WO2012169677A1 - Composition for controlling gastric retention and release - Google Patents

Abstract

The present invention relates to a composition for controlling gastric retention and release of a drug, and specifically, provides a composition, which is orally administered, comprising (a) the drug, (b) a swelling polymer, and (c) a gas generation substance, for controlling the gastric retention and release of the drug, which improves absorption rate and treatment rate of the drug by means of a whole body absorption effect and a local direct effect, improves drug usage and dose thereby enhancing the convenience of a patient taking the drug and adaptability, and effectively increases safety and bioavailability of the drug by securing its prescription for acid stabilization.

Description

[Correction 16.06.2011 by Rule 26] Composition for Controlling Retention and Release

The present invention relates to a composition for controlling gastric retention and release of a drug.

Conventional gastroretentive formulations can be divided into four technologies: swelling system, floating system, bioadhesive system, or mechanically expanding expansion system. Can be. Most of the technologies apply the expansion, suspension, or bioadhesive system alone, and the expansion system is the most applied. However, in the case of the expansion system, if the dosage form does not expand larger than the pylorus in a short time, If it can pass through and does not maintain the size and expansion strength of tablets continuously, it has the disadvantage of passing through the gastric portal vein.In case of the floating system, the collapse of the formulation can be rapid due to the inflow of large amount of water, If lacking, there is a disadvantage that may not be suspended. In addition, the bioadhesive system has a shortcoming that the gastric vein passes rapidly due to periodic gastric mucosal replacement cycles and vigorous gastrointestinal movements, and the gastric retention time is irregular, and the expansion system may have difficulty in injecting drugs. Forms can strain the stomach wall.

The Controlled Release Drug Delivery System allows the drug to be released continuously while the formulation passes through the gastrointestinal tract, resulting in a sustained effect. However, some drugs have a narrow absorption window after the drug is administered into the body. When confined to the top, it may be difficult to achieve sustained drug expression even if the dosage time and rate of drug release can be controlled. Therefore, it is possible to increase the time to stay in the small intestine of the drug as well as the release rate of the drug to increase the likelihood of drug absorption and the drug delivery system for this is a gastroretentive drug delivery system.

Drugs applied to conventional gastroretentive formulations are limited in their absorption to a part of the gastrointestinal tract, mainly due to physicochemical and biochemical properties. Among these, when the solubility of drugs according to physicochemical properties varies greatly depending on the pH, the pH of each part of the gastrointestinal tract ranges from 1 to 8 (gastric pH 1.2-3.5, small intestine 6.3-8.0, large intestine 7.9-8.0). As a result, the pH difference may limit drug uptake in certain parts, and some biochemical properties may limit the uptake by the presence of specific enzymes. P450, hereinafter referred to as CYP3A), are present in large amounts in the stomach and small intestine epidermis, but the number and activity decreases with descending to the large intestine.

Irregular distribution of CYP3A is a drug that can be a substrate of CYP3A. Angiotensin Converting Enzyme inhibitors (hereinafter referred to as ACE inhibitors) and Angiotensin Receptor Blockers (ARB) The absorption may be somewhat changed depending on the location of the gastrointestinal tract, and the lower the absorption of the drug as descending, it may increase the homogeneous drug absorption and bioavailability when applied as a gastroretentive formulation.

In addition, in the case of a fat-soluble or highly water-soluble drug, the amount absorbed by the concentration gradient according to the gastrointestinal tract position of P-glycoprotein (hereinafter referred to as PGP), which acts as an efflux in epithelial cells, It can make a difference.

In the case of having a narrow absorption window, the absorption site is limited by the difference in pH environment, the difference in the concentration of enzyme, the difference in the drug release mechanism, and in this case, the absorption of the drug is mainly limited to the upper part of the small intestine. When orally administered, a phenomenon in which the bioavailability of the drug is significantly lowered appears. In other words, when a drug having a narrow absorption window is applied to an immediate release, the drug is absorbed by the drug released from the upper part of the small intestine, and the drug released after passing through the upper part of the small intestine is not absorbed. In the case of sustained release, if the sustained release of the drug occurs after passing through the upper part of the small intestine, then the released drug is not absorbed.

In addition, certain diseases, such as gastrointestinal disorders, may require a direct response to bacteria or inflammation, such as Helicobacter pylori (HP), in response to the stomach or small intestine locally.

As described above, absorption aims to provide high bioavailability and better drug efficacy and safe drugs by applying drugs in the gastroretentive formulation that are localized or require local action in the upper gastrointestinal tract.

Therefore, pharmaceutical formulation researchers can increase gastric retention time by expanding the tablets by using expandable polymers that are larger than the diameter of the pylorus, which is 1.2 ± 0.7 cm, or by using gas-generating materials. In the case of contact with the gas generated in the formulation, the density of the formulation is reduced and suspended in the gastric fluid, and the like, but the increase in tablet size of the gastric retention formulation or the combination of buoyancy results in the loss of gas and the erosion of the tablet over time. Due to the vigorous movement of the gastrointestinal tract, the tablets are reduced to the size of the pyloric membrane and the dilatation intensity is difficult to maintain, so the gastric residence time of the drug is limited to only 6 hours. More research is needed to achieve the retention effect.

In addition to the increase in the absorption rate of the drug by the gastroretentive method as well as specific diseases that require local action, that is, gastrointestinal diseases caused by HP also requires the application of gastroretentive formulation.

The HP bacteria have long-term parasites in the human gastric mucosa and cause various diseases such as gastroduodenal ulcers, gastric adenocarcinoma and malt gastric lymphoma.

Koreans are infected with HP bacteria from a young age, and most adults are carriers. The infection rate of HP in Korea increased rapidly from 20 years old to 79.4% in the 40s age group, and then decreased. The infection rate of HP is positive in 60-80% of gastric ulcer and 60-95% of duodenal ulcer. In particular, it is reported that 70-92% of patients with chronic active gastritis in Korea. The prevalence of gastric cancer, the destination of infection, is significantly higher than in OECD countries.

In addition, the infection rate does not decrease due to various eating habits such as stress and drinking glasses, and the re-infection and resistance of HP are gradually increased by the prescription of excessive antibiotics. Development of maximized dosage form is urgent.

