WO2006088305A1

WO2006088305A1 - Gastric-retentive controlled release mono-matrix tablet

Info

Publication number: WO2006088305A1
Application number: PCT/KR2006/000512
Authority: WO
Inventors: Hee Jong Shin; Min Hyo Ki; Bok-Young Yoon; Sung Won An
Original assignee: Chong Kun Dang Pharmaceutical Corp.
Priority date: 2005-02-15
Filing date: 2006-02-14
Publication date: 2006-08-24
Also published as: KR100822519B1; KR20060092083A

Abstract

The present invention relates to a gastric-retentive controlled release mono-matrix tablet composition, comprising: a) at least one pharmacologically active substance; b) hydrogel-forming materials consisting of polyethylene oxide and at least one component selected from poloxamers and colloidal silica; and c) a carbon dioxide-generating material. The composition of the present invention floats in gastric juice and can continuously release the active substance in the stomach at a constant rate for at least 2 hours.

Description

GASTRIC-RETENTIVE CONTROLLED RELEASE MONO- MATRIX TABLET

[i]

Technical Field

[2] The present invention relates to a gastric-retentive controlled release preparation, and more particularly to a mono-matrix tablet composition capable of releasing an active substance in the stomach at a constant rate over at least 2 hours.

[3]

Background Art

[4] Gastric-retentive controlled release of active substances is a drug delivery system that is highly advantageous in the controlled release of the drugs without being limited to absorption sites in the gastrointestinal tract. Such g astric-retentive controlled release is particularly and essentially required for the active substances that absorbed mainly in the stomach and/or in the upper part of the small intestine. In the case of such active substances, if released after passing the stomach, it cannot help showing considerably low bioavailability. Gastric-retentive controlled release is a highly efficient oral delivery system from which active substances are released in an initial absorption site of the gastrointestinal tract thereby to allow them to be in contact with all parts of the gastrointestinal tract, enabling continuous delivery of the active substances to the body, irrespective of its absorption site. However, such property does not ensure a complete gastric-retentive delivery system. Active substances must be released at a constant rate for the desired time to maintain their efficacy.

[5] In a matrix-type controlled release system using a common water-soluble polymer, it is nearly impossible to achieve a high degree of zero-order release in which the dissolution rate of an active substance is constantly maintained. It is well recognized by those skilled in the art that, by adding a common surfactant or hydrophobic material to the matrix for control the dissolution rate, the overall dissolution rate may be increased or decreased, but a linear dissolution pattern, such as zero-order release, in a graph of time versus percent dissolution is not attained. The dissolution curves of mono-matrix tablets show that the dissolution rates of active substances are high in the first half of the dissolution, but are gradually decreased after 50% or more of the active substances are released. To overcome these limitations, an Oros system was developed wherein an active substance is pushed by osmosis using a semi-permeable coating composition. The Oros system has the great advantage that a high degree of zero-order release is achieved through release of the active substance at the constant rate. However, the Oros system has the limitation in that the system is applied only to active substances absorbed throughout the gastrointestinal tract because it cannot remain in the gastrointestinal tract. Accordingly, the most ideal controlled release for active substances mainly absorbed in the upper part of the small intestine in the gastrointestinal tract is a system that can exhibit a zero-order release pattern while the preparation stays in the stomach.

[6] Methods for the delivery of active substances to the body while pharmaceutical preparations stay in the stomach are divided into the following three large groups.

[7] Firstly, the delivery of active substances can be achieved by pharmaceutical preparations that can swell to be a larger volume and then maintain the volume without being eroded for a given time period. The pylorus is the passage between the stomach and the duodenum, and consists of the pyloric orifice and the pyloric sphincter. The residence time of preparations in the stomach is determined depending upon the diameter of the pyloric orifice. However, gastric retention by swelling of pharmaceutical preparations cannot help being incomplete due to a greatly difference in the diameter of the pyloric orifice depending on whether the stomach is full or empty. Taking the substantial diameter of the pyloric orifice into consideration, swollen preparations must have a diameter of a minimum of 1.0-1.5 cm. Even though swollen preparations have a diameter of a minimum of 1.0 cm, they can pass through the stomach s ometimes , since the diameter of the pyloric orifice may be increased to 1.0 cm or more even when the stomach is empty,

[8] Secondly, the retention of preparations in the stomach can be achieved by lowering the density of the preparations to allow the preparations to float in gastric juice. This is because floating preparations can be retained in the stomach in an upright position due to the presence of gastric juice within the stomach. When a normal human is in supine position, however, floating preparations, particularly, those having a diameter of 0.5 cm or less, can easily pass through the pylorus. Accordingly, complete gastric retention cannot be achieved by floating preparations.

[9] Thirdly, the retention of preparations in the stomach can be achieved by imparting sufficient adhesiveness to the preparations to adhere the preparations to the mucin of the mucosa of the stomach wall. However, frequent adhesion of preparations to the mucosa for a long period of time causes disorders in the gastric mucosa. Without careful control, the third method is not suitable for active substances requiring continuous administration.

[10] Consequently, a combination of the above three methods is the most preferable method for developing gastric-retentive preparations having maximal gastric retention effects. That is, the most suitable gastric-retentive preparations are swollen in gastric juice, maintain the increased volume for a given time period, float apart from the pylorus due to their low density, and delay the time taken to reach the pylorus due to sufficient adhesion to the gastric mucosa despite reversal of the floating state. Some partially combined systems have been attempted prior to the present invention.

[11] The gastric retention time of preparations can be prolonged when volume swelling effects of the preparations and floating effects due to a low density of the preparations are combined, as taught in the following prior art references. For example, Japanese Patent No. 63014715 discloses a system comprising a water-soluble polymer, preferably cellulose ether or polyvinyl alcohol, insoluble polyvinyl pyrrolidone, and a component to foam in contact with gastric juice. PCT Publication No. WO 00/15198 discloses a pharmaceutical composition comprising an active substance, a gas- generating component, a swelling agent, a viscocity agent, and optionally a gel- forming polymer. According to the prior art, however, superdisintegrants, such as water-insoluble polyvinyl pyrrolidone, are used as essential components to compensate for incomplete swelling. Considering the inherent characteristics of the superdisintegrants, very fast swelling of the water-insoluble materials impairs the continuity of the systems and causes delaminating of particles from the surface in contact with water. As a result, the systems suffer from incomplete controlled release and poor physical integrity in the gastrointestinal tract. For these reasons, the present invention does not need such superdisintegrants.

[12] PCT Publication No. WO 03/011255 discloses a biphasic system comprising a core and a rapidly releasing coat composition wherein the core comprises a drug, a swellable polymer and a gas-generating compound, and the coat composition comprises the same drug as in the core. PCT Publication No. WO 01/10417 discloses a pharmaceutical composition consisting of a first phase comprising an active substance combined with one or several carriers, and a second phase comprising a gas-generating system and a hydrophilic polymer or a porous mineral material wherein the active substance accounts for 80% of the first phase. However, the biphasic systems of these patent publications have defects that, the formation of two phases is considerably difficult and a high degree of zero-order release is not achieved, unlike in the present invention.

