MXPA99011232A - Gastric-retentive oral drug dosage forms for controlled release of highly soluble drugs - Google Patents

Abstract

Los medicamentos que son libres o altamente soluble en agua se formulan en formas de dosificación unitarias incorporando en ellas matrices poliméricas compuestas por polímeros hidrófilos con alto peso molecular que se hinchan cuando se imbiben de agua. La forma de dosificación puede ser una tableta comprimida, o dos o tres tabletas comprimidos retenidas en una sola cápsula. La formulación oral estádestinada para la retención gástrica y el suministro controlado de un medicamento incorporado dentro de la cavidad gástrica y, asíadministrando, el medicamento se libera de la matriz dentro del líquido gástrico mediante la difusión de la solución. La matriz polimérica hinchada, habiendo alcanzado el tamaño suficiente, permanece en la cavidad gástrica durante varias horas si se administra cuando el paciente estáen la modalidad alimentada, y permanece intacta el tiempo suficiente para que substancialmente todo el medicamento sea liberado antes de que ocurra erosión substancial en la matriz. La matriz hinchada disminuye la accesibilidad del líquido gástrico al medicamento y limita, por lo tanto, la velocidad de liberación del medicamento. Este proceso, junto con el retardo en la difusión mediante la selección de polímeros concretos, pesos moleculares de los polímeros y otras variables produce suministro sostenido y controlado del medicamento hacia el ambiente gástrico.

Description

GASTRIC-RETENTIVE ORAL MEDICINE. DOSAGE FORMS FOR THE CONTROLLED RELEASE OF MEDICINES HIGHLY SOLUBLES The present invention is located in the general field of pharmacology and relates in particular to drug delivery systems that retain the stomach for a prolonged period of time, while releasing a highly soluble drug in a controlled manner over a prolonged period of time, to achieve a more effective and efficient use of the medicine. BACKGROUND OF THE INVENTION The rate at which drugs that are administered in conventional tablets or capsules become available to body fluids is initially very high, followed by a rapid decrease. For many medications, this pattern causes a transient overdose, followed by a long period of insufficient dosage. This has limited clinical utility. The supply pattern improved in the 1970s with the introduction of several controlled supply systems. By providing a controlled and relatively constant supply of medications, these systems avoided the effects of overdoses and inadequate doses. These improvements provided a medication with fewer side effects, and these results were achieved with less frequency of dosing. Many of these controlled supply systems use water-swellable polymer matrices that provide useful levels of control for the supply of hardly soluble drugs. For soluble drugs, however, and in particular for highly soluble drugs, the matrices do not provide adequate control over the release rate of the drug, instead causing a release that "approximates first-order kinetics. Release rate is, therefore, an inverse function of the square root of elapsed time.With the kinetics of first-order release, most of the drug that is in the matrix is released within the first two hours in a medium A method for prolonging the release of a highly water-soluble drug is presented in International Patent Application Publication No. 96/26718 (Temple University; inventor, Kim) .The method of this publication is the incorporation of the drug into a polymer matrix to form a tablet that is administered orally.The polymer is susceptible to swelling of water, but is Erosion in the gastric juices, and the polymer and the ratio of the drug to the polymer are chosen in such a way that: (i) the speed at which the polymer swells is equal to the speed at which the polymer erodes, in such a way that the swelling of the polymer is continuously controlled by erosion, the kinetics of zero-order release of a drug from the matrix is maintained; (ii) the release of the drug from the matrix is sustained throughout the period of erosion of the polymer, reaching the tablet, therefore, full solubilization at the same moment in which the last part of the drug is released; and (iii) the release of the medication from the matrix will be extended over a period of 24 hours. A fundamental disclosure of WO 96/26718 is that a polymer with a low molecular weight must be used to achieve drug release in this manner. If, in contrast, a high molecular weight polymer is used and the rate of swelling substantially exceeds the rate of erosion, the lack of erosion will prolong the diffusion of the drug residing closer to the center of the tablet and prevent it from being released. Thus, in document WO 96/26718 it is not noted that a drug of high water solubility can be released from a polymer with high molecular weight in a period of substantially less than 24 hours, or that some advantage can be obtained from the use of a polymer that "does not erode as quickly as it swells." This inability is particularly significant since even swollen tablets will not remain in the stomach for longer than the duration of the fed modality., which usually lasts only from 6 to 8 hours. COMPENDIUM OF THE INVENTION It has now been discovered that drugs that are highly soluble in water can be administered orally in such a way that they prolong their time. supply to extend considerably through the duration of the modality fed but not a considerable time after it. This is achieved by using a formulation in which the medicament is dispersed in a polymeric matrix that is susceptible to swelling of water and not merely hydrophilic, and that erodes at a rate that is