WO2004084867A1 - Compositions pharmaceutiques adaptees au colon de medicaments ameliorant la motilite du tractus gastro-intestinal, et leur utilisation - Google Patents

Compositions pharmaceutiques adaptees au colon de medicaments ameliorant la motilite du tractus gastro-intestinal, et leur utilisation Download PDF

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Publication number
WO2004084867A1
WO2004084867A1 PCT/CN2004/000244 CN2004000244W WO2004084867A1 WO 2004084867 A1 WO2004084867 A1 WO 2004084867A1 CN 2004000244 W CN2004000244 W CN 2004000244W WO 2004084867 A1 WO2004084867 A1 WO 2004084867A1
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Prior art keywords
colon
pharmaceutical composition
capsules
locating
active ingredient
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PCT/CN2004/000244
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English (en)
Chinese (zh)
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Chengguo He
Chengfei Zhang
Mei Li
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Beijing Orientking Pharmaceutical Science & Technology Co., Ltd.
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Publication of WO2004084867A1 publication Critical patent/WO2004084867A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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

Definitions

  • the invention relates to a colon-localized pharmaceutical preparation and use thereof, in particular to a colon-localized targeted preparation of gastrointestinal motility drugs and its application in treating constipation.
  • Constipation is a condition in which bowel is not retained for a long time due to the inability to defecate normally. It is manifested as a decrease in the number of bowel movements, difficulty or inability to defecate, or a dry and hard stool. It has a high incidence. For patients with long-term constipation, patients must not only often endure the great pain caused by constipation, but also because their metabolites stay in the colon and rectum for a long time. Toxins are absorbed into the blood through the intestinal wall and can induce a variety of other disease.
  • Constipation can be divided into two types according to the presence or absence of organic lesions, of which functional constipation accounts for the vast majority.
  • laxatives are mainly used clinically to treat functional constipation, but it is often difficult to completely solve the problem.
  • laxatives mainly include 1) volumetric laxatives, such as agar, methyl cellulose, etc .; 2) lubricating laxatives, such as glycerin, mineral oil or paraffin oil, etc .; 3) hypertonic laxatives, such as magnesium sulfate, Sorbitol, etc .; 4) irritating laxatives, such as senna, lactulose, etc.
  • laxatives Long-term application of laxatives will not only cause the body to produce laxatives Adaptability and tolerance, leading to reduced efficacy and different side effects, such as the long-term application of volumetric laxatives can cause dehydration and electrolyte disturbances, and can cause systemic muscle weakness and symptoms of the heart and kidneys; long-term use of irritant laxatives Can cause reduced bowel stress; long-term application of lubricating laxatives can affect the absorption of vitamins A, D, K and calcium and phosphorus. Laxative bowel disease and colonic melena due to abuse of laxatives in constipated patients have been closely watched by gastroenterologists.
  • the gastrointestinal motility drug's general oral preparation's dynamic effect on the stomach and small intestine may cause the stomach and small intestine to intensify, increase the patient's discomfort, and combined with the inexact treatment effect on constipation, may be currently in clinical practice. This class of drugs is seldom used as one of the main reasons for treating constipation.
  • US6228396A and US6319518A both involve patents for colon-locating capsules. They are filled with drugs in special starch capsules and applied with STREA-1 fluidized bed for spray coating. The coating materials are hydroxypropyl methylcellulose and acrylic acid. Tree shrews, cellulose acetate phenolic peptide esters.
  • the purpose of the present invention is to prevent the pharmaceutical preparation from disintegrating in the stomach and small intestine, the drug is not absorbed, and the preparation begins to disintegrate after reaching the colon to release the drug, so as to increase the local drug concentration in the colon cavity, effectively improve the colonic motility effect of the drug, For the treatment of constipation, reduce the absorption of the drug into the blood circulation, and avoid other side effects or adverse reactions caused by systemic absorption of the drug that are not related to the effect of constipation treatment.
  • the inventors of the present invention creatively targeted administration of colon-localized preparations prepared by gastrointestinal kinetic drugs.
