using an immersion device, according to the method of the dissolution test procedure prescribed by the Pharmacopoeia of Japan: after 2 hours 10-40% after 4 hours 30-65% after 6 hours at least 55%, and (b) in the dissolution test according to with the disintegration test method prescribed by the Pharmacopoeia of Japan: after 3 hours 20-45% after 4 hours 30-65%.
2. 2. A tablet as defined in claim 1, characterized in that the rate of dissolution of the fedipino from the tablet is: (a) in the dissolution test using an immersion device, according to procedure 2 of the dissolution test procedure prescribed by the Pharmacopoeia of Japan: after 2 hours 15-35% after 4 hours 35-60% after 6 hours at least 60%, and (b) in the dissolution test according to the disintegration test procedure prescribed by the Pharmacopoeia of Japan: • after 3 hours 25-40% after 4 hours 35-60%.
3. 3. A tablet as defined in claims 1 or 2, characterized in that the dissolution rate of nifedipine from a tablet of identical composition to the core is: after 45 minutes • 20-70% after at least 2 hours 65%, when tested in accordance with procedure 2 of the dissolution test procedure that does not use an immersion device, prescribed by the Pharmacopoeia of Japan.
4. 4. A tablet as defined in any of the claims 1-3, characterized in that the dissolution speed of nifedipine from a tablet of composition identical to that of the envelope is: (a) in the dissolution test using an immersion device, according to procedure 2 of the dissolution test procedure prescribed by the Pharmacopoeia of Japan: after 2 hours 20-50% after 4 hours 40-90% after 6 hours at least 75%, and (b) in the dissolution test according to the disintegration test procedure prescribed by the Japan Pharmacopoeia: after 3 hours 30-60% after 4 hours 40-90 %.
5. 5. A tablet as defined in any of claims 1-4, characterized in that the core contains 5-90% by weight of a substance of high molecular weight forming a hydrophilic gel and the envelope contains 30-90% by weight of a substance of high molecular weight forming a hydrophilic gel and 5-50% by weight of a substance suppressing the disintegration.
6. 6. A tablet as defined in the claim 5, characterized in that the core contains 10-80% by weight of a substance of high molecular weight forming a hydrophilic gel and the envelope contains 35-85% by weight of a substance of high molecular weight forming a hydrophilic gel and 7, 5-40% by weight of a substance suppressing the disintegration.
7. 7 A tablet as defined in claim 5, characterized in that the core contains 10-70% by weight of a substance of high molecular weight forming a hydrophilic gel and the envelope contains 40-80% by weight of a substance of high molecular weight forming a hydrophilic gel and 10-30% by weight of a substance suppressing the disintegration.
8. 8 A tablet as defined in any of claims 1-7, characterized in that the substance suppressing the disintegration is a polymer of ethyl acrylate, methyl methacrylate and / or trimethylammonioethyl methacrylate chloride.
9. 9. A tablet as defined in any of claims 1-8, characterized in that the high molecular weight substance forming a hydrophilic gel is a lower hydroxyalkyl ether of cellulose.