considerably less than its swelling rate. Furthermore, it has been found that the diffusion rate can be decreased by increasing the particle size of the drug, by the choice of the polymer used in the matrix, or by the molecular weight of the polymer. The matrix is a relatively high molecular weight polymer that swells after ingestion to reach a size that is at least twice its non-swollen volume and promotes gastric retention during the fed mode. When it swells, the matrix also passes, over a prolonged period of time, from a glassy polymer to a polymer with hulled consistency. The penetrating liquid then causes the release of the drug in a gradual and prolonged manner through the process of diffusion of the solution, that is, the dissolution of the drug in the penetrating liquid and the diffusion of the dissolved matrix out of the matrix. The matrix itself is solid before administration and, once administered, remains undissolved in (ie, without eroding) the gastric fluid for a period of time sufficient to allow most of the medication to be released by the "process". diffusion of the solution during the fed mode The factor limiting the rate of drug release is, therefore, the controlled diffusion of the drug from the matrix, rather than the erosion, dissolution or chemical decomposition of the matrix. The swelling of the polymer matrix thus achieves two results: (i) it swells the matrix to a size large enough to cause the stomach to retain it during the fed mode and (ii) retards the diffusion rate of a drug highly soluble at the time enough to provide a controlled supply of the drug to the stomach for multiple hours. Gastric and controlled supply of soluble drugs provides an effective mechanism to use these drugs in the treatment of stomach disorders. For example, the application of the present invention enables a more efficient eradication of a bacterium that causes ulcers in the gastric mucosa with soluble antibiotics. The invention also provides a better absorption of soluble medicaments that are absorbed mainly in the stomach or in the upper part of the gastrointestinal tract, for example, metformin hydrochloride or cyproloxacin. The invention is also useful to provide a multi-hour flow of a drug after the upper part of the small intestine (the most effective absorption site for many agents). The details of these and other features of the invention will become apparent in the description that follows. BRIEF DESCRIPTION OF THE FIGURES FIGURE 1 is a graph showing the release rate of metformin hydrochloride from the three different drug compositions in polyethylene oxide matrices. FIGURE 2 is a graph showing the release rate of captopril from a poldetylene oxide matrix, in accordance with the present invention, both with and without glyceryl monostearate as a solubility modifier. ~~~ FIGURE 3 is a graph showing the rate of release of captopril from hydroxyethyl cellulose, in which the size of the tablet was varied. FIGURE 4 is a graph showing the rate of release of metformin hydrochloride from various polymer matrices. FIGURE 5 is a graph showing the rate of release of metformin hydrochloride from a single tablet in the form of a capsule. FIGURE 6 is a graph showing the rate of release of captopril from vairas polymer matrices. FIGURE 7 is a graph showing additional studies on the rate of release of "metformin hydrochloride from two different polymer matrices." FIGURE 8 is a graph showing the release rate of vancomycin hydrochloride from two different polymer matrices DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS The medicaments to which the present invention is applied are those that are characterized in the Uni ted.

Sta tes Pharmacopeia XXII as at least "freely soluble" in water, that is, a part of the drug dissolves in less than about ten parts of water. The medicines of particular interest are those that require only about five parts of water or less (for a part of medicine) to dissolve, and the drugs of even greater interest are those that require only about three parts of water or less. The parts referred to in this paragraph are parts by weight. The term "medicament" is used herein to denote any composition, compound, complex or chemical that is suitable for oral administration and that has a beneficial biological effect, preferably a therapeutic effect in the treatment of an abnormal physiological disease or condition. . Examples of medicaments to which the present invention can be applied are metformin hydrochloride, captopril, erythromycin lactobionate, ranitidine hydrochloride, sertraline hydrochloride and ticlopidine hydrochloride. Other drugs suitable for use and which meet the solubility parameters described above will be apparent to those skilled in the art. Medicines of particular interest are metformin hydrochloride and sertraline hydrochloride. The drug charges (percentage by weight of the drug in relation to the total drug and polymer) will, in most cases, be approximately 80% or less. The invention is also usable with medicaments "which have been formulated to include additives that impart a small degree of hydrophobic character, to further retard the rate of drug release in the gastric fluid." An example of a release rate retarder is monostearate of glyceryl Other examples are fatty acids and salts of fatty acids, an example of "they is sodium myristate. The amounts of these additives, when present, can vary and, in most cases, the weight ratio of additive to the medicament will vary from about 1:10 to about 2: 1, and preferably about 1: 8. at about 1: 2. The polymer capable of swelling forming the matrix according to the present invention is any polymer that is non-toxic, that swells