MXPA06007781A - Controlled release pharmaceutical compositions - Google Patents

Abstract

A non-disintegrating, non-eroding, non-bioadhesive and non-swelling oral controlled release pharrnaceutical composition and process for preparation of such compositions is provided which comprises at least one high dose water soluble active ingredient;at least one diluent;at least one binder, and a polymer system comprising of at least one release controlling polymer wherein the composition formulated into a suitable dosage form maintains its geometric shape even after the drug has diffused from the dosage form and provides the concentrations of active ingredient above effective levels for extended periods of time, optionally with other pharmaceutically acceptable excipients. The compositions preferably comprise antibiotic(s) as active ingredient, more preferably Amoxicillin or its pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives thereof, most preferably amoxicillin sodium, either alone or in combination with other antibiotic(s). Also described are controlled release compositions which provide an initial burst release of approximately 20%- 40%of the active ingredient within one hour for achieving blood levels equivalent to minimum inhibitory concentration, while maintaining these levels for an extended period of time.

Description

NON-DISINTEGRANT SOLID ORAL COMPOSITION OF A HIGH DOSE OF WATER-SOLUBLE DRUGS FIELD OF THE INVENTION The present invention relates to controlled release pharmaceutical compositions comprising at least one high dose water soluble active ingredient and a process for the preparation of said compositions, preferably comprising antibiotic (s) as the active ingredient, more preferably already either sodium of Amoxilina alone or in combination with other antibiotic (s). The controlled release compositions of the type that do not disintegrate, do not erode, are not bioadhesive and do not dilate, are intended to keep their geometric shape through their transit in the gastrointestinal tract. The controlled release composition is useful for providing effective levels of said active ingredient for extended periods of time. Furthermore, it is expected that said composition does not compromise the bioavailability of the active ingredient under fasting or feeding conditions.

BACKGROUND OF THE INVENTION Amoxilin is a beta-lactam widely used as a broad-spectrum antibiotic for the treatment of a variety of common bacterial infections. Its susceptibility to Amoxicillin has been known to inhibit beta-lactamases produced by resistance organisms. Amoxicillin is available in a variety of formulas, for example, in capsules, tablets, dry powders for reconstitution, chewable tablets, dispersible tablets etc. Amoxicillin is available as tablets of different strengths such as 250 mg, 500 mg, 875 mg, etc. The dose for a standard adult is from 250 mg to 500 mg, three times a day (tid). Additionally, 875 mg tablets are made for a dosing twice a day (bid) instead of 500 mg three times a day. A high dose of 3 g. twice a day is recommended for treatments of recurrent purulent infection of the respiratory tract. The use of 1 g of Amoxicillin is recommended as a combination therapy arm for the eradication of helicobacter pylori in peptic ulcer disease. In the past, attempts have been made to develop the modified release / controlled release formulations of Amoxicillin. Such modified / controlled release tablets can provide better compliance to patients since they need to be administered twice a day compared to the 500 mg doses administered three times a day. European Patent No. EP1044680 discloses two-layer tablets