FR2873924A1 - PHARMACEUTICAL COMPOSITION, FOR ORAL ADMINISTRATION OF HIGHLY GASTRO-LABILE ACTIVE SUBSTANCE (S) AND PREPARATION THEREOF - Google Patents

Abstract

Liquid or solid pharmaceutical composition (A), for oral administration, contains at least one active ingredient (I) that is unstable in the stomach and includes a buffer system (B). In liquid compositions, (B) provides pH 4-9, especially in gastric medium, and in solid compositions, (B) provides the same pH in aqueous media, particularly in the stomach. ACTIVITY : Antiulcer; Antiinflammatory; Gastrointestinal-Gen.; Cytostatic. MECHANISM OF ACTION : Proton pump inhibitor; Gastric secretion inhibitor.

Description

2873924 1

  The present invention relates to pharmaceutical compositions for the oral administration of highly gastro-labile active ingredients and their preparation. Said compositions are interesting in that within them, said highly gastro-labile active ingredients, formulated in an original way, prove to be capable, after taking them orally, of resisting gastric acidity and then of expressing their activity specific unaltered. The formulations in question do not conventionally protect said active principles from the aggressiveness of the gastric medium but prove to be capable of neutralizing said aggressiveness.

  The present invention has more particularly been developed in the field of substituted benzimidazoles with antisecretory activity, but one skilled in the art will readily understand, on reading the following, that its field of application is broader. The original solution, explained below, to protect against the harmful effects of gastric juice, the active principles likely to be strongly altered by said gastric juice, is not, as will be evident from the following remarks, specific to the nature of said active ingredients (a chemical compatibility is only of course necessary).

  The substituted benzimidazoles introduced a completely new principle of inhibition of acidic gastric secretion. They inhibit the proton pump. Proton pump inhibitors are used in gastroenterology in the treatment of many diseases, such as progressive duodenal ulcer, progressive gastric ulcer, erosive esophagitis, Zollinger-Elison syndrome ... The usual dosage is 20 to 40 mg daily, orally.

  Omeprazole (5-methoxy-2 - [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole), lansoprazole (2 - [[[3-methyl-4- (2 - 2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole), pantoprazole (5-difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole), rabeprazole (2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] -methyl] sulfinyl] -1H-benzimidazole), and esomeprazole (S-isomer of omeprazole), 2873924 2 are thus powerful antisecretory agents. These active ingredients are liposoluble substances, rapidly degraded in acidic medium. They can therefore be used orally only if they are effectively protected from the harmful effects of gastric juice, which is very acidic (pH - 1.5). Only on this condition can they reach the upper parts of the intestine.

  The formulation of these active principles, in enteric forms, including granules or gastro-resistant tablets, has been implemented but is a delicate and expensive operation.

  Thus, omeprazole is included in small granules coated with an enteric coating (by microencapsulation); said small granules then being distributed in a capsule.

  According to the invention, an alternative to these gastroresistant forms with a gastro-resistant coating is proposed. According to said alternative, rather than protecting the active principle of the aggressive medium, it neutralizes said aggressive medium (= stomach).

  In the application WO-A-00711770, an original formulation for phloroglucinol (1,3,5-trihydroxybenzene) has been proposed. This active ingredient, with antispasmodic activity, is not a highly gastro- labile active ingredient; the systems responsible for the buffer effect (and advantageously effervescence) recommended (s), are low capacity buffer systems. This document particularly emphasizes the potentiation of the antispasmodic activity of the buffered pharmaceutical compositions described.

  In such a context, the Applicant is presently proposing an original galenic form for the oral administration of highly gastro-labile active principles, especially chosen from substituted benzimidazoles. Said original galenic form can be broken down into numerous variants. It may be per se new (see, for example, the effervescent galenic forms described further herein) or it may be a modified conventional dosage form (see, for example, the tablets described further in this text). . Whatever its variant embodiment (original variant or not per se), said dosage form is, typically, buffered between pH 4 and 9.

  According to its first object, the present invention relates to novel buffered pharmaceutical compositions.

  They are pharmaceutical compositions, in liquid or solid form, intended for the oral administration of highly gastro-labile active principles. Such a composition contains at least one such active ingredient highly gatro-labile.

