MXPA99009337A - Method for producing orally administered, solid pharmaceutical products with controlled release of the active substance - Google Patents

Abstract

The invention relates to a method for producing orally administered solid pharmaceutical products with controlled release of the active substance. According to the invention, it is possible to vary the choice and number of at least three of four compressed tablets containing an active substance or a combination of active substances. Said compressed tablets are then processed into solid pharmaceutical forms according to non-time consuming and technically simple known methods. The inventive method therefore provides a means of producing orally administered, solid pharmaceutical products which can meet diverse pharmaceutical requirements in terms of release of the active substances or combination of active substances, for example delayed release, constant release or timed (pulsatile) release.

Description

METHOD FOR PREPARING SOLID PHARMACEUTICAL FORMS OF ORAL ADMINISTRATION WITH CONTROLLED RELEASE OF THE ACTIVE SUBSTANCE Description of the invention The invention relates to a method for preparing solid dosage forms for oral administration with controlled release of the active substance, with which at least three of four tablets containing an active substance or a combination thereof are prepared. active substances, whose quantity and selection can be varied, to obtain solid pharmaceutical forms by known methods, little apparatus and little time input. This method makes it possible to obtain solid dosage forms for oral administration which have the most varied release profiles of an active substance or a combination of active substances, such as, for example, a delayed, sustained sustained release or a release adapted to special rhythms (pulsatile). The release or delivery of the active substance or a combination thereof as a function of time is referred to herein as the "release profile". Within the pharmaceutical technology, the aim of the present is to find procedures for incorporating a therapeutically active substance into a pharmaceutical form that upon administration guarantees, among others, a release of the active substance appropriate for the prescribed therapy. For this it is necessary to achieve an optimal concentration curve for the therapy in the place to be treated. The mechanisms in which the release of active substance is regulated directly by the concentration of effective active substance that is present in the target site or by a biochemical quantity that characterizes the pathology are ideal, although only applicable in a few cases. Hence, it depends on a controlled release of the active substance. Known methods and techniques for preparing solid dosage forms of oral administration with controlled release point to a delayed release of the active substance, or to a uniform sustained release or to a release subject to special rhythms (pulsatile). A uniform sustained release after the initial rapid release of an active substance attack dose is also possible. Hence, the manufacturer of such pharmaceutical forms must apply several of these methods and techniques, have the necessary equipment and acquire and analyze several auxiliary substances, generally specific, necessary for the different procedures.

