WO2004084867A1

WO2004084867A1 - The colon-targeted pharmaceutical compositions of gastrointestinal motility drugs and their use

Info

Publication number: WO2004084867A1
Application number: PCT/CN2004/000244
Authority: WO
Inventors: Chengguo He; Chengfei Zhang; Mei Li
Original assignee: Beijing Orientking Pharmaceutical Science & Technology Co., Ltd.
Priority date: 2003-03-26
Filing date: 2004-03-24
Publication date: 2004-10-07
Also published as: CN1456148A

Abstract

The invention relates to, the colon-targeted pharmaceutical compositions of gastrointestinal motility drugs and their use. The compositions consist of the colon-targeted materials and the unit dose that comprising clinical effective amount of gastrointestinal motility drugs and the pharmaceutical acceptable excipients. The said colon-targeted materials may be the outer coating surrounding the unit dose or capsules that can solve in the colon. It is experimentally demonstrated that the colon-targeted composition according to, the invention is significant superior to, the common formulation and the drugs that are usually used to, treat constipation clinically.

Description

Gastrointestinal motility drug

Composition and uses thereof

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. Background technique

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.

With the gradual aging of society, the accelerated pace of modern life and changes in diet structure, the incidence of chronic functional constipation in the population has gradually increased, and the effectiveness of its treatment and control has received increasing attention. Constipation not only seriously affects the quality of life of patients, but also has a close relationship with the incidence of colorectal and rectal cancer in the population. Of the total population of 400 million in the United States, more than 2.5 million patients visit for constipation each year, and more patients taking laxatives are outside this statistical range. Domestic Dai Fei and others used a self-assessment questionnaire to survey 1,535 healthy people. The total prevalence of the population was 9. 18%, of which 7.28% were male, 11.4% were female, and 14.8% were 60 years or older. There are huge populations of constipation patients in China.

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. At present, laxatives are mainly used clinically to treat functional constipation, but it is often difficult to completely solve the problem. According to its basic function, 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. 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.

Clinicians have included the gastrointestinal motility drug cisapride in the therapeutic range of constipation indications, and it is expected that the constipation problem of patients will be solved through the gastrointestinal promotive effect of the drug. The common preparation of cisapride disintegrates in the stomach after oral administration, most of the drugs are absorbed in the stomach and small intestine, and very few drugs reach the colon and rectum (the original drug of cisapride in feces is only 4-6%), There are also very few drugs that reach the corresponding receptors of colonic smooth muscle through blood circulation, so that the common pro-acting effect of cisapride on the stomach and upper gastrointestinal tract is clear, but the effect of treating constipation is not clear and the effect is poor. In addition, due to the serious cardiovascular side effects of cisapride, more than 80 patients have reportedly died from the side effects of cisapride. The State Drug Administration has restricted this product since September 1, 2000. Sales and management, so the use of cisapride (oral common preparation), the only gastrointestinal power drug currently available for the treatment of constipation, is severely restricted and there are potential medical risks.

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.

Based on the above-mentioned problems related to the treatment of clinical drugs for constipation, we combined the gastrointestinal promotive effect of gastrointestinal motility drugs with colon-localized release technology, so that the local concentration of the drug in the colon cavity was greatly increased, so as to enhance the local promotive effect of the nodules and rectum. Constipation, while avoiding the side-effects of gastrointestinal promotive effects. The invention uses the colon-targeted targeted release technology of gastrointestinal power drugs to successfully solve the problem of oral administration of such drugs. The result is poor treatment of constipation, and it may cause systemic side effects after absorption into the blood circulation through the gastrointestinal tract.

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. However, for those skilled in the art, it is impossible to know from the above patents the effects of the naproxen and paracetamol prototype drugs after they reach the colon, and to prepare naproxen and paracetamol into colon-targeted release capsules. Later, its clinical effectiveness and changes in the incidence of side effects, and at the same time, it does not provide any solution to the above questions, and the solution of these problems related to colon-localized drug confirmation is very important. It is specially designed in the process of the present invention The experiments on the effect of local release of gastrointestinal motility drugs on colonic smooth muscle were conducted. Such experiments are the key to determine whether gastrointestinal motility drugs can be treated by oral colonic localization and these problems are not inferred by those skilled in the art based on common sense of. Summary of the Invention

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.

