ORAL SOLID PHARMACEUTICAL FORM WITH SEQUENTIAL ACTION FOR THE ADMINISTERING OF DRUGS WITH ULCEROGENIC SIDE EFFECT

Abstract: Oral solid pharmaceutical form with antiinflammatory and analgesic activity, with sequential action, with protective effect on the gastric and duodenal mucosa against the action of the active principles having ulcerogenic effect, contained in the same pharmaceutical form. Said pharmaceutical form is constituted by a tablet comprising: (a) a centre core containing an active principle provided with antiinflammatory and analgesic activity, with ulcerogenic side effects; (b) a layer coating of said core, containing a second active principle provided with protective action for said gastric and duodenal mucosa, which is immediately released.

Description: ORAL SOLID PHARMACEUTICAL FORM WITH SEQUENTIAL ACTION FOR THE ADMINISTERING OF DRUGS WITH ULCEROGENIC SIDE EFFECT. The present invention relates to a new pharmaceutical form with antiinflammatory and analgesic activity, avoiding the ulcerogenic side effect of the antiinflammatory and analgesic active principle. More particularly, the present invention relates to an oral solid pharmaceutical form with antiinflammatory and an algesic activity, with sequential action, showing an effect of protection of the gastric and duodenal mucosa against the action of the active principles having ulcerogenic side effect. It is known that during these last years several nonsteroidic drugs with antiinflammatory and analgesic action, denominated as FANS (Non Steroidic Antiinflammatory Drugs, NSAD) have been prepared and tested. It is knows too that for all these drugs as a side effect a damaging action on the gastric and duodenal mucosa has been evidenced, which makes unadvisable the prolonged use thereof. In order to overcome this problem, several modifications and administering forms have been suggested for these drugs, e.g., the formation of salts with alkaline metals, the formation of complexes with Al, Mg or Cu, the prepara tion of inclusion compounds with B-cyclodextrins and the like. Notwithstanding the attention devoted to this problem, and the large number of solutions proposed, the problem of the ulcerogenic action of antiinflammatory drugs is to be considered as being still open, and always of great interest in the pharmaceutical field. A noticeable step forward has been done with the contemporary administering, in the 1 : 1 ratio, of FANS and sucralfate, which allows an antiinflammatory activity similar to that exerted by the same FANS alone to be obtained, with a considerable reduction in the damaging effects on the gastric and duodenal mucosa (Italian Patent Application Nr. 23205 A.83). Sucralfate L3,4,5,6-tetra-(polyhydroxyalumino)--D-glu copyranosyl sulphate - 2,3,4,5-tetra-(polyhydroxyalumino) 6-D-fructofuranoside sulphate) is a product prepared during these last years, and successfully tested in the management of gastric and duodenal ulcer (R. Nagashima et al., Arzneim. Forsch., 1980: 30: 84/8; 1980: 30: 88/91 "Selective Binding of Sucralfate to Ulcer Lesion"). We have now found that if, instead of contemporaneous ly administering the mixture of the two active principles, the administering in sequence of sucralfate first, and of FANS then is carried out, a more efficacious protection of the mucosa is obtained. The result in practice is such as to allow the same protection level with lower amounts of sucralfate to be obtained. This administering form causes however the drawback that a double administering is to be carried out, with a suitable time interval. Purpose of the present invention is to provide a sol id pharmaceutical form which allows the contemporary admin istering of the two drugs above mentioned, or of other similar drugs, and the release of them in a sequential fashion. This purpose is achieved by means of the pharmaceutical form sequentially relasing the active principles according to the present invention, which is characterized in that it is constituted by a tablet comprising: a) a centre core containing an active principle providing an anti-inflammatory and analgesic activity with side ulcero genic effects; b) a layer coating for said core, containing a second active principle, providing a protective action of the gastric and duodenal mucosa, which is released immediately. These and other characteristics and advantages of the pharmaceutical form according to the present invention shall be evidenced in greater detail by the following detailed disclosure, and by the related Figure 1, which are reported to the purpose of