  Characteristically, such a liquid composition thus contains a system capable of buffering it, in particular in a gastric medium, at a pH of between 4 and 9; such a solid composition thus contains a system capable of exerting, when it is placed in an aqueous medium, in particular in the stomach, a buffering effect between pH 4 and pH 9.

  The pharmaceutical compositions of the invention combine, within them: at least one highly gastro-labile active ingredient; and a buffer capable system, in the above-mentioned pH area, pH area delimited by the values 4 and 9, which includes said values 4 and 9.

  The exercise of said buffer effect in said pH zone (4 <pH <9) is obviously compatible with the stability of the highly gastro-labile active ingredient in question.

  The selected buffer system must be suitable in view of the "fragility" of the active ingredient in question and the "aggression" of the medium (gastric medium) in which it must protect said active ingredient. Buffer systems suitable for the purposes of the invention are a priori buffer systems of high capacity.

  It was in no way acquired, prior to the work which led to the invention, that buffer systems would be suitable for sufficiently reducing the acidity of the stomach, sufficiently with reference to the highly gastro-labile character of the active principles in question.

  In particular according to the invention, omeprazole is formulated with a buffer system, said buffer system decreasing gastric acidity so that said omeprazole and its antisecretory activity are preserved during the passage of said omeprazole in the stomach; prepared effervescent tablets, buffered in the sense of the invention, very effective.

  This is shown in the examples below.

  Advantageously, the pharmaceutical compositions of the invention are buffered (are likely to exert their buffering effect) at a pH of between 5 and 8 (5 <pH <8).

  Within the compositions of the invention, the highly gastro-labile active ingredient is therefore protected from the gastric medium not by a gastro-resistant coating (defensive approach of the problem) but by the buffer system (offensive approach of said problem) capable of neutralize the aggressiveness of said gastric medium.

  This analysis of the invention shows that its field of application can not a priori be limited. Any highly gastro-labile active ingredient is likely to be associated with a suitable buffer system (compatible, of course). Active ingredients for which the invention has been particularly developed are, as indicated above, the substituted benzimidazoles.

  The pharmaceutical compositions of the invention therefore advantageously contain, as highly gastrolabile active ingredients, substituted benzimidazoles, among which we preferentially find omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole. The antisecretory activity of these active ingredients is preserved during the passage of the compositions of the invention containing them in the stomach.

  As regards the buffer system of the pharmaceutical compositions of the invention, it has above been defined in a functional manner. The intensity of the buffering effect must be suitable for the highly gastro-labile active ingredient in question. We have seen that the appropriate buffer systems are a priori buffer systems of high capacity. The person skilled in the art knows such systems and is able to optimize the combination: highly gastro-labile active ingredient / buffer system.

  In no way limiting, it can be said that the system responsible for the buffer effect is advantageously a buffer selected from phosphate, acetate, maleate, phthalate, succinate, citrate, imidazole, tetrabutylammonium, tris (hydroxymethyl) aminomethane, tris glycine , barbital, tris-EDTA BSA, copper sulphate and zwiteronic.

  More generally, the buffer system of the compositions of the invention may be chosen from the list of buffer systems given in the European Pharmacopoeia, 4th edition, pages 389 to 393.

  Said buffer system is advantageously a phosphate buffer.

  The pharmaceutical compositions of the invention (originally associating at least one highly gastro-labile active principle and a buffer system: pH 4-9) can exist in two variants.

  According to a first variant, more conventional, they are formulated in unitary form. All of their constituent ingredients, including the buffer system, are formulated together. In the context of this first variant, numerous possibilities exist. The pharmaceutical compositions of the invention may especially be in liquid forms (directly buffered to an adequate pH) such as solutes, suspensions, syrups or in solid forms (which develop the buffering effect, when they are taken, in a liquid, usually water, or following their intake, in the stomach) such as tablets, dispersible tablets, effervescent tablets, capsules, powders, effervescent powders, granules, effervescent granules, lyophilisates. These lists are not exhaustive. The galenist will be able to formulate, under one or other of the unit forms listed above, the active principle (s) in question with an adequate system, responsible for the desired buffering effect.

  For the preparation of effervescent solid dosage forms, it will be necessary to add the ingredients capable of imparting the desired effervescent character. This type of ingredient (two reagents capable of reacting by releasing gas) is familiar to those skilled in the art. The effervescent forms of the pharmaceutical compositions of the invention, in particular those with antisecretory activity, are particularly preferred.