To achieve the above object, 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 (or excipient) can be acrylic resins, such as Eudragit® from German company Roma, domestic acrylic resin Π 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. This means that within a certain range, if the sensitive pH of the coating material is lower, the thickness of the coating will be larger. Some, if the sensitive pH of the coating material is higher, the thickness of the coating will be smaller. 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%. 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%, 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 25½, 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. If the proportion of Youtech Qi L100 in the mixed material is high, 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. 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. These enzymes 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. However, 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 scholars have prepared compressed coated tablets and matrix tablets of pectin calcium, which both show good colonic localization. Previous studies have shown that the calcium content of pectin calcium is closely related to its colonic localization effect, the calcium content affects the water solubility of pectin calcium, and the presence of calcium ions affects the strength of the enzyme's degradation of pectin calcium. Zhang Goushou proposed in the patent CN1326733 that the colonic positioning effect is good when the calcium content is in the range of 5% to 12%.

When the pectin calcium is used as a colon positioning material in the present invention, 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%;

When pectin calcium is used as a colon positioning material, a coated tablet is prepared by compressing the main drug and auxiliary materials into tablets, and then pressing and coating with pectin calcium. In the pectin calcium coated tablet of the present invention, 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%. If tegaserod is used as the active ingredient, 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. Such 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 Into the pharmaceutical composition, 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 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 experiment proves that the total effective rate and clinical cure rate of the colon-targeted pharmaceutical composition of the present invention in treating constipation are significantly higher than those of common preparations and drugs commonly used in clinical treatment of constipation, while the inefficiency is obviously lower than that of ordinary preparations and clinical treatment of constipation Drug. detailed description

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 Γ 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. Solution B: Take 2.76g of sodium dihydrogen phosphate, dissolve in water, and dilute to 100ml. Take 91.5 ml of the above nail solution and 8. 5 ml of the liquid B, and shake the hook to obtain.

Method for preparing artificial colon fluid of pH 7.8 according to the present invention 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 Nothing. 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. The following examples are provided to further illustrate the present invention, but not to limit the scope of the present invention. Example 1 _PH- sensitive Etopril colon-specific preparation

Etopril hydrochloride 50.0 g

Lactose 30.0 g

Microcrystalline cellulose 40.0 g

Magnesium stearate 1.5 g

Above, 1000 ordinary hollow capsules were loaded.

Formula of colon enteric coating solution:

Youtech L 100 12. 5 g

Youtech S 100 37.5g

Diethyl phthalate 5.0 g

Talc powder 8.0g

85% ethanol 950.0 g was coated with the aforementioned colonic enteric coating solution to the above-mentioned Etopril ordinary capsules, and the thickness of the coating was 110 microns. Relying on this will facilitate an enteric gum Nang colon in vitro dissolution test results: 37 of artificial gastric juice for 2 hours, the dissolution is less than 1%; 37 "C pH6 8 3h dissolution artificial intestinal juice below _{1%; 37 Ρ Η7 8.} . More than 75% of lh was dissolved in phosphate buffer.

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

Example 2 _PH- sensitive Etopril colon-localized preparation-Etopril colon enterosol

Reliability 100. 0g

Lactose 25.0g

Microcrystalline cellulose 25.0g

Magnesium stearate 2 g

Above 1000 capsules of ordinary capsules.

Formula of colon enteric coating solution:

Youtech L 100 22. 5 g

Youtech S 100 17. 5g

Diethyl phthalate 5.0 g

Talc powder 8.0g

85% ethanol 950. 0g was coated with the aforementioned colonic enteric-coated coating solution to the above-mentioned Etopril ordinary capsule, and the thickness of the coating was 240 micrometers. The results of the in vitro dissolution test of this reliance on colonic enterosol: 37X: 2 hours in artificial gastric juice, the dissolution is less than 1%; 37X pH6.8, 3h dissolution in artificial intestinal juice is less than 1%; 37X pH7.8 phosphate More than 90% of lh was dissolved in the buffer.

