KR20130120118A - Gastroretentive sustained release formulation with bilayer structure - Google Patents

Abstract

A gastroretentive sustained release formulation according to the present invention comprises: an upper layer containing an active ingredient and release controlled polymers; and a lower layer containing swelling polymers and gas generating materials. The gastroretentive sustained release formulation enables release control of a drug, shows swelling and suspension properties, and improves drug compliance through a medication once a day. [Reference numerals] (AA) Sustained release layer containing drug;(BB) Swelling + floating layer

Description

[0001] The present invention relates to a sustained release sustained release formulation having a bilayer structure,

The present invention relates to a sustained-release sustained-release preparation having a bilayer structure. More specifically, the present invention relates to a pharmaceutical composition comprising an upper layer that facilitates drug elution control using a release-controlling polymer, a slow-release sustained-release preparation comprising a swellable polymer and a gas generating material and a lower layer that improves the swelling and floating property of the matrix .

Amoxicillin is a β-lactam antibiotic chemical name is (2 S, 5 R, 6 R) - 6 - {[(2 R) -2- amino-2- (4-hydroxyphenyl) -acetyl] amino} 3,3 -Dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. The molecular formula of amoxicillin is C ₁₆ H ₁₉ N ₃ O ₅ S and the molecular weight is 365.4. The structural formula is as follows.

Amoxicillin is white or pale yellowish crystalline powder, which is insoluble in water but has an increased solubility in acidic solutions. However, stability in acidic solutions is low. Amoxicillin is a β-lactam antibiotic that inhibits cell wall formation against gram-positive and gram-negative bacteria and has antimicrobial activity. Specifically, amoxicillin is effective against bacterium such as Streptococcus, Pneumococcus, Staphylococcus, Gram, Influenza, Escherichia, Proteus The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prophylaxis of an infectious disease, , Scarlet fever, bacterial endocarditis, pyelonephritis, cystitis, urethritis, gonococcal urethritis, peritonitis, liver abscess, typhoid, osteomyelitis and intrauterine infection.

Retro class azithromycin is a fluoride-based antibiotics mark roll, chemical name is (3 R, 4 S, 5 S, 6 R, 7 R, 9 R, 11 S, 12 R, 13 S, 14 S) -6 - {[( 2 S, 3 R, 4 S , 6 R) -4- ( dimethyl-amino-3-hydroxy-6-methyl-dioxane-2-yl] oxy} -14- ethyl -12,13- dihydroxy-4 {[(2 R, 4 S , 5 S, 6 S) -5- hydroxy-4-methoxy-4,6-dimethyl-dioxane-2-yl] oxy} -7-methoxy -3,5,7 , 9,11,13-hexamethyl-1-oxacyclotetradecane-2,10-dione, the molecular formula of clarithromycin is C ₃₈ H ₆₉ NO ₁₃ , the molecular weight is 748.0, and the structural formula is as follows.

Claritromycin is also a white crystalline powder, poorly soluble in water and less stable in acidic solutions. Claritromycin is a macrolide antibiotic that binds to a subunit of the 50s ribosome and inhibits translation into peptides and has antimicrobial activity. Specifically, Staphylococcus aureus, Streptococcus pieogenes (Group A-beta (Group B), streptococcus viridans, influenza bacillus, parainfluenza bacillus, moxacella catarrhalis, legionella pneumophila, bordetella pertussis, plant Campylobacter pylori, Helicobacter pylori, Gonorrhea, Animal fascioliellae pathogen, Pneumoniae mycoplasma, Chlamydia trachomatis, Clostridium perfringens, Peptococcus niger, Propionibacterium acnes, Bacteroides melaninogenix, Mycobacterium avium, Mycobacterium intracellular strains, and also has the following infection (bronchitis, Pneumonia, etc.), upper respiratory tract infections (pharyngitis, sinusitis), skin and skin tissue infections, mycobacterium avium, mycobacterial infections caused by mycobacterium intra cellular, and eradication of Helicobacter pylori in patients with duodenal ulcers.

Amoxicillin is commercially available as an immediate release capsule (trade name: Parmsin Capsule, Donghwa Pharm) in Korea and is commercially available in the United States as Slowan (trade name: Moxatag, Shionogi Inc.). Claritromycin has been used in Korea for several years in the domestic market, such as fast-growing tablets (Clarified Film Coatings, Korea Abbott), sustained-release tablets (Claressi X.LL, , Abbott Korea). However, tablets containing both of these components have not been commercially available to date, and there are no sustained release preparations containing both of these components.

Amoxicillin is generally well absorbed, is not affected by food, is mostly absorbed from the upper gastrointestinal tract, has a maximum blood concentration time (t _max ) of about 1.5 hours, and has a half-life of about 1 hour. Claritromycin has a bioavailability of approximately 50%, a peak blood concentration of 2 to 3 hours, and a half-life of 3 to 4 hours.

