MXPA06007780A - Controlled release pharmaceutical composition comprising an acid-insoluble and a bioadhesive polymer - Google Patents

Abstract

Rapidly disintegrating oral controlled release pharmaceutical compositions and process for preparation of such compositions are provided. The compositions preferably comprise antibiotic(s) as active ingredient, more preferably amoxicillin either alone or in combination with other antibiotic(s). The controlled release compositions comprise at least one active ingredient, and a polymer system comprising of at least two polymers which retard the release of the active ingredient in the stomach while providing rapid release of the said active ingredient in the alkaline contents of small intestine, optionally with other pharmaceutically acceptable excipients. The compositions provide therapeutically effective levels of the active ingredient for extended periods of time, and possess bioadhesive properties.

Description

PHARMACEUTICAL COMPOSITION OF CONTROLLED RELEASE COMPRISING AN INSOLUBLE POLYMER IN ACID AND A POLYMER BIOADHESIVE FIELD OF THE INVENTION The present invention relates to controlled release pharmaceutical compositions and methods of preparing said compositions, preferably comprising as active ingredient one or more antibiotics, preferably amoxicillin alone or in combination with other antibiotics. The controlled release compositions are of the disintegrable type and additionally have mucoadhesive properties. The controlled release composition is useful for providing therapeutically effective concentrations of said active ingredient for extended periods. Furthermore, it is expected that said composition does not compromise the bioavailability of the active ingredient under fasting or food ingestion conditions.

BACKGROUND OF THE INVENTION Amoxicillin is a beta-lactam widely used as a broad-spectrum antibiotic for the treatment of a variety of common bacterial infections. Amoxicillin has a known susceptibility to inhibition by beta-lactamases produced by resistant organisms. Amoxicillin is available in a variety of formulations, for example as capsules, tablets, dry powders for reconstitution, chewable tablets, dispersible tablets, etc. Amoxicillin is available in tablets of different potencies, such as 250 mg, 500 mg, 875 mg, etc. The standard dose for adults is 250 mg to 500 mg three times a day. In addition, the 875 mg tablet is designed to be administered twice a day instead of 500 mg three times a day. For the treatment of recurrent purulent infection of the respiratory tract a high dose of 3 g twice a day is recommended. To eradicate Helicobacter pylori in peptic ulcer disease it is recommended to use 1 gram of amoxicillin as part of a combination therapy. Previous efforts have been made to develop modified / controlled release formulations of amoxicillin. These modified / controlled release tablets can help improve patient compliance because it is required to be administered twice a day, unlike the 500 mg dose given three times a day. European Patent No. EP1044680 describes bilayer tablets comprising an immediate release dose of a part of amoxicillin and potassium clavulanate, and a controlled release dose of a second part of amoxicillin. The controlled release layer is a hydrophilic matrix. The aforementioned composition has the disadvantage that excessive amounts of excipients are required to prepare the bilayer tablets. This, combined with the high dose of amoxicillin, results in a product that is too bulky and difficult to administer. The patent of E.U. No. 5,690,959 describes a composition prepared using a hydrophobic material manufactured by a thermal infusion process. Amoxicillin, which is sensitive to temperature, can suffer degradation if subjected to high temperatures for prolonged periods. The patent of E.U. No. 6,399,086 discloses a pharmaceutical amoxicillin composition wherein 50% of the drug is released in the course of 3-4 hours. Said composition is based on water-soluble hydrophilic polymers. The patent of E.U. No. 6,368,635 discloses a solid matrix composition which is solid at room temperature and which comprises a viscogenic agent, such as an acrylic acid polymer capable of developing viscosity upon contact with water, dispersed at least in the vicinity of the surface of a matrix particle, containing a fatty acid ester of polyglycerol or a lipid and an active ingredient. The matrix can be such that a matrix particle containing a fatty acid ester of polyglycerol or a lipid and an active ingredient has been coated with a coating composition containing at least one viscogenic agent. This composition can adhere to the digestive tract and remain there for a prolonged period, thus increasing the bioavailability of the active ingredient. These particles adhering to the gastric mucosa have an unpredictable residence time in the stomach and are very affected by the gastric content. The bioavailability of the active agents of said compositions is very variable. European Patent No. EP0526862 describes a pharmaceutical composition of amoxicillin with prolonged residence due to the high density of the composition. Said composition has the disadvantage that it produces a non-uniform active ingredient release due to the variable passage of the tablet to the intestine by virtue of the density itself, resulting in a significant loss of bioavailability. Hilton and Deasy [J. Pharm. Sci. 82 (7): 737-743 (1993)] describe a controlled release tablet of amoxicillin trihydrate based on the enteric polymer acetatosuccinate of hydroxypropylmethylcellulose. This polymer suppresses the release of the drug in the presence of gastric pH but may increase its release in the small intestine. Therefore, said formulation can not give the desired discharge effect described in the present invention. Single-dose studies in a panel of fasted subjects showed that the tablets had a relative bioavailability of only 64.4%, probably due to the lower absorption of amoxicillin in the distant jejunum and ileum than in the duodenum and nearby jejunum. Other pharmacokinetic parameters confirmed a lack of therapeutic advantage of these factors over an equivalent dose of a conventional capsule.