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

Example 3 pH-sensitive Etopril colon-targeting formulation-Etopril colon enterosol

Heart Relief Formula Based on Bili Colonic Enterosol

Reliability 50. 0g

Lactose 50.0 g

Microcrystalline cellulose 50, 0g

Magnesium stearate 1.5 g

Above, 1000 capsules of the above-mentioned colonic enteric-coated hollow capsules (Guangzhou Chaozhou medicinal gum: manufactured by the factory) were loaded. The results of the in vitro dissolution test of this relied on colonic enterosol 嚢: 37 € 2 hours in artificial gastric juice, the dissolution is less than 1%; 37 pH6.8, 3h dissolution in artificial intestinal juice is less than 1%; 37t pH7. 8 phosphate More than 80% of lh was dissolved in the buffer.

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.

Table 3 Disintegration sites of barium sulfate tracer capsules

Example 4 Formulation of pH-sensitive Etopril colon-targeted formulation-Etopril colon enteric-coated tablets Etopril tablet core (1000 tablets)

Reliability 50. 0g

Starch 20. 0g

Lactose 60. 0 g

Microcrystalline cellulose 15g

Carboxymethyl starch sodium 8g

Magnesium Stearate 1. 5g

Formula of colonic enteric coating solution

Cellulose acetate phthalate 80g

Diethyl phthalate 5.0 g

Talc powder 10.0g

80% ethanol 95.0g

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. 00244 The in vitro dissolution test results of this 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.

It was compressed into tablets with barium sulfate, and coated with the colonic enteric coating solution to make barium sulfate tracer tablets. Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that after taking the tablets, The disintegration site of the three barium sulphate tracer tablets taken by two of them was the ileocele, the three disintegration sites of one took the transverse colon, the three disintegration sites of one took the ascending colon, and the three were taken by one. The disintegration site is the terminal ileum, as shown in Table 4.

Disintegration site of barium sparse acid tracer

Example 5 Formulation of Time-Dependent Etopril Colon Enteric-Coated Tablets-Etopril Colon Enteric-coated Tablets Etopril Tablet Core (1000 Tablets)

Reliability 25.0g

Starch 50.0 g

Lactose 100. 0 g

Microcrystalline savirin 80g

Sodium Carboxymethyl Starch 20g

Magnesium stearate 3g

Formula of colonic enteric coating solution

60 g of ethyl cellulose 0ethyl dibenzyl dicarboxylate 5.0 g

Talc powder 10.0g

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.

The results of the in vitro dissolution test of this Etoile Colon enteric-coated tablet: 37% dissolution in artificial gastric juice for less than 3%; 37 pH6.8 dissolution in artificial intestinal juice for less than 5% in 3h; 37 pH7.8 phosphate buffer Lh dissolved more than 75% in the liquid.

It was compressed into tablets with barium sulfate, and coated with the colonic enteric coating solution to make barium sulfate tracer tablets. Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that after taking the tablets, The disintegration site of the three barium sulfate tracer tablets taken by two of them was the ileocele, the disintegration site of the three tablets taken by one person was the transverse colon, and the disintegration site of the three tablets taken by the two of them was the terminal ileum, as shown in Table 5.

Disintegration site of barium sparse acid tracer

Example 6 pH-sensitive cisapride colon positioning preparation-cisapride colon enterosol

Cisapride 5. 0g

Starch 30.0 g

07.0 g of lactose Microcrystalline cellulose 80. Og

Magnesium stearate 2 g

Above 1000 capsules of ordinary gum ^

Formula of colonic enteric coating solution

Youtech L 100 12. 5 g

Youtech S 100 37.5g

Diethyl Cool Phthalate 5.0 g

Talc powder 8.0g

90% ethanol 950. Og The above-mentioned cisapride common capsule was coated with the aforementioned colon enteric coating solution, and the thickness of the coating was 110 micrometers. The results of in vitro dissolution test of cisapride colon intestinal sol: 2 hours in artificial gastric juice, less than 1% dissolution; 37 "C pH6.8, 3 hours dissolution in artificial intestinal juice, less than 1%; 37 ρΗ7.8 phosphate More than 80% of lh was dissolved in the buffer.

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 嚢 Bacterial or enzyme-sensitive hollow capsule-pectin calcium hollow capsule

15% low methoxyl pectin (LMP) aqueous solution 100ml

5% CaCl ₂ ethanol-water (7: 3) solution 100ml

5% PVP ethanol solution 100ml 100% 8% acrylic resin Π alcohol solution, apply liquid paraffin to the clean stick mold, then immerse it in 15% LMP solution for 30 seconds, then lift out, then immerse in 5% CaCl ₂ ethanol (70%) solution, calcify () for 1 hour, place in Blow dry at 35% RH, then immerse in 5% PVP ethanol solution for 2 minutes, and then put 35C RH35% blow to near dry, then immerse in 8% acrylic resin No. Ⅰ alcohol solution for 1 minute, and put out blow drying.