  • the colon-locating pharmaceutical composition of the present invention consists of a colon-locating material and a dosage unit containing a clinically effective amount of a gastrointestinal motility drug and a pharmaceutical excipient.
  • the colon-locating material may be a coating or a colonic enteric hollow capsule that is wrapped on the outer layer of a dosage unit.
  • the pharmaceutical composition of the present invention can be prepared by conventional techniques in the art. Specifically, the main medicine (active ingredient) and auxiliary materials (inactive ingredient) can be compressed into tablets, and then the above-mentioned composition is used. Intestinal positioning material coating; Or the main medicine and excipients are filled into capsules suitable for coating, and then coated with the colon positioning material; Or the main medicine and excipients are directly filled into the colon positioning capsule; or the main medicine and the excipients are mixed Pellets are made and coated with the colon coating material described above.
  • the gastrointestinal motility drugs referred to in the present invention include domperidone, metoclopramide (metoclopramide X itopride), cisapride, and mosapride ), Prucalopride, tegaserod, etc. Among them, the effects of relying on rebir and cisapride are more prominent.
  • the colon-localized form of the present invention can adopt three types, namely, pH-sensitive type, bacteria or enzyme-sensitive type in the colon, and time-dependent type.
  • the colon localization method of the present invention may be pH sensitive.
  • the pH-sensitive colon-locating material can be acrylic resins, such as Eudragit® from German company Roma, domestic acrylic resin ⁇ and acrylic resin m, or Cellulose acetate phthalate (CAP).
  • the dosage form of the pH-sensitive colon-localized preparation of the present invention may be in the form of tablets, capsules, and pellets.
  • the content range of the active ingredient in the gastrointestinal motility drug pH-sensitive colon-specific administration composition of the present invention is from 0.1 to 90% by weight ratio, and the preferred content range is from 0.3% to 80%. If etopril is used as the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 1% -90% by weight ratio, preferably 5% to 80%, and more preferably 8% to 70%. Cisapride is the active ingredient, and the amount of active ingredient in the pharmaceutical composition is 1% to 90% by weight ratio, preferably 1.5% to 70%, and more preferably 2% to 50%.
  • 5%-Tegaserod is the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 0.1% -80%, preferably 0.3% -60%, more preferably 0.5%- 40%; If the above active ingredient enters the pharmaceutical composition in the form of a derivative, the content of the active ingredient in the composition is calculated based on the active ingredient itself. For example, in a pharmaceutical composition of etopril hydrochloride, the content of the active ingredient is calculated based on etopril.
  • the weight gain of the pH-sensitive colonic enteric coating is 1% to 30%, preferably 1.5 to 25%, and more preferably 2 to 20%.
  • the coating thickness of the coating material is as important as its pH sensitivity, which is the relationship between the two.
  • the content range of the active ingredient in the time-dependent colon-specific administration composition is from 0.1 to 90% by weight ratio, and the preferred content range is from 0.3% to 80%.
  • the amount of the active ingredient in the pharmaceutical composition is 1% -90% by weight ratio, preferably 5% to 80%, more preferably 8% to 70%; if Cisapride is the active ingredient, and the amount of active ingredient in the pharmaceutical composition is 1%-90% by weight ratio, preferably 1.5% to 70%, more preferably 2% to 50%; if 5% ⁇ Tegaserod is the active ingredient, the amount of active ingredient in the pharmaceutical composition is calculated by weight ratio of 0.1% -80%, preferably 0.3% -60%, more preferably 0.5% ⁇ 40%; If the above active ingredient enters the pharmaceutical composition in the form of a derivative, the content of the active ingredient in the composition is calculated based on the active ingredient itself. For example, in a pharmaceutical composition of etopril hydrochloride, the content of the active ingredient is calculated based on etopril.
  • the weight gain of pH-sensitive colonic enteric coating is 1% -30%, preferably 1.5 to 251 ⁇ 2, more preferably 2 to 20%.
  • the characteristics of Eudragit® L100 (Eudragit® L100) is greater than pH 6. It dissolves at 0.