unrestricted in its dimensions after imbibition in water, and that it provides sustained release of a built-in medication. Polymers with molecular weights of about 4,500,000 and "greater are preferred, polymers with molecular weights are more preferred" within the range of about 4,500,000 to about 10,000,000 and polymers with molecular weights within the range of about 5,000,000 are preferred even more. In many cases, polymers are most commonly characterized in terms of the viscosity of the polymer solutions at a given concentration and temperature.The following are the preferred viscosity ranges for various kinds of polymers. " Examples of suitable polymers for use in the present invention are cellulose polymers and their derivatives, polysaccharides and their derivatives, polyalkylene oxides, and degraded polyacrylic acids and SUST derivatives. The term "cellulose" is used herein to denote a linear polymer of anhydroglucose. The preferred polymers are the cellulose polymers with the substituted alkyl radical "which, in the long run," dissolve in the tract. Gastrointestinal (GI) Delayed foreseeable. The cellulose derivatives with the substituted alkyl radical are those with substituted alkyl groups of 1 to 3 carbon atoms each. Examples are methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose. Regarding their viscosities, a class of the celluloses with alkyl substitute group includes those whose viscosity is within the range of about 100 to about 110,000 centipoise in the form of a 2% aqueous solution at 20 ° C. Another class includes those whose viscosity is within the range of about 1,000 to about 4,000 centipoises in the form of a 1% aqueous solution at 20 ° C. Celluloses with a particularly preferred substituted alkyl group are hydroxyethylcellulose and hydroxypropylmethylcellulose. A preferred hydroxyethyl cellulose is NATRASOL® 250HX NF (National Formulary), distributed by Aqualon Company, Wilmton, Delaware, United States of America. The polyalkylene oxides most useful for the present invention are those having the properties described above for the cellulose polymers with substituted alkyl group. A particularly preferred polyalkylene oxide is polyethylene oxide, which term is used herein to denote an unsubstituted linear polymer or ethylene oxide. "Preferred polyethylene oxides are those with an average molecular weight in the range of about 9 x 105 to about 8 x 10X Polyethylene oxides are usually characterized by their solution viscosity For the purposes of the present invention, a preferred viscosity range is from about 50 to about 2,000,000 centipoise for a 2% aqueous solution at 20%. ° C. Two currently preferred polyethylene oxides are POLIOX® NF, WSR grade coagulant, with molecular weight of 5 million, and with WSR 303 quality, molecular weight 7 million, both products of Union Carbide Chemicals and Plastics Company Inc. of Danbury , Connecticut, United States of America, Polysaccharide gums, both natural and modified (semi Examples of these are dextran, xanthan gum, gellan gum, welan gum and rhamsan gum, xanthan gum is preferred. The most useful degraded polyacrylic acids are those whose properties are identical to those described above for the cellulose with substituted alkyl group and the polyalkylene oxide polymers. Preferred degraded polyacrylic acids are those with a viscosity ranging from about 4,000 to about 40,000 centipoise for a 1% aqueous solution at 25 ° C. Three currently preferred examples are CARBOPOL® NF grades 917P, 974P and 934P (BFGoodrich Co., Specialty Polymers and Chemicals Div., Cleveland, Ohio, United States of America). There are additional examples of polymers known as WATER LOCK®, which are starch / acrylate / acrylamide copolymers distributed by Grain Processing Corporation, Muscatine, Iowa, United States of America. The hydrophilicity and susceptibility to swelling of these polymers causes the matrices containing the medicament to swell in the gastric cavity given the ingress of water to achieve a size that is retained in the stomach when introduced during the fed modality. These qualities also cause the matrices to become slippery, which provides resistance to peristalsis and also promotes its retention in the stomach. The release rate of a medically from the matrix depends "mainly on the rate of water imbibition and the speed at which the drug dissolves and diffuses from the swollen polymer., which in turn is related to the speeds of solubility and dissolution of the drug, the particle size and the concentration of this in the matrix. Furthermore, since these polymers dissolve very slowly in the gastric fluid, the matrix retains its integrity for at least a substantial period of time, in many cases at least 90% and preferably more than 100% of the dosing period. The particles will dissolve or decompose then slowly. In most cases, complete dissolution or decomposition will occur no later than 8 to 10 hours after the scheduled dosing period. The amount of polymer in the formulation with the medicament may vary, depending on the rate of release of the desired drug and polymer, its molecular weight and the excipients that may be present in the formulation. The amount of polymer will be sufficient, however, to retain at least 40% of the drug within the matrix one hour after ingestion (or immersion in the gastric fluid). Preferably, the amount of polymer is such that at least 50% of the drug remains in the matrix one hour after ingestion. More preferably, at least 60%, and more preferably at least 80%, of the drug remains in the matrix one hour after ingestion. In all cases, however, the drug will release almost everything from the matrix within "approximately eight