Heart Sickness Formula for Cisapride Colonic Enterosol

20.0g

25.0g

If more than lg is filled with 1000 capsules of the above-mentioned colonic enteric-coated hollow capsules, it is necessary to rely on bilioli colonic enterosol. This cisapride colon enteric gum Nang vitro dissolution test results: 37 X: artificial gastric juice for 2 hours, the dissolution is less than _{3%; 37Χ:. Ρ Η6} 8 3h dissolution artificial intestinal juice below 5%; 37 ρΗ7. 8 lh dissolves more than 75% in artificial colon fluid.

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.

Table 6 Disintegration sites of barium sulfate tracer capsules

Terminal ileum 0

Blinding Department 0

Ascending colon 4

Transverse colon 1 Example 8 pH-sensitive cisapride colon-specific preparation

Heart Sickness Formula for Cisapride Colonic Enterosol

10. 0g

40.0 g

50.0 g

50. 0 g or more are filled with 1000 capsules of the above-mentioned colonic enteric-coated hollow capsules (produced by Guangdong Chaozhou Medicinal Rubber capsule factory). The dissolution test results of this cisapride colon intestinal sol: in 2 hours in 37 * C artificial gastric juice, the dissolution was less than 1%; 37 pH 6. 8 in the artificial intestinal juice was less than 1% in 3h; 37X: pH 7. 8 More than 85% was dissolved in artificial intestinal fluid for 1 hour.

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 9 pH-sensitive cisapride colon-targeted preparation-cisapride colon enteric-coated tablets cisapride tablet core formulation (1000 tablets)

Cisapride 5. 0g

Starch 30.0 g 70.0 g

Microcrystalline cellulose 80.0 g

Magnesium stearate 2g

Formula of colonic enteric coating solution

Youtech L100 12. 5g

Youtech S100 37. 5g

Diethyl phthalate 5. Og

Talc powder 10. Og

80% ethanol 950. 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.

The dissolution test results of this cisapride colon enteric-coated tablet in vitro: 2 hours in 37X artificial gastric juice, less than 1% dissolution; 37 pH6.8 less than 1% in 3h dissolution in artificial intestinal juice; 37t pH 7. 8 artificial intestinal juice lh dissolves more than 85%.

It was compressed into tablets with barium sulfate, and coated with the colonic enteric coating solution to make barium sulfate tracer tablets. Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that after taking the tablets, The disintegration site of the three barium sulfate tracer tablets taken by two of them was the ileocele, the disintegration site of the three tablets taken by the two was the transverse colon, and the disintegration site of the three tablets taken by one was the ascending colon. Example 10 pH-sensitive tegaserod colon-localized preparation-tegaserod enteric-coated tablets Tablet core prescription: (1000 tablets)

Tegasero l. Og

Lactose 70.0 g

0g microcrystalline cellulose Starch 30. Og

Magnesium stearate 2 g

Formula of colon enteric coating solution:

Youtech L100 12. 5g

Youtech S100 37. 5g

Diethyl phthalate 5. Og

Talc powder 10. Og

80% ethanol 950. 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 ρΗ6.8 dissolution less than 1% in 3 hours in artificial intestinal juice; 37t: pH 7.8 artificial intestinal juice The lh dissolves more than 85%.

It was compressed into tablets with barium sulfate, and coated with the colonic enteric coating solution to make barium sulfate tracer tablets. Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that after taking the tablets, The disintegration site of the three barium sulfate tracer tablets taken by two of them was the ileocele, the disintegration site of the three tablets taken by the two was the transverse colon, and the disintegration site of the three tablets taken by one was the ascending colon. Example 11 pH-sensitive tegaserod colon-specific preparation-tegaserod enteric-coated

Capsule Prescription for Tegasero Colon Enterosol

Tegaserod maleate 10. 0g

Starch 15.0g

Lactose 10. 0g Microcrystalline cellulose 25.0g

Above, 1000 capsules of the above-mentioned colon enteric-coated hollow capsules (produced by Guangdong Chaozhou Medicinal capsule factory) were loaded. The in vitro dissolution test results of this tegaserod colon enterosol 嚢: 2 hours in artificial gastric juice, the dissolution was less than 1%; 37 "C _P H6.8. 3 h dissolution in artificial intestinal juice was less than 1%; 37 pH 7. 8 More than 80% of lh was dissolved in artificial intestinal fluid.