According to the 2009 Guidelines for Diagnosis and Treatment of HP Infections in the Treatment of HP Eradication, the Proton pump inhibitor (the standard dose twice a day) plus two antibiotics (twice a day) A combination of 1 to 2 weeks is recommended, and when the medication is done properly, the treatment rate is high (80-90%). (Na Kim, et al., The Maastricht III Consensus Report, 2009) Including inhibitors and antibiotics, three to four types of medications should be taken 2-4 times a day, which complicates the medication and lowers the treatment rate (Graham DY et al., Effect of treatment of Helicobacter). pylori infection on the long-term recurrence of gastric or duodenal ulcer: a randomized, controlled study, Ann Intern Med, 116 , pp. 705-708, 1992).

Antibiotics used in the treatment of HP must act directly on the HP present in the epithelial cells of the stomach, so it is important that the antibiotic's internal and plasma concentrations are maintained for a long time above the minimum inhibitory concentration. In addition, conventional antibiotics have a characteristic of being absorbed mainly in the stomach (narrow absorption window), so that the absorption increases with longer stay in the stomach, thereby enhancing the systemic effect. Considering these characteristics of the drugs, the sterilization effect is maximized due to the dual effect (luminal + systemic effect) when applying the gastroretentive formulation of HP therapeutic antibiotics.

In addition, the same treatment effect is expected at a lower dose than the conventional dose by applying a technology that can stay for a long time in the presence of HP, so the conventional method of taking 4 tablets twice a day once or twice a day This can improve medication compliance.

Conventional antibiotics cause gastrointestinal disorders such as nausea, vomiting and heartburn due to high doses, and in fact 22% of patients have been reported to stop taking antibiotics (McNulty CAM et al., The public's attitudes to and compliance with antibiotics, J. Antimicrob Chemother, 60 Suppl. 1 , pp.i63-8, 2007) Antibiotics remaining after taking them are thrown away, causing environmental pollution and causing ecosystem disturbances and antibiotic resistance. , Ministry of Environment, 2007).

In order to solve the above problems, the inventors of the present invention while studying the composition for the control of high bioavailability, effective drug and safe gastric retention and release of the drug composition for oral administration for the gastric retention and release control of the present invention Is designed to stay in the stomach for 24 hours to improve drug absorption and treatment rate through systemic absorption and local direct action such as suppressing gas loss, tablet erosion and vigorous movement of gastrointestinal tract in the upper gastrointestinal tract. In addition to reducing the misuse of antibiotics by improving the convenience and compliance of the patient to improve the medication, it was confirmed that the effective stability of the drug and increase the bioavailability through the acid stabilization prescription, and completed the present invention.

Therefore, an object of the present invention is designed to stay in the stomach for 24 hours to improve the absorption and treatment rate of the drug through systemic absorption and local direct action, such as inhibiting gas loss and tablet erosion in the upper gastrointestinal tract, violent movement of the gastrointestinal tract, etc. (A) Drugs, (b) which effectively improve the stability and bioavailability of drugs by improving the dosage and improving the convenience and compliance of patients by reducing the abuse of antibiotics, and by securing acid stabilization prescription Swellable polymer and (c) a swelling and suspended gastric composition comprising a gas generating material.

In order to achieve the above object, the present invention provides a composition having swelling and suspended gastric retention characteristics comprising (a) a drug, (b) a swellable polymer and (c) a gas generating material.

In one embodiment of the present invention, the present invention provides a swelling and floating gastric composition comprising (a) a drug, (b) a swellable polymer and (c) a gas generating material.

As another embodiment of the present invention, the present invention provides (d) excipients, (e) control in addition to (a) drugs, (b) swellable polymers, (c) gas generating substances having the effect of preventing and treating gastrointestinal diseases Membrane, and (f) at least one selected from the group consisting of wetting agents.

As another embodiment of the invention, the invention comprises a group consisting of (a) a drug, (b) a swellable polymer, (c) a gas generating substance and (d) an excipient, (e) a control membrane, and (f) a wetting agent Sustained portion including one or more selected from; And (a) an immediate release comprising (a) a drug, (g) an immediate release film coating base and (d) a pharmaceutically acceptable excipient.

Compositions as defined herein include sustained release formulations, delayed release formulations, other pharmaceutical formulations, preferably sustained release formulations or immediate release formulations, including immediate release and / or sustained release compositions.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

(A) a drug that is as defined herein (pharmacologically active ingredient) is a therapeutic agent for diabetes, a therapeutic agent of hypertension, central nervous system (CNS) drug, an antibiotic, a proton pump inhibitor as a pH adjusting agent intragastric (Proton Pump Inhibitor) and H ₂ inhibitors (H ₂ Blocker), wherein Viral agents, prostatic hypertrophy agents, nonsteroidal anti-inflammatory agents, bisphosphonates, antithrombotic agents, or 5-HT4 receptors, and the like, preferably metformin, glymepiride or rosiglitazone as antidiabetic agents; Carvedilol or meptopril as an antihypertensive agent; Central nervous system drugs include gabapentin, pregabalin, carbazepine, oxycarbazepine, topiramate, levodopa, carbidopa, methyldopa or entacapone; Amoxicillin, clarithromycin, vancomycin, ceftinir, ciprofloxacin, ceftodirene, azithromycin or metrodidazole as antibiotics; Lansoprazole, omeprazole, eomeprazole, pantoprazole or ilaprazole as proton pump inhibitors; Cimetidine, pamotidine, ranitidine or bismuth derivatives as H ₂ inhibitors; Antiviral agents such as acyclovir, gancyclovir, lamivudine, zidovudine, adefovirdiboxil or entacavir; Alfzosin or doxazosin as an agent for treating prostatic hyperplasia; Nonsteroidal anti-inflammatory agents, such as loxoprofen, zaltoprofen, naproxen or ketoprofen; As bisphosphonates: alendronate, risedronate, palmidronate or ibandronate; Aspirin or ticlopidine as anti-thrombotic agents; A 5-HT4 receptor comprising at least one drug selected from the group comprising mosapride, cisapride or itopride and the like, more preferably metformin, glymepiride, amoxicillin, clerismycin, mosapride, risedronate, At least one drug selected from the group comprising lansoprazole, omeprazole, eomeprazole, ranitidine, roxofprofen, zaltoprofen or alfzosin, even more preferably metformin, glymepyride, amoxicillin, clerisromycin, It comprises at least one drug selected from the group comprising ranitidine, mosapride or loxopropene, characterized in that the one or more drugs are administered once daily in an amount of 5 mm to 2 g.