  Effervescent forms of highly gastro-labile active ingredients have not yet been developed ...

  According to a second variant, the pharmaceutical compositions of the invention are compositions containing at least two separate components, especially compositions which comprise, separately: a component containing at least the active ingredient (s) -labile (s); and 2873924 6 - another component containing at least the system generating the desired buffering effect.

  These two components, separated, are to be administered jointly or almost jointly, so, of course, that the buffer effect develops during the passage of (the) principle (s) active (s) in the stomach.

  The pharmaceutical compositions of the invention, in addition to said at least one highly gastro-labile active ingredient and the associated buffer system, or in addition to the ingredients capable of rendering them effervescent, are of course capable of containing all the ingredients which are conventionally involved in galenic (sweetener and / or flavor and / or lubricant ...).

  The preparation of the pharmaceutical compositions of the invention - unitary or otherwise - as described above, constitutes the second object of said invention. Said preparation is a buffered or buffer-associated dosage form preparation. Typically, it comprises the formulation of the active principle (s) active (s) strongly gastro-labile (s), in liquid form, with a system capable of buffering said liquid form, especially in gastric medium, at a pH between 4 and 9 or, in solid form, with a system capable of exerting, during the placing in aqueous medium of said solid form, in particular in the stomach, a buffer effect between pH 4 and 9. The term formulation is to be taken in the conventional sense of the term (galenic) for the preparation of unitary compositions, in the broadest sense (formulation = conditioning) for the preparation of compositions with separate components.

  Conventionally, other ingredients may be involved in the preparation of the pharmaceutical compositions of the invention.

  Those skilled in the art have already understood that the preparation of the pharmaceutical compositions of the invention is less expensive than that of the pharmaceutical compositions of the prior art in which the active ingredient is packaged in conventional gastroresistant forms, with a gastric coating. -resistant.

  He also understood that the invention offers buffer systems a completely original outlet galenic. Said buffer systems are associated with gastro-labile active principles to render them gastro-resistant according to the original concept of the invention, to neutralize the gastric acidity of the stomach during their passage in said stomach. According to its third subject, the invention therefore relates to a new use of galenic buffer systems: the use of buffer systems, in particular those identified above, for preparing pharmaceutical compositions, in liquid or solid form, with principle (s) active (s) strongly gastro-labile (s), in particular those specified above, gastro-resistant (without intervention of gastro-resistant coatings).

  For all practical purposes, it is proposed to clarify hereinafter, purely by way of illustration, an advantageous procedure for the preparation, according to the invention, of omeprazole effervescent tablets.

  All the intervening constituents are taken in the quantities indicated in the second column of Table I which follows.

  The manufacture of an effervescent 20 mg tablet of omeprazole firstly comprises the production, by wet process, of a grain containing: the mixture of the two components, capable of generating effervescence (monosodium citrate and sodium bicarbonate), - the two elements of the buffer system (PO4H2Na, 2H20 and PO4HNa2, 2H20), - the two sweeteners (aspartame, saccharin), and - sodium docusate.

  This grain is dried, calibrated and then lubricated in the presence of: - omeprazole (active ingredient) - sodium benzoate - crospovidone, and - mint flavor (powder).

  The lubricated grain is compressed on a rotary press at a unit weight of 3.5 g. It is put in tube immediately after compression.

  This process of making effervescent tablets is not new. It is original in that it is used with omeprazole, omeprazole buffered with a phosphate buffer.

  The tablet obtained, quite conventional appearance generates, dissolved in a glass of water, a buffered solution at a pH of about 7 (see Table II below).

  It is now proposed to illustrate the invention and its great interest by presenting hereinafter comparative results of physiochemical tests carried out in vitro and pharmacological tests carried out in vivo.

  From the ingredients identified in Table I below, taken in the proportions indicated in Table I below, were prepared effervescent tablets of buffered omeprazole (according to the invention) and effervescent tablets of unbuffered omeprazole. (in the sense of the invention).