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)

Tegasero 5.0g

Starch 50.0 g

Powdered sugar 30.0 g

Dextrin 40.0 g

Magnesium Stearate 1. 5g

Formula of colonic enteric coating solution

Ethyl cellulose 60g

Diethyl phthalate 5.0 g

Talc powder 10.0g

80% ethanol 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 results of the in vitro dissolution test of Etobic colon enteric-coated tablets were as follows: Dissolution was less than 3% in 37 * C artificial gastric juice for 2 hours; 37 pH6.8 was less than 5% in 3h in artificial intestinal juice; More than 75% of the intestinal fluid was dissolved by lh.

It was compressed into tablets with barium sulphate, and coated with the colonic enteric coating solution to make barium sulfate tracer tablets. Five in vivo tracking experiments, x-ray inspections, and film recordings were performed. The results showed that after taking the tablets Among them, the disintegration site of the three barium sulfate tracer tablets taken by two persons was the ileocele, the disintegration site of the three tablets taken by the one person was the transverse colon, the disintegration site of the three tablets taken by one person was the ascending colon, and the one taken by the three tablets was The disintegration site is the terminal ileum, see Table 8.

Disintegration site of sulfate lock tracer

Example 13 pH-sensitive tegaserod colon-localized preparation-tegaserod colon enterosol

Tegaserod 6.0g

Lactose 50.0 g

Microcrystalline cellulose 50. 0g

Magnesium stearate 2 g

Above 1000 capsules of ordinary capsules.

Formula of colon enteric coating solution:

Youtech L 100 22. 5 g Youtech S 100 17. 5g

Diethyl phthalate 5.0 g

Talc powder 8.0g

85% ethanol 950. 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 嚢: 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.

Table 9 Disintegration sites of barium sulfate tracer capsules

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.

According to the technical requirements of pharmacodynamics research of new drug approval measures, this experiment observed The effect of the drug on the automatic rhythmic contraction of intestinal smooth muscle of isolated rabbits was evaluated to evaluate its effect on intestinal motility and provide animal experimental basis for clinical application.

After 24 hours of fasting, 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. After equilibrating for 10 to 20 minutes, the contraction amplitude and contraction frequency of the specimen are recorded by a physiological recorder. The contraction status before the drug, and then observe and record the effects of different concentrations of drugs and different time (10min, 20min, 30min) on the amplitude and frequency of duodenal and colon smooth muscle contraction in rabbits. After the effect is stable, the drug solution is released And rinse with fresh Tyrode, s solution 2 ~ 3 times, rinse Fresh bath can stay l ~ 2min then let go to allow liquid on myenteric be sufficiently clean, until a smooth baseline restoration dosing may again.

Contraction amplitude change rate (%) = (post-dose contraction amplitude-pre-dose contraction amplitude) / pre-drug contraction amplitude χ100.

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)

Dose Change rate of contraction amplitude at different times after administration (%)

(xlO ^-6 mol / L) 10 min 20min 30min

_ NS_ __ 2.3, 8 5.4¾.2 4.9 ^ 9.8 Metoclopramide 4.8 ^ 7.1 6.6 ± 11.3 7.5 ± 12.2

4.9¾.5 8.0 ± 12.4 7.9 ^ 9.5 5.3 ^ 7.0 8.5 ± 11.8 8.4 ± 12.3 Tegasero 17.8¾.1 ** 18.4 ± 10.1 ** 21.5 J9.5 **

30.9¾.5 ** 34.0 ± 10.2 ** 39.9 ^ 9.4 ** 45.8 0 ** 48.5 ± 10.8 ** 57.4 ± 10.3 ** Mosapride 12.3¾.9 ** 15.2 ± 12.7 ** 16.6 ± 10.8 **

