SK1832002A3 - Hydrodynamically balancing oral drug delivery system - Google Patents

Abstract

The present invention relates to a gastro-retentive oral drug delivery system comprising a highly porous matrix comprising at least one drug substance, sugar(s), gas generating components and optionally, pharmaceutically acceptable auxiliary components. The pharmaceutical composition, either in the form of pellets (multiparticulate or single unit dosage form), beads, granules or capsules, is retained in the stomach while selectively delivering the drug(s) at gastric levels and upper parts of the small intestine over an extended period of time.

Description

Pharmaceutical compositions for oral administration of a medicament

Technical field

The present invention relates to a gastro-retentional oral drug delivery system consisting of a highly porous matrix comprising at least one drug ingredient, sugar (s), a gas-generating substance, and pharmaceutically acceptable excipients may be present. The pharmaceutical composition, either in the form of tablets (multiparticulate or in unit dose form) or in the form of beads, granules or capsules, is retained in the stomach while selectively delivering the drug (s) at the stomach level and upper small intestine for extended periods.

BACKGROUND OF THE INVENTION

The orally administered drug delivery system is exposed to a wide variety of considerably different conditions, such as pH, different mixing intensity, different gastric emptying times, and different gastrointestinal fluid composition during shifting of the system through the gastrointestinal tract. Further, the presence of food in the gastrointestinal tract may affect the operation of the dosage form. Therefore, to create an optimal orally controlled release system. the physicochemical and physiological environment of the gastrointestinal tract should be taken into account. Conventional approaches to controlled-release formulations commonly known in the art are not applicable to many drugs having so-called " "Absorption window" in the stomach or upper parts of the small intestine. In addition, it is preferred to retain the dosage form in the stomach in order to prolong the contact time of local action and to achieve better therapeutic efficacy in diseases associated with the upper gastrointestinal tract, such as peptic and duodenal ulcers.

Obviously, a sustained release formulation, when the drug is slowly released over a longer period of time and retained in the upper gastrointestinal tract for a longer period of time, would be desirable for the treatment of these diseases.

Earlier reports describe various approaches to formulating therapeutic dosage forms so that they retain in the upper gastrointestinal tract and have sustained release characteristics.

U.S. Pat. No. 5,780,057 discloses a pharmaceutical tablet having a multi-layer structure when at least one layer swells in the presence of biological aqueous liquids

As a result, the total tablet volume is increased by at least 50% and thus reportedly exhibits long-term gastric and / or upper gastrointestinal retention. The swellable layer is a granular mixture of biocompatible hydrophilic polymers and highly swollen (highly disintegrating) polymers, reportedly acting as a barrier and reportedly modulating the slow release of the active ingredient from the pharmaceutical form. It is believed that the expanded dosage forms may block the pyloric sphincter or cause adverse conditions due to multiple dosages due to retention of the swollen dosage form in the stomach.

U.S. Pat. No. 5,651,985 describes a composition of 30 to 90% by weight based on the weight of the composition, a homogeneous blend of polymers containing lactam groups and polymers containing carboxyl groups as gel forming preparations which swell to form a gel with allegedly high mechanical and shape stability in the aquatic environment of the stomach. It is believed that due to the very high concentration of polymers, the dosage form of the drug containing the high dose of drug would be large and unsuitable for oral administration.

U.S. Pat. No. 5,007,790 discloses an orally delivered sustained release formulation comprising a plurality of solid particles of a solid drug that is dispersed in a hydrophilic, water-swellable polymer that swells the stomach fluid to increase the particle size to a level that promotes absorption in the stomach to a predetermined amount. a period of time allowing the dispersed drug to dissolve and the resulting solution to be leached. The swollen polymer also reportedly maintains its physical integrity for at least a substantial portion of the time the drug is released into the stomach and then dissolves rapidly. It will be appreciated by those skilled in the art that it may be difficult to achieve the desired release rate of a drug having high water solubility from such multiparticulate systems as described in this patent, where the drug first undergoes dissolution and then release the resulting solution by leaching.

U.S. Pat. No. 5,169,638 discloses a buoyant controlled-release powder formulation for the release of a drug of basic character regardless of pH environment and comprises up to about 45% by weight of a pH-dependent polymer, which is a water-soluble polyuric acid salt, and up to about 35%. % by weight of a pH independent hydrocolloid gelling additive having a viscosity in the range of 50 to 100,000 Pa.s in a 2% solution at 20 ° C. This formulation reportedly floats on the surface of gastric juice and releases the drug at a controlled rate regardless of the pH of the surrounding environment. Despite of

In particular, the present invention is adapted to release medicaments that are of only basic nature. Acid drugs are not suitable for this system.

U.S. Pat. No. 4,814,179 discloses a sustained release floating therapeutic composition in the form of an uncompressed tablet having a plurality of air holes and ducts and a density of less than one comprising a matrix containing 0.5 to 4% gelling additive, 10 to 20% oil, up to 75% of the therapeutic composition and water. As shown in the examples, the preparation of an uncompressed tablet requires the use of unconventional manufacturing techniques and uses cylindrical hole forms. This means increased production and increased costs.