The patent and specialized literature disclose methods for preparing solid dosage forms of oral administration with controlled release of the active substance that satisfy several of the release profiles mentioned on the basis of a control principle. However, according to E. Mutscier et al., "Arzneimittelwirkungen", Lehrbuc der P armakologie und Toxikologie, 7. Ed., Wissenschaftuche Verlagsgesellschaft mbH Stuttgart, 1996, p. 12, the problematic of the solid pharmaceutical forms (single-unit-form) that have a period of residence in the gastrointestinal tract exceeding 1 h is that due to their size or properties can not pass certain places. For example, a coated tablet resistant to the action of gastric juices is in danger of not being able to leave the stomach. According to K.H. Bauer et al., Pharmazeutische Technologie, 4. Ed., Georg Thieme Veriag Stuttgart, New York, 1993, p. 357, the single-unit forms of delayed effect have, however, the advantage of a homogeneous matrix. In drugs of "multiple unit" form, the tablet is broken down, usually in the stomach, into several secondary units, granules or pellets. One of the disadvantages encountered in the manufacture of "multiple unit" forms is that the pellets or granules are housed in a capsule after being dosed by their volume. Hence, the error of each dose can be at least one pellet or pellet. Minitablets are also used to fill the capsules. The minitabletas require special pressing tools and impose very high accuracy requirements of the recipe. Also E. Nürnberg and P.Surmann (Editors) mention in Hagers Handbuch, Volume 2, Methoden, 5.Ed. corrected, Springer Veriag Berlin, Heidelberg, New York, 1991, p. 1123, the clear differences of residence time conditioned by the pharmaceutical form of the drug forms "single-unit" forms "multiple-unit" The magnitudes that govern the release of active substance are based, in most cases, on osmosis processes, on a diffusion and / or erosion process. According to E.M. Ouriemchi et al., "Oral Dosage Forms with a Core and Shell with the Same Polymer Containing Different Drug Concentrations", Int. J. Pharm. , 102 (1994), p. 47-54, the effect of the controlled release dosage forms of the active substance, such as, for example, monolithic matrix, swellable hydrogel matrix or with coatings, is influenced by several of the aforementioned principles as a whole. R.C. Diluccio et al., "Sustained-Release Oral Delivery of Theophylline by Use of Polyvinyl Alcohol and Polyvinyl Alcohol-Methyl Acrylate Polymers," J.Pharm. Scien. 83 (1994), p. 104-106, describes the controlled release from pharmaceutical forms by means of the release of the active substance theophylline using a mixture of polyvinylalcohol (PVA) and a copolymer of polyvinylalcohol methacrylate (PVA-NM) of low crystallinity. While PVA produces fast-release tablets, PVA-MA allows, depending on the proportion in which it is used, a delayed release of the active substance. It has been found that a PVA: PVA-MA mixture of 1: 9: 10 causes the desired delayed release of the active substance. In a test conducted in dogs, the tablets reach a bioavailability of almost 80%. Also M.M. Meshali et al., "Preparation and evaluation of theophyline -released tablets", Drug Develop, Ind.Pharm., 22 (1996), pp. 373-376 achieve the delayed release of theophylline, based on the combination of different polyacrylates that They create a mixed barrier around the pharmaceutical form and cause a controlled release of the active substance by diffusion of the matrix.The pharmaceutical forms contain 50% thiofilin, Carbopol® 974P as a retarding additive, lactose spray-dried and , 5% of a substance that facilitates sliding, with this principle only two of the usual release profiles could be achieved, with the release developing mostly in a linear fashion, ie in the same time interval the same amount of active substance is released. and the release is proportional to the square root of time. "HE Junginger," Oral Applications of Pulsatile Drug Delivery "describes in R. Gurny, HE Junginger, NAPeppas (Eds., Pulsatile Drug Delivery, l.Ed., issenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp. 113-134, different systems to achieve pulsatile release profiles of active substance, such as coated tablets, pellets or microgranules, OROS®, PULSINCAP®, controlled-time explosion systems, special layered tablets The preparation of these pharmaceutical forms is basically expensive and the proper functioning of the system depends, in general , in a decisive way of the exact maintenance of certain production parameters, such as, for example, the thickness of the coating, the precision of the opening and / or release coating, the properties of the hydrogel, precise sizing and, in some cases, aging of the gel, of the exact relationship between osmotic core material and the external coating and of the precision of pressing and the thickness of the Thus, all these processes have the considerable disadvantage that special production lines are required, as well as costly devices or high-cost precision manufacturing. DE 44 43 175 A1 discloses a pharmaceutical form of pulsatile release that adapts to the accesses of the disease or pain. EP 0 719 555 A2 discloses the use of melatonin to prepare pulsatile oral dosage forms. The pulsatile pharmaceutical form that for this is proposed is a capsule. It contains the active substance embedded in different fillers. Nevertheless, tablets specifically releasing specific parts of the active substance have not been specifically defined. In addition, this pulsatile release dosage form is not claimed for combinations of active substances. From the examples mentioned in DE 44 43 175 A2 it appears that the active substance melatonin was embedded in collagen beads. These collagen beads were dispersed with another amount of melatonin in peanut oil. The packaging of said multi-dispersed oil system in capsules requires a technical knowledge and a special apparatus that is not available to most pharmaceutical laboratories. The object of the invention is to create a method for preparing peroral pharmaceutical forms, solid, controlled release of the active substance that allows obtaining any profile of release required pharmaceutically, and that the pharmaceutical form can be manufactured with little equipment and time input. According to the invention, the task is solved by combining at least three of four tablets containing an active substance or a combination of active substances, whose quantity and selection can be varied, since these are mixed, granulated, converted into tablets and / or they are coated with pharmaceutically suitable excipients and / or fillers according to known methods, so that each required pharmaceutical release profile of the active substance or combination of active substances is produced. A first tablet A of the four tablets performs a rapid release of the active substance, releasing at least 75% of its content of active substance within 45 minutes.

