KR101270751B1 - Composition for the gastric retention and controlled release of therapeutic agents - Google Patents

Abstract

The present invention relates to a composition for controlling gastric retention and release of a drug, and more particularly, the present invention relates to (a) a drug, (b) a swellable polymer, (c) a gas generating substance, (d) an excipient, (e) A composition for oral administration for controlling gastric retention and release, comprising a control membrane and (f) one or more selected from the group consisting of humectants, improving systemic absorption and treatment rate through systemic absorption and local direct action. In addition to improving the dosage and convenience of patients to improve the dosage and compliance, as well as providing a composition that can effectively increase the stability and bioavailability of the drug through obtaining an acid 10 stabilized prescription.

Description

COMPOSITION FOR THE GASTRIC RETENTION AND CONTROLLED RELEASE OF THERAPEUTIC AGENTS}

The present invention relates to a composition for controlling gastric retention and release of a drug, and specifically, the present invention relates to (a) a drug, (b) a swellable polymer, (c) a gas generating substance, (d) an excipient, (e) A composition for oral administration for controlling gastric retention and release, comprising a control membrane and (f) one or more selected from the group consisting of humectants, improving systemic absorption and treatment rate through systemic absorption and local direct action. In addition to improving the dosage convenience and compliance of the patient by improving the dose, it provides a composition that can effectively increase the stability and bioavailability of the drug through the acid stabilization prescription.

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.

[Reference 1] Na Young Kim et al., The Maastricht III Consensus Report, 2009 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 [3] McNulty CAM et al., The public's attitudes to and compliance with antibiotics, J. Antimicrob Chemother, 60 Suppl. 1, pp.i63-8, 2007 [Document 4] Antibiotic Resistance Management Comprehensive Measure, Ministry of Environment, 2007

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', is present in large amounts in the stomach and small intestine epidermis, but the number and activity decreases as it descends into the large intestine.

The irregular distribution of CYP3A is a drug that can be a substrate of CYP3A. Angiotensin Converting Enzyme inhibitors (ACE inhibitors) and Angiotensin Receptor Blocker (ARB) The absorption may be somewhat changed depending on the location of the gastrointestinal tract, and the absorption of the drug decreases as descending, so that homogeneous drug absorption and bioavailability may be increased when applied as a gastroretentive formulation.

In addition, in the case of a fat-soluble or water-soluble drug, the amount absorbed by the concentration gradient according to the gastrointestinal tract position of P-glycoprotein (called 'PGP') that 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 diseases, may require local reactions to the stomach or small intestine and directly act on bacteria or inflammation such as Helicobacter pylori (hereinafter referred to as HP).

As described above, drugs whose absorption is limited to the upper gastrointestinal tract or require local action are aimed at providing high bioavailability, better drug efficacy and safe drugs by applying to the gastroretentive formulation.

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.

HP bacteria have long-term parasites in the human gastric mucosa, causing various diseases such as gastric and duodenal ulcers, gastric adenocarcinoma and Malt's 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 stomach ulcers and 60-95% of duodenal ulcers, especially in patients with chronic active gastritis in Korea, and in 70-92% of Koreans. The prevalence of gastric cancer, the destination of HP 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 left unused are discarded, causing environmental pollution and causing ecosystem disturbances and antibiotic resistance. , Ministry of Environment, 2007).

To date, none of the above documents further includes at least one selected from the group consisting of (a) drugs, (b) swellable polymers, (c) gas generating materials, (d) excipients, (e) control membranes, and (f) wetting agents. No information has been taught or described for gastric retention and release oral compositions that have a prophylactic and therapeutic effect of a gastrointestinal disorder, including.