comprising a dose of immediate release of a portion 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 composition mentioned above suffers from the disadvantage that it requires excessive amounts of excipients to prepare the tablets in two layers. This, combined with the high dose of Amoxicillin, results in a product which is too bulky and difficult to administer. The Patent of E.U.A. No. 5,690,959 describes a composition prepared using the hydrophobic material made by a thermal infusion process. Amoxicillin, which is sensitive to temperature, may experience degradation if subjected to high temperatures for longer periods of time. The Patent E.U.A. 6,399,086 describes a pharmaceutical composition of Amoxicillin, wherein 50% of the drug is released within a period of 3 to 4 hours. Said composition is based on polymers susceptible to hydrophilic erosion. The Patent E.U.A. No. 6,368,635, discloses a solid matrix composition, which is solid at room temperature, which comprises a viscogenic agent, such as an acrylic acid polymer, which has the ability to develop viscosity upon contact with water, as it is dispersed at least in the vicinity of the surface layer 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. Said composition can adhere to the digestive tract and remain there for a prolonged period of time and in this way increase the bioavailability of the active ingredient. Said particles adhering to the gastric mucosa have a residence time that can not be predicted in the stomach and are highly affected by the gastric content. The bio-availabilities of active agents of said compositions are highly variable. European Patent No. EP0526862 describes a pharmaceutical composition of Amoxicillin with prolonged residence due to the high density of the composition. Said composition suffers the disadvantage that the release of the active ingredient is not uniform as a result of the variable passage of the tablet within the intestine by virtue of the density thereof which results in the significant loss of bioavailability. PCT Publication No. WO 200384510 specifically discloses the two-layer tablet formulation comprising the antihistamine decongestant combination. The second zone separated from the tablet in two layers, comprising a decongestant drug and a second vehicle of base material, the second vehicle of base material comprising, a mixture of at least one sustained release compound and at least one slider or pharmaceutically acceptable lubricant, wherein the second carrier of base material provides sustained release of the decongestant. Said publication does not need the use of at least one diluent and a single binder together with a polymer system comprising at least one release controlling polymer, to obtain an oral controlled release pharmaceutical composition, which does not disintegrate, which does not it erodes, is not bio-adhesive and does not expand, where the drug is preferably released by diffusion. PCT Publication No. WO 2004012700 relates specifically to a high dosage, high solubility active ingredient combination dosage formula, such as the modified release and the low dosage active ingredient as the immediate release suitable for swallowing, comprising the double retrace technique, to control the release of the high dosage, the high solubility active ingredient, wherein said dosage form comprises of an inner portion having a low dosage active ingredient such as immediate release and an outer portion having a high dosage the active ingredient of high solubility as the modified release, wherein the inner portion comprises a) micro matrix particles and b) coating on the micro matrix particles.