[13] Further, some systems to which floatability only is applied without control over the particle size of swollen matrices are known, for example, in U.S. Patent Nos. 4,101,650, 4,777,033 and 4,844,905 and PCT Publication No. WO 00/10419. These systems have the disadvantage of small size and are thus undesirable in achieving complete gastric retention. Systems for attempting gastric retention based on high swellability without floating are disclosed in PCT Publication Nos. WO 01/97783 and WO 98/55107, U.S. Patent Publication Nos. 2003-0104052 and 2004-0109891, and U.S. Patent No. 6,660,300. Disadvantageously, these systems have the possibility that they may pass through the stomach due to the broadened pylorus when the stomach is empty. Particularly, PCT Publication No. WO 98/55107 discloses a matrix preparation comprised of a highly water-insoluble active substance and 20% or more of a water- soluble polymer. When the preparation is swollen to about twice its initial size upon imbibitions of water, retains at least about 40% of the drug within the matrix one hour after ingestion, and releases substantially all the drug without substantial erosion of the preparation within 8 hours after ingestion. This preparation is designed for the purpose of achieving zero-order release, but does not substantially achieve zero-order release and floating based on low density, thus resulting in incomplete gastric retention. [14]

Disclosure of Invention

Technical Problem

[15] The present invention relates to a pharmaceutical composition that floats in gastric juice and can continuously release an active substance in the stomach at a constant rate for at least 2 hours. Therefore, it is an object of the present invention to provide a novel pharmaceutical composition that lowers the specific gravity of a tablet to allow the tablet to float in gastric juice and to form a hydrogel system capable of a high degree of zero-order release in a floating state, thereby to release an active substance in the stomach at a constant rate over 2 hours or more and preferably 6 hours or more.

[16]

Technical Solution

[17] The present invention relates to a gastric-retentive controlled release mono-matrix tablet composition, comprising:

[18] a) at least one pharmacologically active substance;

[19] b) hydrogel-forming materials consisting of polyethylene oxide and at least one component selected from poloxamers and colloidal silica; and

[20] c) a carbon dioxide-generating material.

[21] The composition of the present invention floats in gastric juice and can continuously release the active substance in the stomach at a constant rate for at least 2 hours.

[22] The composition of the present invention may further comprise an accelerating agent for hydrogel formation.

[23] Depending on the physicochemical properties and pharmacodynamic factors of the pharmacologically active substance , side effects are incident due to a sudden increase in blood concentration upon immediate release of the active substance from a pharmaceutical preparation. The composition of the present invention achieved a controlled release of the active substance, so that the incidences of such side effects are lowered and the duration of the efficacy of the drug is prolonged. In addition, appropriate contents of the hydrogel-forming materials and the accelerating agent for hydrogel formation provides a release pattern wherein the initial blood concentration of the active substance is rapidly and easily increased above a pharmacologically effective concentration and thereafter the blood concentration of the active substance is maintained.

[24]

[25] The hydrogel-forming materials used in the present invention consist of polyethylene oxide and at least one component selected from poloxamers and colloidal silica. The polyethylene oxide and the poloxamers are a class of polyalkylene oxides, and the colloidal silica is a class of silicon dioxide. Since the polyalkylene oxides and the silicon dioxide have low toxicity but are not orally absorbed, they exert functions as oral delivery vehicles of active substances and are then evacuated from the body. Accordingly, these components are biocompatible. In addition, since the polyalkylene oxides and the silicon dioxide are inert materials, they allow stable preservation of the active substance during storage.

[26] The polyethylene oxide (Trade Mark: Polyox ) used in the present invention is a polymer consisting of a series of repeating ethylene oxide units in structure and has a low surface activity and a high hydrogel viscosity. Commercially available polyethylene oxide products have an average molecular weight of about 100,000 to about 10,000,000. The polyethylene oxide preferably has a molecular weight of 1,000,000 or more and more preferably 3,000,000 or more for ease of control over the dissolution pattern. Polyethylene oxide products can be specifically categorized in terms of their molecular weight. Polyethylene oxide products adapted for the release of the active substance are appropriately selected depending on the polarity of the active substance, but the feature of the present invention is not limited to the products.

[27] The poloxamers (Trade Marks: Lutrol, Pluronic ) used in the present invention are copolymers consisting of ethylene oxide and propylene oxide monomers as repeating units in a particular ratio, and have a high surface activity and a medium hydrogel viscosity. Commercially available poloxamer products have an average molecular weight of about 2,000 to about 20,000. In view of the object of the present invention, it is preferred to use poloxamers having a molecular weight of 5,000 or more. Poloxamer products can be specifically categorized in terms of the ratio between polyethylene oxide and polypropylene oxide. For example, Poloxamer 124 has a ratio of 12 : 20, Poloxamer 188 has a ratio of 80 : 27, Poloxamer 237 has a ratio of 64 : 37, Poloxamer 338 has a ratio of 141 : 44, and Poloxamer 407 has a ratio of 101 : 56 in the alkyl oxide composition. There exist slight differences in the viscosity and surface activity between the poloxamer products. Poloxamer products that are solids at room temperature and suitable for dissolution of the drug depending on the polarity of the active substance are appropriately selected in view of the object of the present invention, but the feature of the present invention is not limited to the products.

[28] The colloidal silica used in the present invention is composed of silicon dioxide and is mainly used as a colloidal agent, a stabilizer, a suspending agent, an adsorbent or a lubricant in the fields of pharmaceuticals. The colloidal silica is commercially available under the trademarks Aerosil, Sylisia, Syloid and Cab-O-Sil. These colloidal silica products have the same chemical structure but have a different surface area per unit weight and hygroscopicity depending on the properties and shapes of the silica particles. Suitable products are selected according to their intended application, but the feature of the present invention is not limited to these products.

[29] Both the polyethylene oxide and the poloxamer are non-ionic polymers consisting of repeating alkyl oxide units, which have low toxicity upon being administered to humans. Since the polyethylene oxide and the poloxamer have complementary physic- ochemical properties, the control of the release patterns of various active substances can be easily attained by changing the mixing ratio of the two polymers. The polyethylene oxide and the poloxamer have been widely used in the fields of pharmaceuticals and medicines. For example, the polyethylene oxide is preferentially used for the purpose of increasing the viscosity rather than the solubilization of active substances, and the poloxamer is preferentially used for the purpose of forming gels, together with the solubilization of active substances. A dissolution pattern of a high degree of zero-order release is achieved through the use of the hydrogel-forming materials utilizing complementary effects of the two polymers. The complementary effects can be attained by homogeneously blending the colloidal silica having high dis- persibility and hygroscopicity due to very large surface area, with the polyethylene oxide. The colloidal silica facilitates dispersion and retention of an active substance within a hydrogel due to its high porosity, and increases the surface area of the active substance, thereby achieving a dissolution pattern of a high degree of zero-order release.