hours after ingestion, and the polymer matrix will remain substantially intact until all of the medication is released." ET "" substantially intact "term is used herein to denote a polymer matrix in which the polymer portion substantially retains its size and shape without deterioration, since it is solubilized in the gastric fluid or because it decomposes into fragments or small particles. Polymers capable of being entrained with water can be used individually or in combination. Certain combinations will often provide a more controlled release of the drug than its elements when used separately. Examples of these are cellulose-based polymers combined with gums, for example, hydroxyethylcellulose or hydroxypropylcellulose combined with xanthan gum. Another example is polyethylene oxide combined with xanthan gum. The benefits of the present invention will be achieved at drug loads of about 80% or less (ie, the weight percent of the drug relative to the total drug and polymer), with preferred fillers within the range of 15 to 80. %, more preferably within the range of 30 to 80%, and more preferably in certain cases within the range of 30 to 70%. The formulations of the present invention can take the form of particles, tablets or particles retained in capsules. A preferred formulation consists of "consolidated particles in a packaged mass for ingestion, even when the packaged mass is separated into individual particles after ingestion.Conventional methods can be applied to consolidate the particles in this manner. placed in gelatin capsules known in the art as "hard-filled" and "soft-elastic" capsules .. The formulations and the manufacture of the medicament know the compositions of these capsules and the procedures for filling them. highly soluble so that the particles are released and dispersed rapidly in the stomach after the capsule is swallowed in. A currently preferred dosage is a size 0 gelatin capsule containing either two or three polymer tablets impregnated with the medicament. For capsules with two tablets, the tablets have Cylindrical shape, 6.6 or 6.7 mm (or more generally 6.5 to 7 mm) in diameter and 9.5 or 10.25 (more generally, 9 to 12 mm) long. For the capsules with three tablets, the tablets again have a cylindrical shape, 6.6 in diameter and 7 mm in length. For a size 00 gelatin capsule with two tablets, the tablets are cylindrical, 7.5 mm in diameter and 11.25 mm in length. For a size 00 gelatin capsule with three tablets, the tablets are cylindrical, 7.5 mm in diameter and 7.5 mm in length. Another currently preferred dosage is a single elongated tablet, with dimensions of 18 to 22 mm long, 6.5 to 7.8 mm wide and 6.2 to 7.5 mm high. A preferred set of dimensions is 20 mm long, 6.7 mm wide and 6.4 mm high. These are only examples; The shapes and sizes can vary considerably. The medicament / polymer particulate mixture or the polymer matrix impregnated with the medicament can be prepared by various conventional mixing, crumbling and manufacturing techniques which are very apparent to those skilled in chemical formulations of medicaments. The following are examples of such techniques: ~~ (1) Direct compression, using appropriate punches and punches, such as those distributed by Elizabeth Carbide Die Company, Inc., McKeesport, Pennsylvania, United States of America; the punches and dies are placed in a suitable rotary tablet press, for example the Elizabeth-Hata single sided Hata Auto Press machine, with yarn 15, 18, or 22 stations, and distributed by Elizabeth-Hata International, Inc., North Huntington, Pennsylvania, United States of America; and (2) injection or compression molding using suitable molds arranged in a compression unit, for example those distributed by Cincinnati Milacron, Plastics Machinery Division, Batavia, Ohio, United States of America. When the particles are manufactured by direct compression, the addition of lubricants can be useful and sometimes important in promoting the flow of the powder and preventing clogging of particles (breaking up a portion of the particle) when the pressure is removed. Magnesium stearate (in a concentration of 0.25% to 3% by weight, preferably less than 1% by weight, in the powdered matrix), and hydrogenated vegetable oil (preferably hydrogenated and acidified triglycerides of acids) are useful lubricants. stearic and palmitic from about 1% to 5% by weight, more preferably about 2% by weight.) Additional excipients can be added to improve the flowability and reduce adhesion The term "dosage form" denotes any form of the formulation containing a sufficient amount to achieve a therapeutic effect with a single administration. When the formulation is a tablet or capsule, the dosage form is usually a tablet or capsule. The frequency of administration that will provide the most effective results in an effective manner overdose will vary according to the characteristics of the drug in particular, including both its pharmacological characteristics and its physical characteristics, for example, solubility, and the characteristics of the matrix susceptible to swelling, for example, its permeability, and the relative amounts of the drug and the polymer In most cases, the dosage form will be such that effective results will be achieved with the administration with a frequency no greater than one. once every eight hours or more, preferably once every twelve hours or more, and even more preferably once every twenty-four hours or more As indicated above, the dosage forms of the present invention find their greatest utility when administered to a subject that is in the digestive mode or "fed." During this In modality, the subject's stomach retains the particulate material