Hilton and Deasy [Int. J. Pharm. 86 (1): 79-88 (1992)] also describe a floating tablet of amoxicillin trihydrate. Initially, a bilayer tablet was formed in which the controlled release drug layer consisted of amoxicillin and hydroxypropylcellulose. This layer was attached to a gas generating layer. However, when the two layers were joined, the mixed tablet could not float and split prematurely along the junction of the two layers. Consequently, it was decided to abandon this proposal in favor of a single layer flotation tablet. This tablet remained floating for 6 hours and had a satisfactory sustained in vitro release. However, compared to conventional fasting capsules in humans at an equivalent dose of 500 mg of amoxicillin, the relative bioavailability of the tablets was 80.5%, and other pharmacokinetic parameters T (0.1 mug / ml) and T (0.5 mug). / ml), which correspond to the time in which the serum concentration remains greater than or equal to 0.1 mug / ml and 0.5 mug / ml, respectively, indicated a lack of improvement in efficacy. Uchida and others [Chem. Pharm. Bull. 37 (12): 3416-3419 (1989)] describe a preparation of amoxicillin microencapsulated in ethylcellulose.

These microcapsules exhibited a sustained release effect when administered to dogs. However, this effect could be predictable, since the gastric pH of the dogs, the test is considerably higher than the human gastric pH (a pH of about 6 in beagle dogs, as opposed to a pH of about 2 in the humans). Amoxicillin is much less soluble at pH 6 than at pH 2. If these same microcapsules were administered to humans, a very rapid release of the drug would be expected. Therefore, such combination may not provide a controlled release of amoxicillin. Arancibia and others [Int. J. Clin. Pharmacol. Ther. Toxicol 25 (2): 97-100 (1987)] investigated the pharmacokinetics and bioavailability of amoxicillin trihydrate. They refer to controlled release tablets whose composition is not described. In any case, the drug was not detectable after 8 hours of oral administration and therefore this formulation has no advantage over conventional formulations. Some of the compositions described in the art are prepared using swellable hydrophilic polymers. However, these compositions require the use of excessive amounts of controlled release agents. This, combined with a high dose of amoxicillin, results in a product that is too bulky to be administered orally. In addition, the ingestion of food has significant effects on these products, resulting in a variable bioavailability. Another proposal available includes the use of bioadhesive polymers. These products are very variable since bioadhesivity is a property that depends significantly on the gastric content. The presence of food in the stomach reduces the bioadhesive property, resulting in lower bioavailability. A third proposal uses enteric polymers. As amoxicillin is predominantly absorbed in the proximal part of the small intestine, the enteric release of the drug results in a loss of bioavailability. Therefore, there is still a need to develop controlled release compositions of amoxicillin, alone or in combination with one or more other antibiotics, which lacks the limitations set forth above.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide a rapidly releasable, controlled release oral pharmaceutical composition comprising one or more active ingredients and a polymer system comprising at least two polymers, wherein one is an acid-insoluble polymer and the other It is a bioadhesive polymer, which slows the release of the active ingredient in the stomach, thus providing a rapid release of said active ingredient at a pH greater than 5.5, optionally with other pharmaceutically acceptable excipients. It is an object of the present invention to provide a rapidly releasable, controlled release oral pharmaceutical composition comprising one or more active ingredients, preferably an antibiotic, most preferably amoxicillin or any of its pharmaceutically acceptable salts, hydrates, polymorphs, esters and derivatives. A further objective of the present invention is to provide a controlled release composition comprising as an active ingredient an antibiotic in combination with at least one other antibiotic.