Table I

  Ingredients Omeprazole Omeprazole effervescent effervescent, unbuffered (mg) buffered (mg) Omeprazole 20 20 Monosodium citrate 748.225 1865.732 Bicarbonate 2244.657 1463.968 sodium 9.4 0 PO4 H2 Na, 2H2O PO4 H Nat, 2H2O 327.4 0 Aspartame 30 Sodium Saccharin 5 Sodium Docusate 0.3 0.3 Crospovidone 35 Sodium Benzoate 70 70 Mint Aroma 10 10 3500 3500 In Vitro Tests 1) Firstly interest was shown in the buffering capacity of tablets effervescent omeprazole unbuffered according to the invention and the stability of said omeprazole.

  The pH of an aqueous solution in which such a tablet was dissolved was followed at 37 ° C; as well as the pH of an aqueous solution in which such a tablet was dissolved and then added 100 ml of a solution of 0.1 N HCl (to be placed under the acidic conditions of the stomach).

Table II

  Time pH pH (min) Solution after cessation Solution after cessation of effervescence effervescence + 100 ml HCl 0.1 N 5.96 3.53 6.68 3.68 6, 83 3.69 6.84 3 , 70 6,84 3,72 The presence of the conventional combination of monosodium citrate and sodium bicarbonate gives the solution obtained by dissolution of the effervescent tablet, after cessation of effervescence, a pH of about 6 which is maintained at 6 , 7-6.8 more than 3 hours.

  Simulation of the passage of omeprazole in solution in the stomach shows that the pH of the solution drops to values below 4. Under these conditions, the amounts of omeprazole remaining in the solution were determined: (Omeprazole content ) after 5 min of contact 10.03 mg after 30 min of contact 1.09 mg after 120 min of contact 0.46 mg after 180 min of contact 0.18 mg It was confirmed that without effective buffer system in the effervescent tablet, the omeprazole content drops rapidly. The degradation is almost complete at 30 min. 2) The buffering capacity of the omeprazole effervescent tablets (according to the invention) and the stability of said omeprazole were similarly interested.

  In the same way, the pH was followed at 37 ° C. by an aqueous solution in which a tablet was dissolved; of an aqueous solution, in which a tablet was dissolved and then 100 ml of a 0.1 N HCl solution (to be placed under the acidic conditions of the stomach).

Table III

  Time pH pH (min) Solution after cessation Solution after cessation of effervescence effervescence + 100 ml HCl 0.1 N 6.9 6.7 8.08 8.38 8, 25 8.62 8.50 8 , 77 8,78 8,88 The combination of omeprazole, mono-sodium citrate and sodium bicarbonate (to ensure effervescence) as well as the aforementioned buffer system (phosphate buffer) gives the solution obtained by dissolving the effervescent tablet, after cessation of effervescence, a pH close to 7 which is maintained above 8 more than 3 hours.

  Simulation of the passage of omeprazole in solution in the stomach shows that the pH of the solution remains close to 7 for the first five minutes and then rises to values close to 9 for three hours. Under these conditions, which simulate the conditions inside the stomach, the omeprazole and impurity contents were determined: after 1 h of contact Omeprazole Impurities 19.72 mg 1.33% after 2 hours of contact 19, 16 mg 1.34 after 3 hours of contact 20.10 mg 1.49% 2873924 11 The variations observed are not significant. Omeprazole remained intact. Said omeprazole has been removed from the harmful action of (gastric) acid by the buffer system.

  The duration of the buffer effect is more than 3 hours. This duration is largely sufficient so that omeprazole, in vivo, remains intact in the stomach and therefore reaches, intact, the upper parts of the intestine.

  In Vitro Tests The antisecretory activity of the two types of effervescent tablets (with and without buffer system of the invention) was studied according to the Lambling-modified Shay technique.

  Omeprazole active ingredient powder suspended in 1% carboxymethylcellulose at a dose of 10 mg / kg and omeprazole active ingredient powder suspended in carboxymethylcellulose was also tested. at 1%, at a dose of 10 ml / kg; said suspension being buffered at a pH of 7.8.

  The test is quite familiar to those skilled in the art. Its principle is summarized below. Ligation of the pylorus in the rat causes gastric acid retention in the stomach.

  Oral administration prior to said ligation of an antisecretory substance decreases or even blocks gastric secretion. The animals (female rats with an average weight of 200 g) are placed in cages with a grid bottom to avoid coprophagia. They have been deprived of solid food for 48 hours with a drink (salt water at 0.8%, glucose 15%) at will.

  The animals are divided into five lots of ten.

