WO2012169677A1 - Composition pour réguler la rétention et la libération gastrique - Google Patents

Composition pour réguler la rétention et la libération gastrique Download PDF

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Publication number
WO2012169677A1
WO2012169677A1 PCT/KR2011/004246 KR2011004246W WO2012169677A1 WO 2012169677 A1 WO2012169677 A1 WO 2012169677A1 KR 2011004246 W KR2011004246 W KR 2011004246W WO 2012169677 A1 WO2012169677 A1 WO 2012169677A1
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WIPO (PCT)
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composition
cellulose
drug
sodium
hydroxypropyl
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PCT/KR2011/004246
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English (en)
Korean (ko)
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서혜란
전명관
안태군
서영대
이준희
최주현
서현미
강승래
서상교
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주식회사 비씨월드제약
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Priority to PCT/KR2011/004246 priority Critical patent/WO2012169677A1/fr
Publication of WO2012169677A1 publication Critical patent/WO2012169677A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • 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.
  • 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.
  • 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.
  • 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).
  • 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
  • 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
  • ARB Angiotensin Receptor Blockers
  • 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.
  • PGP P-glycoprotein
  • 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.
  • the absorption of the drug is mainly limited to the upper part of the small intestine.
  • a phenomenon in which the bioavailability of the drug is significantly lowered appears.
  • 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.
  • 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.
  • 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.
  • bacteria or inflammation such as Helicobacter pylori (HP)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the effective stability of the drug and increase the bioavailability through the acid stabilization prescription, and completed the present invention.
  • 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.
  • 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.
  • 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.
  • the present invention provides a swelling and floating gastric composition comprising (a) a drug, (b) a swellable polymer and (c) a gas generating material.
  • 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.
  • 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.
  • a drug that is as defined herein 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, cef
  • 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, polyvinylpyrroli
  • 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.
  • 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.
  • 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
  • (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.
  • 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 ⁇ -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 ⁇ -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. .
  • 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,
  • L Long-term
  • W short-circuit
  • H 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • FIG. 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.
  • Example 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),
  • Example 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).
  • 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.
  • 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.
  • 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, SiO 2 And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.
  • 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, SiO 2 And Magnesium stearate was added to confirm the swelling rate and the floating capacity of the tablet.
  • Example 2 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).
  • Example 2 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).
  • Example 2-3 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).
  • Example 2 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).
  • Example 2-5 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).
  • 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, 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).
  • 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, 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).
  • 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, 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).
  • Example 3 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 °C 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 ⁇ m syringe filter
  • Table 5 Item Condition Detector UV-visible spectrophotometer (wavelength: 210 nm) column Filling 4.6 x 250 mm stainless steel pipe with 5 ⁇ m octadecylsilylated polyvinyl alcohol for liquid chromatography Column temperature 40 °C 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 ⁇ L
  • 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).
  • 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).
  • Example 3-3 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).
  • 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).
  • 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.

Abstract

La présente invention concerne une composition pour réguler la rétention et la libération d'un médicament dans l'estomac, et en particulier, concerne une composition qui est administrée par voie orale, comprenant (a) le médicament, (b) un polymère gonflant et (c) une substance de génération de gaz, pour réguler la rétention et la libération du médicament dans l'estomac. Selon l'invention, la composition améliore une vitesse d'absorption et une vitesse de traitement du médicament au moyen d'un effet d'absorption du corps entier et d'un effet direct local, améliore l'utilisation et la dose du médicament, augmentant ainsi le confort d'un patient prenant le médicament et l'adaptabilité, et augmente efficacement la sécurité et la biodisponibilité du médicament en rendant sûre une prescription d'une stabilisation d'acide.
PCT/KR2011/004246 2011-06-09 2011-06-09 Composition pour réguler la rétention et la libération gastrique WO2012169677A1 (fr)

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CN108176134A (zh) * 2018-01-24 2018-06-19 华侨大学 一种抗霉型沐浴过滤器用滤料、过滤器及其制作方法
CN110996922A (zh) * 2017-06-16 2020-04-10 卡希夫生物科学有限责任公司 用于持续药物递送的胃滞留剂型
CN112156096A (zh) * 2020-10-20 2021-01-01 北京斯利安药业有限公司 叶酸缓释组合物、缓释制剂及其应用
CN114796142A (zh) * 2022-04-08 2022-07-29 黄山学院 萘普生胃漂浮片及其制备方法

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CN110996922A (zh) * 2017-06-16 2020-04-10 卡希夫生物科学有限责任公司 用于持续药物递送的胃滞留剂型
CN108176134A (zh) * 2018-01-24 2018-06-19 华侨大学 一种抗霉型沐浴过滤器用滤料、过滤器及其制作方法
CN112156096A (zh) * 2020-10-20 2021-01-01 北京斯利安药业有限公司 叶酸缓释组合物、缓释制剂及其应用
CN114796142A (zh) * 2022-04-08 2022-07-29 黄山学院 萘普生胃漂浮片及其制备方法

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