that is above a certain minimum particle size. The modality fed differs from the mode in aid, which prevails during the night "" and until the first hours of the morning. The fasting modality _ is characterized by complex motive "interdigestive migratory waves (MMC), which are intense contractions that begin in the middle of the stomach and continue to the intestinal tract to the distal ileum, cleaning the stomach of the digested materials as well as the non-digestible solids that are within a certain range of size, which would retain if it were in the fed mode.The fed mode starts with the ingestion of food, and causes the suspension of the MMC waves, thus allowing the stomach to retain the particulate material long enough for it to decompose and digest, at least partially.When the powered mode ends, the MMC waves of the fasting mode begin again.The powered mode may start with a signal triggered by ingestion of food, or by a chemical signal based on nutritive and osmotic factors, which can be n the ingestion of food or administered specifically to start the fed mode. These factors include hypertonic solutions, acids, fats, certain carbohydrates, and certain amino acids. Fat is the most powerful of these factors, since it relaxes the fundo with inferior intragastric pressure, increases the function of deposition of the nearby stomach, contracts the pyloric sphincter and changes the intestinal peristalsis from a series of waves to the segmentation activity. The following examples are offered for illustrative purposes and are not intended to limit the invention in any way. EXAMPLE 1 This example illustrates the controlled release behavior of metformin hydrochloride, a highly soluble drug (whose solubility is about 35%), from a polymeric matrix consisting of sodium oxide. polyethylene. Three different dose levels were prepared (system designed to release 90% of its drug content at 3, 6 and 8 hours, respectively). The drug and the polymer were compressed with 0. 5% magnesium stearate as a "tablet" lubricant, in tablets measuring 7.2 mm in diameter x 8.8 mm in length and weighing 390 mg for the samples designated for the release of 3 and 6 hours, and 7.4 mm in diameter x 8.5 mm long and with a weight of 380 mg for the samples designated for the 8 hour release, and two tablets of a given type were incorporated into a single gelatin capsule.Thus, three different types of gelatin capsules were prepared, as follows: t90% 3 hours: metformin hydrochloride 250 00 mg POLYOX® 1105, molecular weight 900,000 138.67 magnesium stearate 1-95 Total 360.92 tg0% 6 hours: metformin hydrochloride 250 00 mg POLYOX® coagulant, molecular weight 5,000,000 138".67 magnesium stearate 1.95 Total 360. 92. _ t90% 8 hours: metformin hydrochloride 125 00 mg POLYOX® 303, molecular weight 7,000,000 266.11 magnesium stearate 1-97 Total 393.08 Release rate tests of these Three formulations were made in a modified artificial gastric fluid using the following procedure: Dissolution was done in a USP Apparatus 2, "modified to include a stainless steel cone (7/8 inch high and 7/8 inch diameter) at the base) on the inside of each vessel, placed directly below the arrow on the paddle to eliminate the "dead zone" effect. A paddle speed of 60 rpm and a bath temperature of 37.4 ° C were applied. The gelatin capsule was opened and the individual tablets and the empty gelatin capsule were dropped into the dissolution vessel containing 900 mL of modified simulated gastric fluid (7 mL of hydrochloric acid and 2 g of sodium chloride in 100 mL of deionized water; the enzyme pepsin was omitted). When the tablets settled on the bottom of the vessel, the rotation of the pallet began. Samples of 5 mL were taken at specific time points, and sample volumes were not replaced. The samples were diluted as necessary to perform a quantitative analysis by HPLC. The results are shown in FIGURE 1 where the filled diamonds represent the t90% 3 formulation, the x represent the t90% 6 formulation and the open circles represent the t90% 8 formulation. The curves show that the t90% value of the first formulation was close to 3.5 hours, that of the second formulation at 6.0 hours and that of the third formulation at 7.5 hours. EXAMPLE 2 This example illustrates the rate of release behavior of captopril from a polymer matrix consisting of polyethylene oxide, both with and without glyceryl monostearate (8% by weight). The formulations that were used were the following. 1. Captopril 925.0 mg polyethylene oxide (POLYOX® 301), molecular weight 4,000,000 4,075.0 Total 5, 000.0 2. Captopril 925.0 mg glyceryl monostearate polyethylene oxide (POLYOX® 301), molecular weight 4,000,000 3, 925.0 Total 5, 000.0 Each formulation was compressed into a tablet measuring 6.0 mm in diameter x 6.7 mm in length and weighing 180 mg. The release rate tests of the two tablets were performed in the modified simulated gastric fluid according to the procedure of Example 1, except that the rotation speed of the paddle was 30 rpm and the tablets were dropped directly into the vessel of dissolution. The results are shown in FIGURE 2, where the filled boxes represent Formulation number 1 which consists of captopril and polyethylene oxide only, and the open circles represent Formulation number 2, which also includes glyceryl monostearate. EXAMPLE 3 This example illustrates the release rate behavior of captopril from a polymeric hydroxyethylcellulose matrix with the inclusion of glyceryl monostearate, but at various tablet sizes. The formulations contained 19% captopril (all percentages by weight) and 4.8% glyceryl monostearate in hydroxyethylcellulose with molecular weight in the range of 1,000,000 to 1,500,000. The