[30] The term 'high degree of zero-order release' as used herein refers to a state wherein the dissolution rate after initial burst release from a preparation containing a highly water-soluble active substance, such as metformin, can be maintained without any change until 80% or more of the drug is released. More specifically, after the mono- matrix tablet of the present invention was subjected to dissolution testing at 50-100 rpm at 37°C in accordance with paddle method among the dissolution test method specified in the pharmacopoeia to measure a percent dissolution at which the active substance began to exhibit a zero-order rate after initial burst release and a percent dissolution at which about 80% of the active substance was dissolved, the measured percent dissolutions were converted into a dissolution rate {i.e. percent dissolution per hour). As a result, the difference between the dissolution rates was 5%/hr or less, which indicates that the mono-matrix tablet of the present invention provides a pattern of a high degree of zero-order release. The relationships are expressed by the following equations: [31] DR (%/hr) = [Percent dissolution when zero-order rate is achieved (%)] ÷ b

[Dissolution time (hr)]

[32] DR ₀ (%/hr) = [ D₈₀ (%) - D₇₀ (%) ] ÷ [ T _Q (hr) - T₇₀ (hr) ]

[33] Difference between dissolution rates = DR (%/hr) - DR (%/hr) < 5 (%/hr) b 80

[34]

[35] D : an actual percent dissolution (%) when 70% of the active substance is substantially dissolved; [36] D : an actual percent dissolution (%) when 80% of the active substance is sub-

80 stantially dissolved; [37] T : a dissolution time required to reach D ;

70 ^ 70

[38] T : a dissolution time required to reach D ;

80 ⁿ 80

[39] DR b : a dissolution rate when zero-order rate is achieved; and

[40] DR : a dissolution rate at D .

80 80

[41]

[42] Dissolution patterns of an active substance from matrices using a general water- soluble polymer are shown in Fig. 1. "a" shown in Fig. 1 is a dissolution pattern of a matrix tablet prepared using a common water-soluble polymer, "b" is a dissolution pattern of a tablet prepared by further adding a surfactant or a solubilization auxiliary to the tablet of "a", and "c" is a dissolution pattern of a tablet prepared by further adding a common hydrophobic material, such as a oil-soluble material, for retarding the dissolution of the active substance to the tablet of "a". As is well recognized by those skilled in the art, the overall rates in the dissolution patterns of the matrices are controlled by the addition of excipients, but the dissolution curves are not changed to straight lines with time, "d" and "d' " shows dissolution patterns of the mono-matrix according to the present invention. The most important requirements in oral controlled release preparations are to deliver therapeutically effective blood concentrations of active substances to patients in need thereof within the shortest time and to provide absorption rates similar to the elimination rates of active substances, so that the effective blood concentrations are continuously maintained for a long time. Accordingly, the dissolution pattern of "d" or "d' " exhibiting a high degree of zero-order release is the most suitable pattern that satisfies the above requirements.

[43] The weight ratio between the polyethylene oxide and the poloxamer of the hydrogel-forming materials may be varied preferably in the range of 1:0.1 to 1:10, more preferably 1:0.2 to 1:5, and further more preferably 1:0.5 to 1:2. The weight ratio between the polyethylene oxide and the colloidal silica may be varied in the range of preferably 1:0.01 to 1:1, more preferably 1:0.02 to 1:0.5, and further more preferably 1:0.05 to 1:0.25. The polyethylene oxide, the poloxamer and the colloidal silica may be mixed all together according to the compositions indicated above. The weight ratio of the final hydrogel-forming materials to the active substance may be preferably in the range of 1:0.1 to 1:100 and more preferably 1:0.1 to 1:10.

[44] The composition of the present invention may further comprise an accelerating agent for hydrogel formation. Examples of suitable accelerating agents for hydrogel formation include guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum, alginic acid, casein, tara gum, tamarind gum, tragacanth gum, pectin, glucomannan, ghatti gum, arabino galactan, furcelleran, pullulan, carrageenan, glucosamine, chitosan, pregelatinized starch, and derivatives thereof. These materials can be used alone or in any combination. The derivatives include salts. The materials have a water-soluble sugar unit in common, and are classified according to the kind, crosslinking degree and molecular weight of the sugar unit. Due to hydration ability common to the sugar structure, the materials can be used as accelerating agents for hydrogel formation. The accelerating agent for hydrogel formation may be preferably at least one selected from the group consisting of carrageenan, alginic acid and derivatives thereof, including salts thereof, and more preferably at least one selected from the group consisting of carrageenan and derivatives thereof, including salts thereof. Since carrageenan and alginic acid are polymers composed of saccharides having chargeable moieties capable of being ionized, such as sulfuric or carboxylic acid group, they enables rapid gelling of the hydrogel-forming materials in an external aqueous phase. Specifically, in the case where an increase in initial burst release is needed for the rapid expression of the efficacy of the active substance after a high degree of zero-order release is achieved, the addition of the accelerating agent for hydrogel formation increases the initial burst release of the active substance, so that a dissolution pattern of a biphasic release profile is exhibited even in a mono-matrix. The accelerating agent for hydrogel formation can be used preferably in an amount of 50% by weight or less, i.e. 0.1-50 w/w%, and more preferably 25% by weight or less, Ie. 0.1-25 w/w%, based on the weight of the hydrogel-forming materials.

[45] The carbon dioxide-generating material used in the present invention can be selected at least one from the group consisting of carbonates and bicarbonates of inorganic metals, particularly of alkali metals. In addition to the carbonates and bicarbonates, at least one component selected from organic and inorganic acids can be further used. The carbonates and bicarbonates of inorganic metals include any material that can generate carbon dioxide under acidic conditions, for example, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium glycine carbonate. The organic or inorganic acids include any acidic material having a pH of 5.0 or lower and preferably 3.0 or lower in an aqueous solution, for example citric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, malic acid, glycolic acid, alanine, taurine, hydrochloric acid, aspartic acid, glutamic acid, glucuronic acid, ascorbic acid, and salts thereof. Although hydrochloric acid is present in gastric juice, it is included for patients with subacidity or anacidity of gastric juice. The content of the acidic material can be controlled in such a manner that the final matrix tablet is naturally foamed in purified water and floats.

[46] The carbon dioxide-generating material can be used preferably in an amount of

1-50% by weight and more preferably 2.5-25% by weight, based on the total weight of the final matrix tablet.