Hilton and Deasy, [J. Pharm, Sci. 82 (7): pages 737 to 743 (1993)] which describes a controlled release tablet of Amoxicillin trihydrate based on the enteric polymer hydroxypropylmethyl cellulose acetate succinate. This polymer suppressed the release of the drug in the presence of gastric pH although it could improve its release in the small intestine. Single dose studies with a panel fasted have shown that the tablet had a relative bioavailability of only 64.4%, probably because the poor absorption of Amoxicillin from the jejunum and the distal ileum from the duodenum and jejunum near. Other pharmacokinetic parameters confirmed a lack of therapeutic advantage of these factors over an equivalent dose of the conventional capsule. Hilton and Deasy Int. J. Pharm. 86 (1): pages 79 to 88 (1992)] also describes a floating tablet of amoxicillin trihydrate. Initially, a two-layer tablet was formed in which the controlled-release drug layer consisted of hydroxypropylcellulose and Amoxicillin. This layer was bonded to a layer that produces gas. However, when the two layers were joined together, the composite tablet failed to float and prematurely separated along the junction of the two layers. Consequently, it was decided to abandon this method in favor of a floating single layer tablet. This tablet remained floating for 6 hours and sustained the in vitro release satisfactorily. However, compared to conventional capsules in equivalent doses of 500 mg Amoxicillin in fasting humans, the relative bioavailability of the tablets was 80.5% and other pharmacokinetic parameters T (0.1 mug / ml) and T (0.5 mug / ml). ml) corresponding to the length of time during which serum levels remained greater than or equal to 0.1 mug / ml and 0.5 mug / ml, respectively, indicated a lack of improved efficiency. Uchida and others. [Chem. Pharm. Bull. 37 (12): pages 3416 to 3419 (1989)] describes a preparation of Amoxicillin, micro-encapsulated in ethylcellulose. These microcapsules exhibited a sustained release effect when administered to dogs. However, such an effect could be predicted, since the gastric pH of the dogs, which was tested, is considerably higher than the human gastric pH (the pH of about 6 in hound dogs, compared to the pH of about 2 humans). Amoxicillin is much less soluble at pH 6 than at pH 2. It could be anticipated that a very rapid release of the drug from the same microcapsules will be obtained if administered to humans. Therefore, said combination can not provide a controlled release of Amoxicillin. Arancibia and others. [Int. J. Clin. Pharmacol. Ther. Toxicol 25 (2): pages 97 to 100 (1987) investigated the pharmacokinetics and bioavailability of amoxicillin trihydrate. They refer to controlled release tablets, the composition of which was not described. In any case, no drug could be detected after 8 hours of oral administration and therefore, this formulation had no advantage over conventional formulations. Some of these compositions raised in the art are prepared using hydrophilic polymers that can be dilated. These compositions require the use of excessive amounts of agents that control the release. This, combined with high doses of Amoxicillin, results in a product which is too bulky to be administered orally. Additionally, these products have significant effects on the diet that results in variable bioavailability. Another method available in the art involves the use of bio-adhesive polymers. These products are highly variable due to the bio-adhesiveness that is a property, which is significantly dependent on the gastric content. The presence of food in the stomach reduces the bio-adhesive property that results in reduced bioavailability. A third method proposed in the art uses enteric polymers. Because Amoxicillin is absorbed predominantly from the proximal part of the small intestine, the enteric release of the drug results in the loss of bioavailability. Therefore, there is still a need to develop the controlled release compositions of Amoxicillin, either alone or in combination with other antibiotic (s), devoid of the limitations set forth above.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide an oral controlled release pharmaceutical composition that does not disintegrate, erode, is not bio-adhesive and does not expand, which comprises at least a high dose of water soluble active ingredient, at least one diluent, at least one binder and a polymer system comprising at least one release control polymer, wherein the composition formulated in a suitable dosage form retains its geometric shape even after the drug has been diffused from the dosage form and provides concentrations of active ingredient above the effective levels for extended periods of time, optionally with other pharmaceutically acceptable excipients. It is an object of the present invention to provide an oral controlled release pharmaceutical composition that does not disintegrate, erode, is not bio-adhesive and does not expand, comprising at least one high-dose water-soluble active ingredient, preferably an antibiotic, more preferably amoxicillin or its pharmaceutically acceptable salts, hydrates, polymorphs, esters or derivatives thereof, more preferably, sodium amoxycillin; at least one diluent; at least one binder, and a polymer system comprising at