Another tablet B has a sustained and uniform release profile of the active substance, releasing 100% of its active substance content only after at least 3 h according to a release profile close to 0. The release of active substance must have a substantially linear trajectory, ie in the same time intervals the same quantities of active substance are released. Such release profiles of the active substance or combination of active substances can be obtained, inter alia, with hydrophilic matrix tablets, with controlled diffusion varnish coatings or lipophilic matrix tablets. A third tablet C has a delayed release of the active substance. With a pH of 6-7.5 corresponding to the conditions in the duodenum and the intestine, this tablet releases at least 75% of its active substance content in the course of 45 minutes. Usually, a release profile of this type can be obtained by coating a fast-release tablet, analogous to tablet A, with a coating resistant to the action of gastric juices, for example on the basis of polymethylacrylate or shellac. The tablet D has a profile of release of the active substance or combination of active substances that combines moments of delay with moments of uniform sustained release. With a pH value of 6-7.5 corresponding to the conditions in the duodenum and intestine, it releases 100% of its active substance content only after at least 3 more hours according to a release profile close to 0. The release profiles that combine moments of delay with moments of uniform sustained release can be achieved, inter alia, with hydrophilic matrix tablets with gastric juice resistant coating or with combined coatings of substances resistant to gastric juices and controlled diffusion varnishes. In claim 2 an advantageous embodiment of this invention is described. The capsule prepared according to this method has the advantages of a "multiple-unit" form. Figure 1 shows the release profile of the active substances taking as a model the tablets A to D. The percentage of release of active substance as a function of time is represented. By varying the selection and number of tablets - there are 12 possibilities - it is possible to make all the desired release profiles.

Thanks to this invention, the application of hormones specific to the human body and related substances is extraordinarily facilitated. Due to its metabolism, a part of the body's own hormones is characterized by its brief residence time in the body. Among the examples of such hormones we will mention: progesterone, testerone, dehydroepiandrosterone, estriol, estradiol. The level of other hormones of the body follows a markedly circadian rhythm, that is to say that its concentration in blood changes over the course of 24 h.

Examples of these hormones include: prednisone, prednisolone, cortisone, corticosterone, cortisol and aldosterone. Melatonin is metabolized mainly during the night. Also the blood level of analogous substances and inhibitors of these hormones may be subject to a circadian rhythm. Among the examples of this class of substances we will mention: antidiabetics, glucocorticoids, mineralocorticoids, antihistamines. To ensure a constant level of active substance that satisfies the therapeutic purposes, in all these cases frequent doses should be applied. The hormonal active substances can also be used in combination. In these cases it may be necessary to use each hormonal active substance with its own release profile or together with a common profile. Examples of such combinations are: progesterone / estradiol, testerone / progesterone, progesterone / estriol, progesterone / estrone, cortisol / aldosterone. With the method of the present invention solid dosage forms of oral administration are prepared which can have all the active substance release profiles or combinations of active substances and which are prepared with few well-known technologies and little apparatus and time input. The invention will be explained below by means of the following examples: Release of active substance The release of the active substance or combination of active substances in vitro was analyzed: Apparatus according to DAB 96, V.5.4. Stirring speed 100 rpm ± 2 rpm Temperature 37 ° C ± 0.5 K Volume of medium 1000 ml Medium 0.1 N HCl, 0.2 trisodium phosphate buffer According to USP 23 <; 724 > , Method A EXAMPLE 1 Progesterone 50 mg, estradiol 1.6 mg Proposed Release Profile Pulsatile Progesterone is rapidly released at an initial dose of 10 mg then, sustained and uniformly, and Estradiol is rapidly released Composition: Compressed A Compressed C Compressed D ( mg) (mg) (mg) Progesterone 10 10 30 Estradiol 1.6 Hydroxypropylmethylcellulose Type 2208 10 Lactose 20.9 9 Corn starch 12 12 5.5 PVP K25 2 2 2 Magnesium stearate 0.5 0.5 0.5 Talc 1.5 1.5 1.5 Water (as TV) 1.5 1.5 1.5 Tablet 50 mg, 0 5 mm 50 mg, 0 5 mm 60 mg, 0 5 mm Coating none Compressed A Compressed C Compressed D (mg) (mg) (mg) Eudragite L30 D (as LTS) 7. 5 7. 5 Talc 1 .75 1. 75 Triethylcitrate 0.75 0.75 Preparation Progesterone, estradiol and hydroxypropylmethylcellulose are mixed and granulated with a solution of 96% PVP in ethanol. The granulate is dried, mixed with talc and magnesium stearate and tablets of the indicated diameter and mass are pressed. The coating of a dispersion of eudragite, talc and triethylacitrate is applied to the tablets with an appropriate device and dried. The tablets thus obtained are presented in capsules.