Accordingly, the present inventors, while studying the composition for controlling the gastric retention and release of the drug, in addition to the (a) drug, (b) swellable polymer, (c) gas generating material of the present invention (d) excipient, (e ) Gastric and release composition comprising at least one selected from the group consisting of a control membrane and (f) a humectant is designed to remain in the stomach for 24 hours to prevent gas loss and tablet erosion in the upper gastrointestinal tract, Systemic absorption and local direct action, such as suppressing vigorous exercise, improve the absorption and treatment rate of drugs, improve the dosage and dosage, improve the convenience and compliance of patients, and reduce the misuse of antibiotics. By confirming the effective increase in the stability and bioavailability of the drug through the stabilization prescription, the composition for the prevention and treatment of gastrointestinal diseases Completed in the present invention.

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 (a) drug, (b) swellable polymer, (c) gas generating substance (d) excipient, (e) control Membrane, and (f) at least one selected from the group consisting of wetting agents.

As another embodiment of the present invention, the present 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 portion comprising (a) a drug, (g) an immediate release film coating base and (d) a pharmaceutically acceptable excipient.

"Composition" as defined herein includes 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. .

The components of the formulation of the present invention and the principles of the invention will be described in more detail below.

As (a) "drug (pharmacologically active ingredient)" is a therapeutic agent for diabetes, a therapeutic agent of hypertension, central nervous system drugs, antibiotics, intragastric pH control agents defined herein proton pump inhibitors (Proton Pump Inhibitor) and H ₂ inhibitors (H ₂ Blocker) , Antiviral agents, prostatic hypertrophy agents, nonsteroidal anti-inflammatory agents, bisphosphonates, antithrombotic agents, or 5-HT receptor agonists, 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, ceftitorene, 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-HT receptor agonist, comprising at least one drug selected from the group comprising mosapride, cisapride or itopride, and more preferably metformin, glymepiride, amoxicillin, clarithromycin, mosapride, risedro At least one drug selected from the group comprising nates, lansoprazole, omeprazole, esomeprazole, ranitidine, loxoprofen, zaltoprofen or alfzosin, even more preferably metformin, glymepiride, amoxicillin, clarithro It comprises at least one drug selected from the group comprising mycin, 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 polymer" as defined herein includes hydroxypropyl methyl cellulose (HMC), hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose (Hydroxypropyl cellulose) Hydroxymethyl cellulose, Hydroxyethyl cellulose, Carboxymethyl cellulose, Carboxymethyl cellulose sodium, Carboxymethyl cellulose sodium, Methylcellulose, Ethyl cellulose Ethylcellulose, polyethylene oxide, Locost bean gum, Guar gum, Xanthan gum, Acacia gum, Tragacanth gum, Alginic acid, sodium alginate, sodium alginate, ammonium algina te, 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) “Gas generating material” as defined herein includes sodium bicarbonate, sodium glycine carbonate, calcium carbonate, sodium sulfite, sodium bisulfite, sodium metabisulfite, calcium bicarbonate, and the like. It is preferably characterized in that it comprises one or more selected from the group containing sodium bicarbonate or calcium bicarbonate.

(D) "Excipient" as defined herein is selected from the group comprising binders, lubricants, disintegrants, colorants, preservatives, flavors, stabilizers, buffers, antibacterial agents, bulking agents, antioxidants or diluents, and the like. Preferably a binder, a lubricant, a disintegrant, a buffer, an antioxidant.

As defined herein, the (e) "control membrane" 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, polyvinylacetate ( Polyvinyl acetate, Cellulose acetate, Ethyl cellulose, Cellulose acetate phthalate, Hydroxypropyl methyl cellulose Acetate succinate, Hydroxypropyl methyl cellulose Phthalate, polyethyl acetate-methyl acetate copolymer, Eudragit RS ^® and Eudragit RL (a mixture of Eudragit RL, polyvinyl phthalate acetate, shellac) and polyvinylpyrrolidone, a water-soluble film coating base Vinyl alcohol- polyethylene glycol graft copolymer, hydroxypropyl methyl cellulose, A substance containing at least one selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and the like, preferably polyvinylacetate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetsuccinate or polyvinyl alcohol-polyethylene glycol graft Membrane prepared by using a polymer containing one or more selected from the group comprising a copolymer alone, for example, relative combination ratio of about 1: 9 to 9: 1 (w / w) when the two are combined More preferably, it is a control film prepared by using a relative blending 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 initial dissolution delay time (lag time) in advance, and specifically, potassium chloride, sodium chloride, xylitol, poly Oxyethylene sorbitan monolaurate (Polyoxyethylen sorbitan monolaurate) or polyethylene glycol, and the like, preferably one or more selected from the group containing calcium chloride, polyoxyethylene sorbitan monolaurate (Polyoxyethylene sorbitan monolaurate) It is characterized by.