U.S. Pat. No. 4,702,918 discloses a sustained release floating formulation made by heating mixtures of a gelling agent (a cellulose or starch derivative) with a fat / oil that is solid at room temperature. The sustained release capsules of the patent description in this case comprise a mixture of (a) from about 10 to about 90% by weight of a cellulose derivative or starch derivative that forms a gel in water, and (b) about 90 to 10% by weight of glyceride higher fatty acids, or higher alcohol, or mixtures thereof, which is solid at room temperature; and (c) from 0.01 to 85% by weight of the drug. Capsules are made by filling said mixture (a), (b), (c) by heating to a temperature higher than the melting point of the higher fatty acid glyceride or higher alcohol or mixtures thereof, and cooling and freezing said mixture. More than just mixing is required to achieve the buoyancy of the formulation, i. additional melting operations followed by cooling. The specific gravity of the digestive juices, especially the gastric juices, is in the range of 1.004 to 1.101. It will be appreciated by those skilled in the art that it may be difficult to achieve a low specific gravity of a sustained release composition, as described herein, over a prolonged period of time. Further, as also exemplified, the desired concentration of gelling additives and fat / oil is high, and thus the system is suitable for low-dose dosing, while a high-drug dose would be bulky and unsuitable for oral drug delivery.

U.S. Pat. No. 4,126,672 discloses a formulation comprising one or more drugs in combination with a hydrocolloid or hydrocolloid mixtures such that a bulk density of less than one is hydrodynamic equilibrium in contact with gastric juice. The sustained release capsule dosage as described comprises a homogeneous mixture of fine particles of adiazepam chloriazepoxide, further 5% to 60% by weight of therapeutically inert, pharmaceutically acceptable excipients, further about 0% to 60% by weight of fatty material having a specific weight less than one and between 20% and 75% by weight of one or a mixture of hydrocolloids selected from the group

- consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and sodium carboxymethylcellulose. On contact with gastric juice, the hydrophilic colloid hydrates and this hydrated layer then dissolves slowly as drug is released. It is also said that drug release occurs by leaching on or near the surface. The hydrated colloid data forms an outer barrier that maintains the capsule shape and thus protects it from disintegration. However, it is clear that the use of such a system to obtain the desired rate of drug release by erosion of the polymer is difficult to maintain.

For the above reasons and because the prior art describes either complex devices and systems that are difficult to manufacture on an industrial scale or the components used are not very user-oriented, none of the oral drug delivery systems described hitherto is entirely satisfactory.

Our patent application no. 09/152 932, which is still pending, discloses a pharmaceutical composition in the form of tablets or capsules which provides a combination of spatial and time management of drug delivery for ingestion by a patient. The pharmaceutical composition comprises an oral controlled drug delivery system comprising a drug, a gaseous component, a swellable formulation, a viscous formulation, and optionally a gelling polymer. The viscous formulation and the agglomerate polymer form a hydrated gel matrix that captures the gas that holds the tablet or capsule in the stomach or upper small intestine (spatial control) and also creates a diffuse zig-zag pathway for the drug, allowing sustained drug release (time control).

The sustained release principle that characterizes the formulation of the present invention is unique in the art, and no technique has yet been found that uses the application of such a porous matrix to maintain and level the drug as described herein.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a pharmaceutical composition in the form of tablets, beads, granules or capsules that form a gastro-retention oral drug delivery system which:

(a) forms a gas to form a highly porous (preferably in the shape of bee plastic) matrix with good buoyancy properties and also evolves gas in contact with gastric juice, helping to maintain the drug dose at the stomach level; (b) provides increased gastric retention and thereby increasing drug retention in the gastrointestinal tract, (c) delivering the drug at a controlled rate and exhibiting repeatability of release to the aquatic environment when swimming in the stomach, (d) providing greater absorption of the drug from the upper gastrointestinal tract compared to other oral drug delivery systems tract.

It is also an object of the present invention to provide a pharmaceutical composition that provides an oral drug delivery system that maintains its physical integrity and dimensional stability in contact with gastric juices. The system floats in vitro on the surface of simulated gastric juice until substantially all of the drug is eliminated.

The present invention describes a therapeutic system either in the form of spheres, tablets or granules filled in a capsule (multiparticulate) or in the form of individual tablets and capsules from a matrix (monolithic system) that forms an orally administered buoyant drug delivery system capable of prolonged retention in gastric juices. The drug delivery system is structurally composed of a highly porous matrix (preferably in the form of bee plastic) with a large volume of trapped air, which makes the system light and gives it good buoyancy properties.

The therapeutic system consists of the drug, sugar, gas-generating ingredients and optionally pharmaceutically acceptable excipients.

The components used herein generate gas and are a combination of at least one thermostable and at least one thermolabile composition. During preparation of the formulation at high temperature exposure, the thermolabile composition generates gas and aids in the formation of an internal porous structure, while the thermostable formulation reacts with the acidic stomach components of the stomach to produce a gas that helps this form of dosage float. Thus, the combination of gas generating components helps the therapeutic system to act as a floating matrix that prolongs retention of the dosage form in the stomach and also prolongs its release in the stomach and upper intestine. This means that the system is not transported by the 'absorption window' before the release of all or substantially all of the drug and maximum bioavailability is ensured.

Preferably, the orally controlled drug delivery system of the present invention, which is in the form of a multiparticulate or monolithic system, comprises an amount ranging from a pharmaceutically acceptable amount of up to 35% drug, about 5% to about 90% sugar by weight, about 1% to about 30%. % by weight of gas generating components and pharmaceutically acceptable excipients.

According to the invention, the oral pharmaceutical composition comprises at least one drug substance, sugar (s), a combination of gas generating formulations and optionally other pharmaceuticals.

Auxiliary ingredients that can be used by one of ordinary skill in the art to formulate a therapeutic system. The choice of excipients and the amounts to be used are within the skill of the art. It is to be understood, however, that conventional pharmaceutical excipients which may negatively affect the hydrodynamic balance of the formulation of the present invention are not suitable for the present invention.