TABLE 1 Release of the active substance in vitro (cumulative) Compressed Time Compressed Compressed Form [h] A C D pharmaceutical (mg) (mg) (mg) (mg) proges estra proges proges proges estra terona diol terona terona terona diol 0.25 10 1.6 0 0 10 1.6 1 10 1.6 0 0 10.0 1.6 2 10 1.6 0 0 10.0 1.6 2.5 10 1.6 10 3.2 23.2 1.6 3 10 1.6 10 7.0 27.0 1.6 4 10 1.6 10 15.2 35.2 1.6 10 1.6 10 23.8 43.8 1.6 6 10 1.6 10 30 50 1.6 Figure 2, in combination with Table 1, shows the quantitative release profile of the active substances progesterone and estradiol as a function of time. Three tablets were used, one of each embodiment: Compressed A - 10 mg progesterone, 1.6 mg estradiol Compressed C - 10 mg progesterone Tablet D 30 mg progesterone Each active substance is applied with its own release profile. Tablet A rapidly releases the active substance, 10 mg progesterone and 1.6 mg estradiol in the course of 0.25 h; Tablet C has a delayed release profile, 10 mg progesterone after 2.5 h; and Tablet D has a release profile that combines the moments of delayed release with moments of uniform sustained release, 30 mg progesterone after 6 h. EXAMPLE 2 Melatonin 10 mg Proposed release profile cumulative release of melatonin Composition: Tablet A Tablet C Tablet D (mg) (g) (mg) Melatonin 2.5 2.5 5 Hydroxypropyl methylcellulose Type 2208 5 5 Lactose 26.5 22.5 20 Corn starch 15 15 15 PVP K25 1.5 1.5 1.5 Magnesium stearate 0.5 0.5 0.5 Tablet A Tablet C Tablet D (mg) (mg) (mg) Talc 1.5 1.5 1.5 Croscara elosa-Na 1 Water (as TV) 1.5 1.5 1.5 Tablet 50 mg, 0 5 mm 50 mg, 0 5 mm 50 mg, 0 5 mm Coating none none Eudragite L30 D (as LTS) 3.76 Talc 0.81 Glycerol triacetate 0.38 Antifoam emulsion 0.05 Preparation: Melatonin, corn starch and hydroxypropylmethylcellulose are mixed and granulated with a 96% solution of PVP in ethanol. The granulate is dried, mixed with talc and magnesium stearate and tablets of the indicated diameter and mass are pressed. The coating of a dispersion of eudragite, talc and glycerol triacetate is applied to the tablets with an appropriate device and dried.