least one controlled release polymer, wherein the composition formulated in a suitable dosage form maintains its geometric shape even after the drug has diffused from the dosage form and provides the concentrations of active ingredient above effective levels for extended periods of time, optionally with other pharmaceutically acceptable excipients. It is also an object of the present invention to provide a controlled release composition comprising an antibiotic as an active ingredient in combination with at least one different antibiotic. It is a further object of the present invention to provide a controlled release composition, wherein the composition provides an initial burst of release of about 20% to 40% of the active ingredient within a period of one hour to achieve blood levels equivalent to the minimum inhibitory concentration, while maintaining these levels for an extended period of time. It is still another object of the present invention to provide a process for the preparation of said composition, which comprises the following steps: i) mixing the active ingredient (s), the diluent (s), the binder (s) and the polymer (s), ii) optionally adding one or more other pharmaceutically acceptable excipients and iii) formulating the mixture in a suitable dosage form.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oral controlled release pharmaceutical composition which does not disintegrate and erode, is not bio-adhesive and does not expand which comprises at least one high-dose water soluble active ingredient, at least one diluent, at least one agglutinator and a polymer system comprising at least one release control polymer, optionally with other pharmaceutically acceptable excipients. The composition is formulated in a suitable dosage form, which maintains its geometric shape even when the drug has been diffused from the dosage form and provides the concentrations of the active ingredient above the effective levels for extended periods of time. The active ingredient of the present invention can be selected from, but not limited to, the group comprising high-dose water-soluble drugs such as metformin, potassium chloride, nicotinic acid, phenformin, clindamycin, ciprofloxacin, erythromycin, quetiapine, balsalazide, valproate. of sodium, vancomycin or its pharmaceutically acceptable salts or derivatives thereof. The active ingredient of the present invention is selected from a group comprising antibiotics, such as cephalosporins and penicillins, and their pharmaceutically acceptable salts, hydrates, polymorphs, esters or derivatives thereof. The active ingredient is preferably an antibiotic, more preferably amoxicillin or its pharmaceutically acceptable salts, hydrates, polymorphs, esters or derivatives thereof, more preferably sodium amoxycillin. In another embodiment, the present invention relates to controlled release formulations of sodium amoxicillin to maintain concentrations above acceptable levels, for extended periods of time. The release mechanism predominantly involves diffusion and the product is in the form of a tablet that does not disintegrate. The tablet maintains its geometric shape even after the drug has spread from the system. In addition, the formulation has been found to have a unique release profile with a monolithic structure. This provides an initial burst release of about 20% to 40% within a one hour period to achieve blood levels equivalent to the minimum inhibition concentration, while maintaining these levels for an extended period of time. In another embodiment of the present invention, controlled release tablets prepared using said composition can provide better patient compliance because they require to be administered twice a day compared to the 500 mg dose provided three times a day. The present invention relates to controlled release formulations of antibiotic, either alone or in combination with other antibiotic (s) to maintain concentrations above effective levels, for extended periods of time. Preferably, the present invention relates to the controlled release formulation of sodium amoxycillin. The release mechanism predominantly involves diffusion and the product is in the form of a tablet that does not disintegrate. The tablet maintains its geometric shape even after the drug has spread from the system. Nicotinic acid, also known as "niacin", has been used due to the treatment of hyperlipidemia. This compound has been known for a long time for exhibiting beneficial effects in the reduction of total cholesterol, low density lipoproteins or "LDL cholesterol", triglycerides and apolipoproteine a (Lp (a)) in the human body, while increasing the lipoproteins of desirable high density or "HDL cholesterol". However, the use of nicotinic acid tends to be limited due to its side effects, such as cutaneous flushing and inconvenient dosing regimens. Most existing nicotinic acid formulations are hydroxypropylmethylcellulose (HPMC) based on disintegrating and disintegrating type dosage forms, which mainly provide an unpredictable release of the drug for extended periods of time and plasma drug concentration profiles. erratic In one embodiment, the active ingredient of the present pharmaceutical composition is nicotinic acid or its pharmaceutically acceptable salts or derivatives thereof.