On the other hand, Helicobacter pylori infection has been recognized as the most important cause of gastric cancer and the need for eradication of Helicobacter pylori has been suggested for the prevention of gastric cancer. There have been many attempts to eradicate Helicobacter pylori. Currently, PPI (proton pump inhibitor) based triple therapy is considered to be the best treatment regimen in Korea and abroad. In the current study, it was reported that a high rate of resistance to metronidazole was observed in domestic helicobacter isolates. Therefore, PPI (standard dose bid) + claritromycin (0.5 g bid) + amoxicillin g bid) combination is recommended as the first-line treatment.

The eradication rate of standard triple therapy was found to be very effective, reaching more than 90% by 1998, but since then the success rate has decreased to 75%. Although H. pylori is susceptible to many antibiotics in vitro, it may be difficult to clinically treat eradication. The reason for this may be resistance to antibiotics such as metronidazole or clarithromycin and the inoculum effect due to the high number of H. pylori in the stomach, and pylori are present in the gastric mucosal gel layer, which may make it difficult to penetrate antibiotics. In addition, failure to eradicate is associated with environmental factors such as low compliance, smoking, and antibiotic resistant H. pylori strains, virulence factors of strains such as cagA or vagA s2, insufficient gastric acid suppression associated with PPI dose or interval Of the total population. In addition, the clinical use of Helicobacter pylori infection treatment, which is twice daily three times therapy, is quite inconvenient for patients, especially during 1 to 2 weeks of treatment, there is a high probability of failure of sterilization due to poor compliance with medication.

As a result, there is a growing interest in new forms of PPI replacement therapy, and there is an increased interest in slow release drugs as part of this new type of PPI study.

On the other hand, many documents have been published on the non-linearity of absorption of amoxicillin and the difference in absorption in the gastrointestinal tract from the stomach to the colon. Amoxicillin is well absorbed from the duodenum to the jejunum at the upper part of the small intestine, but rapidly decreases from the ileum and is not absorbed from the colon at all. This means that the mean absorption time of amoxicillin is less than 6 hours, and the nonlinearity of this absorption site means that release of drug to the lower gastrointestinal tract after 6 hours using the general slow release technique is not clinically effective.

Rajinikanth and others have suggested that the above-mentioned amoxicillin formulation is more effective in eradicating Helicobacter pylori, and that the difference in eradication power is about 10 times.

U.S. Patent No. 6,340,475 (Korean Patent No. 10-0545480) discloses an over-the-stick oral drug formulation for controlled release of highly soluble drugs. However, when designing the above-mentioned retentive preparation using only polyethylene oxide or hypromellose (hydroxypropylmethylcellulose), there is a high probability of collapse of the preparation due to dissolution of the drug, lack of floating property, and high stomach retention effect And it is very difficult to control the release of the drug in vivo.

 U.S. Patent No. 5,972,389 (Korean Patent No. 10-0685303) discloses a sustained-release oral drug formulation for the controlled release of slightly soluble drugs and insolubles. However, in this formulation, there is a problem in that the preparation does not stay in the stomach sufficiently because it is released upward as the stagnant formulation gradually corrodes.

United States Patent Application Publication No. 2007-0269511 (Korean Patent Application Publication No. 2008-0059427) discloses a sustained-release preparation using a stagnation system of pregabalin. This is done by using a mixture of polyvinyl acetate and polyvinylpyrrolidone for the purpose of release control as a matrix and using crosslinked polyvinylpyrrolidone as a swelling agent to remain on top of the pregabalin, And at least 9 mm. However, these preparations have the problem that the hardness of the preparation in the body may be influenced by the crosslinked polyvinylpyrrolidone used for rapid swelling, and there is a problem in that the stomach retention ability is lacked due to lack of floating power.

In order to solve the above problems, the inventors of the present invention have found that by controlling the dissolution of a drug by constituting an upper layer by using a release-controlling polymer and constituting a lower layer by using a swelling polymer and a gas generating material, Which is capable of improving the retention properties of the sustained-release pharmaceutical composition of the present invention.

It is an object of the present invention to provide a sustained-release sustained-release preparation having a bilayer structure.

Another object of the present invention is to provide a sustained-release sustained-release preparation which is easy to control dissolution of a drug.

Still another object of the present invention is to provide a sustained-release sustained-release preparation excellent in swelling property and floating property.

It is another object of the present invention to provide a sustained-release sustained-release preparation that improves adherence compliance.

The sustained release sustained release preparation according to the present invention comprises an upper layer comprising an active ingredient and a release-controlling polymer; And a lower layer comprising a swelling polymer and a gas generating material.