During the preparation of the formulation, the gas generating components develop a gas which causes the formulation to have a highly porous structure. The medicament is involved in this highly porous matrix preferably with bee plastic structure.

The composition may be in the form of tablets, spheres or granules embedded in a capsule or sachet (multiparticulate drug delivery system), or a matrix and tablet capsule as a single unit (monolithic system). The method of producing round tablets by extrusion and spheronization techniques or by spheronization using high shear granulation techniques or by using fluid bed techniques is well known and can be used to prepare tablets, beads or granules for the purposes of the present invention. Tablets as a whole can be manufactured on an industrial scale using punching machines.

Drugs that are thermostable may be added to the matrix, while thermolabile medicaments may be introduced into nasal beads (drug-free tablets) using a fluid bed-based drug insertion technique (equipment such as Glatt), which is well known in the art. The pharmaceutical composition of the invention may be in the form of a multiparticulate drug delivery system (up to 4 mm tablet, granule or bead size) or in the form of discrete units such as a matrix capsule or a large tablet (greater than 5 mm in size). The capsules of the matrix of the invention may be formed by filling the capsule with the powder of the invention, which capsule is made of either gelatin, starch or hydroxypropylmethylcellulose followed by heat treatment.

Additional polymers known in the art of pharmaceutical compositions for their release retarding properties can also be incorporated into the gastroretenic formulation of the invention. These release retarding polymers may be hydrophilic or hydrophobic or may be pH dependent or independent. Examples of polymers suitable for the present invention include hydroxypropylmethylcellulose, hydroxypropylcellulose, eudragit, ethylcellulose, xanthan gum and the like.

The pharmaceutical composition of the present invention may be coated with a film-forming polymer to address drug release or to better / improved buoyancy properties (resulting from better gas capture) or to improve the organoleptic properties of the composition. Additionally, the pharmaceutical composition may comprise bioadhesive polymers incorporated in the package, or

They may be present as a film covering tablets, granules, beads or capsules to improve their gastro-retention effects. In another application, high-swelling polymers may be added to increase the dosage form size to improve gastric retention.

Upon addition, the pharmaceutical composition of the invention, to simulated gastric juices, floats on the fluid until substantially all of the drug is released. The thermostable gas generating composition contained herein reacts with the acid present in the medium to form gases that are trapped in the matrix, thereby improving the buoyancy of the formulation.

The following is a more detailed description of the various components of the invention.

Medicine

According to the present invention, the pharmaceutical composition is in the form of tablets, spheres or granules that fill the capsule, or is a matrix capsule or matrix tablet, as a unit providing controlled release of at least one therapeutic preparation or medicament. The drug may be pharmacologically active per se or may be brought into active form by biotransformation in the body. The drug may be any drug that improves therapy as a result of a controlled dose of drug and increased retention and stomach.

The medicament or combination of medicaments that are subject to controlled-release therapy using the novel formulations of the invention comprise any of the formulations suitable for oral administration. The present invention is not designed to limit its use to one particular drug or class of drugs.

Gastro-retention formulations of the invention are particularly amenable to administration of drugs that are predominantly absorbed by the upper gastrointestinal tract having pH-dependent solubility, i. more soluble at gastric pH compared to intestinal pH. Further, they are amenable to administration of a medicament that acts in the stomach that contains H-2 receptor antagonists, acid neutralizing agents, antimuscarinic agents, proton pump inhibitors, anti-H. Pylori drug, cytoprotective agents and the like.

Illustrative examples of drugs that are predominantly absorbed from the upper parts of the gastrointestinal tract are ciprofloxacin, cyclosporin, furosemide, metoprolol, oxprenolol, baclofen, allopurinol, sumatriptan, benazepril, enalapril, quinapril, lexipillatol, lexipinlatol, lexipinlatol, mexiprol, imidapril, benezeprilat, cilazapril, captopril, delapril, tosinopril, libenzapril, pentopril, perindopril, altiopril, quinaprilat, ramipril, spiraprilate, zofenopril and the like; all of which are suitable for use in the present invention.

Medicaments that act in the stomach include H-2 receptor antagonists such as ranitidine, famotidine, nizatidine, bifentidine, erbrotidine, nifentidine, roxatidine and cimetidine and the like; proton pump inhibitors such as omeprazole, lanzoprazole, pentaprazole and the like; acid neutralizing agents such as magnesium carbonate, aluminum hydroxide, magnesium oxide and simethicone and the like; cytoprotectants such as sucralpate, sodium carbenoxolone, amisoprostol, and the like; antimuscarinic agents such as pirenzepine, telenzepine and propantelen bromide and the like; drugs effective against H. Pylori such as bismuth salts such as bismuth subsalicylate, trisodium bismuth dicitrate, bismuth rantidincitrate and the like; antibiotics such as clarithromycin, amoxycillin and the like; all of which are suitable for use in the present invention.

Other drugs that are suitable for the present invention are acid-soluble drugs or drugs that have specific absorption sites in the upper gastrointestinal tract and drugs that undergo first-pass gastrointestinal metabolism (as is known from some reports that absorption in stomach omits gastrointestinal metabolism of the first pass) including anti-hypertensive agents such as verapamil, nifedipine, propranolol, nimodipine, nicardipine, amolodipine, prazosine, ketanzerine, quanabenzacetate, hydralazide, carvedilol, methyldopa, levodopa; antiviral agents such as acyclovir, inosine, pranobex, zidovudine (AZT), tribavirin, vidarabine; lipid lowering agents such as simvastatin, pravastatin, atorvastatin and lovastatin; antipsychotic preparations such as selegiline; sedatives such as midazolam; all of which are suitable for use in the present invention.