As defined herein, (g) "fast-release film coating base" includes hydroxypropyl methyl cellulose (Hydroxypropyl Methylcellulose), hydroxypropyl cellulose (Hydroxypropyl Cellulose), poly vinyl pyrrolidone, polyvinyl alcohol (Poly vinyl alcohol), polyvinyl alcohol, or polyvinyl alcohol-polyethylene glycol graft copolymer (Poly vinyl alcohol-Polyethylene glycol block copolymer) and the like, preferably one or more selected from the group hydroxypropylmethylcellulose or hydroxypropyl cellulose Characterized in that it comprises a.

As defined herein, "stabilizers" include meglumine, magnesium oxide, calcium carbonate, sodium bicarbonate, calcium dihydrogen phosphate, potassium monohydrogen phosphate dihydrate, calcium phosphate tribasic, monoethanol Amines, potassium bicarbonate, potassium citrate, sodium borate, sodium citrate dihydrate or triethanolamine, and the like, preferably meglumine, magnesium oxide, calcium carbonate, sodium bicarbonate At least one stabilizer selected from calcium dihydrogen phosphate, potassium dihydrogen 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 potassium metabisulfide, sodium metabiasulfate, propionic acid, propionic acid, sodium ascorbate, sodium sulfate, tymol At least one antioxidant selected from cyclodextrin 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, a “composition” as defined herein, swells within about 8 hours, preferably within about 4 hours, and floats within about 30 minutes, preferably about 15 minutes, upon contact with the eluent or gastric juice, and about 2 hours. Long axis (L), shortening (W), which is the size of the formulation within about 12 hours, preferably about 8 hours after administration of the composition of the present invention, preferably for about 8 to 24 hours, preferably for about 8 to 24 hours. ), Or the maximum width in the height (H) is in the range of about 10 to 50mm, preferably in the range of about 15 to 35mm in size.

The preferred dosage of the composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can 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, including, for example, amoxicillin and clarithromycin as the main active ingredients, and the above pharmaceutically acceptable additives are mixed and compressed into tablets. Formulations such as tablets, compression coated tablets, double tablets, triple tablets and the like can be prepared.

As described above, 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. Oral administration composition for gastric retention and release control including the above to improve the absorption and treatment rate of the drug through systemic absorption and local direct action, improve the dosage and improve the convenience and compliance of patients In addition, it can be usefully used as a composition and formulation that can effectively increase the stability and bioavailability of the drug by securing an acid stabilization prescription.

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.
Figure 3 is a graph showing the dissolution test results of Table 10 which is a control film tablet of Example 3-3, that is, a tablet coated with a control film,
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 (A) elution start floating and (B) swelling and floating even after 24 hours of the control film tablet of Example 3-3, that is, the tablet coated with the control film.

Hereinafter, the present invention will be described in detail. However, the following Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

Example  1. Single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability

1-1. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (One)

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 Bicarbonate, calcium chloride, light anhydrous silicic acid and Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results, Polyox N750 ^® swellable As shown in Table 1 were not able to confirm the expansion chalryul the collapse of the tablet after 16 hours, the unit was able to determine the wealth within 20 minutes (see Table 1).

1-2. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (2)

In order to confirm the swelling ratio and the floating capacity of tablets containing a single swellable polymer excluding the drug to select a swellable polymer suitable for gastric retention formulation, Polyox 301 ^® , sodium, which is the same ratio as shown in Table 1 Bicarbonate, calcium chloride, light silicic anhydride and magnesium stearate were added to confirm the swelling rate and the floating capacity of the tablet.