In one embodiment of the present invention, the active ingredient is at least one selected from the group consisting of hypertension, diabetes, hyperlipidemia, cardiovascular system, A pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, and a mixture thereof.

In one embodiment of the invention, the active ingredient is selected from the group consisting of metformin, glimepiride, amoxicillin hydrate, clarithromycin, carvedilol, urtopril, vancomycin, azithromycin, cefdinir, cefditoren, olopatadine, ciprofloxacin, The present invention relates to the use of a compound selected from the group consisting of cimetidine, famotidine, lansoprazole, omeprazole, s omeprazole, ranitidine, metodidazole, bismuth derivatives, bisphosphonate, gabapentin, pregabalin, loxoprofen, But are not limited to, acyclovir, ganciclovir, lamivudine, zidovudine, adefovir dipivoxil, carbazepine, oxycarbazepine, topiramate, levodopa, carbidopa, methyldopa, entacapone, entacavir, rosiglitazone, aspirin, ≪ / RTI > and mixtures thereof.

In one embodiment of the invention, the active ingredient is selected from the group consisting of metformin, amoxicillin hydrate, clarithromycin, amoxicillin hydrate-clarithromycin combination, pregabalin, bisphosphonate, loxoprofen, , Cefditoren, and mixtures thereof.

In one embodiment of the present invention, the release-controlling polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxy Methyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, lucostein gum, guar gum, xanthan gum, acacia gum, Tragacanth gum, alginic acid, sodium alginate, calcium alginate, ammonium alginate , Agar, gelatin, poloxamer, polymethylacrylate, carbomer, polycarbophil, polyvinylacetate, polyethylene glycol, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol Copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, bentonite , Hectorite, carrageenan, ceratonia, cetostearyl alcohol, chitosan, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly (methyl vinyl ether / male Propylene glycol alginate, saponate, and mixtures thereof.

In one embodiment of the present invention, the swelling polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose Cellulose derivatives such as sodium cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, lucostein gum, guar gum, xanthan gum, acacia gum, Tragacanth gum, alginic acid, sodium alginate, calcium alginate, Polyvinyl pyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl alcohol-polyvinyl alcohol copolymer, polyvinyl alcohol-polyvinyl alcohol copolymer, Polyvinyl pyrrolidone-polyvinyl acetate copolymer, bentonite, Carrageenan, ceratonia, cetostearyl alcohol, chitosan, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly (methyl vinyl ether / maleic anhydride) Hydrosol), propylene glycol alginate, saponate, and mixtures thereof.

In one embodiment of the invention, the gas generating material is selected from the group consisting of sodium bicarbonate, potassium bicarbonate and mixtures thereof.

In one embodiment of the present invention, the release-controlling polymer, the swelling polymer, or both have a viscosity of 5 to 150,000 cps.

In one embodiment of the present invention, the release-controlling polymer has a viscosity of 5 cps or more and 100,000 cps or less, and the swelling polymer has a viscosity of 10,000 cps or more and 150,000 cps or less.

In one embodiment of the present invention, the active ingredient is contained in an amount of 1 to 70% by weight, based on the total weight of the sustained release sustained release preparation, and the release controlled polymer has a total weight of the sustained release sustained release preparation , The swelling polymer is contained in an amount of 10 to 70% by weight, based on the total weight of the sustained release sustained release preparation, and the gas generating substance is contained in an amount of 1 to 50% Based on the total weight of the stabilizer, 1 to 40% by weight.

In one embodiment of the present invention, the upper layer, the lower layer or both of them are selected from the group consisting of a binder, a lubricant, a disintegrant, a colorant, a preservative, a flavor, a stabilizer, a buffer, an antibacterial agent, a bulking agent, ≪ / RTI > and an excipient selected from the group consisting of.

In one embodiment of the present invention, the uptake sustained release preparation is a tablet, and the upper layer is composed of a granule containing the active ingredient and a first matrix comprising the release-controlling polymer, And the lower layer is composed of the swellable polymer and the second matrix containing the gas generating material, and the lower layer is integrally bonded to the upper layer.

In one embodiment of the invention, the gastric retentive agent is for the treatment of gastrointestinal disorders.

In one embodiment of the present invention, the sustained-release sustained-release preparation is an oral tablet.

In one embodiment of the present invention, the above-mentioned sustained-release sustained release preparation has a floating holding time of 10 hours or more measured under the conditions of 50 rpm and 37 캜 according to the dissolution second method paddle method in pH 4.0 buffer solution.

In one embodiment of the present invention, the above-mentioned sustained-release sustained-release preparation has a degree of swelling of 150% or more after 9 hours measured at 50 rpm and 37 캜 according to the dissolution second method paddle method in a pH 4.0 buffer solution.