The drug or the pharmacologically active salt or ester thereof may be used in the present invention. In addition, a combination of drugs that are commonly administered together may be used as a drug component. The amount of drug is as normally administered over a given period of time. Accordingly, the medicament may be present in an amount ranging from pharmaceutically acceptable to up to 35% by weight of the total weight of the composition.

sugars

According to the present invention, the pharmaceutical composition comprises sugars that provide a low density airy structure with the desired matrix texture. The sugars preferably comprise a pharmaceutically acceptable carbohydrate, including a monosaccharide, a disaccharide or a more saturated alcohol, and / or mixtures thereof. Examples of preferred sugars for the present invention include sucrose, glucose and corn syrup, crystalline fructose, fructose, lactose, dextrose, galactose, maltodextrin, maltose and the like; sugar alcohols such as sorbitol, mannitol, maltol, maltitol, xylilol, lactitol. In a more preferred embodiment of the invention it is a sugar

-9glucose syrup either in dry form or as a liquid. The sugars may be used alone or in combination with other similar sugars to achieve suitable matrix properties. In one preferred embodiment, sugar can be used under the trade name Glucidex (Riquete, UK).

The sugar may be present in an amount of from about 5% to about 90%, preferably from about 10% to about 85%, and more preferably from about 15% to about 85% by weight of the total weight of the composition.

Gas-forming components

According to the present invention, the pharmaceutical composition comprises a combination of thermostable and thermolabile gas forming compositions which assist in the formation of a highly porous structure, preferably a bee-shaped plastic structure, and improve the buoyancy of the formulation. As the name suggests, the thermolabile gas-generating component produces gas upon exposure to a high temperature (about 200 ° C or less) during the heating phase, while the thermostable composition does not decompose at the above temperatures and generates gas upon contact with gastric juices. As an example of the thermolabile gas-forming components useful in the present invention may be sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium bisulfite and the like. The thermostable gas-forming composition interacts with the acid source upon contact with water or only stomach acid to form carbon dioxide or sulfur dioxide which is trapped in the highly porous matrix of the composition, preferably in the form of bee plastics, and enhances the flow of the composition. Examples of thermostable gas forming compositions are calcium carbonate and sulfites such as sodium sulfite.

In those embodiments of the invention where the pharmaceutical composition is in the form of capsules, the thermostable gas-forming compositions may be used alone or combined in combination with an acid source. The acid source may be one or more edible organic acids, an edible organic acid salt, or mixtures thereof. Examples of organic acids that can be used as the acid source in the present invention include citric acid or salts thereof such as sodium citrate or calcium citrate, malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid or the like, and the like. Organic acid salts that can be used as the acid source in the present invention include, for example, a monoalkali organic acid salt with more than one carboxyl function,

-10balkalic metal salts of organic acid having more than two carboxylic acid functionalities and the like.

The gaseous components may be present in an amount of from about 1% to about 40%, preferably from about 1% to about 35%, and more preferably from about 1% to about 30% by weight of the total weight of the composition.

Auxiliary components

Alternatively, other conventional pharmaceutical excipients known in the art of formulation development may be added to the resulting formulation of the present invention, such as solvents, release retardants, inert oils, binder formulations and spheronization formulations.

According to the invention, the pharmaceutical composition may comprise a solvent that is stable in the heating process and forms part of a highly porous structure, preferably a bee plastic structure. The solvent which can be used in this invention belongs to the group of excipients well known in the art of pharmaceutical formulations. In preferred embodiments of the invention, the solvent is starch. Examples of starches that may be used in this invention include corn, rice, potato or wheat starch. Examples of other solvents include calcium monohydrogen phosphate, powdered cellulose, microcrystalline cellulose and the like.

The solvent may be present in an amount of from about 3% to about 5% by weight of the total weight of the composition, preferably from about 5% to about 40%, and more preferably from about 7% to about 35% by weight of the total weight of the composition.

The pharmaceutical composition of the invention may also contain polymers that retard drug release. These polymers may be present in the matrix structure of tablets or capsules, or they may cover the composition, or they may be added to various capsule forms of the invention in powder form. The obtained polymers in the form of aqueous dispersions can replace water as granulating agents in tablet formulations. Solid polymers can be added directly to the powder mixture.

The polymers used may, of course, be of the hydrophilic or hydrophobic type or may be pH dependent or independent. Examples of polymers suitable for the present invention include polymers well known in the pharmaceutical art for their delayed release properties, for example cellulose ethers such as hydroxypropylcelluloses of varying degrees of purity, hydroxyethylcellulose, methylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylmethylcellulose; acrylic

- 11 polymers which are available as aqueous dispersions such as Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, Eudragit RSPO, L30D or as powders such as Eudragit RSPO, Eudragit RLPO, Eudragit L10055 (all supplied by Rohm Pharma, Germany), ethylcellulose dispersion or in powder form. Examples of high-swelling polymers that can be used in the present invention include hydroxypropylmethylcellulose of varying degrees of purity, xanthan gums, sodium alginate and the like.

The release retarding polymers may also be selected from the group of natural gums such as karaya gum, locust bean gum, guar gum, gellan gum and the like.

One or more release retarding agents for the same or two different classes may be present from about 0.3% to about 25%, preferably from about 1.0% to about 20%, or more preferably from about 1.5% to about 15% by weight. % of the total weight of the composition.