The tablets thus obtained are presented in capsules, TABLE 2 Melatonin release in vitro (cumulative) Compressed Time Compressed Tablet Form [h] Pharmaceutical A B D [mg [mg [melatonin] melatonin] melatonin] 0.17 2.5 0 0 2.48 1 2.5 1.03 0 3.51 2 2.4 1.65 0.14 4.26 3 2.5 2.13 2.14 6.75 4 2.5 2.5 4.65 9.51 2.5 2.5 4.89 9.75 6 2.5 2.5 5 10 Figure 3, in combination with Table 2 shows the quantitative release profile of the active substance melatonin as a function of time. Three tablets were used, one of each embodiment: Tablet A - 2.5 mg melatonin Tablet B - 2.5 mg melatonin Tablet D - 5 mg melatonin Compressed A rapidly released the active substance, 2.5 mg melatonin in the course of 0.17 h; Tablet B has a uniform sustained release profile, 2.5 mg melatonin after 4 h; and tablet D has a release profile combining the moments of delayed release with moments of uniform sustained release, 5 mg melatonin after 6 h. EXAMPLE 3 Hydrocortisone 10 mg Proposed release profile uniform sustained release with prolongation of release time Composition: Compressed A Compressed C Compressed D (mg) (mg) (mg) Hydrocortisone 1 3 6 Hydroxypropyl methylcellulose Type 2208 5 5 Lactose 27 22 19 Cornstarch 16 15 15 PVP K25 1.5 1.5 1.5 Magnesium stearate 0.5 0.5 0.5 Tablet A Tablet C Tablet D (mg) (mg) (mg) Talc 1.5 1.5 1.5 Croscaramellose-Na 1 Water (as TV) 1.5 1.5 1.5 Tablet 50 mg, 0 5 mm 50 mg, 0 5 mm 50 mg, 0 5 mm Coating none none Eudragite L30 D (as LTS) 3.76 Talc 0.81 Glycerol triacetate 0.38 Antifoam emulsion 0.05 Preparation Hydrocortisone, lactose, corn starch and hydroxypropylmethylcellulose are mixed and granulated with a 96% solution of PVP in ethanol. The granulate is dried, mixed with talc and magnesium stearate and tablets of the indicated diameter and mass are pressed. The coating of a dispersion of eudragite, talc and glycerol triacetate and antifoaming dispersion is applied to the tablets with an appropriate device and dried. The tablets thus obtained are presented in capsules.

TABLE 3 Hydrocortisone release in vitro (cumulative) Compressed Time Compressed Tablet Form [h] Pharmaceutical A B D [mg hydro [mg hydro [mg hydro cortisone] cortisone] cortisone] 0.25 1 0 0 1.06 1 1 0.9 0 1.86 2 1 2.1 0 3.06 2.47 1 2.3 0.8 4.13 3 1 2.6 1.7 5.32 4 1 3 3.1 7.07 1 3 4.4 8.38 6 1 3 6 10 Figure 4, in combination with Table 3, shows the quantitative release profile of the active substance hydrocortisone as a function of time. Three tablets were used, one of each embodiment: Compressed A 1 mg hydrocortisone Tablet B 3 mg hydrocortisone Tablet D 6 mg hydrocortisone Tablet A rapidly releases the active substance, 1 mg hydrocortisone in the course of 0.25 h; tablet B has a uniform sustained release profile, 3 mg hydrocortisone after 4 h; and tablet D has a release profile combining the moments of delayed release with moments of uniform sustained release, 6 mg hydrocortisone after 6 h.

Claims (1)

1. Method for preparing solid dosage forms for peroral administration with controlled release of the active substance, characterized in that a) at least three of the four tablets mentioned under b) which contain an active substance or a combination of active substances are combined, The amount and selection can be varied, being that they are mixed, granulated, tabletted and / or coated with pharmaceutically suitable auxiliary substances and / or fillers according to known methods, b) by this, each pharmaceutically required release profile is obtained. the active substance or combination of active substances, such as for example a delayed release, sustained uniform and adapted to certain rhythms (pulsatile), since one tablet A of the four tablets used releases at least 75% of its content of active substance in the course of 45 minutes, another tablet B releases 100% of its content active use only after at least 3 h. according to a release profile close to 0 that is obtained with lipophilic matrix tablets, hydrophilic, or with controlled diffusion coatings; a third tablet C releases at least 75% of its content of active substance in a medium with a pH value of 6-7.5 over the course of 45 minutes, which is obtained analogously to a Tablet A with a juice-resistant coating gastric the fourth tablet D releases 100% of its active substance in a medium with a pH value of 6-7.5 only after at least 3 h according to a 0 release profile, which can be obtained with resistant matrix tablets to gastric juices or combinations of coatings resistant to gastric juices and controlled diffusion. Method for preparing solid dosage forms for oral administration with controlled release of clause 1, characterized in that the solid dosage form for oral administration is a capsule. Solid pharmaceutical forms of peroral administration with controlled release of the active substance, which is obtained according to claim 1 and / or 2