In one embodiment of the present invention, the above-mentioned sustained-release sustained-release preparation is prepared by performing the elution second method paddle method at pH 4.0 buffer under the conditions of 50 rpm and 37 ° C, and after 8 hours, the texture measured according to ASTM E4 0.30 to 2.00 N / cm < ^{2 &} gt ;.

The sustained-release sustained-release preparation having a double layer according to the present invention is easy to control the elution of the drug, is excellent in swelling and floating property, and can be administered once a day, thereby improving the compliance with the medication.

1 is a graph showing dissolution rates of amoxicillin in Examples 1 and 6-9 over time.
FIG. 2 is a graph showing dissolution rates of claritromycin in Examples 1 and 6-9 over time. FIG.
FIG. 3 is a view showing the form of a sustained-release sustained-release preparation having a bilayer structure according to the present invention.

The sustained release sustained release preparation according to the present invention comprises an upper layer comprising an active ingredient and a release-controlling polymer; And a lower layer comprising a swelling polymer and a gas generating material. FIG. 3 is a view showing the form of a sustained-release sustained-release preparation having a bilayer structure according to the present invention. 3, it can be seen that the upper layer comprising the drug is composed of the upper layer and the upper layer having swelling and floating properties is composed of the lower layer.

Examples of the above active ingredients include antihypertensive agents, diabetic agents, hyperlipidemia agents, cardiovascular system drugs, expectorants, antibiotics, sedatives, steroid compounds, asthma treatment agents, nonsteroidal antiinflammatory agents, antidepressant agents for prostatitis, antidepressants, antihistamines, , Salts thereof, mixtures thereof, and the like.

Specifically, examples of the active ingredient include metformin, glimepiride, amoxicillin hydrate, clarithromycin, carvedilol, bentofuril, vancomycin, azithromycin, cefdinir, cefditoren, olopatadine, ciprofloxacin, cimetidine, But are not limited to, morotidine, lansoprazole, omeprazole, s omeprazole, ranitidine, metodidazole, bismuth derivatives, bisphosphonates, gabapentin, pregabalin, loxoprofen, , Levodopa, methyldopa, entacapone, entacavir, rosiglitazone, aspirin, and the pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and / And salts. These may be used alone or as a mixture of two or more.

In one embodiment of the invention, the active ingredient is selected from the group consisting of metformin, amoxicillin hydrate, clarithromycin, amoxicillin hydrate-clarithromycin combination, pregabalin, bisphosphonate, loxoprofen, , Cefditoren, and mixtures thereof.

In one embodiment of the invention, the active ingredient may comprise amoxicillin trihydrate and clarithromycin.

The active ingredient may be included in a therapeutically effective amount, for example, from 1 to 70% by weight, based on the total weight of the sustained release sustained release preparation.

In the present invention, the release-controlling polymer serves to control the release rate of the active ingredient. Examples of the release-controlling polymer include hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose Xanthan gum, acacia gum, tragacanth gum, alginic acid, sodium alginate, calcium alginate, ammonium alginate, agar, alginic acid, Gelatin, poloxamer, polymethymethylacrylate, carbomer, polycarbophil, polyvinyl acetate, polyethylene glycol, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpoly Lauridone-polyvinyl acetate copolymer, bentonite, hectorite, Carrageenan, Ceratonia, Cetostearyl alcohol, Chitosan, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly (methyl vinyl ether / maleic anhydride) , Propylene glycol alginate, and saponate. These may be used alone or as a mixture of two or more. In one embodiment of the present invention, the release-controlling polymer may include hypromellose. Examples of the hypromellose include Metolose (Shin-etsu), Metocel (Dow chemical) and the like.

In one embodiment of the present invention, the release-controlling polymer has a viscosity of 5 to 150,000 cps, preferably 5 cps to 100,000 cps.

In one embodiment of the present invention, the release-controlling polymer may be contained in an amount of 1 to 50% by weight, based on the total weight of the sustained-release sustained-release preparation.