  • the characteristics of Eudragit® S100 (Eudragit® S100) is that it dissolves at a pH greater than 7.0. If the two materials are mixed at different ratios as coating materials, a series of pH 6.0 will be obtained. -A coat that begins to dissolve between 7. 0.
  • the coating dissolves earlier and faster, so the coating should be thicker, about 150-300 microns; if the proportion of Youtech Qi S100 in the mixed material is high, then The coating dissolves later and slower, so the coating should be thinner, approximately between 70-150 microns.
  • the colon-localized form of the present invention may also be bacterial or enzyme sensitive in the colon.
  • bacteria there are a large number of bacteria in the colon, which can account for 20% -30% of the total solids. Some of these bacteria can produce P-glucuronidase, glucosidase, cellulase, nitroreductase, azoreductase Wait.
  • P-glucuronidase glucosidase
  • cellulase nitroreductase
  • azoreductase Wait are scarce in the stomach and small intestine, but abundant in the colon.At the same time, these enzymes have the ability to specifically degrade certain materials. Therefore, these characteristics can be used to make Prepare preparations for colon administration.
  • Such materials include pectin, amylose, azo polymers, disulfide polymers, chitosan, guar gum, crosslinked glucose, chondroitin, ethyl cellulose, and mixtures thereof.
  • Pectin is a water-soluble polysaccharide that is not degraded by enzymes in the stomach and small intestine, but can be degraded by enzymes produced by certain bacteria in the colon. This feature can be used in colon-specific preparations.
  • pectin is water-soluble and has a poor effect when used directly for colonic localized administration. After calcification results in gelled calcium, its water solubility is reduced and its degradation properties remain unchanged. Therefore, it is an ideal colon-localized material.
  • Foreign researchers have prepared compressed coated tablets and matrix tablets of pectin calcium, which both show good colonic localization.
  • the dosage forms may be tablets and capsules. 1-90%, the preferred content range is 0 by weight ratio of the active ingredient in the pectin calcium matrix tablet of the present invention. . 3% ⁇ 80%. If etopril is used as the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 1% -90% by weight ratio, preferably 5% to 80%, and more preferably 8% to 70%.
  • Cisapride is the active ingredient, and the amount of active ingredient in the pharmaceutical composition is 1% to 90% by weight ratio, preferably 1.5% to 70%, more preferably 2% to 50%; if 5%-Tegaserod is the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 0.1% -80%, preferably 0.3% -60%, more preferably 0.5%- 40%; If the above active ingredient enters the pharmaceutical composition in the form of a derivative, the content of the active ingredient in the composition is calculated based on the active ingredient itself. For example, in the pharmaceutical composition of etopril hydrochloride, the content of the active ingredient is calculated based on etopril. The content of pectin calcium is 20% -80%;
  • a coated tablet is prepared by compressing the main drug and auxiliary materials into tablets, and then pressing and coating with pectin calcium.
  • the content of the active ingredient is 0.1% to 90% by weight, preferably 0.5 to 70%. If etopril is used as the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 1% to 90% by weight. %, Preferably between 5% and 80%, more preferably between 8% and 70%; if cisapride is used as the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 1%-90% by weight ratio, It is preferably 1.5% to 70%, more preferably 2% to 50%.
  • the amount of the active ingredient in the pharmaceutical composition is 0.1% -80% by weight ratio, preferably 0.3% to 60%, more preferably 0.5% to 40%; if the above active ingredient enters the pharmaceutical composition in the form of a derivative, the content of the active ingredient in the composition is calculated based on the active ingredient itself. For example, in a pharmaceutical composition of etopril hydrochloride, the content of the active ingredient is calculated based on etopril.
  • the weight gain of the coating is 1% to 30%, preferably 2% to 20%.
  • the preparation method of capsules is to directly load the main medicine (active ingredient) and auxiliary materials into pectin calcium colon enterosol.
  • the preparation method of pectin calcium colon enterosol tincture is that the mold stick is first immersed in the pectin solution and then immersed in the calcium chloride solution for calcification.