  Lot 1: control animals receiving 10 ml / kg of 1% gummy water; Lot 2: animals receiving 10 mg / kg of omeprazole contained in an unbuffered effervescent tablet, in a volume of ml / kg of distilled water; Lot 3: animals receiving 10 mg / kg of omeprazole contained in a buffered effervescent tablet, in a volume of 10 ml / kg of distilled water; Lot 4: animals receiving 10 mg / kg of omeprazole active ingredient in powder form suspended in 1% gummy water, in a volume of 10 ml / kg; Lot 5: animals receiving 10 mg / kg of omeprazole active ingredient in powder suspended in 1% gummy water, in a volume of 10 mg / kg, said suspension being buffered at a pH of 7.8.

  The results are shown in Table IV below as a percentage decrease in gastric secretion compared to controls (Lot 1).

Table IV

  Lot Percentage inhibition of gastric secretion Lot 2 23 * Lot 3 60 *** Lot 4 15 Lot 5 50 ** * p = 0.05 ** p = 0.01 *** p = 0.001 The analysis of results shows: the non-buffered omeprazole effervescent tablets have low activity, barely significant; p = 0.05; the buffered omeprazole effervescent tablets have a very good gastric secretion inhibitory activity: p = 0.001; omeprazole active ingredient powder has a very low activity, not significant; the omeprazole buffered active ingredient has a good inhibitory activity of gastric secretion: p = 0.01 (significant at the threshold of 0.01).

  These results show that the phosphate buffer system used has made it possible to preserve the antisecretory activity of omeprazole, which is entirely compatible with the results obtained in vitro.

  The results, both in vitro and in vivo, demonstrate the effectiveness of the buffer system to preserve the activity of the active ingredient: - in vitro, in the presence of acid, the unbuffered preparations have their pH drop to values below 4 Under these conditions, omeprazole is almost completely damaged. The buffered preparations maintain, for more than 3 hours, their pH at values higher than 8 and the omeprazole remains, under these conditions, intact; in vivo, the non-buffered preparations show practically no activity whereas the omeprazole, buffered at a pH of 7.8, has a good activity, be it the buffered powder or effervescent tablet.

  In consideration of these results, one can not fail to understand the whole point of the present invention.

Claims (2)

14 Claims   1. Pharmaceutical composition, in liquid or solid form, intended for oral administration and containing at least one highly gastro-labile active ingredient, characterized in that, liquid, it contains a system capable of buffering, especially in medium gastric, at a pH between 4 and 9 or in that, solid, it contains a system capable of exerting, when placed in an aqueous medium, especially in the stomach, a buffering effect between pH 4 and 9.   2. Pharmaceutical composition according to claim 1, characterized in that said buffer pH is between 5 and 8.   3. Pharmaceutical composition according to claim 1 or 2, characterized in that said at least one highly gastrolabile active ingredient is a substituted benzimidazole, in particular selected from omeprazole, lansoprazole, pantaprazole, rabeprazole and esomeprazole.   4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that said system, responsible for the buffer effect, is a buffer selected from phosphate, acetate, maleate, phthalate, succinate, citrate, imidazole, tetrabutylammonium, tris (hydroxymethyl) aminomethane, tris-glycine, barbital, tris-EDTA BSA, copper sulfate and zwitterionic.   5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that it is formulated in unitary form.   6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it is liquid, in the form of a solute, a suspension or a syrup or, solid, in the form tablets, dispersible tablets, effervescent tablets, capsules, powder, effervescent powder, granules, effervescent granules or lyopholisate.   7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that it is in the form of effervescent solid galenical preparations, especially effervescent tablets.   The pharmaceutical composition according to any one of claims 1 to 4, characterized in that said system responsible for the buffering effect is formulated separately from said at least one highly gastro-labile active ingredient.   9. Process for the preparation of a pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises the formulation of said at least one highly gastrolabile active ingredient, in liquid form, with a system capable of buffering said liquid form. , in particular in a gastric medium, at a pH of between 4 and 9 or in solid form, with a system capable of exerting, during the placing in aqueous medium of said solid form, in particular in the stomach, a buffering effect between pH 4 and pH 9.   10. Use of a buffer system, in particular chosen from those according to claim 4, for the preparation of a pharmaceutical composition, liquid or solid, containing at least one highly gastrolabile active ingredient, especially chosen from those according to claim 3, gastroresistant .