In the present invention, the swelling polymer swells upon contact with water to form a gel layer, thereby causing stagnation. Examples of the swelling polymer include hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, But are not limited to, ethyl cellulose, polyethylene oxide, lucostein gum, guar gum, Xanthan gum, acacia gum, Tragacanth gum, alginic acid, sodium alginate, calcium alginate, ammonium alginate, , Poloxamer, polymethylacrylate, carbomer, polycarbophil, polyvinylpyrrolidone, polyvinyl acetate, polyethylene glycol, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer Polyvinyl pyrrolidone-polyvinyl acetate copolymer, bentonite, But are not limited to, hectorite, carrageenan, ceratonia, cetostearyl alcohol, chitosan, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly (methyl vinyl ether / Hydrosol), propylene glycol alginate, and saponate. These may be used alone or as a mixture of two or more. In one embodiment of the present invention, the swelling polymer may include hypromellose. In another embodiment of the present invention, the swellable polymer may comprise hypromellose and polycarbophil. The polycarbophil is a polymer in which acrylic acid is crosslinked with divinyl glycol, and examples of the polycarbophil include NOVEON AA-1 (trade name in the United States) of Lubrizol Corporation OH. One gram of polycarbophil absorbs about 62 grams of water. Polycarbophil is stable in the steady state and does not undergo hydrolysis or oxidation. In one embodiment of the present invention, the polycarbophil has a weight average molecular weight of 700,000 to 4,000,000,000 g / mol.

In one embodiment of the present invention, the swelling polymer has a viscosity of 5 to 150,000 cps, preferably 10,000 cps to 150,000 cps or less.

In one embodiment of the present invention, the swelling polymer may be contained in an amount of 10 to 70% by weight, based on the total weight of the sustained release sustained release preparation. In another embodiment of the present invention, the swelling polymer contains 10 to 50% by weight, preferably 15 to 50% by weight, more preferably 20 to 50% by weight, based on the total weight of the sustained release sustained- 40% by weight. In another embodiment of the present invention, the swellable polymer may comprise 15 to 50% by weight of the hydromellose and 1 to 20% by weight of the polycarbophil, based on the total weight of the sustained release sustained release preparation . In another embodiment of the present invention, the weight ratio of the hydro-melose to the polycarbophil in the swelling polymer is from 5: 1 to 1.1: 1.

Examples of the gas generating material include sodium bicarbonate, sodium glycine carbonate, calcium carbonate, sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium bicarbonate, Or a mixture of two or more. In one embodiment of the invention, the gas generating material is sodium bicarbonate, potassium hydrogencarbonate or mixtures thereof.

In one embodiment of the present invention, the gas generating material is contained in an amount of 1 to 40% by weight, based on the total weight of the sustained release sustained release preparation.

In one embodiment of the present invention, the upper layer, the lower layer or both of them are selected from the group consisting of a binder, a lubricant, a disintegrant, a colorant, a preservative, a flavor, a stabilizer, a buffer, an antibacterial agent, a bulking agent, ≪ / RTI > and an excipient selected from the group consisting of.

Examples of the binder include water, an organic solvent, polyvinylpyrrolidone (povidone), microcrystalline cellulose, dextrin, hydroxy-cellulose, polyvinyl alcohol, pregelatinized starch, and gum arabic.

Examples of the lubricant include magnesium stearate, talc, stearic acid, and anhydrous hard silicic acid (SiO ₂ ).

Examples of the disintegrant include sodium starch glycolate, crospovidone, cross-linked sodium carboxymethyl cellulose, starch, and carboxymethylcellulose calcium.

Examples of the colorant include titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lake and the like.

Examples of the preservative include benzoic acid, methylparaben, ethylparaben, propylparaben, and the like.

Examples of such stabilizers include, but are not limited to, magnesium stearate, magnesium stearate, calcium carbonate, calcium monohydrogenphosphate, potassium monohydrogenphosphate dihydrate, calcium phosphate tribasic acid, monoethanolamine, potassium citrate, sodium borate, sodium citrate dihydrate, Magnesium chloride, calcium monohydrogen phosphate, potassium monohydrogen phosphate dihydrate, calcium phosphate tribasic acid or monoethanolamine.

Examples of the antioxidant include α-tocopherol, Ascorbic acid, vitamin C palmitate, butylhydroxyanisole, dibutylhydroxytoluene, citric acid, erythorbic acid, fumaric acid, , Malic acid, maltodextrin, potassium metabisulfide, sodium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium sulphate, tymol, cyclodextrin Or sulfobutyl ether? -Cyclodextrin.

In one embodiment of the present invention, the sustained-release sustained release preparation is a tablet. In addition, the upper layer may be composed of granules containing the active ingredient and a first matrix comprising the release-controlling polymer. The granules may be dispersed within the first matrix. The lower layer may be composed of the swellable polymer and a second matrix including the gas generating material. The lower layer may be integrally bonded to the upper layer.

In one embodiment of the invention, the gastric retentive agent is for the treatment of gastrointestinal disorders.

In one embodiment of the present invention, the sustained-release sustained-release preparation is an oral tablet.

In one embodiment of the present invention, the above-mentioned sustained-release sustained-release preparation has a suspension holding time of at least 10 hours measured under the conditions of 50 rpm and 37 캜 according to the dissolution second method paddle method in a pH 4.0 buffer solution, 10 to 40 hours.