[47] Examples of suitable pharmacologically active substances that can be used in the present invention include, but are not limited to, a ntihypertensive agents, antihyper- lipidemic agents, antiobesity agents , antidiabetic agents, prostate therapeutics , agents for improving sexual functions , immunosuppressive agents, antiulcer agents, opioid and non-opioid analgesic agents , anesthetic agents, a ntiinflammatory analgesic agents, antirheumatic agents, steroidal hormones, tranquilizers , antidepressant agents, sedative hypnotics, antipsychotic agents, anticonvulsant agents, anti- spasmodics,antinauseant agents, antitussive agents for treating asthma, rhinitis therapeutics, antibiotics, antifungal agents, antiviral agents, blood-circulating agents, cardiovascular agents, and osteoporosis therapeutics. Non-limiting s pecific examples of these pharmacologically active substances include as follows: a ntihypertensive agents, such as amlodipine maleate, amlodipine besilate, felodipine, nifedipine, ler- canidipine, nicardipine, isradipine, diltiazem, lacidipine, enalapril, ramipril, fosinopril, cilazapril, imidapril, captopril, atenolol, carvedilol, doxazosin, terazosin, and prazosin; antihyperlipidemic agents, such as simvastatin, atorvastatin, lovastatin, fenofibrate, pravastatin, fluvastatin, gemfibrozil, and bezafibrate; antiobesity agents, such as orlistat, sibutramine, camellia sinensis, cholestyramine, colestipol, phentermine, ben- zphetamine, diethylpropion, phendimetrazine, bontril; antidiabetic agents, such as glimepiride, rosiglitazone, pioglitazone, CKD-501

(5-[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylaminoethoxy}benzyl)thiazolid ine-2,4-dione sulfate], metformin, gliclazide, acarbose, voglibose, glibenclamide, and repaglinide; prostate and bladder therapeutics , such as finasteride, tamsulosin, tolterodine, propiverine, and oxybutynin; agents for improving sexual functions, such as tadalafil, sildenafil, vardenafil, yohimbine, yohimbe, apomorphine, phentolamine, and testosterone; immunosuppressive agents, such as cyclosporin, tacrolimus, my- cophenolate (mofetil), and azathioprine; antiulcer agents, such as ranitidine, rebamipide, cimetidine, omeprazole, famotidine, nizatidine, teprenone, misoprostol, rabeprazole, roxatidine, ecabet, pantoprazole, lansoprazole , and esomeprazole; opioid and non-opioid analgesic agents , such as paracetamol, caffeine, propyphenazone , ibuprofen, tramadol, deanol, ketorolac, clonixin, mefenamic acid, acetylsalicylic acid, methionine, pranoprofen, fentanyl, codein, oxycodone, morphine, pethidine, and dihy- drocodein; anesthetic agents, such as lidocaine, bupivacaine, oxybuprocaine, propofol, sevoflurane, enflurane, midazolam, and isoflurane; antiinflammatory analgesic agents, such as aceclofenac, talniflumate, diclofenac, loxoprofen, naproxen, meloxicam, celecoxib, nabumetone, etodolac, piroxicam, rofecoxib, nimesulide, dexibuprofen, diacerhein, and zaltoprofen; antirheumatic agents, such as hydroxychloroquine, bu- cillamine, and penicillamine; steroidal hormones, such as methylprednisolone, prednisolone, deflazacort, dexametasone, triamcinolone, hydrocortisone, be- tametasone, colistin, clobetasol, desoxymethasone and desonide; tranquilizers, such as alprazolam, buspirone, tofisopam, diazepam, clotiazepam, etizolam, lorazepam, hydroxyzine, bromazepam, and ethyl loflazepate; antidepressant agents, such as paroxetine, fluoxetine, sertraline, venlafaxine, mirtazapine, hypericum perforatum, quinupramine, trazodone, amitriptyline, moclobemide, and milnacipran; sedative hypnotics, such as triazolam, Zolpidem, doxylamine, flunitrazepam, chloral hydrate, brotizolam, phenobarbital, zopiclone, estazolam, flurazepam, and midazolam; a ntipsychotic agents , such as risperidone, olanzapine, clozapine, quetiapine, haloperidol, zotepine, and nemonapride; anticonvulsant agents , such as valproic acid, gabapentin, carbamazepine, topiramate, oxcarbazepine, vigabatrin, lamotrigine, phenytoin, and methylphenidate; antispasmodics , such as tiropramide, cimetropium bromide, otilonium, pinaverium bromide, phloroglucinol, caroverine, scopolamine butyl hydroxide, difemerine, mebeverine, glycopyrronium hydroxide, aclatonium na- padisilate , and fenoverine; antinauseant agents , such as ondansetron, granisetron, scopolamine, tropisetron, dimenhydrinate, pyridoxine, ramosetron, meclozine , and chlorphenamine; antitussive agents for treating asthma , such as methylephedrine, chlorphenamine, dextromethorphan, dihydrocodeine, guaifenesin, noscapine, lysozyme, acebrophylline, levodropropizine, sulfogaiacol , phenylephrine, ben- properine, pseudoephedrine, albuterol, formoterol, salbutamol, bambuterol, fenoterol, terbutaline, clenbuterol, procaterol, fluticasone, salmeterol, formoterol, and budesonide; rhinitis therapeutics , such as phenylpropanolamine, chlorphenamine, Atropa belladonna, brompheniramine, phenylephrine, triprolidine, glycyrrhizinic acid, cetirizine, ebastine, and terfenadine; antibiotics, such as netilmicin, isepamicin, ri- bostamycin, micronomicin, amikacin, astromicin , tobramycin, gentamicin, clarithromycin, sisomicin, kanamycin, cefaclor, ceftriaxone, cefmetazole, cefazedone, cefixime, cefotiam, flomoxef, ceftezole, cefradin, cefotaxime, cefadroxil, cefprozil, cefpiramide, cefoperazone, ceftazidime, cefdinir, cefpodoxime proxetil, sulbactam, cefminox, ceftizoxime, cefditoren pivoxil, cefuroxime axetil, cefamandol, cefotetan, cephalexin, ceforanide, cefbuperazone, cefatrizine, cefuroxime, cefepime, cefteram pivoxil, cefroxadine, cefazolin, cefmenoxim, vancomycin, teicoplanin, fusidic acid, spectinomycin, fosfomycin, meropenem, imipenem, cilastatin, aztreonam, loracarbef, amoxicillin, clavulanic acid, ampicillin, bacamcillin, piperacillin, ciclacillin, tazobactam, sultamicillin, ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, to- sufloxacin, perfloxacin, lomefloxacin, and sparfloxacin; antifungal agents, such as itraconazole, fluconazole, terbinafine, amphotericin B, ketoconazole, and nystatin; antiviral agents, such as lamivudine, acyclovir, famcyclovir, valacyclovir, me- thisoprinol, ribavirin, oseltamivir, gancyclovir, imiquimod, indinavir, nelfinavir, stavudine, and zidovudine; blood-circulating agents, such as Ginkgo biloba, nicergoline, nimodipine, pentoxifylline, proxyphylline, coumarin, kallidinogenase, Melilotus officinalis, ajmalicine, almitrine, citicoline, vinburnine, ascorbic acid, acetyl carnitine, oxiracetam, choline, and piracetam; cardiovascular agents, such as digoxin, methyldigoxin, nicorandil, trimetazidine, molsidomine, dilazep, isosorbide nitrate, and nitroglycerin; and osteoporosis therapeutics, such as alendronic acid, pamidronic acid, menatetrenone, salcatonin, and elcatonin. In addition, their pharmaceutically acceptable salts are also included within the scope of the active substances of the present invention.