According to the invention, the pharmaceutical composition may further comprise a therapeutically inert oil which is solid at room temperature but softens at higher temperatures, i. about 50 to 80 ° C. If present, the oil acts as a release retardant. The oil is preferably a fully saturated or partially saturated vegetable fat or oil. Examples of oils that can be used in the present invention include fully saturated or partially saturated cottonseed oil, coconut, soybean, palm, palm kernel, peanut, sunflower oil and the like. Preferred oils for the present invention are contained in the United States Pharmacopoeia as saturated vegetable oils of type 1. These oils may be used alone or in combination with other oils having the same properties.

The oil may be present in an amount of from about 0.2% to about 50%, preferably from about 0.2% to about 45%, and more preferably from about 0.4% to about 35% by weight of the total weight of the composition.

The bead-like pharmaceutical composition may also contain a binder to provide cohesion to the powder mass. Binders commonly known in pharmaceutical practice can be used in the present invention. Examples of binders include pregelatinized starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, starch wax, gelatin, xanthan, gum arabic, guar gum and the like.

The binder may be present in an amount of from about 0.1% to about 15%, preferably from about 0.2% to about 12%, and more preferably from about 0.5% to about 10% by weight of the final weight of the composition.

According to the present invention, the pharmaceutical composition is prepared either in the form of tablets, granules, spheres, or as capsules from a matrix. Tablets / beads may be prepared by conventional extrusion and spheronization techniques as well as other granulation techniques. The spheronizing agents are added to the composition to provide uniformly round granules or tablets. Commonly used spheronizing agents include microcrystalline cellulose (Avicel PH 101 from FMC Corpn. AEmcocel 50M or Emcocel 90M from Mendell), a mixture of microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC 591 from FMC Corpn.).

The spheronizing agent may be present in an amount of from about 1% to about 30%, preferably from about 2% to about 20%, and more preferably from about 4% to 15% by weight of the final weight of the composition.

In addition to the aforementioned ingredients, the pharmaceutical composition of the present invention may contain a pharmaceutical grade of magnesium stearate or stearic acid and similar ingredients such as a lubricant, talc and the like such as antiadherents, silica or saturated vegetable oil or sodium stearyl fumarate and the like as glidants.

Optionally, the pharmaceutical composition of the invention may be coated with a rapidly dissolving, water-soluble film. Examples of water-soluble polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose and the like. The pharmaceutical composition may be coated from about 1% to about 10%, preferably from about 1% to 4% by weight of the total weight of the composition.

According to the present invention, the capsule coating may be of a hard or soft type of gelatin. Further, capsules of starch or hydroxypropylmethylcellulose may be used.

The following examples illustrate the invention.

Example No. 1

This example illustrates the present invention in the form of tablets in which eudragit NE 30D is used as a release-retarding polymer in conjunction with a saturated vegetable oil in a matrix. The active ingredient is diltiazem hydrochloride. The pharmaceutical composition is given in Table no. First

- 13Table. 1

ingredients % wt. Diltiazem hydrochloride 20.40 Saturated Cotton Seed Oil (Lubritab) 16.48 Starch (maize) 22,09 dried glucose syrup (Glucidex 40 *) 16.48 starch gelatin (Starch 1500) 1.32 microcrystalline cellulose (Avicel PH 101) 9.88 ammonium bicarbonate 2.75 calcium carbonate 4.95 Eudragit NO 3 OD 5.65 (as a solid)

* dextrose equivalent - 40%

Diltiazem hydrochloride, saturated cottonseed oil, starch, glucose syrup, pregelatinized starch, microcrystalline cellulose, ammonium bicarbonate and calcium carbonate were sieved (British Standard Sieve (BSS) 44; 355 µm) and blended. The mixture was granulated with a dispersion of Eudragit NE 30D and extruded with an extruder (GA 65, Alexanderwerk) equipped with a 3.5 mm roller. The extruded products were spheronized in a spheronizer (Caleva 120 mm) for 20 minutes. The tablets were allowed to cool to room temperature.

The tablets were tested for their buoyancy and drug release in 900 ml of 0.1 N HCl using USP Apparatus 2 (paddle type) at 50 rpm. Tablets equivalent to 30 mg diltiazem hydrochloride were added to the dissolution flask.

At the periodic time intervals, the buoyancy of the tablets was visually checked if any remained there. We noted that all tablets remained floating for 21 hours. Dissolution medium samples were taken periodically and analyzed spectrophotometrically for diltiazem content. The results are shown in Table 2. Second

53.95

67.95

76.91

85.00

88.42

Table no. 2_______________________________________________________ _______ Time (hours) ______________________ total drug release (%)

Example 2

This example illustrates the present invention in the form of matrix capsules using propanolol hydrochloride as the active agent. The pharmaceutical composition is illustrated in Table 3.

- 14Table no. 3

ingredients % wt. Propanol hydrochloride 20.00 Saturated Cotton Seed Oil (Lubritab) 22.86 Starch (maize) 14.28 dried glucose syrup (Glucidex 40 *) 16.48 ammonium bicarbonate 7.14 calcium carbonate 7.14

* dextrose equivalent - 40%

Propranolol hydrochloride, saturated cottonseed oil, starch, glucose syrup, ammonium bicarbonate and calcium carbonate were sieved through a sieve (British Standard Sieve (BSS) 44; 355 pm) and blended. The mixture was manually filled into size 2 gelatin capsules. The average capsule weight of the filled composition was 320 mg. The filled capsules were left in the oven at 110 ° C for 2.5 minutes, after which they were allowed to cool to room temperature.