  • the colon positioning method adopted in the present invention may also be a time-dependent colon positioning method, that is, the purpose of colon positioning is achieved by using the transit time of drugs in the gastrointestinal tract.
  • the transit time of the small intestine is relatively stable and is not affected by the nature of the food or drug delivery system, typically 4 ⁇ 1 hour.
  • Such drug delivery systems are generally coated with a hydrophobic material. The coating is designed to slowly erode and release the drug after a predetermined time.
  • hydrophobic materials include ethylcellulose, palmitic acid, beeswax, and polyoxyethylene mannitol monooleate.
  • the time-dependent colon-localized mode dosage form of the present invention may be a tablet. Specifically, the main medicine and the auxiliary materials are compressed into tablets, and then coated with the mixture of the colon positioning material or one of them.
  • the content of the active ingredient in the pharmaceutical composition of the present invention ranges from 0.1 to 90% by weight. The preferred content range is 0.3% to 80%. If etopril is used as the active ingredient, the amount of the active ingredient in the pharmaceutical composition is 1% -90% by weight ratio, preferably 5% -80%, more preferably 8% -70%.
  • Cisapride is the active ingredient, and the amount of active ingredient in the pharmaceutical composition is 1% to 90% by weight ratio, preferably 1.5% to 70%, and more preferably 2% to 50%.
  • Siro is the active ingredient
  • the amount of the sexual component in the pharmaceutical composition is calculated as 0.1% to 80% by weight ratio, preferably 0.3% to 60%, more preferably 0.5% to 40%; if the above active ingredient is a derivative
  • the content of the active ingredient in the composition is calculated based on the active ingredient itself.
  • the content of the active ingredient is calculated based on etopril.
  • the weight gain of the coating is 1% to 30%, preferably 2% to 20%; the time for dissolution of the coating of the present invention is set to 5-6 hours, specifically 2 hours insoluble in artificial gastric juice, at pH 6.
  • the artificial intestinal fluid of 8 was not dissolved in 3 hours, and was dissolved within 1 hour in the artificial intestinal fluid of pH 7.8.
  • the in vitro dissolution measurement of the present invention adopts the method under the "Chinese Pharmacopoeia” 2000 version two appendix tablets, but this method does not specify the test time in a phosphate buffer at pH 6.8.
  • the present invention is designed to This time is designed to be 3 hours, and the rest are the same. The following method is obtained:
  • Degassed artificial gastric juice was taken as a solvent, and 900 ml of the solvent was injected into 6 dissolution cups of the ZRS-4 intelligent dissolution apparatus, and the temperature of the solvent was maintained at +0.5 ⁇ by heating, and the rotation speed of the basket was adjusted to 100 revolutions per minute. Put 6 pieces (pieces) of test product into 6 baskets, lower the basket into the container, start timing immediately, filter an appropriate amount of solution in 2 hours, and measure the dissolution amount. In addition, the cup is transferred to the blue and taken out, rinsed with steamed water; the dissolution cup is washed and poured into 900ml of artificial intestinal fluid that has been warmed to 37X, and the solvent temperature is adjusted to 37 * ⁇ 0.5C.
  • the rotation speed of the basket is adjusted to 100 per minute. Turn, lower the basket into the container, start the timing immediately, and take an appropriate amount of solution and filter it at 3 hours to determine the dissolution amount. Then transfer the cup to blue and take it out. Rinse it with distilled water. Wash the dissolution cup and pour 900ml of phosphate buffer solution (or artificial colon fluid) which has been heated to pH 37 to 37. Adjust the solvent temperature. Keep 37X ⁇ 0.5 * C, adjust the rotating speed of the basket to 100 revolutions per minute, lower the rotating basket into the container, start timing immediately, and take an appropriate amount of solution to filter in 1 hour to determine the dissolution amount.
  • the pharmaceutical compositions of the present invention is not released 2 hours no disintegrate in artificial gastric juice;. 37 pH6 8 simulated intestinal fluid without disintegrating 3 hours is not released;. 37 "P H7 8 phosphate buffer (or simulated intestinal fluid) in Dissolve more than 70% in 1 hour.