The experimental results, Polyox ^® 301 As shown in Table 1 The expansion rate was 144.9%, and in the floating capacity, it was suspended within 20 minutes, and it was confirmed that the suspension was maintained for 16 hours (see Table 1).

1-3. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (3)

Single, except drug, to select swellable polymers suitable for gastric retention formulations Polyox 1105 ^® , sodium bicarbonate, KCL, SiO ₂ , 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 the tablet containing the swellable polymer And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results showed that the polyox 1105 ^® 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. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (4)

HPMC 4,000cps, which is the hydroxypropylmethylcellulose in the same ratio as shown in Table 1, to determine the expansion 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 , Sodium bicarbonate, KCL, SiO ₂ And 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 4,000cps 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. 1).

1-5. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (5)

HPMC 15,000 cps, hydroxypropylmethylcellulose in the same ratio as shown in Table 1, in order to confirm the expansion rate and the floating capacity of tablets containing a single swellable polymer excluding the drug to select a swellable polymer suitable for gastric retention formulation. , Sodium bicarbonate, KCL, SiO ₂ And 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 hydroxypropylmethylcellulose was 142.3%, and it was found to be suspended within 30 minutes in floating capacity and to remain suspended for 16 hours (Table 1). 1).

1-6. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (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, hydroxypropyl methyl cellulose 100,000 cps in the same ratio as shown in Table 1, Sodium Bicarbonate, KCL, SiO ₂ And 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. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (7)

In order to check the swelling rate and the floating capacity of tablets containing a single swellable polymer excluding the drug to select a swellable polymer suitable for gastric retention formulation, xanthim gum, sodium bicarbonate, KCL, SiO ₂ And 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 xanthan gum was 166.7%, and it was found to be suspended within 20 minutes in floating capacity, and maintained for 16 hours (see Table 1).

1-8. single Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (8)

Carbomer 71G ^® , sodium bicarbonate, KCL 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 , SiO ₂ And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.

Experimental results showed that Carbomer 71G ^® 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).

Example  2. Composite Swelling  Expansion rate of the polymer and Secondary ability

2-1. complex Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (One)

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 ^® and Carbomer 71G ^® (3 : 7), Poloxamer 407 ^® Sodium Bicarbonate, KCL, SiO ₂ And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result of the experiment, 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 (see Table 2). ).

2-2. complex Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (2)

In order to confirm the expansion ratio and the floating capacity of the tablet containing the composite swellable polymer, Polyox 301 ^® and Carbomer 71G ^® (5: 5), poloxamer 407 ^® , sodium bicarbonate, KCL, SiO ₂ And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

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

2-3. complex Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (3)

In order to confirm the expansion ratio and the floating capacity of the tablet containing the composite swellable polymer, Polyox 301 ^® and Carbomer 71G ^® (7: 3), poloxamer 407 ^® , sodium bicarbonate, KCL, SiO ₂ And 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 2-3 was 150.84%, and it was found to float within 5 minutes in the floating capacity, and it was confirmed that the suspension was maintained for 24 hours (see Table 2). ).

2-4. complex Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (4)

In order to confirm the expansion rate and the floating capacity of the tablet containing the composite swellable polymer, hydroxypropylmethylcellulose 100,000 cps and Carbomer 71G ^® (3: 7), poloxamer 407 ^® , sodium bis in the same ratio as shown in Table 2 below Carbonate, KCL, SiO ₂ And 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 ratio of Example 2-4 was 168.5%, and it was confirmed that the suspension was suspended within 5 minutes in floating capacity, and maintained floating for 24 hours (see Table 2). ).

2-5. complex Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (5)

In order to confirm the expansion rate and the floating capacity of the tablet containing the composite swellable polymer, hydroxypropylmethylcellulose 100,000 cps and Carbomer 71G ^® (5: 5), poloxamer 407 ^® , in the same ratio as shown in Table 2 below. Sodium Bicarbonate, KCL, SiO ₂ And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet containing the composite swellable polymer.