Another objective of the present invention is to provide a process for the preparation of said composition, comprising the following steps: i) mixing the active ingredients and the polymers, ii) optionally adding one or more other pharmaceutically acceptable excipients, and ) formulating the mixture in a suitable dosage form.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oral pharmaceutical composition of controlled release, rapidly disintegrable, comprising at least one active ingredient or any of its salts, hydrates, polymorphs, esters or pharmaceutically acceptable derivatives, and a polymer system, optionally with other excipients pharmaceutically acceptable The polymer system comprises at least two polymers, wherein one is an acid insoluble polymer and the other is a bioadhesive polymer. The polymer system retards the release of the active ingredient in the stomach, providing a rapid release of said active ingredient at a pH greater than 5.5. In one embodiment, the present invention describes a mucoadhesive, controlled release, disintegrable type formulation of amoxicillin, preferably in its trihydrate form. Said composition disintegrates into particles that have a longer residence time in the stomach, thus maintaining concentrations above the effective concentrations for prolonged periods. The controlled release formulation helps to improve patient compliance since it is required to be administered twice a day, unlike a dose of 500 mg administered three times a day. The present invention also relates to controlled release compositions, preferably of an antibiotic, preferably of amoxicillin trihydrate alone or in combination with other antibiotics, to maintain concentrations above the effective concentrations for extended periods. The release mechanism includes predominantly diffusion, and preferably the product is in the form of a rapidly disintegrable tablet. Controlled release compositions prepared according to the present invention provide a rapidly disintegrable tablet, wherein the granules behave as controlled release particles. These particles have a unique combination of polymers to delay release into the stomach, while providing a rapid dissolution in the alkaline content of the small intestine. In addition, the controlled release compositions have bioadhesive properties. In one embodiment of the present invention, the controlled release composition comprises as an active ingredient an antibiotic in combination with at least one other antibiotic. Antibiotics are selected, without limitation, from the group comprising amoxicillin, ampicillin, cloxacillin, clavulanic acid, cephalosporins, and the like. In one embodiment, the active ingredient of the present pharmaceutical composition is cephalexin, or any of its pharmaceutically acceptable salts, hydrates, polymorphs, esters or derivatives. The polymer system of the present invention comprises polymers selected from the group comprising polyvinylpyrrolidone, polyvinyl acetate, methacrylic acid polymers, acrylic acid polymers, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetatosuccinate, cellulose acetate phthalate, cellulose acetatebutyrate, cellulose acetatepropionate, and alginates, cellulose derivatives, polyethylene oxide, chitosans, and polycarbophil; or mixtures thereof. Preferably, the polymer system comprises a polymer of methacrylic acid and polycarbophil. The acid-insoluble polymer of the present invention is selected, without limitation, from the group comprising polymers of methacrylic acid, polymers of acrylic acid, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetatosuccinate, cellulose acetate phthalate, cellulose acetatebutyrate, cellulose acetatepropionate, alginates , and similar; or mixtures thereof; and the other polymer is a bioadhesive polymer selected, without limitation, from the group comprising polycarbophil, such as Noveon® AA1 (B.F. Goodrich Specialty Polymers), and chitosans, or mixtures thereof. Polycarbophil is a polyacrylic acid that is entangled with divinyl glycol. The methacrylic acid polymer is selected from the group comprising, without limitation, Eudragit® (Degussa), such as Eudragit® L-100, ammonium methacrylate copolymer of type A USP (Eudragit® RL), ammonium methacrylate copolymer of Type B USP (Eudragit® RS), Eudragit® RSPO, Eudragit® RLPO and Eudragit® RS30D. In a preferred embodiment of the present invention, the rapidly-disintegrating, controlled release oral pharmaceutical composition comprises amoxicillin trihydrate and a polymer system comprising a polymer of methacrylic acid and polycarbophil, optionally with other pharmaceutically acceptable excipients. In one embodiment of the present invention, the ratio of methacrylic acid polymer to polycarbophil is from 20: 1 to 1: 20 by weight of the composition. Preferably, the ratio of methacrylic acid polymer to polycarbophil is from 10: 1 to 1: 10 by weight of the composition. In another preferred embodiment of the present invention, the composition further comprises a cellulose derivative, selected without limitation from the group comprising alkyl cellulose, such as ethyl cellulose, methyl cellulose, and the like; carboxyalkylcellulose, such as carboxyethylcellulose, carboxymethylcellulose, carboxypropylcellulose, and the like; hydroxyalkylcellulose, such as hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, and the like; hydroxypropyl alkylcellulose, such as hydroxypropylmethylcellulose and the like. Preferably, the cellulose derivative is alkylcellulose, such as ethylcellulose or propylcellulose. The pharmaceutically acceptable excipients of the present invention are selected from the group comprising diluents, disintegrants, binders, fillers, bulking agents, coating agents, plasticizers, organic solvents, colorants, stabilizers, preservatives, lubricants, glidants, chelating agents, and similar ones known in the art. In one embodiment of the present invention there is provided a process for the preparation of the composition described herein, comprising the following steps: i) mixing the active ingredients and the polymers, ii) optionally adding one or more other excipients pharmaceutically acceptable, and iii) formulating the mixture in a suitable dosage form. In one embodiment, the composition of the present invention is in the form of tablets. The tablets can be prepared by direct compression, dry compression (formation of pills) or by granulation. The granulation technique is aqueous or non-aqueous. Preferably, the tablets of the present invention are prepared by the non-aqueous granulation technique. The non-aqueous solvent used is selected from the group comprising ethanol or isopropyl alcohol. In another embodiment, controlled release formulations prepared in accordance with the present invention disintegrate into particles that adhere to the stomach mucosa. These particles provide a controlled release of amoxicillin during the time they are retained in the stomach. The passage of these granules to the small intestine results in the dissolution of the release controlling polymers, thus releasing any residual drug trapped in the particles. This unique combination of polymers provides a controlled release formulation that does not result in a significant loss of bioavailability. Said formulation does not use swellable polymers, waxy hydrophobic materials. Said product can be prepared using polymers such as polyvinylpyrrolidone, polyvinyl acetate, methacrylic acid polymers, acrylic acid polymers, and the like, alone or in combinations thereof. The controlled release composition of the present invention can be formulated in oral dosage forms, such as tablets, capsules, and the like. The examples given below serve to illustrate the modalities of the present invention. However, they are not considered to be limiting of the scope of the present invention.