  • the preparation method of the artificial gastric juice referred to in the present invention is to take 16.4ml of dilute hydrochloric acid, add 800ml of water and 10g of pepsin, shake it and add water to dilute to 1000ml.
  • the preparation method of the artificial intestinal juice referred to in the present invention takes 6.8 g of potassium dihydrogen phosphate, adds 500 ml of water to dissolve, adjusts the pH value to 6.8 with a 0.4% sodium hydroxide solution, and takes another 10 g of pancreatin, and adds an appropriate amount of water. Dissolve, mix the two solutions, dilute with water to 1000ml.
  • the method for preparing the phosphate buffer solution of pH 7.8 referred to in the present invention A solution: Take 35.9 g of disodium hydrogen phosphate, dissolve it with water, and dilute it to 500 ml.
  • a solution Dissolve 35.9 g of disodium hydrogen phosphate, dissolve in water, and dilute to 500 ml.
  • Liquid B Take 2. 76 g of sodium dihydrogen phosphate, dissolve in water, and dilute to 100 ml. Take 91.5 ml of the above solution A, 8. 5 ml of the solution B, and lg of pectin decomposing enzyme, dissolve, and shake the hook to obtain.
  • the in vivo localization research method of the present invention uses the barium sulfate tracer method proposed by Li Hanyun in Chinese patent CN1334083. Although there is no active ingredient in the preparation of this method, because colon positioning is mainly achieved by coating, the accuracy of positioning is entirely determined by the coating prescription and process, and whether the active ingredient in the content is still barium sulfate None.
  • the specific method is to use barium sulfate to make colon-targeted preparations. Each person takes 3 tablets (capsules), performs x-ray inspection at certain intervals, and records records.
  • Example 1 PH- sensitive Etopril colon-specific preparation
  • Barium gallate was filled into ordinary capsules and coated with the above-mentioned colonic enteric coating solution to make barium sulfate tracer capsules.
  • Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that taking After the capsule, one of the three barium sulfate tracer capsules taken by one person disintegrated in the ileocele, the three capsules of the barium sulfate tracer capsule taken by one person all disintegrated in the ascending colon, and the other three The disintegration site of the three capsules is the terminal ileum, as shown in Table 1. Table 1 Disintegration sites of barium sulfate tracer capsules
  • Barium sulfate is filled into ordinary capsules and coated with the above-mentioned colon enteric coating solution to prepare Barium sulfate was used to trace the capsules, and five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that after taking the capsules, three of the three barium sulfate tracer capsules taken by the two were in the ileocecal department. All of them disintegrated. The three capsules of barium sulfate tracer capsules taken by one person all disintegrated in the transverse colon. The disintegration site of the three tablets taken by the other two was the terminal ileum, as shown in Table 2. Table 2 Disintegration sites of barium sulfate tracer capsules
  • Barium sulfate was filled into this colon enteric-coated hollow capsule, and a barium sulfate tracing capsule was prepared.
  • Five in vivo tracking experiments, x-ray inspections, and film recordings were performed, and the results showed that after taking the capsule, three of the three barium sulfate tracer capsules disintegrated in the ileocele were taken by one person.
  • the three capsules of barium sulfate tracer capsule all disintegrated in the ascending colon.
  • the disintegration site of the three capsules taken by one person is the terminal ileum, as shown in Table 3.
  • the tablets are made according to the above-mentioned prescription of Etopril tablet core, and then coated with the prescription of the aforementioned enteric-coated coating solution to obtain Etopril-coated enteric-coated tablets.
  • Etopril colon enteric-coated tablet 2 hours in artificial gastric juice, the dissolution is less than 1%; 37 * C pH6.8, 3h dissolution in artificial intestinal juice is less than 1%; 37t pH7.8 phosphate More than 90% of lh was dissolved in the salt buffer.
  • Lactose 100 0 g
  • 80% ethanol 950. 0g made into tablets according to the prescription of Etopril tablet cores, and then coated with the formula of the colonic enteric coating solution, to obtain Etopril enteric-coated tablets.