In another embodiment, the composition of the present invention provides an initial burst release of about 20% to 40% of the active ingredient within a period of one hour to achieve blood levels equivalent to a minimum inhibitory concentration, while maintaining these levels for an extended period of time. In one embodiment of the present invention, the controlled release composition comprises an antibiotic as an active ingredient in combination with at least one different antibiotic. Antibiotics are selected from, but are not limited to, the group comprising amoxicillin, ampicillin, cloxacillin, clavulanic acid, cephalosporins, and the like or pharmaceutically acceptable salts or derivatives thereof. In the present invention, the diluent is selected from, but is not limited to a group comprising lactose, cellulose, microcrystalline cellulose, manityl, dicalcium phosphate, pre-gelatinized starch and the like, used either alone or in combination thereof .

Preferably, the diluent used is lactose. In the present invention, the binder is selected from, but is not limited to, a group comprising polyvinylpyrrolidone, cellulose derivatives, such as hydroxypropylmethylcellulose, methacrylic acid polymers, acrylic acid polymers and the like. The polymer system of the present invention comprises at least one release control polymer which is selected from a group comprising polyvinylpyrrolidone / polyvinyl acetate copolymer (Kollidon® SR), methacrylic acid polymers, acrylic acid polymers, cellulose, and the like. Preferably, the polymer system comprises the polymer of methacrylic acid and polyvinylpyrrolidone / polyvinyl acetate copolymer. More preferably, the polymer system comprises polyvinylpyrrolidone / polyvinyl acetate copolymer. The methacrylic acid polymer is selected from a group comprising, but not limited to Eudragit® (Degusta) such as Ammonium methacrylate copolymer type A USP (Eudragit® RL), Ammonium methacrylate copolymer type B USP (Eudragit® RS), Eudragit® RSPO, Eudragit® RLPO and Eudragit® RS30D. The ratio of methacrylic acid polymer and polyvinylpyrrolidone / polyvinyl acetate copolymer is from 20: 1 to 1: 20 by weight of the composition, preferably from 10: 1 to 1: 10 by weight of the composition. The pharmaceutically acceptable excipients of the present invention are selected from the group comprising diluents, disintegrants, binders, fillers, bulking agents, anti-adherents, anti-oxidants, regulating agents, colorants, flavoring agents, coating agents, plasticizers, solvents. organic, stabilizers, preservatives, lubricants, glidants, chelating agents and the like known in the art. In one embodiment, the lubricant (s) used in the present invention is selected from, but is not limited to, a group comprising stearic acid, magnesium stearate, zinc stearate, glyceryl behenate, ketosilic alcohol, hydrogenated vegetable oil and the like used either alone or in combination thereof. In one embodiment of the present invention, there is provided a process for the preparation of a composition, which comprises the following steps: i) mixing the active ingredient (s), diluent (s), binder (s) and polymer (s) . ii) optionally adding one or more of the pharmaceutically acceptable excipients, 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. Tablets can be prepared either by direct compression, dry compression (blow compression), or by granulation. In a preferred embodiment of the present invention, the oral composition is in the form of tablets directly compressed. The granulation technique is, either aqueous or non-aqueous. Preferably, the tablets of the present ition are prepared by the non-aqueous granulation technique. The non-aqueous solvent used is selected from a group comprising ethanol or isopropyl alcohol. The present ition relates to the controlled release formulation, either alone or in combination with another antibiotic (s), which is a product that is not muco-adhesive, does not disintegrate, does not expand and does not erode. In one embodiment, the present ition discloses a non-muco-adhesive controlled release type formulation, does not disintegrate, is not dilated and does not erode from sodium amoxycillin. This composition retains its geometric shape through its stay in the gastrointestinal tract. The product also has the advantage of showing minimal food effect. The release of drug from the product is predominantly carried out through the diffusion mechanism. The controlled release formulations prepared according to said ition do not lose their geometric shape through their transit through the gastrointestinal tract. Said formulation does not involve the use of dilateable polymers, hydrophobic wax materials or muco-adhesive agents. The controlled release composition of the present ition can be formulated as oral dosage forms, such as tablets, capsules and the like. The examples presented below serve to illustrate the embodiments of the present ition. However, these are not intended to limit the scope of the present ition.