(B) Swellable polymers as defined herein include hydroxypropyl methyl cellulose (HMC), hydroxyethyl methyl cellulose (Hydroxyethyl methyl cellulose), hydroxypropyl cellulose (Hydroxypropyl cellulose), hydroxymethyl cellulose (Hydroxymethyl cellulose) ), Hydroxyethyl cellulose, Carboxymethyl cellulose, Carboxymethyl cellulose sodium, Carboxymethyl cellulose natrium, Methyl cellulose, Ethyl cellulose Polyethylene oxide, Locost bean gum, Guar gum, Xanthan gum, Acacia gum, Tragacanth gum, Alginic acid ( Alginic acid, sodium alginate, sodium alginate, ammonium alginate ), Agar, Gelatin, Poloxamer, Polymethacrylate, Carbomer, Polyvinyl pyrrolidone, Polyvinyl alcohol , Polyvinyl acetate, polyethylene glycol, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer (polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, bentonite, hectorite, carrageenan, ceratonia, cetostearyl alcohol (Cetostearyl alcohol), Chitosan, Hydroxypropyl starch, Magnesium aluminum silicate, Polydextrose (Polydextrose), poly (methyl vinyl ether / maleic anhydride) (Poly (methyl vinyl ether / maleic anhydride)), propylene glycol alginate (Saponite), etc. It includes at least one, preferably at least one selected from the group comprising carbomer, hydroxypropylmethylcellulose, polyethylene oxide, and poloxamer, the swellable polymer is used alone, for example two When used in combination, the relative mixing ratio of about 1: 9 to 9: 1 (w / w), more preferably 2: 8 to 8: 2 (w / w).

(C) a gas generating substance as defined herein is sodium bicarbonate, sodium glycine carbonate, calcium carbonate, sodium sulfite, sodium bisulfite, sodium metabisulfite and calcium bicarbonate, It is preferably characterized in that it comprises one or more selected from the group containing sodium bicarbonate or calcium bicarbonate.

(D) excipients as defined herein are selected from the group comprising binders, lubricants, disintegrants, colorants, preservatives, flavors, stabilizers, buffers, antibacterial agents, bulking agents, antioxidants or diluents, and the like, preferably It is characterized in that it is selected from the group comprising binders, lubricants, disintegrants, buffers, antioxidants.

As defined herein, the control membrane (e) is used to maintain the strength of the tablet and to maintain continuous drug release, which prevents leakage of CO ₂ gas generated in the tablet and decreases when swollen, and specifically, polyvinyl acetate , Cellulose acetate, Ethyl cellulose, Cellulose acetate phthalate, Hydroxypropyl methyl cellulose acetate succinate, Hydroxypropyl methyl cellulose phthalate, Poly Ethyl acetate-methyl acetate copolymer, Eudragit RS  ) And Eudragit RL (mixture of Eudragit RL, polyvinyl phthalate acetate, shellac) and polyvinylpyrrolidone, a polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropylmethylcellulose, hydroxypropyl cellulose And a material containing at least one selected from the group consisting of polyvinyl alcohol, and the like, preferably polyvinylacetate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetsuccinate or polyvinyl alcohol-polyethylene glycol graft copolymer Membrane prepared by using a polymer containing one or more selected from the group to be used alone, for example, when combining two, the relative compounding ratio of about 1: 9 to 9: 1 (w / w), more preferably Is a control film prepared by using a relative mixing ratio of 2: 8 to 8: 2 (w / w).

As defined herein, (f) wetting agent is used to maintain the dissolution rate of zero emission by preventing the dissolution delay time (lag time) of the initial dissolution in advance, and specifically, potassium chloride, sodium chloride, xylitol, polyoxyethylene Sorbitan monolaurate (Polyoxyethylen sorbitan monolaurate) or polyethylene glycol, and the like, preferably containing one or more selected from the group comprising calcium chloride, polyoxyethylene sorbitan monolaurate It features.

As defined herein, the (g) immediate release film coating base includes hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxypropyl cellulose (Hydroxypropyl Cellulose), poly vinyl pyrrolidone, poly vinyl alcohol , Polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer (Poly vinyl alcohol-Polyethylene glycol block copolymer) and the like, preferably containing at least one member selected from hydroxypropyl methyl cellulose or hydroxypropyl cellulose group It is characterized by.

Stabilizers as defined herein are meglumine, magnesium oxide, calcium carbonate, sodium bicarbonate, calcium dihydrogen phosphate, potassium dihydrogen phosphate dihydrate, calcium phosphate tribasic, monoethanolamine, Potassium bicarbonate, potassium citrate, sodium borate, sodium citrate dihydrate or triethanolamine, and the like, preferably meglumine, magnesium oxide, calcium carbonate, sodium bicarbonate, phosphoric acid At least one stabilizer selected from calcium monohydrogen, potassium monohydrogen phosphate dihydrate, calcium phosphate tribasic or monoethanolamine.

Antioxidants as defined herein include α-tocopherol, vitamin C (Ascorbic aicd), vitamin C palmitate, butylhydroxyanisole, dibutylhydroxytoluene, citric acid, erythorbic acid, Fumaric Acid, Malic Acid, Maltodextrin, Potassium Metabisulfide, Sodium Metavia Sulfate, Propionic Acid, Propyl Gallate, Sodium Ascorbate, Sodium Sulfate, Tymol, Cyclo At least one antioxidant selected from dextrin or sulfobutylether β-cyclodextrin.

The forms of the formulations defined herein are characterized as powders, granules, tablets, capsules, solutions, membranes, uncoated tablets, mucoadhesives, and fast disintegrating agents.

The immediate release of the composition as defined herein is characterized in that disintegration is completed within about 15 minutes, preferably within about 10 minutes, and the sustained release is continuously released for about 6 to 48 hours, preferably about 8 to 24 hours. .

In addition, the compositions as defined herein swell within about 8 hours, preferably within about 4 hours, swell within about 30 minutes, preferably within about 15 minutes when in contact with the eluent or gastric juice, and from about 2 hours to 48 Long-term (L), short-circuit (W), which is the size of the formulation within a period of time, preferably about 8 to 24 hours, and within about 12 hours, preferably about 8 hours after administration of the composition of the present invention, Or the maximum width of the height (H) is in the range of about 10 to 50mm, preferably characterized in that the size in the range of about 15 to 35mm.