illustrating and not of limiting the invention itself. Referring to the numerical indices of fig. 1, the centre core (1) of the pharmaceutical form according to the present invention is prepared by making into a paste the antiinflammatory and analgesic active principle, suitably formulated, with an alcoholic solution of ethylcellulose; the paste is granulated, dried, blended with lubricating and disintegrating substances, and then transformed into tablets. The coating layer (2) is prepared by mixing sucralfate in suitable formulations, and is applied to the core (1) by means of the double-compression technique, i.e., by compress ing two coating layers respectively positioned on and under the core. The coating layer can contain as mucose protecting ac tive principles, in addition to sucralfate, also mucin, cel lulose derivatives, natural or synthetic polymeric materials, alone, or as different combinations with each other. The coating layer is so formulated, as to release an extremely subdivided dispersion of sucralfate before that the FANS composing the core comes in contact with the gastric and duodenal mucosa. The action of this farmaceutical form is hence developed in two sequential steps, whose sequence is evidenced by observations related to tests carried out on animal. The steps of this action are: A) Disintegration quick and of microgranular type, in the acidic medium of the stomach, of the coating layer, with formation of a wide dispersion of the protective agent composing it. The active principle of the coating has hence the time and the possibility of lining the gastric and intestinal mucosa, protecting it from the subsequent contact with the ulcerogenic drug contained in the core. B) Slow disintegration of the core in a medium wherein the protective active substance has already lined the mucosa. In this way, the lesioning action of the drug contained in the core is limited by the action of the protective drug. Several compositions containing sucralfate : FANS in weight ratios comprised within the range of from 1: 4 to 8 : 1 have been tested on rats by means of the test of pylorus ligature according to the technique Linda J et al., J. Pharmac., 1978, 30, 244 - 246 "Inhibitors of Gastric Lesions in the Rat". The testing has been carried out on Charles River Wis tar rats of 230 - 270 g of weight and in the number of 8 rats per each group. The rats, fasting from 15 hours, have been submitted to etheric anesthesia and then to the liga ture of the pylorus. The rats have been treated, immediate ly after the recovery, by means of gastric probe, with the FANS alone, with the FANS in the sucralfate-FANS form with sequential action according to the present invention, and by means of the administering of sucralfate first, and then, after a 10 minutes interval, of FANS. The single active principles have been administered as aqueous suspension in sodium-CMC at 0.5% p.o. Six hours later than the intervention, the rats have been sacrificed and the stomach, after having been withdrawn, has been cut along the line of the greater curvature. The stomach, after having been slightly washed with bidistilled water has been spread out and mounted an a support for the evaluation of induced ulceration. The alterations detected on the gastric mucosa have been quantified on the basis of their type and largeness, with a value ranging from 0 to 1 (ulcerating index, UI), according to the following empirical scale: 0 = mucose not damaged (control submitted to surgical han dling and to placebo) 0.25 = diffused accentuated hyperemia 0.50 = diffused erosion 0.75 = diffused hemorrhagic ulceration 1 = diffused hemorrhagic ulceration with perforation and damaging of the whole gastric mucosa. The activity of the form of sucralfate and FANS with sequential action according to the invention has been expressed as percentage inhibition of the lesion relatively to that observed in the control group as treated with the ligature of pylorus and administering of FANS only, and com pared to that obtained from the contemporary administering of sucralfate and FANS. The ID (Inhibitin Dosis 50) was 50 computated by the probit method. In Table 1 the values of ID50 of sucralfate for va 50 rious FANS are reported, in the case of the contemporary ad ministering of FANS and sucralfate, and in the case of the administering in the form with sequential activity according to the present invention. TABLE 1 Inhibiting Dosis 50 of sucralfate for the ulcerogenic activity of some FANS (mg) Contemporary ad- Administering of ministering of the sucralfate sucralfate