sizes of the tablets were from (a) 3.3 mm in diameter x 3.5 mm in length to 35 mg "(referred to herein as" 3mm tablets "), (b) 4.3 mm in diameter x 4.9 mm in length at 75 mg (referred to in the present document as 4mm tablets), (a) 6.3 mm in diameter x 6.5 mm in length at 187 mg (referred to herein as 6mm tablets). of the 3 tablet sizes (fifteen of the 3 mm tablets, seven of the 4 mm tablets and three of the 6 mm tablets) were made by applying the procedures of Example 1, except that "a weighted meter was used instead of the cone , and the analysis of the samples was carried out by UV / Vis. The "thirst results are shown in FIGURE 3, where the filled boxes" represent the 3-mm tablets, the 4-mm compressed filled triangles and the filled circles-the 6-mm tablets. This demonstrates that the variation in tablet size is an additional mechanism for varying the release schedule, with the "larger tablets having smaller surface area." EXAMPLE 4 This example further illustrates the controlled release of metformin hydrochloride using a loading of medicament. greater, and several polymers "- and combinations of polymers. The procedures applied are the same as those described above, and the formulations, together with the symbols used in FIGURE 4 where the results are expressed graphically, were the following (all percentages are by weight): Closed circles: 79.6% metformin hydrochloride; 20% polyethylene oxide) POLYOX® 303, molecular weight 7,000,000); 0.4% magnesium stearate. Dimensions of the tablet 6.04 mm in diameter x 9.48 mm in length; with an "approximate content of 478 mg of metformin hydrochloride.

Filled frames: 79.6% metformin hydrochloride; 20% xanthan gum (KELTROL® F, Kelco, Div. Of Merck &Co., Inc., San Diego, California, United States of America); 0.4% magnesium stearate. Dimensions of the tablet 6.06 mm in diameter x 9.40 mm in length; with an approximate content of 4.83 mg of metformin hydrochloride. Addition signs: 79.6% metformin hydrochloride; 20% hydroxypropylmethylcellulose (BENECEL® -824- Aqualon Co. Wilmington, Delaware, United States of America), viscosity (2%, 20 ° C) 11,000 to 15,000 cps; 0.4% magnesium stearate. Dimensions of the tablet 6.06 mm in diameter x 9.49 mm long; with an approximate content of 480 mg of metformin hydrochloride. x: 79.6% metformin hydrochloride; 20% xanthan gum (KELTROL® F); 1.99% WATER LOCK® D.223 (poly (2-propenamid-co-2-propenoic acid) with starch graft, mixed sodium and aluminum salts, Grain Processing Corporation, Muscatine, Iowa, United States of America); 0.4% magnesium stearate. Dimensions of the tablet 6.06 mm in diameter x 9.24 mm in length, - with an approximate content of 476 mg of metformin hydrochloride. EXAMPLE 5 This example further illustrates the controlled release of metformin hydrochloride from a tablet in the form of a capsule. The procedures applied are the same as those described above and the resulting curve is expressed graphically in FIGURE 5. The formulation was as follows (all percentages are by weight): 64% metformin hydrochloride; 35.5% polyethylene oxide) POLYOX® 303, molecular weight 7,000,000); 0.5% magnesium stearate; plus an additional 2% of a clear coating of hydroxypropylmethylcellulose OPADRY®, Colorcon, West Point, Pennsylvania (United States of America). Dimensions of the tablet 6.48 mm in diameter x 7.20 mm in height x 19.21 in length, and with an approximate content of 506 mg of metformin hydrochloride. EXAMPLE 6 This example further illustrates the controlled release of captopril, using various polymers and polymer combinations. The procedures applied were the same as those described above, and the formulations together with the symbols used in Jla FIGURE 6 where the results are expressed graphically, were as follows (all percentages are by weight): Addition sign: ~ Signs of Addition: 80.0% captopril; 20% hydroxypropylmethylcellulose (BENECEL® 824, viscosity (2%, 20 ° C) 11,000 to 15,000 cps). Dimensions of the tablet 6.03 mm in diameter x 9.25 mm in length, - 2 tablets, weighing 299 mg each and with a total content of approximately 468.6 mg captopril. - - - Diamonds filled: 80.0% captopril; 20% xanthan gum (KELTROL®). Dimensions of the tablet 6.04 mm in diameter x 9. 18 mm long; 2 tablets, weighing 299 mg each and with a total content of approximately 477.8 mg captopril. Filled triangles: 80.0% captopril; 20% hydroxyethylcellulose (250HX molecular weight 1,000,000). Dimensions of the tablet 6.03 mm in diameter x 9.53 mm in length; 2 tablets, weighing 299 mg each and having a total content of approximately 478.2 mg of captopril, open circles: 80.0% captopril, 20% polyethylene oxide, POLYOX® 303, molecular weight 7,000,000). Dimensions of the tablet 6.04 mm in diameter x 9.59 mm in length, 2 tablets, weighing 301 mg each and with an approximate total content of 481 6 mg of captopril, filled squares: 80.0% captopril, 20% carboxymethylcellulose (12M31P, molecular weight "250,000). Dimensions of the tablet 6.04 mm in diameter x 9.18 mm in length; 2 tablets, weighing 299 mg each and with a total content of approximately 477 6 mg captopril. Open triangles: 79.93% captopril; 10.03% hydroxyethylcellulose (250HC, molecular weight 1,000,000); 10.04% xanthan gum (KELTROL®). Dimensions of the tablet 6.04 mm in diameter x 9.26 mm long; 2 tablets, weighing 296 mg each and with a total content of approximately 4.78.3 mg captopril. x: 79.96% captopril; 10.03% hydroxyethylcellulose (250HC, molecular weight 1,000,000); 10.01% "polyethylene oxide) POLYOX® 303, molecular weight 7,000,000). Dimensions of the tablet 6.04 mm in diameter x 9.41 mm in length, 2 tablets, weighing 2971 mg each and with a total content of approximately 483 mg of captopril.