Preferred dosages of the compositions of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art.

Binders usable herein include, as conventional binders, preferably water, organic solvents, polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, dextrin, gelatin, methylcellulose, hydroxycellulose, hydroxy May further comprise one or more components selected from oxymethylcellulose, polyvinyl alcohol, pre-gelatinized starch or gum arabic,

Disintegrants usable herein include, as conventional disintegrants, sodium starch glycolate, crospovidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose. Hydroxypropylcellulose), hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, carboxymethyl cellulose calcium and combinations thereof, and may include one or more thereof.

As the glidants usable herein, one or more mixtures of magnesium stearate, talc, stearic acid or light silicic anhydride (SiO ₂ ) may be used as a conventional glidant,

In addition, if necessary, a colorant may be included in the tablet, and may include one or more selected from titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lake, and the like.

Preservatives usable herein may include one or more selected from benzoic acid, methylparaben, ethylparaben or propylparaben, etc., and may further contain sweetening, flavoring, stabilizing, diluent.

The composition of the present invention can be used to prepare a variety of gastric oral compositions, for example tablets tableted by direct compression by mixing amoxicillin and clarithromycin as the main active ingredients and the pharmaceutically acceptable additives described above. Formulations, such as compression coated tablets, double tablets, triple tablets, can be prepared.

As described above, by providing a swelling and floating gastric retention composition comprising (a) a drug, (b) a swellable polymer, and (c) a gas generating substance of the present invention, the composition is capable of systemic absorption and local direct Actions to improve the absorption and treatment rate of the drug, improve the dosage and improve the convenience and compliance of the patient's medication, as well as compositions and formulations that can effectively increase the stability and bioavailability of the drug by securing acid stabilization prescription It can be usefully used.

1 is a diagram showing a manufacturing method for preparing gastric retention tablets in a simple flow chart,

FIG. 2 is a graph showing the dissolution test results of Tables 6 and 7 as tablets of Example 3-3, that is, tablets without a control film.

3 is a graph showing the dissolution test results of Table 10 as a control film tablet of Example 3-3, that is, a tablet coated with a control film (coated tablet),

4 is a view showing the (A) elution start suspension and (B) swelling and suspension after 24 hours of the tablet of Example 3-3, that is, the tablet without a control film,

FIG. 5 is a view showing the swelling and swelling after (A) elution start and (B) 24 hours in the control film tablets of Example 3-3, that is, tablets coated with a control film (coated tablets).

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the following Examples and Experimental Examples.

Example 1.Expansion and Suspension Capacity of Tablets Containing Single Swellable Polymers

1-1. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (1)

Polyox N750, which is a polyethylene oxide in the same ratio as shown in Table 1, in order to confirm the expansion rate and the floating capacity of a tablet containing a single swellable polymer except a drug to select a swellable polymer suitable for gastric retention formulation

Sodium bicarbonate, calcium chloride, light silicic anhydride and Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results, Polyox N750 as shown in Table 1 below

 The swellability was not able to confirm the expansion rate due to the collapse of the tablet after 16 hours, it was confirmed in the floating capacity within 20 minutes (see Table 1).

1-2. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (2)

Polyox 301, which is a polyethylene oxide of the same ratio as shown in Table 1, in order to confirm the expansion rate and the floating capacity of a tablet containing a single swellable polymer except a drug to select a swellable polymer suitable for gastric retention formulation

, Sodium bicarbonate, calcium chloride, light silicic anhydride and magnesium stearate were added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results, as shown in Table 1 below Polyox 301

                of The expansion rate was 144.9%, and it was found to be suspended within 20 minutes in the floating capacity, and to remain suspended for 16 hours (see Table 1).

1-3. Swelling and Susceptibility of Tablets Containing Single Swellable Polymers (3)

Single, except drug, to select swellable polymers suitable for gastric retention formulations In order to confirm the expansion rate and the floating capacity of the tablet containing the swellable polymer, Polyox 1105 which is a polyethylene oxide in the same ratio as shown in Table 1 below.

, Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results, Polyox 1105 as shown in Table 1 below

of The expansion rate was 134.5%, and it was confirmed that it floated within 20 minutes in floating capacity, and maintained floating for 16 hours (see Table 1).

1-4. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (4)

HPMC 4,000 cps, which is the hydroxypropylmethylcellulose in the same ratio as shown in Table 1, in order to confirm the expansion rate and the floating capacity of the tablet containing the single swellable polymer except the drug to select a swellable polymer suitable for gastric retention formulation. , Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

As a result, as shown in Table 1, the expansion rate of 4,000 cps of hydroxypropylmethylcellulose was 136.5%, and it was found to be suspended within 30 minutes in floating capacity and to remain suspended for 16 hours ( See Table 1).

1-5. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (5)

HPMC 15,000 cps hydroxypropylmethylcellulose in the same ratio as shown in Table 1 to determine the swelling ratio and the floating capacity of tablets containing a single swellable polymer except drug to select a swellable polymer suitable for gastric retention formulation , Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

As a result, as shown in Table 1, the expansion rate of 15,000 cps of hydroxypropyl methyl cellulose was 142.3%, and it was found to be suspended within 30 minutes in floating capacity and to remain suspended for 16 hours ( See Table 1).

1-6. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (6)

In order to confirm the swelling rate and the floating capacity of the tablet containing a single swellable polymer except the drug to select a swellable polymer suitable for gastric retention formulation, 100,000cps of hydroxypropylmethylcellulose in the same ratio as shown in Table 1, Sodium Bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

As a result, as shown in Table 1, the expansion rate of 100,000 cps, which is hydroxypropyl methyl cellulose, was 130.7%, and it was found to be suspended within 30 minutes in floating capacity and to remain suspended for 16 hours. (See Table 1).

1-7. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (7)

In order to determine the swelling polymer and the swelling capacity of tablets containing a single swellable polymer except the drug to select a swellable polymer suitable for gastric retention formulation, xanthim gum, sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

As a result of the experiment, as shown in Table 1, the expansion rate of xanthan gum was 166.7%, and it was confirmed that it was suspended within 20 minutes in floating capacity, and maintained floating for 16 hours (see Table 1). .

1-8. Swelling and Flotation Capacity of Tablets Containing Single Swellable Polymers (8)

Carbomer 71G in the same ratio as shown in Table 1 below to determine the swelling and floating capacity of tablets containing a single swellable polymer except drug to select a swellable polymer suitable for gastric retention formulations.

, Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results, Carbomer 71G as shown in Table 1 below

                of The swelling property was 179.1%, showing the best result. In the floating capacity, it was suspended within 10 minutes, and it was confirmed that the suspension was maintained for 16 hours (see Table 1).

Table 1

Name	Example
	1-1	1-2	1-3	1-4	1-5	1-6	1-7	1-8
Polyox N750	60.10	-	-	-	-	-	-	-
Polyox 301	-	60.10	-	-	-	-	-	-
Polyox 1105	-	-	60.10	-	-	-	-	-
HPMC 4,000	-	-	-	60.10	-	-	-	-
HPMC 15,000	-	-	-	-	60.10	-	-	-
HPMC 1,000,000	-	-	-	-	-	60.10	-	-
Xanthan gum	-	-	-	-	-	-	60.10	-
Carbomer 71G	-	-	-	-	-	-	-	60.10
Poloxamer 407	13.01	13.01	13.01	13.01	13.01	13.01	13.01	13.01
Sodium Bicarbonate	19.95	19.95	19.95	19.95	19.95	19.95	19.95	19.95
KCL	4.34	4.34	4.34	4.34	4.34	4.34	4.34	4.34
SiO2	1.30	1.30	1.30	1.30	1.30	1.30	1.30	1.30
Mg stearate	1.30	1.30	1.30	1.30	1.30	1.30	1.30	1.30
Swelling rate (%)	-	144.9	134.5	136.5	142.3	130.7	166.7	179.1
Floating ability	Within 20 minutes	Within 20 minutes	Within 20 minutes	Within 30 minutes	Within 30 minutes	Within 30 minutes	Within 20 minutes	Within 10 minutes

            

Example 2. Expansion rate and floating capacity of the composite swellable polymer

2-1. Swelling and Flotation Capacity of Tablets Containing Composite Swellable Polymers (1)

In order to determine the swelling polymer and the swelling capacity of the tablet containing the composite swellable polymer except the drug to select a swellable polymer suitable for gastric retention formulation, Polyox 301 of the same ratio as shown in Table 2 below

                 And Carbomer 71G

                 (3: 7), Poloxamer 407

,Sodium Bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result, as shown in Table 2, the expansion rate of Example 2-1 was 162.6%, and the floating capacity was suspended within 5 minutes, and it was confirmed that the suspension was maintained for 24 hours (Table 2 Reference).

2-2. Swelling and Floating Capacity of Tablets Containing Composite Swellable Polymers (2)

In order to confirm the expansion ratio and the floating capacity of the tablet containing the composite swellable polymer, Polyox 301 of the same ratio as shown in Table 2 below

                 And Carbomer 71G

                 (5: 5), Poloxamer 407

, Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result, as shown in Table 2, the expansion rate of Example 2-2 was 150.53%, and the suspension capacity was suspended within 5 minutes, and it was confirmed that the suspension was maintained for 24 hours (Table 2 Reference).

2-3. Swelling and Flotation Capacity of Tablets Containing Composite Swellable Polymers (3)

In order to confirm the expansion ratio and the floating capacity of the tablet containing the composite swellable polymer, Polyox 301 of the same ratio as shown in Table 2 below

                 And Carbomer 71G

                 (7: 3), Poloxamer 407

, Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result, as shown in Table 2 below, the expansion rate of Example 2-3 was 150.84%, and the floating capacity was suspended within 5 minutes, and it was confirmed that the suspension was maintained for 24 hours (Table 2 Reference).

2-4. Swelling and Flotation Capacity of Tablets Containing Composite Swellable Polymers (4)

In order to confirm the expansion rate and the floating capacity of the tablet containing the composite swellable polymer, hydroxypropylmethylcellulose 100,000cps and Carbomer 71G in the same ratio as shown in Table 2 below

                 (3: 7), Poloxamer 407

, Sodium bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result, as shown in Table 2 below, the expansion rate of Example 2-4 was 168.5%, and the floating capacity was suspended within 5 minutes, and it was confirmed that the suspension was maintained for 24 hours (Table 2 Reference).

2-5. Swelling and Flotation Capacity of Tablets Containing Composite Swellable Polymers (5)

In order to confirm the expansion rate and the floating capacity of the tablet containing the composite swellable polymer, hydroxypropylmethylcellulose 100,000cps and Carbomer 71G in the same ratio as shown in Table 2 below

                 (5: 5), Poloxamer 407

, Sodium Bicarbonate, KCL, SiO₂And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result, as shown in Table 2 below, the expansion rate of Example 2-5 was 160.3%, and the floating capacity was suspended within 5 minutes, and it was confirmed that the suspension was maintained for 24 hours (Table 2 Reference).

2-6. Swelling and Flotation Capacity of Tablets Containing Composite Swellable Polymers (6)

In order to confirm the expansion rate and the floating capacity of the tablet containing the composite swellable polymer, hydroxypropylmethylcellulose 100,000cps and Carbomer 71G in the same ratio as shown in Table 2 below

                 (7: 3), Poloxamer 407

, Sodium bicarbonate, KCL, SiO₂And The swelling rate and the floating capacity of the tablet containing the composite swellable polymer to which magnesium stearate was added were confirmed.

Experimental results, Polyox 301 as shown in Table 2 below

 Polyox 301 for both 100,000cps and hydroxypropylmethylcellulose

 (Hydroxypropylmethylcellulose 100,000cps): Carbomer 71G

 The best results were found at 7: 3. Polyox 301 in expansion

 Carbomer 71G

 7: 3 and hydroxypropylmethylcellulose 100,000cps: Carbomer 71G

 = 7: 3 showed results of 162.6% and 168.5%, and also showed expansion strength after 16 hours. The floating capacity was suspended within 5 to 10 minutes to maintain floating for 24 hours (see Table 2).