EXAMPLES EXAMPLE 1 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg of amoxicillin) 860 ii) Eudragit® L-100 180 iii) Polycarbophil 70 iv) Eudragit® L-100 (binder) 20 v) Alcohol isopropyl Lost in processing vi) Dichloromethane Lost in processing Procedure: 1. Mix (i), (ii) and (iii). 2. Dissolve (iv) in a 1: 2 mixture of (v) and (vi). 3. Granulate the mixture from step 1 with the solution from step 2. 4. Pass the wet mass through a 20 mesh screen and dry. 5. Pass the dried granulate through a 30 mesh screen.

B. Coating the granules in the FBC (fluid bed coating apparatus) No. Ingredients% p / p i) Eudragit® L-100 12.5 i) Polycarbophil 0.625 iii) Triethyl citrate 2.5 iv) Isopropyl alcohol q.s. v) Dichloromethane q.s. vi) Ponceau color lacquer 4R 0.1 Procedure: 1. Mix (i) and (ii) 2. Pass (vi) through a No. 120 mesh screen. 3. Disperse the mass of steps 1 and 2 in a 1: 2 mixture of (iv) and (v). 4. Add (iii) to the dough from step 3 and shake. 5. Coat the granules of part A in the BCF with solution B.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) - 1399.7 ii) Microcrystalline cellulose - 100.0 iii) Croscarmellose sodium - 50.0 iv) Talc - 10.0 v) Magnesium stearate - 10.0 Procedure: 1. Mix (ii), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with ()-3. Compress the blended granules into tablets.

EXAMPLE 2 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) 860 ii) Eudragit® L-100 150 iii) Polycarbophil 60 iv) Eudragit (R) L-100 (binder) - 20 v) Isopropyl alcohol Lost in processing vi) Dichloromethane Lost in processing Procedure: 1. Mix (i), (ii) and (iii). 2. Dissolve (iv) in (v). 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a 20 mesh screen and dry, . Pass the dried granulate through a 30 mesh screen.

B. Coating No, Ingredients% p / p i) Eudragit® L-100 - 20.0 ii) Polycarbophil - 1.0 iii) Triethyl citrate - 2.0 iv) Isopropyl alcohol - q.s. v) Dichloromethane - c.s. vi) - Ponceau color lacquer 4R - 0.1 Procedure: 1. Mix (i) and (ii). 2. Pass (vi) through a No. 20 mesh screen. 3. Disperse the mass from step 1 and 2 into a 1: 2 mixture of (iv) and (v). 4. Add (iii) to the mass of step 3 and stir for 45 minutes. 5. Coat the granules of part A in the BCF with solution B.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) - 1310.0 i) Microcrystalline cellulose - 150.0 ii) Croscarmellose sodium - 20.0 iv) Talc - 10.0 v) Magnesium stearate - 10.0 Procedure: 1. Mix (ii), (ii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with ()-3. Compress the blended granules into tablets.

EXAMPLE 3 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg of amoxicillin) 860.00 i) Eudragit® L-100 180.00 iü) Polycarbophil 70.00 iv) PVP K-30 20.00 v) Pure water Lost in the process Procedure: 1. Mix (i), (ii) and (iii) and pass through a 30 mesh. 2. Dissolve (iv) in water. 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a 20 mesh screen and dry. 5. Pass the dried granulate through a 30 mesh screen.