EXAMPLES EXAMPLE 1 Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 750 797.00 mg of amoxicillin) ü) Lactose 100.00 ¡i) Polyvinylpyrrolidone / co-polymer of polyvinyl acetate 200.00 (PVP / PVA) (Kollidon® SR) iv ) Polyvinylpyrrolidone (PVP) 50.00 v) Magnesium stearate 10.00 (vi) Talc 10.00 The ingredients (i) to (vi) were hovered. They were mixed separately (i), (ii), (iii) and (iv). The mixture hit and stopped hitting. It was mixed with the ingredients (v) and (vii), previously sifted and kept separately. They were compressed into tablets.

EXAMPLE 2 Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 750 797.00 mg of amoxicillin) 0 Lactose 150.00 iii) Eudragit® RS 75.00 iv) Eudragit® RL 150.00 v) Polyvinylpyrrolidone (PVP) 50.00 vi) Isopropyl alcohol Was lost during the procedure vii) Magnesium stearate 10.00 viii) Talc 10.00 The ingredients (i), (ii), (iii) and (iv) were sifted and mixed. It was dissolved (v) in (vi) and the mixture was granulated. The granules were dried and sized. The ingredients were mixed with (vii) and (viii) previously sifted and kept separately. They were compressed into tablets.

EXAMPLE 3 Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 500 530.00 mg of amoxicillin) i) Lactose 50.00 iii) Polyvinylpyrrolidone / co-polymer of polyvinyl acetate 125.00 (PVP / PVA) (Kollidon® SR) iv) Eudragit® RL 25.00 v) Polyvinylpyrrolidone 10.00 vi) Magnesium stearate 5.00 vii) Talc 5.00 Ingredients (i) to (vi) were sieved. They were mixed separately (i), (ii), (iii), (iv) and (v). He hit and stopped hitting the mix. It was mixed with the ingredients (vi) and (vii), previously sieved and kept separately. It was compressed into tablets.

EXAMPLE 4 Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 500 530.00 mg of amoxicillin) ü) Lactose 100.00 iii) Eudragit® RS 50.00 iv) Eudragit® RL 100.00 v) Polyvinylpyrrolidone (PVP) 25.00 vi) Isopropyl alcohol Was lost during the procedure vii) Magnesium stearate 5.00 viii) Talc 5.00 The ingredients (i), (i), (ii) and (iv) were sifted and mixed. It was dissolved (v) in (vi) and the mixture was granulated. The granules were dried and sized. The ingredients were mixed with (vii) and (viii) previously sifted and were kept separately. They were compressed into tablets.

EXAMPLE 5 Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 500 530.00 mg of amoxicillin) i) Lactose 100.00 iii) Eudragit® RS 150.00 iv) Polyvinylpyrrolidone (PVP) 25.00 v) Soapropyl alcohol Was lost during the procedure vi) Magnesium stearate 5.00 vii) Talc 5.00 The ingredients (i), (ii) and (ii) were mixed. It was dissolved (iv) in (v) and the mixture was granulated. The granules were dried and sized. It was mixed with the ingredients (vi) and (vii) previously sifted and kept separately. They were compressed into tablets.

EXAMPLE 6 A Composition of controlled release granules of amoxicillin Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 500 530.00 mg of amoxicillin) i) Lactose 100.00 iii) Polyvinylpyrrolidone / co-polymer of polyvinyl acetate 175.00 (PVP / PVA) iv) Polyvinylpyrrolidone (PVP) 25.00 v) Isopropyl alcohol Lost during the process vi) Magnesium stearate 5.00 vii) Talc 5.00 B Potassium clavulanate / 250.00 1: 1 mixture of microcrystalline cellulose (equivalent to 125 of clavulanic acid Process: 1. Ingredients A (i), A (i) and A (iii) were sieved and mixed. A (iv) was dissolved in A (v) and the mixture was granulated. The granules were dried and sized. They were mixed with ingredients A (vi) and A (iii), previously sifted. 2. Mix B was sifted 3. The granules of step 1 and step 2 were compressed in embedded tablets, where the mixture of potassium clavulanate was embedded in the Amoxicillin granule tablet.

EXAMPLE 7 A Composition of controlled release granules of amoxicillin Step No. Ingredient Mg / tablet i) Amoxicillin sodium (equivalent to 500 530.00 mg of amoxicillin) i) Lactose 100.00 iü) Polyvinylpyrrolidone / co-polymer of polyvinyl acetate 175.00 (PVP / PVA) iv) Polyvinylpyrrolidone (PVP) 25.00 v) Isopropyl alcohol Lost during the procedure vi) Magnesium stearate 5.00 vii) Talc 5.00 Procedure: 1. Sift and mix the ingredients (i), (i¡) and (iií). 2. Dissolve (iv) in (v) and granulate the mixture 3. Dry and digest the granules and mix with the ingredients (vi) and (vii), previously sifted.

B Composition of potassium clavulanate granules Step No. Ingredient Mg / tablet i) Potassium clavulanate / 250.00 Mix 1: 1 microcrystalline cellulose (equivalent to 125 mg clavulanic acid i) Croscarmellose sodium 50.00 iü) Talc 10.00 iv) Magnesium stearate 10.00 Procedure: 1. Mix (i), (ii), (iii) and (iv) 2. Strike and stop hitting the mixture from step 1 and pass it through a 30 mesh size sieve.

C. Compression in two-layer tablets Compress granules of controlled release granules of Amoxicillin and potassium clavulanate granules in two-layer tablets.