[48] The mono-matrix tablet of the present invention may further contain at least one excipient selected from diluents, disintegrants, coloring agents, sweetening agents, flavors, preservatives and lubricants that are commonly used to form tablets and are pharmaceutically acceptable. The mono-matrix tablet of the present invention may also contain an excipient having two or more combined functions. As diluents, at least one selected from the group consisting of, but is not limited to, lactose, dextrose, micro- crystalline cellulose and starch may be used. As disintegrants, at least one selected from the group consisting of, but is not limited to, croscarmellose sodium, sodium starch glycolic acid, crosslinked polyvinylpyrrolidone and low-substituted hydrox- ypropylcellulose may be used. As coloring agents, at least one selected from the group consisting of, but is not limited to, water-soluble coloring agents and tar coloring agents may be used. As sweetening agents, at least one selected from the group consisting of, but is not limited to, dextrose, sorbitol, mannitol, aspartame and acesulfame may be used. As flavors, at least one selected from the group consisting of, but is not limited to, orange-flavored, grape-flavored, strawberry-flavored and blueberry-flavored powders may be used. As preservatives, at least one selected from the group consisting of, but is not limited to, benzoic acid, m ethyl paraben , ethyl paraben and propyl paraben may be used. As lubricants, at least one selected from the group consisting of, but is not limited to, magnesium stearate, talc, light anhydrous silicic acid, oil-soluble sucrose fatty acid esters and glyceryl behenate may be used.

[49] The mono-matrix tablet composition of the present invention can be formed into a tablet by processes that are widely recognized in the fields of pharmaceuticals, such as blending, sieving, filling and compressing. The mono-matrix tablet composition of the present invention can be formed into solid preparations for oral administration.

[50]

[51] The present inventors have made an intensive investigation on dissolution patterns of mono-matrix tablets using general water-soluble polymers, and as a result, found that a high degree of zero-order release cannot be achieved. The reason for this is erosion of the water-soluble polymers constituting the matrices. This erosion reduces the surface area of the matrices in contact with media and decreases the concentration of active substances contained in the matrices, leading to a decrease in the concentration gradient of the active substances formed between the media and the matrices. The present inventors have earnestly and intensively conducted research to provide a mono-matrix tablet capable of overcoming the above problems. As a result, the present inventors have designed a gastric-retentive mono-matrix tablet containing a polyalkylene oxide that exhibits a high degree of zero-order release even in the case of a water-soluble drug for which the release control is difficult.

[52] The density of the hydrogel formed in the present invention is lowered in gastric juice within a few minutes to allow the preparation to float in the gastric juice, and at the same time, the hydrogel is hydrated and swollen uniformly from the surface to the core, contacting with a medium. Such properties are essential requirements for achieving a high degree of zero-order release. This uniformity can be accomplished by a mixture of polyethylene oxide and at least one component selected from poloxamers and colloidal silica. Since the hydrogel-forming matrix of the present invention floats in gastric juice, one side surface of the matrix is mainly used as a release surface. In addition, although the concentration gradient of the active substance is continuously decreased with increasing dissolution, highly uniform swelling of the matrix increases the diffusion rate of the active substance, so that the release rate of the active substance is constantly maintained. Furthermore, even though a high degree of zero-order release is achieved, in the case where an increase in initial burst release close to a biphasic release profile is needed for the rapid expression of the efficacy of the active substance, the initial burst release of the active substance may be further increased by the addition of the accelerating agent for hydrogel formation.

[53] The present invention also provides a mono-matrix tablet offering superior controlled release of not only water-soluble materials but also substantially water- insoluble active substances. For controlled release of a substantially water-insoluble active substance, it is generally required to dissolve the water-insoluble active substance by adding a surfactant or a solubilizer to the water-soluble polymer matrix or by a highly complicated solid dispersion process. However, these approaches increase the release rate of the active substance but fail to achieve zero-order release. In contrast, the hydrogel containing a polyalkylene oxide has a high degree of zero-order release ability while exhibiting a very high surface activity. Accordingly, the hydrogel is suitable for controlled release of also substantially water-insoluble active substances and thus control effects due to the kind and composition of water-soluble polymers, which have to be commonly varied depending on the physical properties of the active substance, can be attained by using a polyalkylene oxide only.

[54] In the case where polyethylene oxide only is used to prepare a gastric-retentive floating tablet or a sustained release tablet, the system from which a drug is completely released may remain uneroded even after 12 hours of the release. At this time, the system has negligible toxicity, but may be adhered to the mucosa of the stomach or gastrointestinal tract, causing secondary disorders in the gastrointestinal tract. Portions of the system remaining after all or 90% of the drug is released are unnecessary, despite the necessity for controlled release of the drug. The hydrogel containing a polyalkylene oxide is completely eroded after 90% or more of a drug is released. At this time, the time required for the complete erosion can be easily controlled by adjusting the mixing ratio between the polyethylene oxide and the poloxamer.

[55] Since the hydrogel containing a polyalkylene oxide is highly elastic, it easily retains carbon dioxide generated from the mono-matrix tablet of the present invention. Accordingly, the density of the matrix is lowered within 30 minutes and preferably 10 minutes to allow rapid floating of the preparation. As is well recognized in the art, effervescent tablets can generate gases, similarly to the tablet of the present invention, but quickly collapse into small particles, unlike the tablet of the present invention whose density is lowered to float. In addition, since the particles of effervescent tablets have no ability to retain the generated gases, they do not float. Accordingly, when the hydrogel is rapidly formed and foamed at the same time, the desired controlled release can be achieved in a floating state. If the foaming mechanism is too fast, the shape of the matrix may collapse before the formation of the hydrogel. Meanwhile, if the foaming mechanism is too slow, the hydrogel is adhered to the gastric mucosa and subsequent foaming of the hydrogel causes no floating. This problem can be easily solved by the mono-matrix tablet of the present invention in which the carbon dioxide- generating material and the hydrogel-forming materials containing a polyalkylene oxide are homogeneously dispersed.