B. Coating the granules in the FBC (fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® NE 30 D (Weight of the dry polymer in dispersion at 30% w / w) - 12.50 i) Polycarbophil - 0.625 iii) Talc - 6.25 iv) Ponceau Color Lacquer 4R - 0.10 v) Pure water - Lost in processing Procedure: 1. Mix (ii), (iii) and (iv). 2. Pass the mass from step 1 through a No. 100 mesh screen. 3. Disperse the mass from step 2 in (v) and pass it through a colloid mill. 4. Add (i) to the mass from step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) - 1350.09 ii) Microcrystalline cellulose - 100.00 iii) Croscarmellose sodium - 50.00 iv) Talc - 10.00 v) Magnesium stearate - 10.00 Procedure: 1. Mix (ii), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix it with (i). 3. Compress the blended granules into tablets.

EXAMPLE 4 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 i) Eudragit® L-100 - 100.00 iii) Polycarbophil - 40.00 iv) Eudragit® L-30-D55 ( weight of dispersed dry polymer at 30% w / w) - 150.00 v) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii) and pass through a No. 30 mesh. 2. Disperse (iv) in water. 3. Granulate the mass from step 1 with the dispersion from step 2. 4. Pass the wet mass through a 20 mesh screen and dry. 5. Pass the dried granulate through a 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-30-D55 (weight of the dry polymer in 30% dispersion w / w - 12.50 i) Polycarbophil 0.625 iii) Talc 6.25 v) Triethyl citrate 1.25 v) Ponceau color lacquer 4R - 0.10 vi) Pure water lost in processing Procedure: 1. Mix (ii), (ni) and (v). 2. Pass the mass from step 1 through a No. 100 mesh screen. 3. Disperse the mass from step 2 in (vi) and pass it through a colloid mill. 4. Add (i) and (iv) to the mass of step 3 and shake. 5. Coat the granules of part A in the BCF with a solution from step 4.

C. < Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1388.34 ü) Microcrystalline cellulose 100.00 iü) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (ii), (iii) ), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i) 3. Compress the blended granules into tablets.

EXAMPLE 5 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 ii) Eudragit® L-100 - 120.00 ii) Polycarbophil - 40.00 iv) Eudragit® L-30-D55 ( weight of the dry polymer in dispersion at 30% w / w) - 80.00 v) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii), and pass through a No. 30 mesh. 2. Disperse (iv) in water. 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a 20 mesh screen and dry. 5. Pass the dried granulate through a 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-30-D55 (weight of the dry polymer in dispersion at 30% w / w) - 16.00 i ) Polycarbophil 0.09 iü) Talc 8.00 iv) Triethyl citrate 3.20 v) Ponceau color lacquer 4R - 0.10 vi) Pure water Lost in processing Procedure: 1. Mix (ii), (iii) and (iv) 2. Pass the mass of step 1 through a No. 100 mesh screen. 3. Disperse the mass of step 2 in (vi) and pass it through a colloidal mill. 4. Add (i) and (iv) to the mass of step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. < Compression No. I nq network mq / tablet i) Amoxicillin granules (coated in B) 1401.29 i) Microcrystalline cellulose 100.00 iü) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix ( ii), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i) 3. Compress the blended granules into tablets.

EXAMPLE 6 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg of amoxicillin) - 860.00 ii) Ethylcellulose - 100.00 iii) Polycarbophil - 40.00 iv) Eudragit® L-30-D55 (weight of dry polymer in dispersion at 30% w / w) - 20.00 v) Pure water - Lost in processing Procedure: 1. Mix (i) and (iii) and pass through a No. 30 mesh. 2. Pass (i) through a No. 100 mesh screen and mix with the mass from step 1. 3 Disperse (iv) in pure water. 4. Granulate the mass from step 2 with the solution from step 3. 5. Pass the wet mass through a No. 20 mesh screen and dry. 6. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-30-D55 (weight of the dry polymer in dispersion at 30% w / w) - 12.50 ii) Talc - 6.25 iii) Triethyl citrate - 3.75 iv) Ponceau color lacquer 4R - 0.10 v) Pure water - Lost in processing Procedure: 1. Mix (ii) and (v). 2. Pass the mixture from step 1 through a No. 100 mesh screen. 3. Disperse the mass from step 2 in (v) and pass it through a colloid mill. 4. Add (i) and (ii) to the mass of step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1251.34 i) Microcrystalline cellulose 100.00 ü) Croscarmellose sodium - 50.00 iv) Talc - 10.00 v) Magnesium stearate - 10.00 Procedure: 1. Mix (ii), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i) 3. Compress the blended granules into tablets.