EXAMPLE 8 Procedure: 1. Mix nicotinic acid, lactose and Eudragit® RSPO (40 mg) and pass through a size 40 mesh. 2. Dissolve Eudragit® RSPO (20 mg) and stearic acid in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve of size 60 mesh. 5. Pass the magnesium stearate and stearic acid through a size 40 mesh and mix with the dry granules. 6. Compress the mixed dough in tablets. 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 9 Procedure: 1. Mix ciprofloxacin, lactose and Eudragit® RSPO (20 mg) and pass through a size 40 mesh. 2. Dissolve Eudragit® RSPO (10 mg), Eudragit® RLPO and stearic acid in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve of size 60 mesh. 5. Pass magnesium stearate and stearic acid through a sieve of size 40 mesh and mix with the dry granules. 6. Compress the mixed mass in the tablets 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 10 Procedure: 1. Mix nicotinic acid, lactose and Eudragit® RSPO and pass it through a size 40 mesh. 2. Dissolve Eudragit® RLPO and ethylcellulose in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve with size 60 mesh. 5. Pass the magnesium stearate and stearic acid through a sieve with size 40 mesh and mix it with the dry granules. 6. Compress the mixed dough in tablets. 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 11 Procedure: 1. Mix erythromycin, lactose and Eudragit® RSPO and pass it through a size 40 mesh. 2. Dissolve Eudragit® RLPO and ethylcellulose in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve of size 60 mesh. 5. Pass the magnesium stearate and the glyceryl behenate through a sieve of size 40 mesh and mix it with the dry granules. 6. Compress the mixed dough in tablets. 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 12 Procedure: 1. Mix the nicotinic acid, lactose and Eudragit® RSPO and pass it through a size 40 mesh. 2. Dissolve Eudragit® RLPO and ethylcellulose in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve of size 60 mesh. 5. Pass the magnesium stearate and the cetostearyl alcohol through a sieve of size 40 mesh and mix it with the dry granules. 6. Compress the mixed dough in tablets. 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 13 Procedure: 1. Pass the niacin, lactose, stearic acid and Eudragit® RSPO through a size 40 mesh and mix 2. Disperse Eudragit® RS30D in water and neutralize Eudragit® RS30D with sodium hydroxide, granulate the paste from step 1. 3. Dry the granules and pass them through a size 16 mesh. 4. Pass the magnesium stearate and the stearic acid through a 40 mesh size sieve and mix it with the dry granules. 5. Compress the mixed dough in tablets. 6. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 14 Procedure: 1. Mix the metformin hydrochloride, lactose and Eudragit® RSPO (40 mg) and pass it through a size 40 mesh. 2. Dissolve Eudragit® RSPO (20 mg) and stearic acid in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve of size 60 mesh. 5. Pass the magnesium stearate and stearic acid through a sieve of size 40 mesh and mix it with the dry granules. 6. Compress the mixed dough in tablets. 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

EXAMPLE 15 Procedure: 1. Mix the metformin hydrochloride, lactose and Eudragit® RSPO and pass it through a size 40 mesh. 2. Dissolve Eudragit® RLPO and ethylcellulose in IPA and dichloromethane. 3. Granulate the material from step 1 with the material from step 2 and dry the granules. 4. After drying the granules, pass them through a sieve of size 60 mesh. 5. Pass the magnesium stearate and the glyceryl behenate through a sieve of size 40 mesh and mix it with the dry granules. 6. Compress the mixed dough in tablets. 7. Cure the tablets at a temperature of 60 ° C for 18 hours.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - An oral controlled release pharmaceutical composition which does not disintegrate, does not erode, is not bio-adhesive and does not expand, comprising at least one high-dose water soluble active ingredient, at least one diluent, less a binder and a polymer system comprising at least one release control polymer, characterized in that the composition formulated in a suitable dosage form maintains its geometric shape even after the drug has diffused from the dosage form and provides concentrations of active ingredient above effective levels for extended periods of time, optionally with other pharmaceutically acceptable excipients.