The capsules were tested for buoyancy and drug release in 900 ml of 0.1 N HCl using USP Apparatus 2 (paddle) at 50 rpm. At periodic time intervals, the buoyancy of the capsules was visually checked. We have noticed that the capsules have remained floating for 20 hours. Samples of dissolution medium were taken periodically and analyzed spectrophotometrically for propranolol content. The dissolution results are shown in Table 2. 4th

Table no. 4

Time (hours) total drug release (%)

12.41

21.02

34.96

81.71

Example 3 t

This example illustrates individual tablets (6 to 8 mm in diameter) that can be used as single doses containing diltiazem hydrochloride as the active ingredient. The pharmaceutical composition is shown in Table 1. 5th

Table 5___________________________________________

% ____________________________________% wt.

Diltiazem hydrochloride 22.37

Saturated cottonseed oil (Lubritab) 10,28 Starch (corn)

- 15Dried glucose syrup (Glucidex 40 *) 12.12 Pregelatinized starch (Starch 1500) 6.04 Microcrystalline cellulose (EMCOCEL 50M) 9.62 Ammonium bicarbonate3.87 Calcium carbonate 5.40 * Dextrose equivalent - 40%

Diltiazem hydrochloride, saturated cottonseed oil, starch, glucose syrup, pregelatinized starch, microcrystalline cellulose, ammonium bicarbonate and calcium carbonate were sieved (British Standard Sieve (BSS) 44) and blended. The mixture was granulated with water to achieve a consistency similar to that of the dough. The dough was entangled in a cylindrical shape and weighed small pieces with 30 mg diltiaz hydrochloride. They were cut and hand rolled into the shape of a ball.

The tablets were dried in an oven at 120 ° C for 0 minutes and then allowed to cool to room temperature. The tablets were tested as in Example 1. The tablets floated at the medium level for 20 hours. The dissolution results are shown in Table 2. 6th

Table no. 6_______

Time (hours) total drug release (%)

36.29

52.39

67.06

75.14

82.97

86.72

87.74

Example 4

This example illustrates a capsule type dosage form wherein the organic acid is used in combination with gas formulations. The pharmaceutical composition is shown in Table 1. 7

Table 7

ingredients % wt. Propanolol hydrochloride Saturated cottonseed oil (Lubritab) starch (corn) dried glucose syrup (Glucidex 40 *) citric acid, anhydrous ammonium bicarbonate 21.46 28,06 10.52 22.45 3.51 7.00

-16 Calcium butyrate _________________________________ 7,00 ____________________________________ * Dextrose equivalent - 40%

All ingredients were sieved through a 355 µm sieve (British Standard Sieve (BSS), 44) and blended. The mixture was manually filled into size 2 gelatin capsules. The average weight of the filled capsule was 320 mg. The filled capsules were subjected to a heat treatment at 110 ° C for 2.5 minutes and allowed to cool to room temperature.

The capsules were tested for in-vitro dissolution and buoyancy as described in Example 2. The capsules remained float on the dissolution medium during the dissolution test for 24 hours. The dissolution results are shown in Table 8.

Table no. 8 Time (hours) total drug release (%) 1 22.77 2 33.46 4 49,06 6 60.18 10 73.24 24 86.39

Example 5

This example illustrates a capsule type dosage form made in accordance with the present invention containing a polymer in a matrix (xanthan resin) together with a gaseous substance consisting of an organic acid and gaseous formulations. The mixture was filled into gelatin capsules of size 2 and into HPMC capsules of size 0. 9 illustrates a pharmaceutical composition.

Table no. 9

ingredients % wt. propanolol hydrochloride 19.41 Saturated Cotton Seed Oil (Lubritab) 25.38 Starch (maize) 9.52 dried glucose syrup (Glucidex 40 *) 20,30 citric acid, anhydrous 3.17 xanthan resin 9.52 ammonium bicarbonate 6.35 calcium carbonate 6.35

* dextrose equivalent - 40%

- 17 All components were weighed and sieved through a 355 μπι mesh screen (British Standard Sieve (BSS) 44) and blended. The mixture was manually filled into size 2 gelatin capsules (average capsule filled weight was 325 mg) and into size 0 hydroxypropylmethylcellulose capsules (average filled capsule weight 520 mg). The capsules were left in the oven at 110 ° C for 2.5 minutes, then allowed to cool to room temperature.

The capsules were tested for buoyancy and dissolution profile as described in the example

2. The capsules remained floating on the medium surface for 24 hours. The dissolution results are shown in Table 2. 10th

Table no. 10

Time (hours) total drug release (%)

Size 2 Size 0

1 19.02 6.60 2 32.15 19.52 4 57.54 50.24 6 73.42 70,59 10 87.80 88,09 24 92.41 95,08

Example 6

This example illustrates the invention as a capsule formulation using carvedilol as an active preparation. Table no. 11 illustrates a pharmaceutical composition.

Table no. 11 ingredients % wt. Carvedilol 10.00 Dried glucose syrup 79.50 Calcium carbonate 6.00 Ammonium bicarbonate 2.00 Sodium alginate 2.00 Saturated Cotton Seed Oil (Lubritab) 0.50

All ingredients were sieved through a 180 μπ mesh (British Standard Sieve (BSS), 85) and blended in a blender (Turbula mixer) for 30 minutes. The mixture was manually filled into size 0 gelatin capsules. The average weight of the filled capsule was 500 mg. The capsules were heat treated at 100 ° C for 9.0 minutes, then allowed to cool to room temperature.