EXAMPLE 7 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 ii) Ethylcellulose - 20.00 iii) Polycarbophil - 40.00 iv) Eudragit® L-100 - 50.00 v) Eudragit® L- 30-D55 (weight of dry polymer in dispersion at 30% w / w) - 100.00 vi) Pure water - Lost in processing Procedure: 1. Mix (i), (iii) and (iv) and pass it through a No. 30 mesh. 2. Pass (ii) through a No. 100 mesh screen and mix with the mass from step 1. 3. Disperse (v) in pure water. 4. Granulate the mass from step 2 with solution from step 3. 5. Pass the wet mass through a No. 20 mesh screen and dry. 6. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-30-D55 (weight of the dry polymer in dispersion at 30% w / w) - 12.50 i ) Polycarbophil - 0.625 iii) Talc - 6.25 iv) Triethyl citrate - 2.50 v) Ponceau color lacquer 4R - 0.10 vi) Pure water - Lost in processing Procedure: 1. Mix (ii), (iii) and (v). 2. Pass the mass from step 1 through a No. 100 mesh screen. 3. Disperse the mass from step 2 in (vi) and pass it through a colloid mill. 4. Add (i) and (iv) to the mass of step 3 and shake.

. Coat the granules of part A with the solution from step 4 in the FBC.

C. (Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1305.13 i) Microcrystalline cellulose 100.00 iii) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (ii) ), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i). 3. Compress the blended granules into tablets.

EXAMPLE 8 A. Core Granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 ii) Eudragit® RSPO - 100.00 ii) Polycarbophil - 40.00 v) Eudragit® L-30-D55 (weight of the dry polymer in 30% dispersion w / w) - 100.00 v) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii), and pass it through a No. 30 mesh. 2. Disperse (iv) in pure water. 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry. 5. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-100 12.50 ii) Polycarbophil 0.625 iii) Triethyl chloride 2.50 iv) Isopropyl alcohol Lost in processing v) Dichloromethane Lost in processing vi) Ponceau color lacquer 4R - 0.10 Procedure: 1. Mix (i) and (ii) and pass through a No. 100 mesh. 2. Pass (vi) through a No. 120 mesh screen. 3. Disperse the mass from step 1 and 2 into a 1: 2 mixture of (iv) and (v). 4. Add (iii) to the dough from step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. < Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1272.97 i) Microcrystalline cellulose 100.00 iii) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (ii), ( iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i) 3. Compress the blended granules into tablets.

EXAMPLE 9 A. Core Granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 ii) Eudragit® RLPO - 100.00 iii) Polycarbophil - 40.00 iv) Eudragit® L-30-D55 (polymer weight dry in dispersion at 30% w / w) - 100.00 v) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii), and pass it through a No. 30 mesh. 2. Disperse (iv) in pure water. 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry.

. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-100 - 12.50 ii) Polycarbophil - 0.625 iii) Triethyl citrate - 2.50 iv) Isopropyl alcohol - Lost in processing v) Dichloromee - Lost in processing vi) Ponceau color lacquer 4R - 0.10 Procedure: 1. Mix (i) and (ii) and pass it through a No. 100 mesh. 2. Pass (vi) through a No. 120 mesh screen. 3. Disperse the mass from step 1 and 2 into a 1: 2 mixture of (iv) and (v). 4. Add (iii) to the dough from step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1272.97 ii) Microcrystalline cellulose 100.00 iii) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (ii), (iii), (v) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (¡) - 3. Compress the granules into tablets.

EXAMPLE 10 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 i) Eudragit® RLPO - 100.00 iii) Polycarbophil - 40.00 iv) Triethyl citrate - 20.00 v) Eudragit® L -30-D55 (weight of dry polymer in dispersion at 30% w / w) - 100.00 vi) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii), and pass it through a No. 30 mesh. 2. Disperse (iv) and (v) in water. 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry. 5. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-100 12.50 ü) Polycarbophil 0.625 ü¡) Triethyl citrate 2.50 iv) Isopropyl alcohol Lost in processing v) Dichloromee Lost in the processing v¡) Ponceau color lacquer 4R 0.10 Procedure: 1. Mix (i) and (ii) and pass it through a No. 100 mesh. 2. Pass (vi) through a mesh screen No. 120. 3. Disperse the mass from step 1 and 2 in a 1: 2 mixture of (iv) and (v). 4. Add (ii) to the mass of step 3 and stir. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1296.12 ii) Microcrystalline cellulose 100.00 i) Croscarmellose sodium 50.00 iv) Talc - 10.00 v) Magnesium stearate - 10.00 Procedure: 1. Mix ( I), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i) - 3. Compress the mixed granules into tablets.