  • Barium sulfate was filled into ordinary capsules and coated with the aforementioned colonic enteric coating solution to prepare barium sulfate tracer capsules.
  • Five in vivo tracking experiments, X-ray inspections, and film recordings were performed. The results showed that taking this After the capsules, one of the three barium sulfate tracer capsules taken by one of them disintegrated in the ileocele, and the three capsules of one barium sulfate tracer capsule taken by one disintegrated in the ascending colon.
  • the disintegration site of the three capsules is the terminal site of the ileum.
  • Example 7 Preparation of a bacterial or enzyme-sensitive cisapride colon-locating formulation-cisapride colon enterosol ⁇ Bacterial or enzyme-sensitive hollow capsule-pectin calcium hollow capsule
  • Barium sulfate was filled into this colon enteric-coated hollow capsule to make a barium sulfate tracer capsule.
  • Five in vivo tracking experiments, X-ray inspections, and film recordings were performed. The results showed that after taking the capsule, four of them All three capsules of barium sulfate tracer capsules disintegrated in the ascending colon, and three capsules of one barium sulfate tracer capsules disintegrated in the transverse colon are shown in Table 6.
  • Og was made into tablets according to the prescription of the above-mentioned cisapride tablet core, and then coated with the prescription of the above-mentioned colon enteric coating solution, and the thickness of the coating was 120 micrometers.
  • Og was made into tablets according to the prescription of the tegaserod tablet core described above, and then coated with the formula of the colonic enteric coating solution described above, the thickness of the coating was 120 microns.
  • Dissolution test results of this tegaserod colon enteric-coated tablet in vitro dissolution less than 1% in artificial gastric juice for 2 hours; 37 ⁇ 6.8 dissolution less than 1% in 3 hours in artificial intestinal juice; 37t: pH 7.8 artificial intestinal juice The lh dissolves more than 85%.
  • Tegaserod maleate 10. 0g
  • Barium sulfate was filled into this colon enteric-coated hollow capsule, and a barium sulfate tracer capsule was made.
  • Five in vivo tracking experiments, X-ray inspections, and film recordings were performed. The results showed that after taking the capsule, three of them All three capsules of barium sulfate tracer capsules disintegrated in the ileocele, all three capsules of barium sulfate tracer capsules disintegrated in the ascending colon, and the disintegration site of three capsules taken by one person was the ileum The tip.
  • Example 12 Telageros colon-localized preparation of delayed type-Tegaserod enteric-coated tablets Tegaserod core formulation (1000 tablets)
  • the tablets are made according to the above-mentioned prescription of Etopril tablet core, and then coated with the prescription of the aforementioned enteric-coated coating solution to obtain Etopril-coated enteric-coated tablets.
  • the tegaserod common capsule was coated with the above-mentioned colon enteric coating solution, and the thickness of the coating was 240 micrometers.
  • the in vitro dissolution test results of this tegaserod colon enterosol ⁇ 37X in artificial gastric juice for 2 hours, the dissolution is less than 1%; 37 pH6.8 in the artificial intestinal fluid is less than 1% in 3h; 37t pH7.8 artificial intestine In lh, more than 90% was dissolved.
  • Barium sulfate was filled into ordinary capsules and coated with the aforementioned colonic enteric coating solution to make barium sulfate tracer capsules.
  • Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that taking this After the capsules, the three barium sulfate tracer capsules taken by two of them disintegrated in the ileocele, the three barium sulfate tracer capsules taken by one disintegrated in the transverse colon, and the other two took The disintegration site of the three capsules is the terminal site of the ileum, as shown in Table 9.
  • the common capsules described in the present invention include gelatin capsules, starch capsules and HPMC capsules.
  • Example 14 Test of isolated intestinal smooth muscle contraction in rabbits This experiment confirmed the possibility of gastrointestinal motility drugs binding to receptors through the colonic mucosa, and studied the gastrointestinal motility drugs metoclopramide (Metoprolol), Dynamic effects of casserole, mosapride, cisapride, and etoride on isolated intestinal smooth muscle in rabbits.