and FANS form with se FANS of FANS sequential action Sodium indoprof en betainate (200 mg/ 206 85.6 kg as indoprofen) Diclofenac Na (50 157 96.6 mg/kg) Indomethacin (100 204 97 mg/kg) It results from Table 1 in a clear way that the administering of the form of sucralfate-FANS with sequential action is capable of protecting to a significantly greater extent the gastric mucosa against the lesioning power of FANS. To illustrative, but not limitative, purpose of the present invention, the following Example is reported, relating to a formulation of the pharmaceutic form with sequential action (the numbers indicate parts by weight): a) Formulation of the core of sodium indoprofen betainate Sodium indoprofen betainate 290 Ethylcellulose 5 Carboxymethyl starch 12 Magnesium stearate 3 b) Preparation of the core Indoprofen betainate is made into a paste with an alcohol ic solution of ethylcellulose, the paste is granulated and dried. The dried granulate is mixed with the lubri cant agent (magnesium stearate) and then with the disin tegrating agent (carboxymethyl starch), and is compress ed to form tablets of slightly crowned shape, with punches of 9 mm in diameter. c) Formulation of the coating layer Sucralfate 100 Crosslinked carboxymethylcellulose 10 Microcrystalline cellulose 40 Magnesium carbonate 10 CL Polyvinylpirrolidone 5 Magnesium stearate 2 The components of the formulation are mixed in a V-mix er. d) Application of sucralfate coating on the core of sodium indoprofen betainate. The application of the coating layer on the core is car ried out by means of the double-compression technique, by compressing two layers of coating positioned on the core and under it, a coated tablet of suitable diameter being obtained, wherein the outer coating is constituted by sucralfate, and the inner core is constituted by in doprofen betainate (see figure 1).

Claims: Claims 1. Solid pharmaceutical form, for administration by oral way, with sequential release of the contained active principles, characterized in that it is constituted by (a) a centre core containing an active principle display ing antiinflammatory and analgesic activity, with ul cerogenic side effects; (b) a coating layer for said core, containing a second ac tive principle displaying a protective action for the gas tric and duodenal mucosa1 which is immediately releas ed. 2. Pharmaceutical form according to claim 1, characterized in that the active principle contained in said core is constitutend by FANS (Non Steroidic Antiinflammatory drugs, NSAD), such as ASA, Indoprofen, Naproxen, Ketoprofen, Indomethacin, Diflunisal, Diclofenac or derivatives. 3. Pharmaceutical form according to claim 1, characterized in that said core shows a slow disintegration, or constitutes a system with bioeroded matrix and however of the type with properties of controlled release of the contained active principle. 4. Pharmaceutical form according to claim 1, characterized in that said core containes active principles provided with anti-inflammatory and analgesic activity, with ulcerogenic side effects, combined with each other or with other medicaments. 5. Pharmaceutical form according to claim 1, characterized in that said coating layer is constituted by active principles capable of performing a protective action on the gastric and duodenal mucosa such as, e.g., sucralfate, mucin, cellulose derivatives, natural or synthetic polymeric mate rials capable of forming a protective lining. 6. Pharmaceutical form according to claim 1, characterized in that said coating layer shows a disinegration quick and of the microgranular type in the acidic medium of the stomach, determining an immediate dispersion of the contained protective agent. 7. Pharmaceutical form according to claim 1, characterized in that sucralfate or another mucose-protecting agent and FANS are contained in a weight ratio comprised within the range of from 1 : 4 to 8 : 1. 8. Pharmaceutical form for oral usage according to claims from 1 to 7 and method for the preparation thereof, which is carried out by means of the double-compression tec nique, i.e., by compressing around said core containing the active principle provided with antiinflammatory and analgesic activity with ulcerogenic side effects,-said coating layer containing an active principle provided with protective action for the gastric and duodenal mucosa.

Inventors: COLOMBO, PAOLO, CONTE, UBALDO, ZAGNOLI, GIORGIO
Applicants: LABORATORIO ITALIANO BIOCHIMICO FARMACEUTICO LISAPHARMA S.P.A.
Application year: 1985
Main classification: A61K9
IPC codes: A61K9