The cartridges were tested in-vitro for drug release in 1000 ml dissolution medium consisting of 0.1 N HCl containing 1% sodium lauryl sulfate. A USP device 2 with a paddle speed of 50 rpm was used for examination. The paddles were mounted 4.5 cm from the bottom of the vessel and the basket, at the open end covered with a lid, used as a means to draw the samples below the surface. Media samples were taken periodically at predetermined time intervals and analyzed spectrophotometrically for carvedilol content. The dissolution results are shown in Table 2. 12th

Table no. 12

Time (hours) total drug release (%) 0.05 1.0 2.0 3.0 4.0 6.0 15.39 27.83 47.36 58,00 63.34 71.00

Example 7

This example illustrates the invention as a capsule dose. The active ingredient is carvedilol. Table no. 13 illustrates a pharmaceutical composition.

Table no. 13

ingredients % wt. Carvedilol Dried glucose syrup Calcium carbonate Ammonium bicarbonate Xanthan gum Sodium stearyl fumarate 9.99 79,65 5.99 1.99 1.59 0.79

A capsule dose was prepared as described in Example 6; The capsules were heat treated at 100 ° C for 13 minutes, then allowed to cool to room temperature.

The capsules were evaluated for the dissolution profile as described in Example 6. The dissolution results are shown in Table 2. 14

- 19Table no. 14

Time (hours) total drug release (%) 0.5 11.95 1.0 29,63 2.0 63.70 3.0 80,24 4.0 90.34

Example 8

This example illustrates the present invention as a capsule dose using pravastatin sodium as an active ingredient. Table no. 15 illustrates a pharmaceutical composition.

Table no. 15 ingredients % wt. Pravastatin sodium 8.10 Dried glucose syrup 74.77. Calcium carbonate 5.72 Ammonium bicarbonate 1.91 Xanthan resin 7.62 Saturated Cotton Seed Oil (Lubritab) 1.91

The pharmaceutical composition was prepared as described in Example 6. The average weight of the filled capsules was 525 mg. The capsules were heat treated at 100 ° C for 7.5 minutes, then allowed to cool to room temperature.

The capsules were tested for drug release in 1000 ml of water using USP device 2 (paddle type) at 50 rpm. Media samples were taken periodically at predetermined time intervals and analyzed spectrophotometrically for pravastatin content. The dissolution results are shown in Table 2. 16th

Table no. 16

Time (hours) total drug release (%) 0.5 9.15 1.0 19.54 2.0 36.89 3.0 55,19 4.0 74.76 5.0 93,91

-20Example 9

This example illustrates the present invention in the form of capsules from a matrix using pravastatin sodium as an active ingredient. The pharmaceutical composition is illustrated in a table. 17

Table no. 17

ingredients % wt. Pravastatin sodium 7.73 Dried glucose syrup 71.37 Calcium carbonate 5.46 Ammonium bicarbonate 1.82 Xanthan resin 7.28 Microcrystalline cellulose (Emcocel 90M) 4.55 Saturated Cotton Seed Oil (Lubritab) 1.82

The pharmaceutical composition was prepared as described in Example 6. The average weight of the filled capsules was 550 mg. The capsules were heat treated at 100 ° C for 7.0 minutes, then allowed to cool to room temperature.

The dosage form was evaluated for the dissolution profile as described in Example 8. The dissolution results are described in Table 1. 18th

Table no. 18

Time (hours) total drug release (%) 0.5 10.79 1.0 20.68 2.0 39.01 3.0 59,44 4.0 81.75 6.0 99.22

Although the present invention has been illustrated by specific examples, it was for illustrative purposes only. It will be apparent to those skilled in the art that many alternative embodiments can be made and are considered within the scope of the present invention.

Claims (44)