TABLE 2

Name	2-1	2-2	2-3	2-4	2-5	2-6
Polyox 301	42.07	30.05	18.03	-	-	-
HPMC 100,000 cps	-	-	-	42.07	30.05	18.03
Carbomer 71G	18.03	30.05	42.07	18.03	30.05	42.07
Poloxamer 407	13.01	13.01	13.01	13.01	13.01	13.01
Sodium Bicarbonate	19.95	19.95	19.95	19.95	19.95	19.95
KCL	4.34	4.34	4.34	4.34	4.34	4.34
SiO2	1.30	1.30	1.30	1.30	1.30	1.30
Mg stearate	1.30	1.30	1.30	1.30	1.30	1.30
Swelling rate (%)	162.6	150.53	150.84	168.5	160.3	158.2
Floating ability	Within 5 minutes	Within 5 minutes	Within 5 minutes	Within 5 minutes	Within 5 minutes	Within 5 minutes

            

Example 3. Preparation of Gastric Retention Tablet

3-1. Gastric Retention Formulation Preparation

Amoxicillin, clarithromycin, Poloxamer 407 in the same order and ratio as shown in process 1 and Table 3 below

, 100,000 cps of hydroxypropylmethylcellulose and Meglumine are mixed, and granules are prepared by adding a binder solution dissolved in 10-fold 50% ethanol. The dried granules were appled with a No. 18 sieve, and then placed in a drying oven at 40 ° C. for 12 to 16 hours, followed by Carbomer 71G.

, Sodium bicarbonate, KCL, SiO₂And Mix magnesium stearate. The mixed granules were pressurized under normal pressure to a tablet press (Korsch NR 100062/83) to obtain tablets (see Table 3).

3-2. Gastric Retention Formulation Preparation

Amoxicillin, clarithromycin, Poloxamer 407 in the same order and ratio as shown in process 1 and Table 3 below

4,000 cps of hydroxypropylmethylcellulose and Meglumine were mixed, and granules were prepared by adding a binder solution dissolved in 10-fold 50% ethanol. The dried granules were appled with a No. 18 sieve, and then placed in a drying oven at 40 ° C. for 12 to 16 hours, followed by Carbomer 71G.

, Sodium bicarbonate, KCl, SiO₂And Add magnesium stearate and mix. The mixed granules were pressurized under normal pressure to a tablet press (Korsch NR 100062/83) to obtain tablets (see Table 3).

3-3. Gastric Retention Formulation Preparation

Amoxicillin, clarithromycin, Poloxamer 407 in the same order and ratio as shown in process 1 and Table 3 below

                 And Meglumine is mixed, and granules are prepared by adding the binding solution dissolved in 10-fold 50% ethanol. The dried granules were appled with a No. 18 sieve, and then placed in a drying oven at 40 ° C. for 12 to 16 hours, followed by Carbomer 71G.

, Sodium bicarbonate, KCl, SiO₂And Add magnesium stearate and mix. The mixed granules were pressurized under normal pressure to a tablet press (Korsch NR 100062/83) to obtain tablets (see Table 3).

3-4. Gastric Retention Formulation Preparation

Amoxicillin, clarithromycin, Poloxamer 407 in the same order and ratio as shown in process 1 and Table 3 below

, 100,000 cps of hydroxypropylmethylcellulose and Meglumin are mixed, and a binder solution dissolved in 10 times 50% ethanol is added to prepare granules. The dried granules were appled with a No. 18 sieve, and then placed in a drying oven at 40 ° C. for 12 to 16 hours, followed by Polyox 301.

, Carbomer 71G

, Sodium bicarbonate, KCL, SiO₂And Add magnesium stearate and mix. The mixed granules were pressurized under normal pressure to a tablet press (Korsch NR 100062/83) to obtain tablets (see Table 3).

TABLE 3

Name	Example (%)
	3-1	3-2	3-3	3-4
Amoxicillin	30.57	30.57	30.57	30.57
Clarithromycin	13.16	13.16	13.16	13.16
Poloxamer 407	4.11	4.11	0.00	0.00
Meglumine	2.11	2.11	2.11	2.11
Tween 80	1.05	1.05	5.16	5.16
HPMC 100,000 cps SR	29.74	0.00	29.74	0.00
HPMC 4,000 SR	0.00	29.74	0.00	0.00
Polyox 301	0.00	0.00	0.00	29.74
Carbopol 71G	12.74	12.74	12.74	12.74
Sodium Bicarbonate	4.84	4.84	4.84	4.84
KCl	1.05	1.05	1.05	1.05
SiO2	0.32	0.32	0.32	0.32
Mg stearate	0.32	0.32	0.32	0.32
Tablet weight	950	950	950	950

            

Experimental Example 1. Dissolution Test

1-1. Dissolution test of tablets (1)

The dissolution test of gastric retention tablets prepared in Example 3 (Examples 3-1 to 3-4) was performed. The dissolution test was performed under the same conditions as in Table 4 below in accordance with the Dissolution Test Method No. 2 (paddle method) of the Korean Pharmacopoeia General Test Method (see Table 4).

Table 4

Item	Condition
Dissolution test device	DT810 (Jasco Corporation)
Eluate	pH 1.2
Eluent temperature	37 ℃
Eluent amount	900 mL
Rotation speed	50 rpm
Sample collection time	0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours
Sampling	8 ml
filter	0.45 μm syringe filter

Assay: Amoxicillin and clarithromycin were analyzed under the conditions of Table 5 below using HPLC (MD-2010 plus, Jasco) (see Table 5).

Table 5

Item	Condition
Detector	UV-visible spectrophotometer (wavelength: 210 nm)
column	Filling 4.6 x 250 mm stainless steel pipe with 5 μm octadecylsilylated polyvinyl alcohol for liquid chromatography
Column temperature
	40 ℃
Mobile phase	Dissolve 6.7 g of dipotassium hydrogen phosphate in water to exactly 1000 mL, and adjust the pH to 11.0 with 10 mol / L potassium hydroxide solution. Add 600 mL of acetonitrile to 400 mL of this solution.
flux	1.0 mL / min
Injection volume
	10 μL

Experimental results, as shown in Tables 6 and 7, as a result of confirming the dissolution rate of amoxicillin and clarithromycin, Example 3-3 showed the most excellent dissolution effect (see Table 6 and Table 7), also, Figure 4 As shown in the expansion of about 30 mm and the floating capacity was confirmed that the suspension started at the same time as the elution was kept constant for about 24 hours, but after 24 hours the swelling strength and tablets were weakened (Fig. 4).