As a result of the experiment, as shown in Table 2, 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 (see Table 2). ).

2-6. complex Swelling  Expansion rate of the tablet containing the polymer and Secondary ability (6)

In order to confirm the expansion rate and the floating capacity of the tablet containing the composite swellable polymer, hydroxypropylmethylcellulose 100,000 cps and Carbomer 71G ^® (7: 3), poloxamer 407 ^® , sodium bis in the same ratio as shown in Table 2 below Carbonate, KCL, SiO ₂ And 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 As shown in Table 2 Polyox ^® 301 and hydroxypropyl methylcellulose 100,000cps all Polyox ^® 301 (hydroxypropyl methylcellulose 100,000cps): shows the best results in 3: Carbomer 71G ^® 7. The expansion coefficient ^{Polyox 301 ®: Carbomer 71G ® =} 7: 3 and hydroxypropyl methylcellulose ^{100,000cps: Carbomer 71G ® = 7:} 3 all exhibited a result of 162.6%, 168.5% exhibited a swelling strength after 16 hours. The floating capacity was suspended within 5 to 10 minutes to maintain floating for 24 hours (see Table 2).

Example  3. Gastric retention  Manufacture of tablets

3-1. Gastric retention  Formulation Preparation

Amoxicillin, clarithromycin, Poloxamer 407 ^® , hydroxypropylmethylcellulose 100,000cps and Meglumine were mixed in the same order and ratio as shown in FIG. 1 and Table 3 below, and dissolved in 10-fold 50% ethanol. Granules are prepared by adding the liquid. 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, and SiO _2. And 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 ^® , 4,000 cps of hydroxypropylmethylcellulose and Meglumine were mixed in the same order and ratio as shown in Table 1 and Table 3 below, and dissolved in 10-fold 50% ethanol. Granules are prepared by adding the liquid. 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, and SiO _2. And 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 ^® and Meglumine are mixed in the same order and ratio as shown in FIG. 1 and Table 3 below, 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, SiO ₂ And 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 ^® , hydroxypropylmethylcellulose 100,000cps and Meglumin were mixed and dissolved in 10-fold 50% ethanol in the same order and ratio as shown in Table 1 below. Granules are prepared by adding the liquid. 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, SiO ₂ And 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).

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).

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

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).

Experimental Example  2. Tablet coating and dissolution test

2-1. Tablet Control film  coating

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).

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.

Experimental results, 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).

Claims (20)

(a) a drug; (b) hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyethylene oxide, xanthan gum, sodium alginate, poloxamer, carbomer or polyethylene glycol At least one swellable polymer selected from the group; (c) in addition to at least one gas generating substance selected from the group consisting of sodium bicarbonate, sodium glycine carbonate, calcium carbonate, sodium sulfite, sodium bisulfite, sodium metabisulfite, or calcium bicarbonate; Excipients selected from the group comprising lubricants, disintegrants, stabilizers, buffers and antioxidants; And (e) polyvinyl acetate, cellulose acetate, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, polyethyl acetate-methyl acetate copolymer, Eudragit RS and Eudra Swelling and swelling comprising at least one selected from the group consisting of a control membrane comprising at least one selected from the group consisting of a mixture of RL, polyvinyl phthalate acetate or shellac, and characterized by systemic absorption and local direct action. Oily gastric retention composition. delete delete delete The method of claim 1,
The composition comprises a sustained release composition. delete 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 consisting of hypertrophic agents, nonsteroidal anti-inflammatory agents, bisphosphonates, antithrombotic agents, or 5-HT receptor agonists. delete The method of claim 1,
The (b) swellable polymer is a composition characterized in that one or more selected from the group comprising carbomer, hydroxypropylmethylcellulose, polyethylene oxide, or poloxamer. delete delete delete delete delete The method of claim 1,
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. The method of claim 1,
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. delete delete 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. 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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