In one embodiment of the present invention, the above-mentioned sustained-release sustained-release preparation has a degree of swelling of not less than 150% after 9 hours measured under the conditions of 50 rpm and 37 캜 according to the dissolution second method paddle method in a pH 4.0 buffer solution, For example, it is 150 to 1,000%.

In one embodiment of the present invention, the above-mentioned sustained-release sustained-release preparation is prepared by performing the elution second method paddle method at pH 4.0 buffer under the conditions of 50 rpm and 37 ° C, and after 8 hours, the texture measured according to ASTM E4 0.30 to 2.00 N / cm < ^{2 &} gt ;.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this is for the purpose of illustrating the present invention, and the present invention is not limited by these examples.

Example  One

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. After that, the tablets were compressed with a rectangular tablet of 1082.68 mg using a Riva tablet machine. Table 1 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 0   Hypromellose (4000 cps) 50   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 100   Magnesium stearate 5   all 1082.68

Example  2

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, polycarbophil and meglumine, sieving with a No. 20 sieve, and mixing 5 mg of magnesium stearate. After that, using a Riva tablet machine, the tablets were compressed into rectangular tablets of 1152.68 mg. Table 2 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 0   Hypromellose (4000 cps) 50   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 170   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 100   Meglumine 20   Magnesium stearate 5   all 1152.68

Example  3

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, and hypromellose, blending with a No. 20 sieve, and then mixing 5 mg of magnesium stearate. After that, the tablets were tableted with 982.68 mg rectangular tablet using a Riva tablet machine. Table 3 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 0   Hypromellose (4000 cps) 50   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Magnesium stearate 5   all 982.68

Example  4

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. Thereafter, the tablet was tableted with a rectangular tablet of 1282.68 mg using a Riva tablet machine. Table 4 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 0   Hypromellose (4000 cps) 50   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 300   Magnesium stearate 5   all 1282.68

Example  5

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. After that, it was tableted with 932.68mg rectangular tablet using Riva tablet machine. The contents of the components in the obtained tablets are shown in Table 5.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 0   Hypromellose (4000 cps) 50   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 100   Polycarbophil 100   Magnesium stearate 5   all 932.68

Example  6

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. After that, the tablets were compressed with a rectangular tablet of 1082.68 mg using a Riva tablet machine. The content of each component in the obtained tablets is shown in Table 6.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 12.5   Hypromellose (4000 cps) 37.5   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 100   Magnesium stearate 5   all 1082.68

Example  7

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. After that, the tablets were compressed with a rectangular tablet of 1082.68 mg using a Riva tablet machine. Table 7 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 25   Hypromellose (4000 cps) 25   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 100   Magnesium stearate 5   all 1082.68

Example  8

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. After that, the tablets were compressed with a rectangular tablet of 1082.68 mg using a Riva tablet machine. Table 8 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 37.5   Hypromellose (4000 cps) 12.5   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 100   Magnesium stearate 5   all 1082.68

Example  9

For the preparation of the tablets, granules were prepared using 286.98 mg of amoxicillin trihydrate and 125 mg of clarithromycin in 10.7 mg of povidone and water, and the mixture was sieved through a No. 20 sieve. Then, the above granules, hypromellose and starch glycolic acid sodium were mixed and sieved with a No. 20 sieve. This mixture was mixed with 5 mg of magnesium stearate to form an upper layer. The lower layer was prepared by mixing sodium hydrogencarbonate, sodium starch glycolate, hypromellose, and polycarbophil in a 20-mesh sieve, followed by mixing 5 mg of magnesium stearate. After that, the tablets were compressed with a rectangular tablet of 1082.68 mg using a Riva tablet machine. Table 9 shows the content of each component in the obtained tablets.

Configuration ingredient Content (mg) Upper layer In the granule   Amoxicillin Trihydrate 286.98   Claritromycin 125   Povidone 10.7   Distilled water Enough Out of granule   Hypromellose (15 cps) 50   Hypromellose (4000 cps) 0   Starch glycolate sodium 30   Magnesium stearate 5 substratum   Sodium hydrogencarbonate 120   Starch glycolate sodium 100   Hypromellose (100000 cps) 250   Polycarbophil 100   Magnesium stearate 5   all 1082.68

Test Example  One

The degree of suspension, swelling, and texture for Examples 1-5 were evaluated according to the following test methods.

(1) Measurement of the degree of floating (buyancy test)

elution in pH 4.0 buffer Second method The paddle method (50 rpm, 37 캜) was performed. The samples were periodically observed from the complete layer solution, and the time taken to float, the retention time, and the final shape after 24 hours are shown in Table 10 below.