[56] The mono-matrix tablet of the present invention is swollen in gastric juice and then maintains its initial volume for a given time period. At the same time, the density of the mono-matrix tablet according to the present invention is lowered by the trapped carbon dioxide to allow the tablet to float in gastric juice and has an adhesive force to the mucosa to some extent. Accordingly, the mono-matrix tablet of the present invention can achieve zero-order release of the active substance in the gastrointestinal tract over 2 hours or more and preferably 6 hours or more. Common sustained release tablets induce a reduction in the bioavailability of active substances absorbed only in the upper part of the gastrointestinal tract, whereas the gastric-retentive mono-matrix tablet of the present invention enables controlled release of the active substance without any loss in bioavailability. Accordingly, the gastric-retentive mono-matrix tablet of the present invention is a very efficient controlled release system for active substances absorbed in the upper part of the gastrointestinal tract. If without optimum gastric-retentive effects attained by the matrix tablet of the present invention, an active substance absorbed only in the upper part of the gastrointestinal tract passes through the stomach to the small intestine within 2 hours, which is a general gastric retention time. Since the active substance passes the main absorption site without being absorbed, the blood concentration is not maintained for a long time, and particularly the time required reaching the maximum blood concentration is not extended. In contrast, since the gastric-retentive mono-matrix tablet of the present invention retains an active substance in the gastrointestinal tract for 2 hours or more and preferably 6 hours or more, the time required to reach the maximum blood concentration of the active substance can be further properly extended.

[57]

Description of Drawings

[58] The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

[59] Fig. 1 is a graph showing dissolution patterns of an active substance from conventional mono-matrix tablets using a general water-soluble polymer;

[60] Fig. 2 is a graph showing the dissolution patterns of metformin hydrochloride released from mono-matrix tablets prepared in Examples 1 to 4;

[61] Fig. 3 is a graph showing the dissolution patterns of metformin hydrochloride released from mono-matrix tablets prepared in Examples 5 and 6;

[62] Fig. 4 is a graph showing the dissolution patterns of metformin hydrochloride released from mono-matrix tablets prepared in Comparative Examples 1 and 2;

[63] Fig. 5 is a graph showing the dissolution patterns of ciprofloxacin hydrochloride released from mono-matrix tablets prepared in Examples 7 and 8 ;

[64] Fig. 6 is a graph showing in the blood concentration-time profiles of metformin following the oral administration of mono-matrix tablets prepared in Examples 1 and 5 to human subjects; and

[65] Fig. 7 is a graph showing the dissolution patterns of gabapentin released from mono-matrix tablets prepared in Examples 9 and 10.

[66]

Mode for Invention [67] The following examples are given for the purpose of illustration and are not to be construed as limiting the scope of the invention. These examples can be readily reproduced by those highly skilled in the art.

[68] Examples 1 to 4 [69] Metformin hydrochloride as a pharmacologically active substance, polyethylene oxide and poloxamer as hydrogel-forming materials, carrageenan as an accelerating agent for hydrogel formation, a gas-generating material, and a lubricant were mixed in accordance with the compositions indicated in Table 1. Each mixed compositions was passed through a 60-mesh U.S. standard sieve, and compressed into tablets without the use of a superdisintegrant or a binder.

[70] Table 1 Mono-matrix tablet compositions of Examples 1-4 (unit: mg)

[71] [72] Examples 5 and 6 [73] Metformin hydrochloride as a pharmacologically active substance, polyethylene oxide and poloxamer as hydrogel-forming materials, colloidal silica, a gas-generating material, and a lubricant were mixed in accordance with the compositions indicated in Table 2. Each mixed compositions was passed through a 60-mesh U.S. standard sieve and compressed into tablets without the use of a superdisintegrant or a binder. [74] [75] Table 2 Mono-matrix tablet compositions of Examples 5 and 6 (unit: mg)

[76] [77] Comparative Examples 1 and 2 [78] Metformin hydrochloride as a pharmacologically active substance, polyethylene oxide as a hydrogel-forming material, carrageenan as an accelerating agent for hydrogel formation, lactose as a diluent, and a lubricant were mixed in accordance with the compositions indicated in Table 3. Each mixed compositions was passed through a 60-mesh U.S. standard sieve and compressed into tablets without the use of a superdisintegrant or a binder.

[79] [80] [81] [82] [83] Table 3

Mono-matrix tablet compositions of Comparative Examples 1 and 2 (unit: mg)

[84] [85] Examples 7 and 8 [86] Ciprofloxacin hydrochloride as a pharmacologically active substance, polyethylene oxide and poloxamer as hydrogel-forming materials, colloidal silica, a gas-generating material, and a lubricant were mixed in accordance with the compositions indicated in Table 4. Each mixed compositions was passed through a 60-mesh U.S. standard sieve and compressed into tablets without the use of a superdisintegrant or a binder.

[87] [88] Table 4

Mono-matrix tablet compositions of Examples 7 and 8 (unit: mg)

[89] [90] Examples 9 and 10 [91] Gabapentin as a pharmacologically active substance, polyethylene oxide and poloxamer as hydrogel-forming materials, colloidal silica, guar gum as an accelerating agent for hydrogel formation, a gas-generating material and a lubricant were mixed in accordance with the compositions indicated in Table 5. Each mixed compositions was passed through a 60-mesh U.S. standard sieve and compressed into tablets without the use of a superdisintegrant or a binder.

[92] [93] Table 5 Mono-matrix tablet compositions of Examples 9 and 10 (unit: mg)

[94]

[95] Experimental Example 1 [96] Dissolution test was conducted on the tablets prepared in Examples 1 to 4 to confirm the dissolution patterns. Specifically, s ix tablets from the respective examples were sampled and dissolved at 50 rpm and 37 + 0.5 °C . At 0, 1, 2, 4, 6 and 8 hours after initiation of the dissolution test using 900 ml of simulated gastric fluid without enzyme as a dissolution medium, 5 ml of dissolution sample was withdrawn from the medium. Each of the samples was filtered through a membrane filter having a pore diameter of 0.45 μm and the resulting filtrate was analyzed by HPLC under the following conditions, thereby to calculate percent dissolution and to plot dissolution curves, as shown in Fig. 2.

[97] <HPLC analysis of metformin>

[98] Column: Kromasil Cl 8 (4.6 x 250 mm, 5 μm)

[99] Detector: UV 236 nm

[100] Row rate: 1.0 ml/min.

[101] Injection volume: 20 μl

[102] Mobile phase: Mixed solution (pH 7.3) of phosphate buffer/acetonitrile (62.5/37.5)

[103] As a result, a high degree of zero-order release was achieved in the metformin mono-matrix tablets from about one hour after initiation of the dissolution until 80% of the active substance was released, as shown in Fig. 2.

[104] [105] Experimental Example 2 [106] Dissolution test was conducted on the tablets prepared in Examples 5 and 6 to confirm the dissolution patterns. Specifically, s ix tablets from the respective examples were sampled and the samples were treated in the same manner as in Experimental Example 1, thereby to calculate dissolution rates and to plot dissolution curves, as shown in Fig. 3.

[107] As a result, a high degree of zero-order release was achieved in the metformin mono-matrix tablets from about one hour after initiation of the dissolution until 80% of the active substance was released, as shown in Fig. 3.