  • the rabbits were sacrificed by air embolism in the ear veins, and then the abdominal midline incision was immediately taken out.
  • the duodenum and the colon close to the ileocecal region were taken out about 10 cm, and placed in Tyrode, S solution, and 95 % 0 2 and 5% (: 0 2 mixed gas in the flat, wash the contents of the intestine with Tyrode, s solution, separate the mesentery along the intestinal wall.
  • Take 2 ⁇ 3cm duodenum or colon put in the container 20ml Tyrode, s bath of liquid (previously 02 through 95% and 5% C0 2 gas mixture, incubated at 37.C).
  • bowel ends two diagonally hanging hook, fixed to the lower end of the bath ventilation On the hook of the side tube, the other end is suspended by a muscle tension transducer with a thread, and the specimen is given a load of 2.0 g.
  • the contraction amplitude and contraction frequency of the specimen are recorded by a physiological recorder.
  • Contraction amplitude change rate (%) (post-dose contraction amplitude-pre-dose contraction amplitude) / pre-drug contraction amplitude ⁇ 100.
  • Each experiment consists of sixteen groups, namely metoclopramide high, middle and low dose groups, tegaserod high, middle and low dose groups, mosapride high, middle and low dose groups, and cisapride high, middle and low dose groups.
  • the results are shown in Tables 1, 2, 3, and 4 based on the three high-dose, low-dose, and blank (N.S) control groups.
  • Table 1 Effects of drugs on the rate of change in duodenal contraction in isolated rabbits (X ⁇ SD)
  • Cisapride 1 11.6 ⁇ 1.5 11.9 ⁇ 1.7 12.1 ⁇ 1.8 11.7 ⁇ 1.4
  • Drug dosage Frequency of contraction at different times before and after administration (times / minute)
  • Etolycol colon-locating capsule group (group A, samples were prepared according to Example 3) 15 cases, 6 males and 9 females, aged 20 to 64, with an average of 41.0 ⁇ 16.1 years old, with a course of March to 12 years, with an average of 3.38 ⁇ 2. 14 years; Etopril capsules (Group B, homemade sample.
  • constipation formulated in the 1990 National Symposium on Secret Diagnosis and Treatment Standard, constipation manifests as 1 the stool is indurated, with a small amount, and it is sheep-feces-like, and it is difficult to defecate, and the time is prolonged; 2 the stool is indurated, and then the stool is soft, the defecation is weak or unclean, and the defecation time is prolonged; 3 intentionally, but Defecation, no defecation, prolonged defecation, normal stool, the above symptoms may be accompanied by abdominal pain, bloating; bowel movements once every two or more days; colonoscopy found no intestinal organs such as swelling, ulcers, erosions Sexual lesions, heart, liver, kidney function, blood routine were normal.
  • Treatment method Laxative drugs are stopped before treatment.
  • Patients in group A take colon-targeted release of etopril capsule, 50mg once, twice a day, orally at 8 am and 8 pm every day.
  • Patients in group B take etopril commonly Capsules, once a day 50mg, twice a day, orally at 8 am and 8 pm daily;
  • Group C took 1 tablet of fruit guide (100 mg), which was taken orally before bedtime. The course of treatment was 7 days.
  • Efficacy criteria Efficacy criteria Clinical cure: Normal stool, or return to pre-illness, all other symptoms disappear. Significant effect: Refers to the disappearance or obvious improvement of constipation, the complete or partial disappearance or obvious improvement of the accompanying symptoms such as abdominal pain and bloating. Effective: Means that constipation or accompanying symptoms are improved compared to before medication. Ineffective: means that the above symptoms do not improve significantly, or even worsen. Addition of effective and significant effects is always effective.
  • Defecation interval time index 0 Defecation interval time ⁇ 24 hours.
  • Level 1 Defecation interval between 24 and 48 hours.
  • Level 2 Defecation interval 48-72 hours.
  • Level 3 Defecation interval> 72 hours.
  • Fecal Property Index Grade 0 Normal (fecal softening). Level 1: Feces are slightly dry, but excretion is not difficult. Level 2: Feces are dry but sticky. Level 3: The stool is dry and it looks like sheep faeces. It is difficult to excrete.