(2) Swelling test

elution in pH 4.0 buffer Second method The paddle method (50 rpm, 37 캜) was performed. Samples were periodically observed from the complete layer solution, and the final form after 9 hours is shown in Table 11 below.

(3) Texture analyzing

elution in pH 4.0 buffer Second method The paddle method (50 rpm, 37 캜) was performed. Samples were measured after 8 hours with a TA1 Texture Analyzer (TA plus, Lloyd Instruments LTD., UK, ASTM E4) and the results are shown in Table 12 below.

Suspension measurement (Examples 1-5) Example 1 Example 2 Example 3 Example 4 Example 5 Initial float time (minutes) Immediate floating Immediate floating 8.50 ± 1.00 Immediate floating Immediate floating Float hold time (hours) 24 hours 24 hours 24 hours 20.57 ± 0.87 22.19 ± 1.59 Floating aspect Shape Shape Shape Layer separation Loss of form

Swelling degree measurement (Example 1-5) Swelling degree L (mm) S (mm) H (mm) V (mm ³ ) Remarks Example 1 Before swelling 19.08 9.06 8.05 1391.56 567.15% After swelling 30.96 17.45 14.60 7363.54 Example 2 Before swelling 19.08 9.06 8.35 1443.21 510.15% After swelling 31.10 16.72 14.11 7363.54 Example 3 Before swelling 19.08 9.06 6.96 1209.65 305.49% After swelling 23.88 11.98 12.92 3695.40 Example 4 Before swelling 19.08 9.06 10.30 1790.15 661.03% After swelling 38.17 18.00 17.19 11833.44 Example 5 Before swelling 19.08 9.06 6.92 1202.70 814.64% After swelling 36.89 20.49 12.94 9797.80

Tablet Texture Test (Examples 1-5) Example 1 Example 2 Example 3 Example 4 Example 5 Texture (N / cm ² ) 0.84 0.09 0.41 + 0.02 1.84 + - 0.38 1.02 + 0.21 0.72 ± 0.00

Based on the above results, the comparative dissolution test of Test Example 2 and the uptake test of tablets of beagle dog of Test Example 3 were carried out.

Test Example  2

The preparations of Example 1 and Example 6-9 were run in a pH 4.0 buffer elution second method paddle method (50 rpm, 37 ° C). The results are shown in Figs. 1 and 2. Fig. As shown in FIGS. 1 and 2, the elution of tablets can be effectively controlled by controlling the weight ratio of the hypromellose having a different viscosity in the upper layer.

Test Example  3

The retention test of the tablets in beagle dogs was performed. The uptake of the test preparations of Example 1 and Example 2 against 8 beagle dogs was photographed using X-ray. The stomachs were observed after fasting and dietary status and were taken at 1 hour intervals after administration. BaSO ₄ was used as a contrast agent and 100 mg per tablet was added to the tablet. The fasting did not provide any food from the night before the administration, and the diets were fed one canned food 30 minutes before the tablet administration. The results are shown in Table 13 below.

Invisibility upper stay time Dietary resting time Example 1 6.67 ± 2.31 hr 6.00 ± 2.65 hr Example 2 1.33 ± 1.53 hr 6.00 0.00 hr

Claims (17)