[108]

[ 109] Experimental Example 3

[110] Dissolution test was conducted on the tablets prepared in Comparative Examples 1 and 2 to confirm the dissolution patterns. Specifically, s ix tablets from the respective experimental examples were sampled and the samples were treated in the same manner as in Experimental Example 1, thereby to calculate dissolution rates and to plot dissolution curves, as shown in Fig. 4.

[Ill] As a result, the metformin mono-matrix tablets composed of polyethylene oxide and an accelerating agent for hydrogel formation retard the release of the metformin, as shown in Fig. 4, but no zero-order release occurs even after one hour following the dissolution.

[112]

[113] Experimental Example 4

[114] Dissolution test was conducted on the tablets prepared in Examples 7 and 8 to confirm the dissolution patterns. Specifically, s ix tablets from the respective examples were sampled and dissolved at 50 rpm and 37 + 0.5 °C . At 0, 1, 2, 4, 6 and 8 hours after initiation of the dissolution test using 900 ml of simulated gastric fluid without enzyme as a dissolution medium, 5 ml of dissolution sample was withdrawn from the medium. Each of the samples was filtered through a membrane filter having a pore diameter of 0.45 μm and the resulting filtrate was analyzed by HPLC under the following conditions, thereby to calculate percent dissolution and to plot dissolution curves, as shown in Fig. 5.

[115] <HPLC analysis of ciprofloxacin>

[116] Column: Kromasil C 18 (4.6 x 150 mm, 5 μm)

[117] Detector: UV 278 nm

[118] Row rate: 1.2 ml/min.

[119] Inj ection volume : 20 μl

[120] Mobile phase: Mixed solution (pH 3.0) of phosphate buffer/acetonitrile (85/15)

[121] As a result, a high degree of zero-order release was achieved in the ciprofloxacin mono-matrix tablets from about one hour after initiation of the dissolution until 80% of the active substance was released, as shown in Fig. 5.

[122]

[ 123] Experimental Example 5

[124] Each of the tablets prepared in Examples 1 and 5 were administered orally to six healthy male subjects (average body weight: about 60 kg, age: 20-40 years) by one tablet per a subject. The blood concentration of the active substances was determined with the passage of time. The subjects were given a meal before experiment, and then the test drugs prepared in Examples 1 and 5 were administered to the subjects ten minutes after dinner with the same meal. Eating, smoking, drinking, exercising and drinking drug-containing beverage except drinking w ater were prohibited until 6 hours after initiation of the experiment. Next day, t he subjects were given breakfast with the same meal. Blood was collected until 24 hours after initiation of the experiment. After the collected blood samples were pre-treated by deproteinization, the resulting samples were analyzed by HPLC under the following conditions, thereby to calculate the blood concentrations and to plot blood concentration curves, as shown in Fig. 6.

[ 125] <HPLC analysis of metformin>

[126] Column: Zorbox 300-SCX (4.6 x 150 mm, 5 μm)

[127] Detector: UV 236 nm

[128] Row rate: 1.5 ml/min.

[129] Injection volume: 50 μl

[130] Mobile phase: Mixed solution of acetonitrile/water/methanol (50/45/5) containing

12 mM KH 2 PO 4.

[131] As a result, it was found that the mono-matrix tablets of the present invention constantly maintained the blood concentration of metformin, which is absorbed only in the upper part of the gastrointestinal tract. The time required to reach the maximum blood concentration of a common metformin tablet is about 1.9 hour (The Pharmacological Basis of Therapeutics, Gooddman and Gilman). In contrast, the time required to reach the maximum blood concentration of the tablets prepared in Examples 1 to 5 was 5-7 hours. This proves that the compositions of the present invention exert very ideal gastric retention effects in the stomach of humans and achieve a high degree of zero-order release.

[132]

[133] Experimental Example 6

[134] Dissolution test was conducted on the tablets prepared in Examples 9 and 10 to confirm the dissolution patterns. Specifically, s ix tablets from the respective examples were sampled and dissolved at 50 rpm and 37 + 0.5 °C . At 0, 1, 3, 6, 9 and 12 hours after initiation of the dissolution test using 900 ml of simulated gastric fluid without enzyme as a dissolution medium, 5 ml of dissolution sample was withdrawn from the medium. Each of the samples was filtered through a membrane filter having a pore diameter of 0.45 μm and the resulting filtrate was analyzed by HPLC under the following conditions, thereby to calculate percent dissolution and to plot dissolution curves, as shown in Fig. 7. [135] <HPLC analysis of gabapentin>

[136] Column: Kromasil C 18 (4.6 x 250 mm, 5 μm)

[137] Column Temperature: 35°C

[138] Detector: UV 206 nm

[ 139] Flow rate: 1.0 ml/min.

[140] Inj ection volume : 20 μl

[141] Mobile phase: Mixed solution of water/acetonitrile (980/20)

[142] As a result, a high degree of zero-order release was achieved in the ciprofloxacin mono-matrix tablets from about one hour after initiation of the dissolution until 80% of the active substance was released, as shown in Fig. 7.

[143]

Industrial Applicability

[144] The amounts of the active substances released per unit time from the tablets prepared in Examples and Comparative Examples were determined. As a result, about 20-22% of the active substance was released from the tablets prepared in Examples 5 and 6 one hour after initiation of the dissolution, and thereafter about 9-10% of the active substance per hour was uniformly released over 6 hours. Meanwhile, about 33% of the active substance was released from the tablet prepared in Comparative Example 1 at one hour after initiation of the dissolution, 19% of the active substance per hour was released until 2 hours, 11 % of the active substance per hour was released until 4 hours, and 6% of the active substance per hour was released until 6 hours. This proves that the dissolution rate of the active substance from the tablet prepared in Comparative Example 1 decreases rapidly all through the dissolution test from the initiation of the dissolution. That is, a high degree of zero-order release was not achieved in the tablet prepared in Comparative Example 1, unlike the tablets of the present invention. About 52% of the active substance was already released from the tablet prepared in Comparative Example 1 within 2 hours after initiation of the dissolution. It means that the tablet lost the substantial controlled release effects. A release of about half of a pharmaceutically active substance from a preparation, irrespective of controlled release, and thereafter a decrease in release rate with the passage of time are very undesirable for the maintenance of the blood concentration of the active substance.

[145] Accordingly, achievement of a high degree of zero-order release after initial burst release is a pharmaceutically important controlled release technique. The mono-matrix tablet containing a polyalkylene oxide according to the present invention provides a tablet dosage form for optimum controlled release, which is a pharmaceutically essential requirement for the absorption of active substances at a constant rate into the body. [146] In addition, the most direct method proving the gastric retention effects in vivo, particularly in humans, is to observe the blood concentration of active substances after oral administration. The oral administration tests in human of the tablets prepared in Examples 1 through 5 prove that gastric retention effects are achieved for the active substances, of which absorption window is the upper part of the gastrointestinal tract. The result of the test shows also that the time required to reach the maximum blood concentration is extended twice or more according to the present invention. Such extension of the time and the maintenance of the blood concentration for 12 hours or more clearly reveal that the gastric retention effects are maintained for 2 hours or more and preferably 6 hours or more.