Table 6

TIME	Amoxicillin Elution (pH 1.2)
	3-1		3-2		3-3		3-4
	Average(%)	Deviation(%)	Average(%)	Deviation(%)	Average(%)	Deviation(%)	Average(%)	Deviation(%)
0	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
0.25	3.68	0.25	4.58	0.69	13.89	0.17	3.29	0.09
0.5	6.26	0.9	7.07	0.24	16.91	0.13	5.84	0.12
One	18.77	0.51	19.69	0.45	21.49	0.15	17.16	0.11
1.5	22.33	0.61	23.6	0.71	25.69	0.12	21.39	0.13
2	25.52	0.64	27.08	0.81	36.28	0.08	24.95	0.33
3	31.43	0.66	33.53	0.95	45.83	0.19	32.06	0.49
4	36.77	0.7	39.15	0.99	51.38	0.4	38.38	0.71
6	46.23	0.96	49.16	0.73	63.73	0.46	50.15	0.89
8	54.42	1.34	57.65	0.64	71.52	0.92	60.81	0.71
10	59.82	1.59	63.09	0.61	76.63	0.64	69.08	0.62
12	65.85	1.79	68.92	0.85	84.54	0.83	77.4	0.95
16	76.97	2.99	79.63	1.39	93.2	One	92.74	1.44
20	84.5	3.55	87.47	2.61	96.51	1.05	97.31	1.16
24	91.07	3.16	93.89	3.19	104.72	1.4	103.79	0.49

TABLE 7

TIME	Clarithromycin elution (pH 1.2)
	3-1		3-2		3-3		3-4
	Average(%)	Deviation(%)	Average(%)	Deviation(%)	Average(%)	Deviation(%)	Average(%)	Deviation(%)
0	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
0.25	0	0	2.74	3.16	9.8	0.1	2.74	3.16
0.5	9.73	0.46	14.5	0.54	19.73	0.46	10.5	0.54
One	14.58	0.83	15.87	0.74	24.58	0.83	15.87	0.74
1.5	18.73	0.79	19.85	0.84	28.73	0.79	19.85	0.84
2	22.58	0.74	24.26	0.69	32.58	0.74	24.26	0.69
3	29.11	0.74	31.07	1.1	39.11	0.74	31.07	1.1
4	33.63	0.64	36.72	1.23	43.63	0.64	36.72	1.23
6	43.65	0.54	46.65	1.04	53.65	0.54	46.65	1.04
8	52.03	1.44	55.65	0.43	62.03	1.44	55.65	0.43
10	57.16	1.97	60.03	0.64	67.16	1.97	60.03	0.64
12	62.08	1.83	65.06	0.63	72.08	1.83	65.06	0.63
16	71.92	3.07	73.69	1.35	81.92	3.07	73.69	1.35
20	81.58	4.59	82.13	2.27	91.58	4.59	82.13	2.27
24	90.03	3.79	89.81	2.65	100.03	3.79	89.81	2.65

Experimental Example 2. Coating and Dissolution Test of Tablets

2-1. Control Membrane Coating of Tablets

In order to determine the elution effect of the gastroretentive tablet coated with a control membrane was performed as follows.

First, the primary coating of the tablet of Example 3-3 with excellent swelling and floating properties in the same components and ratios as shown in Table 8 below was dissolved in 10-fold multiples of the solid amount with a ratio of 5: 5 of purified water and ethanol. The secondary coating was prepared by dissolving the ratio of purified water and ethanol in a solid quantity of 10-fold to 3: 7 (see Table 8).

Table 8

	Name	%
Primary coating	Kollicoat IR White	11.11
Secondary coating	Kollicoat SR30D	38.89
	Kollicoat IR White	38.89
	PEG400	5.56
	TiO2	2.78
	Talc	2.78
sum		100.00

            

The tablet prepared in Example 3-3 was placed in a coating pan (Hi-coater, Sejong Pharmatech Co., Ltd.) and subjected to the same conditions as Table 9 below, and the exhaust air temperature filled in the coating pan was about 30 to 45 ° C. Kept as possible. The coating liquid (coating agent) prepared in the ratio as shown in Table 8 was sprayed onto the dried tablet with a spray device operated by air pressure, and then dried at room temperature for about 10 minutes, and the coating amount of the coating agent was applied to the tablet. The primary coating was 1% and the secondary coating was 8% (see Table 9).

The tablets coated with the control film were subjected to the dissolution test under the same conditions and methods as in Experimental Example 1, and the results of the zeroth order release were shown.

Table 9

Item	Condition
Inflow temperature	50 to 65 ℃
Exhaust temperature	30 ~ 45 ℃
Fan speed
	5 to 11 rpm
Coating liquid inflow rate	3 to 5 rpm

As a result of the experiment, as shown in Table 10, the control membrane tablet dissolution rate of Example 3-3 showed the results of zero-order release for 24 hours for both amoxicillin and clarithromycin (see Table 10), and also shown in FIG. As shown, the expansion ratio showed a size of around 30 mm, and the floating capacity was suspended within 10 minutes and maintained constant for 24 hours, and the control membrane tablets showed better swelling strength and tablet form than those without the control membrane. (See Figure 5).

Table 10

Time	Coated tablet of Example 3-3 (pH 1.2)
	Amoxicillin		Clarithromycin
	Average (%)	Deviation (%)	Average (%)	Deviation (%)
0	0	0	0	0
0.25	3.25	0.21	2.73	0.07
0.5	5.74	0.14	4.59	0.18
One	5.43	0.1	7.97	0.13
1.5	9.88	0.3	11.13	0.11
2	13.87	0.59	14.15	0.08
3	21.63	1.34	19.4	1.53
4	28.32	0.92	24.62	3.05
6	38.23	1.35	33.57	4.26
8	45.8	0.59	41.83	4.94
10	55.72	0.32	49.53	5.27
12	63.62	0.6	56.69	5.47
16	79.62	1.11	71.81	7.07
20	88.52	2.26	85.11	8.62
24	98.52	3.49	94.18	7.48

The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments and the experimental examples described above are exemplary in all respects and not limiting.

As described above, the swelling and floating gastric retention compositions comprising (a) the drug, (b) the swellable polymer, and (c) the gas generating material of the present invention have the absorption rate of the drug through systemic absorption and local direct action. And improve the treatment rate, improve the dosage and improve patient convenience and compliance, as well as the composition and formulation that can effectively increase the stability and bioavailability of the drug by securing acid stabilization prescription Can be.