Scripts: 80.0% captopril; 10% hydroxyethylcellulose (250HX molecular weight 1,000,000); 10% hydroxypropylmethylcellulose (BENECEL® 824, viscosity (2%, 20 ° C) 11,000 to 15,000"cps). Dimensions of the tablet 6.04 mm in diameter x 9.41 mm in length, 2 tablets, weighing 298 mg each and with an approximate total content of 476.6 mg captopril Open diamonds: filled: 79.96% captopril; 18.05% "xanthan gum (KELTROL®); 1.99% WATERLOCK® D-223X Tablet dimensions 6.04 mm in diameter x 9.16 mm in length; 2 tablets, weighing 297 mg each and with a total content of approximately 475 mg captopril. EXAMPLE 7 This example presents additional data on "formulations of metformin hydrochloride, and illustrates the effect of the drug loads lower than those used in the previous examples." The procedures applied were the same as those described above, and the formulations together with the symbols used in FIGURE 7 where the results are expressed graphically, the following were used (all percentages are by weight): Tables filled: 32.5% metfbrmin hydrochloride; 67% polyethylene oxide) POLYOX® 303, molecular weight 7,000,000); 0.5% magnesium stearate. Dimensions of the tablet 6.62 mm in diameter x 10.40 mm in length, 2 tablets each weighing 400 mg, with a total content of approximately 260 mg of metformin hydrochloride. Open circles: 32.5% metformin hydrochloride; 67% xanthan gum (KELTROL®); 0.5% magnesium stearate. Dimensions of the tablet 6.65 mm in diameter x 9.28 mm in length; 2 tablets, each weighing 401 mg, with a total content of approximately 261 mg of metformin hydrochloride. EXAMPLE 8 This example illustrates the sustained release of vancomycin hydrochloride from various polymers. The procedures applied were the same as those described above, and the formulations together with the symbols used in FIGURE 8 where the results are expressed graphically, were the following: Open frames: 31.5% vancomycin hydrochloride; 68% polyethylene oxide) POLYOX® 303, molecular weight 7,000,000); 0.5% magnesium stearate. Dimensions of the tablet 6.59 mm in diameter x 10.23 mm in length, 2 tablets each with a weight of 403 mg, with a total content of approximately 253 mg of vancomycin hydrochloride. "- - Open triangles 31.5% of dedvancomycin hydrochloride; 68% polyethylene oxide) POLYOX® 301, molecular weight 4,000,000); 0.5% magnesium stearate. Dimensions of the tablet 6.59 mm in diameter x 10.28 mm in length, 2 tablets each weighing 402 mg, with a total content of approximately 253 mg of vancomycin hydrochloride. x: 31.5% vancomycin hydrochloride; 68% polyethylene oxide) (BENECEL® 824, viscosity, 11,000 to 15,000 cps (2% solution at 20 ° C), - 0.5% magnesium stearate.: Dimensions of the tablet 6.59 mm in diameter x 10.10 mm in length , 2 tablets each weighing 405 mg, with a total content of approximately 255 mg of vancomycin hydrochloride Open circles: 31.5% vancomycin hydrochloride 68% xanthan gum (KELTROL®) 0.5% Magnesium Stearate Dimensions of the tablet 6.62 mm in diameter x 9.77 mm in length, 2 tablets, each weighing 401 mg, with a total content of approximately 253 mg of vancomycin hydrochloride, filled squares: 62.5% hydrochloride vancomycin, 37% polyethylene oxide) POLYOX® 303, molecular weight "7,000,000), 0.5% magnesium stearate, tablet dimensions 6.60 mm in diameter x 01.23 mm in length, 2" ~ tablets each with a weight of 409 mg, with an approximate total content of 508 mg vancomic hydrochloride In the prior art, vancomycin and its salts were administered by injection, given the poor absorption when administered orally. By providing all or at least a part of the total of the administered amount that will have to be delivered by controlled delivery to the retentive gastric system of the present invention, the portion thus delivered is directed to the proximal portion of the small intestine, the most effective site for the absorption of this medicament, which produces a better absorption of the oral dosage form of the present invention. Illustrative purposes It will be apparent to those skilled in the art that the elements, additives, proportions, methods of the formulation and other parameters of the invention can be modified or substituted in various ways, without departing from the spirit and scope of the invention.