[147] In conclusion, since the gastric-retentive mono-matrix tablet of the present invention exhibits a high degree of zero-order release of active substances while retaining the active substances in the stomach for 2 hours or more and preferably 6 hours or more, it possesses pharmaceutical advantages.

Claims

[1] [Claim 1]

A gastric-retentive controlled release mono-matrix tablet composition, comprising: a) at least one pharmacologically active substance; b) hydrogel-forming materials consisting of polyethylene oxide and at least one component selected from poloxamers and colloidal silica; and c) a carbon dioxide-generating material. [2]

[Claim 2]

The composition according to claim 1, wherein further comprising an accelerating agent for hydrogel formation.

[3] [Claim 3]

The composition according to claim 1 or 2, wherein the mono-matrix tablet has a difference in dissolution rates of 5%/hr or less and provides a pattern of a high degree of zero-order release wherein the dissolution rates are a percent dissolution per hour at which the active substance begins to exhibit a zero-order rate after initial burst release and a percent dissolution per hour at which about 80% of the active substance is dissolved, as measured at 50-100 rpm at 37°C in accordance with the paddle method among the dissolution test method specified in the pharmacopoeia .

[4] [Claim 4]

The composition according to claim 1 or 2, wherein the weight ratio between the polyethylene oxide and the poloxamer is in the range of 1 :0.1 to 1 : 10.

[5] [Claim 5]

The composition according to claim 1 or 2, wherein the weight ratio between the polyethylene oxide and the colloidal silica is in the range of 1:0.01 to 1:1.

[6] [Claim 6]

The composition according to claim 2, wherein the carbon dioxide-generating material is used in an amount of 1-50% by weight, based on the total weight of the hydrogel-forming materials.

[7] [Claim 7]

The composition according to claim 2, wherein the accelerating agent for hydrogel formation is used in an amount of 0.1-50% by weight, based on the total weight of the hydrogel-forming mterials.

[8] [Claim 8]

The composition according to claim 2, wherein the accelerating agent for hydrogel formation is at least one component selected from the group consisting of guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum, alginic acid, casein, tara gum, tamarind gum, tragacanth gum, pectin, glucomannan, ghatti gum, arabino galactan, furcelleran, pullulan, carrageenan, glucosamine, chitosan, pregelatinized starch, and derivatives thereof.

[9] [Claim 9]

The composition according to claim 7, wherein the accelerating agent for hydrogel formation is at least one component selected from carrageenan, alginic acid, and derivatives thereof.

[10] [Claim 10]

The composition according to claim 8, wherein the accelerating agent for hydrogel formation is at least one component selected from carrageenan and derivatives thereof.

[11] [Claim 11]

The composition according to claim 1 or 2, wherein the carbon dioxide- generating material is at least one component selected from the group consisting of carbonates and bicarbonates of alkali metals.

[12] [Claim 12]

The composition according to claim 1 or 2, wherein the carbon dioxide- generating material is

(a) at least one component selected from the group consisting of carbonates and bicarbonates of alkali metals; and

(b) at least one component selected from the group consisting of organic and inorganic acids.

[13] [Claim 13]

The composition according to claim 1 or 2, wherein the pharmacologically active substance is selected from the group consisting of glimepiride, rosiglitazone, pi- oglitazone, 5-[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl] methy- laminoethoxy}benzyl)thiazolidine-2,4-dione sulfate, metformin, gliclazide, acarbose, voglibose, glibenclamide, repaglinide, and pharmaceutically acceptable salts thereof.

[14] [Claim 14]

The composition according to claim 12, wherein the pharmacologically active substance is selected from the group consisting of metformin and pharmaceutically acceptable salts thereof.

[15] [Claim 15]

The composition according to claim 1 or 2, wherein the pharmacologically active substance is selected from the group consisting of netilmicin, isepamicin, ri- bostamycin, micronomicin, amikacin, astromicin , tobramycin, gentamicin, clarithromycin, sisomicin, kanamycin, cefaclor, ceftriaxone, cefmetazole, cefazedone, cefixime, cefotiam, flomoxef, ceftezole, cefradin, cefotaxime, cefadroxil, cefprozil, cefpiramide, cefoperazone, ceftazidime, cefdinir, cefpodoxime proxetil, sulbactam, cefminox, ceftizoxime, cefditoren pivoxil, cefuroxime axetil, cefamandol, cefotetan, cephalexin, ceforanide, cefbuperazone, cefatrizine, cefuroxime, cefepime, cefteram pivoxil, cefroxadine, cefazolin, cefmenoxim, vancomycin, teicoplanin, fusidic acid, spectinomycin, fosfomycin, meropenem, imipenem, cilastatin, aztreonam, loracarbef, amoxicillin, clavulanic acid, ampicillin, bacamcillin, piperacillin, ciclacillin, tazobactam, sultamicillin, ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, tosufloxacin, perfloxacin, lomefloxacin, sparfloxacin, and pharmaceutically acceptable salts thereof.

[16] [Claim 16]

The composition according to claim 14, wherein the pharmacologically active substance is selected from the group consisting of ciprofloxacin and pharmaceutically acceptable salts thereof.

[17] [Claim 17]

The composition according to claim 1 or 2, wherein the pharmacologically active substance is selected from the group consisting of alprazolam, buspirone, tofisopam, diazepam, clotiazepam, etizolam, lorazepam, hydroxyzine, bromazepam, and ethyl loflazepate, paroxetine, flouxetine, sertraline, venlafaxine, mirtazapine, hypericum perforatum, quinupramine, trazodone, amitriptyline, moclobemide, milnacipran, triazolam, Zolpidem, doxylamine, flu- nitrazepam, chloral hydrate, brotizolam, phenobarbiral, zopiclone, estazolam, flurazepam, midazolam, risperidone, olanzapine, clozapine, quetiapine, haloperidol, zotepine, nemonapride, valproic acid, gabapentin, carbamazepine, topiramate, oxcarbazepine, vigabatrin, lamotrigine, phenytoin, methylphenidate, and pharmaceutically acceptable salts thereof.

[18] [Claim 18]

The composition according to claim 16, wherein the pharmacologically active substance is selected from the group consisting of gabapentin and pharmaceutically acceptable salts thereof.

[19] [Claim 19]

The composition according to claim 1 or 2, wherein the polyethylene oxide has a molecular weight of 100,000 to 10,000,000.

[20] [Claim 20]

The composition according to claim 1 or 2, wherein the poloxamer has a molecular weight of 2,000 to 20,000.