A pharmaceutical composition for oral administration of a medicament with prolonged retention in the stomach, characterized in that it has a highly porous matrix and comprises at least one drug substance, sugar (s), a gas-forming component which is a combination of at least one thermostable and at least one thermolabile component; optionally, pharmaceutically acceptable excipients, wherein the pharmaceutical composition maintains its hydrodynamic balance and physical integrity as the drug (s) is (are) released into the stomach. Pharmaceutical composition according to claim 1, characterized in that the medicament comprises at least one active compound selected from the category of anti-ulcer, analgesic, antihypertensive, antibiotic, antipsychotic, anticancer, antimuscarinic, diuretic, anti-viral, antiviral, anti-inflammatory, sedative, antidepressant, , antihistaminic, antiparasitic, antiepileptic, fat-reducing drugs and mixtures thereof. Pharmaceutical composition according to claim 1, characterized in that the medicament is selected from the group of medicaments consisting of enalpril, captopril, benazepril, lizonopril, ranitidine, famotidine, bismuth ranitidincitrate, diltiazide, propranolol, verapamil, carvedilin, ciflovipin, ciflovipin, ciflovipin, nifedloxin simvastatin, atorvastatin, pravastatin, lovastatin, selegiline, midazolam, fluoxetine, acarbose, buzpirone, nimesulide, captopril, nabumetone, glimepiride, glipizide, etodolac, nefazodone and mixtures thereof. The pharmaceutical composition of claim 1, wherein the medicament is present in an amount from a pharmaceutically acceptable amount up to 35% by weight of the composition. Pharmaceutical composition according to claim 1, characterized in that the sugar is selected from the group consisting of a carbohydrate and a polyhydric alcohol and mixtures thereof. Pharmaceutical composition according to claim 15, characterized in that the sugar is selected from the group consisting of sucrose, glucose syrup, corn syrup, fructose, lactose, dextrose, galactose, maltose, maltodextrin, sorbitol, mannitol, maltol, maltitol, xylitol and lactitol . Pharmaceutical composition according to claim 1, characterized in that the sugar is present in an amount of from 5% to 90% by weight of the composition. Pharmaceutical composition according to claim 1, characterized in that the sugar is present in an amount of from 10% to 85% by weight of the composition. Pharmaceutical composition according to claim 1, characterized in that the sugar is present in an amount of from 15% to 85% by weight of the composition. Pharmaceutical composition according to claim 1, characterized in that the gas generating component comprises a sulphite, carbonate or bicarbonate salt. The pharmaceutical composition of claim 1, wherein the gas forming component is selected from the group consisting of ammonium bicarbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium glycine carbonate, sodium sulfite, sodium bicarbonate, and sodium metabisulfite. The pharmaceutical composition of claim 1, wherein the gas forming component comprises a pair of gases comprising a thermostable gas forming salt and an edible organic acid or an edible organic acid salt. The pharmaceutical composition of claim 12, wherein the edible organic acid is selected from the group consisting of citric acid, ascorbic acid, tartaric, succinic, fumaric, malic, maleic, glycine, sarcosine, alanine, taurine, and glutamic acid. Pharmaceutical composition according to claim 1, characterized in that the gas-generating component is present in an amount of 1% to 40% by weight. composition. Pharmaceutical composition according to claim 1, characterized in that the gaseous component is present in an amount of 1% to 35% by weight. composition. Pharmaceutical composition according to claim 1, characterized in that the gas-generating component is present in an amount of 1% to 30% by weight. composition. 17. The pharmaceutical composition of claim 1 wherein the pharmaceutical excipient is selected from the group consisting of solvents, release retardants, inert oils, binder formulations and spheronization formulations. The pharmaceutical composition of claim 17, wherein the solvent is selected from the group consisting of starch, starch derivatives, cellulose derivatives, dibasic calcium phosphate and calcium sulfate. 19. The pharmaceutical composition of claim 17 wherein the solvent is starch. The pharmaceutical composition of claim 17, wherein the starch is selected from the group consisting of corn starch, rice starch, potato starch and wheat starch. Pharmaceutical composition according to claim 17, characterized in that the solvent is present in an amount of 3% to 50% by weight. composition. The pharmaceutical composition of claim 17, wherein the solvent is present in an amount of 7% to 35% by weight. composition. The pharmaceutical composition of claim 17, wherein the release retarding agent is either incorporated into the matrix or forms a coating of the composition. 24. The pharmaceutical composition of claim 17 wherein the release retarding agent is selected from the group consisting of cellulose ethers, acrylate polymers, natural resins, and mixtures thereof. 25. The pharmaceutical composition of claim 24, wherein the cellulose ethers are selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylmethylcellulose and hydroxyethylcellulose. 26. The pharmaceutical composition of claim 24, wherein the acrylic polymer is selected from the group consisting of methacrylates, polyacrylate copolymers, and mixtures thereof. The pharmaceutical composition of claim 24, wherein the natural resin is selected from the group consisting of xanthan gum, karaya resin, locust bean gum, sodium alginate, guar gum, gellan resin, and mixtures thereof. 28. The pharmaceutical composition of claim 17, wherein the release retarding agent is present in an amount of 0.3% to 25% by weight of the composition. The pharmaceutical composition of claim 17, wherein the release retarding agent is present in an amount of 0.3% to 25% by weight of the composition. 30. The pharmaceutical composition of claim 17 wherein the inert oil comprises a saturated or unsaturated vegetable oil. 31. The pharmaceutical composition of claim 17 wherein the inert oil is selected from the group consisting of saturated or unsaturated cottonseed oil, castor oil, coconut, palm kernel, palm, soy, peanut oil, and mixtures thereof. 32. The pharmaceutical composition of claim 17 wherein the inert oil is present in an amount of 0.2% to 50% by weight of the composition. The pharmaceutical composition of claim 17, wherein the inert oil is present in an amount of 0.4% to 35% by weight of the composition. 34. The pharmaceutical composition of claim 17 wherein the binding agent is selected from the group consisting of pregelatinized starch, polyvinylpyrrolidone, gelatin, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, natural resins, and mixtures thereof. The pharmaceutical composition of claim 17, wherein the binding agent is present in an amount of 0.1% to 15% by weight of the composition. 36. The pharmaceutical composition of claim 17 wherein the binding agent is present in an amount of from 0.5 to 10% by weight. % of the composition. The pharmaceutical composition of claim 17, wherein the spheronizing agent is microcrystalline cellulose or a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. 38. The pharmaceutical composition of claim 17 wherein the spheronizing agent is present in an amount of 1% to 30% by weight of the composition. The pharmaceutical composition of claim 17, wherein the spheronizing agent is present in an amount of 4% to 15% by weight of the composition. 40. The pharmaceutical composition of claim 1, further comprising a bioadhesive polymer. 41. The pharmaceutical composition of claim 1, further comprising a highly swellable polymer. 42. A pharmaceutical composition according to claim 17, which is shaped into a physical form selected from the group of multiple or single tablets, beads, granules, capsules with a light gelatin shell or a hard gelatin shell. The pharmaceutical composition of claim 42, wherein the tablet, bead or granule form is coated with a pharmaceutically acceptable film-forming polymer or pharmaceutical excipient. 44. The pharmaceutical composition of claim 42, wherein the capsule shell is formed of gelatin, hydroxypropylmethylcellulose or starch.