EXAMPLE 11 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 ii) Eudragit® RLPO - 100.00 iii) Polycarbophil - 40.00 iv) Triethyl citrate - 20.00 v) Eudragit® L- 30-D55 (weight of dry polymer in dispersion at 30% w / w) - 100.00 vi) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii), and pass through a No. 30 mesh. 2. Disperse (iv) and (v) in pure water. 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry.

. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Ethylcellulose (Surelease®) (weight of the dry polymer in 25% dispersion w / w) - 12.50 i) Polycarbophil 0.18 iii) Talc 6.25 iv) Triethyl citrate 2.50 v) Ponceau color lacquer 4R - 0.10 vi) Water lost in processing Procedure: 1. Mix (ii), (iii) and (v). 2. Pass the mass from step 1 through a No. 100 mesh screen. 3. Disperse the mass from step 2 in (vi) and pass it through a colloid mill. 4. Add (i) and (iv) to the mass of step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Compression No. Ingredient mg / tablet i) Amoxicillin granules (coated in B) 1361.14 i) Microcrystalline cellulose 100.00 iü) Croscarmellose sodium 50.00 iv) falco 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (ii) , (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i) 3. Compress the blended granules into tablets.

EXAMPLE 12 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg amoxicillin) - 860.00 i) Eudragit® L-100 - 100.00 ii) Polycarbonate - 40.00 iv) Eudragit® L-100 - 20.00 v) Ethanol - Lost in processing vi) Pure water - Lost in processing Procedure: 1. Mix (i), (ü) and (iii), and pass through a No. 30 mesh. 2. Dissolve (iv) in a mixture of (v) and (vi) (in a proportion of 6: 4). 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry.

. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% P / P i) Eudragit® L-100 12.50 i) Polycarbophil 0.625 iii) Triethyl citrate 2.50 iv) Isopropyl alcohol Lost in Processing v) Dichloromethane Lost in processing vi) Ponceau color lacquer 4R 0.10 Procedure: 1. Mix (i) and (¡i) and pass it through a No. 100 mesh. 2. Pass (vi) through from a No. 120 mesh screen. 3. Disperse the mass from step 1 and 2 into a 1: 2 mixture of (v) and (v). 4. Add (iü) to the mass of step 3 and shake.

. Coat the granules of part A with the solution from step 4 in the FBC.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1180.39 i) Microcrystalline cellulose 100.00 iü) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (i ), (Ii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with (i). 3. Compress the blended granules into tablets.

EXAMPLE 13 A. Core Granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg of amoxicillin) - 860.00 i) Eudragit® L-100 100.00 iii) Polycarbophil 40.00 iv) Eudragit® L-100 20.00 v) Lost Ethanol in processing vi) Pure water Lost in processing Procedure: 1. Mix (i), (ii) and (ii), and pass it through a No. 30 mesh. 2. Dissolve (iv) in a mixture of (v) and (vi) (in a proportion of 6: 4). 3. Granulate the mass from step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry.

. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (Fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-100 12.50 i) Potassium clavulanate 12.25 iü) Polycarbophil 0.625 iv) Triethyl citrate 2.50 v) Isopropyl alcohol Lost in processing vi) Dichloromethane Lost in processing vii) Ponceau color lacquer 4R 0.10 Procedure: 1. Mix (i), (¡i) and (iii). 2. Pass (vii) through a No. 120 mesh screen. 3. Disperse the mass from step 1 and 2 into a 1: 2 mixture of (v) and (vi). 4. Add (iv) to the mass of step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Compression No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 13505.34 ii) Microcrystalline cellulose 100.00 iii) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1. Mix (ii), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix it with (i). 3. Compress the blended granules into tablets.

EXAMPLE 14 A. Core granules No. Ingredients mg / tablet i) Amoxicillin trihydrate (equivalent to 750 mg of amoxicillin) - 860.00 i) Eudragit® L-100 - 100.00 iü) Polycarbophil - 40.00 iv) Eudragit L-100 - 20.00 v) Ethanol - Lost in processing vi) Pure water - Lost in processing Procedure: 1. Mix (i), (ii) and (iii), and pass it through a No. 30 mesh. 2. Dissolve (iv) in a mixture of (v) and (vi) (in a proportion of 6: 4) 3. Granulate the mass of step 1 with the solution from step 2. 4. Pass the wet mass through a No. 20 mesh screen and dry.

. Pass the dried granulate through a No. 30 mesh screen.

B. Coating the granules in the FBC (fluid bed coating apparatus) No. Ingredients% p / pi) Eudragit® L-100 - 12.50 ii) Polycarbophil - 0.625 iii) Triethyl citrate - 2.50 iv) Isopropyl alcohol - Lost in processing v) Dichloromethane - Lost in processing vi) Ponceau color lacquer 4R - 0.10 Procedure: 1. Mix (i) and (ii) and pass it through a No. 100 mesh. 2. Pass (vi) through a No. 120 mesh screen. 3. Disperse the mass from step 1 and 2 into a 1: 2 mixture of (iv) and (v). 4. Add (iii) to the mass of step 3 and shake. 5. Coat the granules of part A with the solution of step 4 in the FBC.