An upper layer comprising the active ingredient and a release controlling polymer; And
An underlayer comprising a swellable polymer and a gas generating material;
Gastric retention sustained-release preparation consisting of.
According to claim 1, wherein the active ingredient is a hypertension, diabetes, hyperlipidemia, cardiovascular, expectorant, antibiotic, sedative, steroid compound, asthma, nonsteroidal anti-inflammatory, prostatic hypertrophy, antidepressant, antihistamine, And a drug selected from the group consisting of a combination thereof.
The method according to claim 2, wherein the active ingredient is metformin, glymepiride, amoxicillin hydrate, clarithromycin, carvedilol, meptopril, vancomycin, azithromycin, ceftinir, cephditorene, olopatadine, ciprofloxacin, cimetidine, Pamotidine, lansoprazole, omeprazole, esomeprazole, ranitidine, metrodidazole, bismuth derivatives, bisphosphonates, gabapentin, pregabalin, loxoprofen, zaltoprofen, naproxen, ketoprofen, alfzosin, doxazosin, acyclo Beer, gancyclovir, lamivudine, zidovudine, adefovirdipixil, carbazepine, oxycarbazepine, topiramate, levodopa, carbidopa, methyldopa, entacapone, entacaper, rosiglitazone, aspirin, pharmaceutically acceptable Gas-retentive sustained-release agent, characterized in that selected from the group consisting of salts and mixtures thereof. .
The method according to claim 3, wherein the active ingredient is metformin, amoxicillin hydrate, clarithromycin, amoxicillin hydrate- clarithromycin complex, pregabalin, bisphosphonate, roxofene, zaltoprofen, alfzosin, ceftinir, cefe Gastric sustained-release sustained-release preparation, characterized in that it is selected from the group consisting of diethylene and mixtures thereof.
The method of claim 1, wherein the release controlling polymer is hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose Sodium, Methylcellulose, Ethylcellulose, Polyethylene oxide, Lucostin gum, Guar gum, Xanthan gum, Acacia gum, Tragacanth gum, Alginic acid, Sodium alginate, Calcium alginate, Ammonium alginate, Agar (Agar), gelatin, poloxamer, polymethmethylacrylate, carbomer, polycarbophil, polyvinylacetate, polyethyleneglycol, polyvinylpyrrolidone-polyvinylacrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer , Polyvinylpyrrolidone-polyvinylacetate copolymer, bentonite, hectory , Carrageenan, ceratonia, cetostearyl alcohol, chitosan, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly (methylvinylether / maleic anhydride) Ross), propylene glycol alginate, saponate and mixtures thereof.
The swellable polymer according to claim 1, wherein the swellable polymer is hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium , Methyl cellulose, ethyl cellulose, polyethylene oxide, lucost bean gum, guar gum, xanthan gum, acacia gum, tragacanth gum, alginic acid, sodium alginate, calcium alginate, ammonium alginate, agar ( Agar), gelatin, poloxamer, polymethmethylacrylate, carbomer, polycarbophil, polyvinylpyrrolidone, polyvinylacetate, polyethyleneglycol, polyvinylpyrrolidone-polyvinylacrylate copolymer, polyvinyl alcohol Polyethyleneglycol Copolymer, Polyvinylpyrrolidone-Polyvinylacetate Copolymer, Bento Nitrate, hectorite, carrageenan, ceratonia, cetostearyl alcohol, chitosan, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly (methylvinylether / Maleic anhydrous), propylene glycol alginate, saponate, and mixtures thereof.
The gastroretentive sustained release preparation of claim 1, wherein the gas generating material is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
The gastroretentive sustained-release preparation according to claim 1, wherein the release controlling polymer, the swellable polymer, or both thereof has a viscosity of 5 to 150,000 cps.
The gastroretentive sustained-release preparation according to claim 1, wherein the release controlling polymer has a viscosity of 5 cps or more and 100,000 cps or less, and the viscosity of the swellable polymer is more than 10,000 cps and 150,000 cps or less.
The method according to claim 1, wherein the active ingredient is contained in 1 to 70% by weight, based on the total weight of the gastroretentive sustained release formulation, the release control polymer, based on the total weight of the gastroretentive sustained release preparation By, 1 to 50% by weight, the swellable polymer, 10 to 70% by weight based on the total weight of the gastroretentive sustained-release preparation, the gas generating material, the gastroretentive sustained-release preparation Gastric sustained-release sustained-release preparations, characterized in that it comprises 1 to 40% by weight based on the total weight of.
The method of claim 1, wherein the upper layer, the lower layer, or both, consists of a binder, a lubricant, a disintegrant, a colorant, a preservative, a flavoring agent, a stabilizer, a buffer, an antimicrobial agent, a bulking agent, an antioxidant, a diluent, and mixtures thereof. Gastric sustained-release sustained-release preparation, characterized in that it further comprises an excipient selected from the group.
The method of claim 1, wherein the gastroretentive sustained release formulation is a tablet, and wherein the upper layer is composed of a granule comprising the active ingredient and a first matrix comprising the release controlling polymer, wherein the granule is contained in the first matrix. Dispersed, wherein the lower layer is composed of a second matrix comprising the swellable polymer and the gas generating material, the lower layer is an integrally held slow release formulation, characterized in that the lower layer is integrally bonded.
2. A gastroretentive sustained release formulation according to claim 1, for the treatment of diseases of the gastrointestinal tract.
The gastroretentive sustained-release preparation according to claim 1, wherein the gastroretentive sustained release preparation is an oral tablet.
The gastroretentive sustained-release preparation according to claim 1, wherein the suspension retention time measured under a condition of 50 rpm and 37 ° C. in accordance with the elution method 2 paddle method in a pH 4.0 buffer is 10 hours or more.
The gastroretentive sustained-release preparation according to claim 1, wherein the swelling degree is 9 or more after 9 hours measured under the conditions of 50 rpm and 37 ° C. in accordance with the elution method 2 paddle method in a pH 4.0 buffer.
The method according to claim 1, wherein the second eluting paddle method in a pH 4.0 buffer is performed under conditions of 50 rpm and 37 ° C., and the texture measured according to ASTM E4 after 8 hours is 0.30 to 2.00 N / cm ² . Gastric retention sustained-release preparation which consists of.

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