  • Defecation effort index 0 effortless.
  • Level 1 Can be excreted with light pressure during defecation.
  • Level 2 Strong help during bowel movements (represented by complexion redness, nervousness, clenched hands) before discharge.
  • Level 3 Strong help during bowel movements (represented by complexion turning red, nervous, grasping both hands), and need help by hand or other means to excrete.
  • Abdominal pain index 0 No abdominal pain.
  • Level 1 Slight abdominal pain, which can be relieved within half an hour without affecting life.
  • Level 2 Abdominal pain persists, partially affecting normal life, but acceptable.
  • Level 3 Abdominal pain persists, life is affected, unacceptable, and pain medication is needed.
  • Grades 0, 1, 2, and 3 set out above are calculated as 0, 1, 2, and 3 points, respectively, and the scores before and after treatment in each group are compared.
  • Table 6 The comparison of symptom score improvement before and after treatment in each group is shown in Table 6.
  • the results in Table 6 show that after treatment, the main clinical symptoms of group A and group C are significantly improved, the scores are decreased, and there are significant differences compared with before treatment (P ⁇ 0.05).
  • the main clinical symptoms of group B were partially improved, and the scores were slightly decreased, but after statistical processing, the difference was not significant (P> 0.05).
  • the index scores of defecation interval, stool properties, and defecation effort were significantly reduced. Compared with group B, the difference was significant (P ⁇ 0.05).

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne des compositions pharmaceutiques adaptées au colon de médicaments améliorant la motilité du tractus gastro-intestinal et leur utilisation. Ces compositions sont constituées de substances adaptées au colon, d'une dose unitaire contenant une quantité cliniquement efficace de médicaments améliorant la motilité du tractus gastro-intestinal, et d'excipients pharmaceutiquement acceptables. Lesdites substances adaptées au colon peuvent se présenter sous la forme d'un revêtement extérieur entourant la dose unitaire ou bien de capsules qui peuvent se dissoudre dans le colon. Il a été démontré de façon expérimentale que la composition adaptée au colon présentée a un effet bien supérieur à celui des formulations habituelles et des médicaments utilisés habituellement pour traiter cliniquement la constipation.
PCT/CN2004/000244 2003-03-26 2004-03-24 Compositions pharmaceutiques adaptees au colon de medicaments ameliorant la motilite du tractus gastro-intestinal, et leur utilisation WO2004084867A1 (fr)

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CN03120970A CN1456148A (zh) 2003-03-26 2003-03-26 胃肠动力药在制备结肠定位药物组合物中的用途
CN03120970.X 2003-03-26

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WO2004084867A1 true WO2004084867A1 (fr) 2004-10-07

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CN100413502C (zh) * 2006-09-15 2008-08-27 天津市中央药业有限公司 治疗高血压药物
CN102600091B (zh) * 2012-02-13 2014-01-29 迪沙药业集团有限公司 一种盐酸伊托必利分散片组合物
CN112022878A (zh) * 2019-06-04 2020-12-04 鲁南制药集团股份有限公司 一种用于缓解或治疗便秘的联合用药物用途

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CN1084386A (zh) * 1993-04-19 1994-03-30 李加海 靶向结肠给药肠溶空心胶囊生产新工艺
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CN1326733A (zh) * 2000-06-07 2001-12-19 张昊 结肠定位释放的口服制剂及其制备方法
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CN1084386A (zh) * 1993-04-19 1994-03-30 李加海 靶向结肠给药肠溶空心胶囊生产新工艺
CN1239425A (zh) * 1996-11-15 1999-12-22 普罗克特和甘保尔公司 供结肠释放的具有多层肠溶聚合物包衣的药剂
CN1326733A (zh) * 2000-06-07 2001-12-19 张昊 结肠定位释放的口服制剂及其制备方法
CN1343488A (zh) * 2000-09-15 2002-04-10 付俊昌 一种胶囊体及其制备方法和用途

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