C. Preparation of amoxicillin granules SR No. Ingredients mg / tablet i) Amoxicillin granules (coated in B) 1180.39 ii) Microcrystalline cellulose 100.00 i) Croscarmellose sodium 50.00 iv) Talc 10.00 v) Magnesium stearate 10.00 Procedure: 1 Mix (ii), (iii), (iv) and (v). 2. Pass the mixture from step 1 through a No. 40 mesh and mix with 5. The composition according to claim 1, further characterized in that it comprises at least two active ingredients selected from the group consisting of amoxicillin, ampicillin , cloxacillin, clavulanic acid, cephalosporins, or their pharmaceutically acceptable salts or derivatives. 6. The composition according to claim 1, further characterized in that the polymer system comprises polymers selected from a group comprising polyvinylpyrrolidone, polyvinyl acetate, polymers of methacrylic acid, polymers of acrylic acid, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetatosuccinate, cellulose acetate phthalate, cellulose acetate butyrate, cellulose acetate propionate, and alginates, cellulose derivatives, polyethylene oxide, chitosans, and polycarbophil; or mixtures thereof. 7. The composition according to claim 1, further characterized in that the acid-insoluble polymer is selected from a group comprising polymers of methacrylic acidacrylic acid polymers, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetatosuccinate, cellulose acetate phthalate, cellulose acetatebutyrate, cellulose acetatepropionate, alginates, or mixtures thereof. 8. The composition according to claim 1, further characterized in that the bioadhesive polymer is selected from a group comprising polycarbophil and chitosans. 9. The composition according to claim 6,

Claims (5)

0). D. Preparation of potassium clavulanate granules No. Ingredients mg / tablet i) 1: 1 mix of potassium clavulanate / microcrystalline cellulose (equivalent to 125 mg of clavulanic acid) - 250.00 ii) Croscarmellose sodium - 50.00 iii) Talc - 10.00 iv) Magnesium Stearate - 10.00 Procedure: 1. Mix (i), (ii), (ii) and (iv). 2. Form pills from the mixture from step 1 and grind them, and pass the product through a No. 30 mesh screen. E. Compression of embedded tablets Compress the amoxicillin SR granules and the potassium clavulanate granules to form embedded tablets, wherein the potassium clavulanate granules are embedded in the amoxicillin granule tablet. NOVELTY OF THE INVENTION CLAIMS

1. - A controlled-release, rapidly disintegrable oral pharmaceutical composition, comprising at least one active ingredient and a polymer system comprising at least two polymers, wherein one is an acid insoluble polymer and the other is a bioadhesive polymer, which retard the release of the active ingredient in the stomach, providing a rapid release of said active ingredient at a pH greater than 5.5, optionally with other pharmaceutically acceptable excipients.

2. The composition according to claim 1, further characterized in that said active ingredient is selected from the group comprising antibiotics, such as cephalosporins and penicillins, and their pharmaceutically acceptable salts, hydrates, polymorphs, esters and derivatives.

3. The composition according to claim 1, further characterized in that said active ingredient is amoxicillin trihydrate.

4. The composition according to claim 1, further characterized in that said active ingredient is cephalexin, or its pharmaceutically acceptable salts, hydrates, polymorphs, esters and derivatives. further characterized in that the polymer system comprises a polymer of methacrylic acid and polycarbophil. 10. The composition according to claims 1-9, further characterized in that it also comprises a cellulose derivative. 11. The composition according to claim 10, further characterized in that the cellulose derivative is selected from a group comprising alkylcellulose and carboxyalkylcellulose. 12. The composition according to claim 11, further characterized in that the alkylcellulose is selected from a group comprising ethylcellulose, methylcellulose, or mixtures thereof. 13. The composition according to claim 11, further characterized in that the carboxyalkylcellulose is selected from a group comprising carboxyethylcellulose, carboxymethylcellulose, carboxypropylcellulose, or mixtures thereof. 14. The composition according to claims 9 to 13, further characterized in that the ratio of the polymer of methacrylic acid to polycarbophil is from 10: 1 to 1.10 by weight of the composition. 1

5. A process for preparing a composition of claim 1, comprising the following steps: (i) mixing the active ingredients and the polymers; (ii) optionally adding one or more other pharmaceutically acceptable excipients; and (iii) formulating the mixture in a suitable dosage form.