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

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

4. - The composition according to claim 1, further characterized in that said active ingredient is nicotinic acid, or pharmaceutically acceptable salts or derivatives thereof.

5. The composition according to claims 1 to 4, further characterized in that the composition provides an initial release burst of about 20% to 40% of the active ingredient within a period of one hour to achieve equivalent blood levels. at the minimum inhibitory concentration, while maintaining these levels for an extended period of time.

6. The composition according to claim 1, further characterized in that it comprises at least two active ingredients selected from the group comprising amoxicillin, ampicillin, cloxacillin, clavulanic acid and cephalosporins or pharmaceutically acceptable salts or derivatives thereof.

7. The composition according to claim 1, further characterized in that the diluent is selected from a group comprising lactose, cellulose, microcrystalline cellulose, manityl, dicalcium phosphate, previously gelatinized starch, used either alone or in combination with the same.

8. The composition according to claim 1, further characterized in that the binder is selected from a group comprising polyvinyl pyrrolidone, cellulose derivatives, methacrylic acid polymers and acrylic acid polymers.

9. - The composition according to claim 1, further characterized in that the polymer system comprises the polymers selected from a group comprising polyvinylpyrrolidone / polyvinyl acetate copolymer; methacrylic acid polymers, acrylic acid polymers and cellulose derivatives or mixtures thereof.

10. The composition according to claim 9, further characterized in that the polymer system comprises polyvinylpyrrolidone / polyvinyl acetate copolymer.

11. The composition according to claim 9, further characterized in that the polymer system comprises polymer of methacrylic acid and polyvinylpyrrolidone / polyvinyl acetate copolymer.

12. The composition according to claim 11, further characterized in that the methacrylic acid polymer is selected from the group comprising ammonium methacrylate copolymer type A USP and ammonium methacrylate copolymer type B USP.

13. The composition according to claim 1, further characterized in that the pharmaceutically acceptable excipients are selected from the group comprising disintegrants, binders, fillers, bulking agents, coating agents, plasticizers, organic solvents, dyes, stabilizers, preservatives , lubricants, glidants, and chelating agents.

14. - The composition according to claims 1 to 13, further characterized in that it is formulated in the form of tablets, capsules and the like.

15. The composition according to claim 14, further characterized in that it is in the form of tablets compressed directly.

16. A process for the preparation of a composition according to claim 1, characterized in that it comprises the following steps: i) mixing the active ingredient (s), the diluent (s), the agglutinators) and the polymer (s), i) optionally adding one or more other pharmaceutically acceptable excipients, and iii) formulating the mixture in a suitable dosage form.

17. The use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for the preparation of a medicament for the treatment of bacterial infections and for the eradication of helicobacter pylori in peptic ulcer disease in a patient. SUMMARY OF THE INVENTION An oral controlled release pharmaceutical composition is provided which does not disintegrate, is not eroded, is not bio-adhesive and does not expand, and the process for the preparation of said compositions, which comprise at least one active ingredient soluble in high-dose water; at least one diluent; at least one binder, and a polymer system comprising at least one release control polymer, wherein the composition is formulated in a suitable dosage form that maintains its geometric shape even after the drug has been diffused from the dosage form and provides the concentrations of the active ingredient above its effective levels for extended periods of time, optionally with other pharmaceutically acceptable excipients; the compositions preferably comprise antibiotic (s) as the active ingredient, more preferably amoxicillin or its pharmaceutically acceptable salts, hydrates, polymorphs, esters and derivatives thereof, more preferably amoxicillin sodium, either alone or in combination with another antibiotic (s). ); controlled release compositions are also described, which provide an initial burst of release of about 20% to 40% of the active ingredient within a period of one hour to achieve blood levels equivalent to the minimum inhibitory concentration, while maintaining these levels for an extended period of time. Preferred polymer systems are polyvinylpyrrolidone / polyvinyl acetate copolymer (Kollidon® SR) and ammonium methacrylate copolymer (e.g., Eudragit RS), or ethyl cellulose. 24B / cgt * P06 / 1151 F