Claims (20)

1.  A swelling and floating gastric composition comprising a) a drug, (b) a swellable polymer and (c) a gas generating substance.
2. The method of claim 1,

   A composition having swelling and suspended gastric retention, comprising (a) a drug, (b) a swellable polymer, and (c) a gas generating substance.
3. The method of claim 1,

   A composition comprising at least one selected from the group consisting of (a) a drug, (b) a swellable polymer, (c) a gas generating substance, (d) an excipient, (e) a control membrane, and (f) a wetting agent.
4. The method of claim 1,

   The composition comprises a sustained portion comprising at least one selected from the group consisting of (a) a drug, (b) a swellable polymer, (c) a gas generating substance and (d) an excipient, (e) a control film, and (f) a wetting agent; And (a) an immediate release portion comprising (a) a drug, (g) an immediate release film coating base and (d) a pharmaceutically acceptable excipient.
5. The method of claim 1,

   The composition comprises a sustained release composition.
6. The method of claim 1,

   The composition comprises a immediate release composition.
7. The method of claim 1,

   The (a) drug (pharmacologically active ingredient) is a therapeutic agent for diabetes, a therapeutic agent of hypertension, central nervous system drugs, antibiotics, intragastric pH adjusting agents, proton pump inhibitors (Proton Pump Inhibitor) and H ₂ inhibitors (H ₂ Blocker), anti-viral agents, prostate At least one composition selected from the group comprising a hypertrophic therapeutic agent, a nonsteroidal anti-inflammatory agent, a bisphosphonate, an antithrombotic agent or a 5-HT4 receptor.
8. The method of claim 1,

   The (b) swellable polymer is hydroxypropyl methyl cellulose (Hydroxypropyl methyl cellulose, HPMC), hydroxyethyl methyl cellulose (Hydroxyethyl methyl cellulose), hydroxypropyl cellulose (Hydroxypropyl cellulose), hydroxymethyl cellulose (Hydroxymethyl cellulose), hydroxy Hydroxyethyl cellulose, Carboxymethyl cellulose, Carboxymethyl cellulose sodium, Carboxymethyl cellulose natrium, Methyl cellulose, Ethyl cellulose, Ethyl cellulose (Polyethylene oxide), Locost bean gum, Guar gum, Xanthan gum, Acacia gum, Tragacanth gum, Alginic acid , Sodium alginate, sodium alginate, ammonium alginate, agar, Latin, Poloxamer, Polymethacrylate, Carbomer, Polyvinyl Pyrrolidone, Polyvinyl Alcohol, Polyvinyl Acetate ), Polyethylene glycol, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpi Polyvinyl pyrrolidone-polyvinyl acetate copolymer, bentonite, hectorite, carrageenan, ceratonia, cetostearyl alcohol, chitosan Chitosan), hydroxypropyl starch, Magnesium aluminum silicate, Polydextrose, Contains at least one member selected from the group consisting of poly (methyl vinyl ether / maleic anhydride), propylene glycol alginate, saponite, and the like. Composition characterized in that.
9. The method of claim 8,

   The (b) swellable polymer is a composition characterized in that one or more selected from the group comprising carbomer, hydroxypropylmethylcellulose, polyethylene oxide, or poloxamer.
10. The method of claim 1,

    The gas generating material (c) is selected from the group consisting of sodium bicarbonate, sodium glycine carbonate, calcium carbonate, sodium sulfite, sodium bisulfite, sodium metabisulfite or potassium bicarbonate A composition comprising at least one kind.
11. The method of claim 1,

    The control film (e) is polyvinylacetate, cellulose acetate, ethyl cellulose (Ethyl cellulose), cellulose acetate phthalate (Cellulose acetate phthalate), hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl Methylcellulose phthalate, polyethyl acetate-methyl acetate copolymer, Eudragit RS  And mixture of Eudragit RL, polyvinyl phthalate acetate, shellac, polyvinylpyrrolidone, polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropylmethylcellulose, hydroxypropyl cellulose or A composition comprising at least one material selected from the group comprising polyvinyl alcohol.
12. The method of claim 1,

    (F) the wetting agent, characterized in that it comprises at least one member selected from the group comprising potassium chloride, sodium chloride, xylitol, polyoxyethylene sorbitan monolaurate or polyethylene glycol.
13. The method of claim 1,

    The (g) immediate release film coating base may be hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxypropyl cellulose (Hydroxypropyl Cellulose), poly vinyl pyrrolidone, poly vinyl alcohol (Poly vinyl alcohol) or poly A composition comprising at least one member selected from the group of polyvinyl alcohol-polyethylene glycol graft copolymers.
14. The method of claim 1,

    (D) the excipient is selected from the group consisting of binders, lubricants, disintegrants, colorants, preservatives, flavoring agents, stabilizers, buffers, antibacterial agents, bulking agents, antioxidants or diluents.
15. The method of claim 14,

    The stabilizer is meglumine, magnesium oxide, calcium carbonate, sodium bicarbonate, calcium dihydrogen phosphate, potassium monohydrogen phosphate dihydrate, calcium phosphate tribasic, monoethanolamine, calcium bicarbonate (potassium bicarbonate), potassium citrate, sodium borate, sodium citrate dihydrate or at least one stabilizer selected from triethanolamine.
16. The method of claim 14,

    The antioxidants include α-tocopherol, vitamin C (Ascorbic aicd), vitamin C palmitate, butylhydroxyanisole, dibutylhydroxytoluene, citric acid, erythorbic acid, fumaric acid, malic Acids, Maltodextrins, Potassium Metabisulfide, Sodium Metabiasulfate, Propionic Acid, Propyl Gallate, Sodium Ascorbate, Sodium Sulfate, Tymol, Cyclodextrin or Sulfo At least one antioxidant selected from butylether β-cyclodextrin.
17. The method of claim 1,

    The composition is a powder, granules, tablets, capsules, solutions, membranes, uncoated tablets, mucoadhesives, fast disintegrating composition, characterized in that.
18. The method of claim 1,

    The disintegration portion of the composition is disintegrated within 15 minutes, and the sustained portion is continuously released for 6 hours to 48 hours.
19. The method of claim 1,

    The composition swells within 8 hours upon contact with the eluent or gastric fluid, floats within 30 minutes, and retains suspension for 2 to 48 hours.
20. The method of claim 1,

    The composition is characterized in that within 12 hours after administration, the maximum width of the long axis (L), short axis (W), or height (H) of the size of the formulation within the range of 10 to 50mm in size.

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