Claims (7)

1. CLAIMS 1. A controlled release oral dosage form for releasing a medicament whose solubility in water is such that one part of the medicament is dissolved in less than ten parts by weight of water, the dosage comprising a solid polymer matrix in which it is dispersed the medicament at a ratio of weight to the drug of about 80:20 or less, swelling the polymer matrix to at least twice its volume after imbibition of water, which releases the drug into the gastric fluid by dissolving and diffusion of the drug by the gastric fluid out of the matrix, which upon immersion in the gastric fluid retains at least about 40 & of the medication one hour after the immersion and substantially releases all of the medication no later than eight hours after the immersion and remains substantially intact until all of the medication is released.
2. 2. A dosage form of claim 1 wherein the solubility of the drug in "water is such that a part of the medicament dissolves in less than about five parts by weight of water."
3. 3. A dosage form of claim 1. wherein the solubility of the medicament in water is such that a part of the medicament dissolves in less than about three parts by weight of water
4. 4. A dosage form of claim 1 wherein the medicament is a member selected from a group consisting of metformin hydrochloride, vancomycin hydrochloride, captopril, erythromycin lactobionate, ranitidine hydrochloride, sertraline hydrochloride and ticlopidine hydrochloride
5. 5. A dosage form of claim 1 wherein the medicament is metformin hydrochloride. 6. A dosage form of claim 1 wherein the medicament is sertraline hydrochloride. 7. A dosage form of claim 1 wherein the medicament is captopril. 8. A dosage form of claim 1 wherein the medicament is vancomycin hydrochloride. 9. A dosage form of claim 1 wherein "polymeric matrix" is formed with a polymer selected from the group consisting of polyethylene oxide, xanthan gum, cellulose, celluloses with the - "substituted alkyl group and degraded polyacrylic acids. 10. A dosage form of claim 1 wherein the polymer matrix is formed with a polymer selected from a group consisting of polyethylene oxide, xanthan gum, hydroxymethyl cellulose, hydroxyethyl cellulose; hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose. 11. A dosage form of claim 1 wherein the polymeric matrix is formed formed with polyethylene oxide having a molecular weight of at least about 4,500,000 12. A dosage form of "claim 1 wherein the polymer matrix is formed with "polyethylene oxide with a molecular weight ranging from about 4,500,000 to about 10,000,000 13. A dosage form of claim 1 wherein the matrix is formed with polyethylene oxide having a molecular weight of range of 5,000 to about 8,000,000 14. A dosage form of claim 1 wherein the weight ratio of the drug to the polymer is from about 15:85 to 80:20. Claim 1 wherein the ratio by weight of the medicament to the polymer is from about 30:70 to about 80:20 16. A dosage form of the rei Vindication 1 wherein the ratio by weight of the drug to the polymer is from about 30:70 to about 70:30. 17. A dosage form of claim 1 wherein the polymer matrix retains, after immersion in the gastric fluid of approximately 50% of the medicament one hour after immersion. 18. A dosage form of claim 1 wherein the polymer matrix retains, after immersion in the gastric fluid of approximately 60% of the medication one hour after the immersion. 19. A dosage form of claim 1 wherein the polymer matrix retains, after immersion in the gastric fluid of approximately 80% of the medicament one hour after immersion. 20. A dosage form of claim 1 further comprising a hydrophobic additive formulated with the medicament to further delay the release of the medicament to the gastric fluid. 21. A dosage form of claim 1 wherein the polymer matrix consists of two cylindrical tablets, each measuring from about 9 mm to about 12 mm in length and about 6.5 mm to about 7 mm in diameter. 22. A dosage form of claim 1 wherein the polymer matrix consists of two cylindrical tablets, each measuring from about 18mm to about 22mm long, about 6.5mm to about 7.8mm diameter from about
6. 6.2 to about
7. 7.5mm Tall.