25.7 ± 17.0 ** 29.0 ± 19.9 ** 38.1 ¾3.7 **

10 45.2¾1.5 ** 47.5 ¾6.4 ** 57.3 ± 40.5 ** Cisapride

Reliable

Number of animals in each group N = 10, compared with NS group: * P <0.05, ** P <0.01,

Effects of drugs on the rate of change in colon contraction amplitude in isolated rabbits (XiSD) Drug dose Rate of change in contraction amplitude at different times after administration (%)

(xlO " ^e mol / L) 10 min 20min 30min

NS-1.5 ± 1.8 1.4¾.1 1.9 ± 1.0 Metoclopramide 1 0.7 ± 1.0 1.7 ± 1.9 2.2¾.1

3 1.5 ± 1.3 2.1¾.7 2.6¾.2

10 1.3 ± 1.6 1.8 ± 1.8 2.3 ± 1.9 Tegaserod 1 21.8 ^ 7.1 ** 22.6 ± 11.3 ** 27.5 ± 12.2 **

3 44.9 5 ** 50.0 ± 12.4 ** 61.9 ^ 9.5 **

10 65.3 0 ** 67.5 ± 11.8 ** 68.4 ± 12.3 ** Mosapride 1 3.3¾.3 * 3.9 ¾.5 ** 3.2¾.8

3 5.1 ¾.0 ** 6.8 .5 ** 6.9 ^ .9 **

10 7.4 ± 4.3 ** 8.6¾.5 ** 8.7 4 ** Cisapride 1 22.5 ± 19.6 ** 19.3 ¾0.0 ** 27.9 ¾6.1 **

3 42.2¾5. 8 ** 53. 3 ¾9.2 ** 60.6 ¾8.7 **

10 64.7 ¾2.7 ** 62.9 ^ 5.3 ** 69.9 ¾7.3 ** Reliable 1 24.2¾1.8 ** 21.6¾2.0 ** 29.0¾7.4 **

3 45.2 ¾8.5 ** 54.3 ¾3.9 ** 62.6 ¾8.5 **

10 67.2 ¾0.1 ** 67.9 ± 13.2 ** 71.5 ^ 46.0 ** The number of animals in each group is N = 10, compared with the NS group: * P <0.05, ** P <0.01.

Effects of drugs on the frequency of duodenal contraction in isolated rabbits (XiSD) Drug dose Frequency of contraction at different times before and after administration (times / minute)

(xlO " ⁶ mol / L) 10 min before administration 20 min 30 min

NS-1 12.3 ± 1.7 11.6 ± 1.4 11.9¾.1 12.3 ± 1.5 Metoclopramide 1 11.3J0.9 11.74.9 11.5 ± 1.1 11.2 ± 1.3

3 11.6 ± 1.1 11.3 ^ 0.7 11.9 ± 1.0 11.7 ± 1.9

10 10.8 ^ 0.8 11.2 ± 1.4 10.8 ± 1.3 10.7 ^ 0.6 Tegaserod 1 11.5 ± 1.9 11.7 ^ 0.9 11.8 ± 1.3 11.4 ± 1.0

3 11.9 ± 1.8 11.9¾). 7 11.6 ± 1.5 12.0 ± 1.2

10 12.0 ± 1.8 11.8 ± 1.0 11.8 ± 1.3 11.9 ^ 0.8 Mosapride 1 11.7 ± 1.4 11.3 ± 1.9 12.0 ^ 0.7 12.1 ± 1.5

3 12.4 ± 1.6 12.1 ± 1.8 11.7 ± 1.7 11.5 ± 1.0

10 11.5 ^ 0.8 11.4 ± 1.2 10.7 ^ 0.7 11.3 ± 1.4 Cisapride 1 11.6 ± 1.5 11.9 ± 1.7 12.1 ± 1.8 11.7 ± 1.4

3 11.9 ± 1.1 12.3 ± 1.0 11.8 ± 1.3 11.3 ± 1.6

10 11.8 ^ 0.9 12.0 ^ 0.9 11.5 ± 1.4 11.7 ± 1.2 Reliabil 1 11.9 ± 1.3 12.4 ± 1.9 12.3 ¾.0 11.7 ± 1.5

3 11.8 ± 1.0 12.0 ± 1.1 12.0 ± 1.3 11.6 ± 1.8

10 11.6 ± 1.3 12.2 ^ 0.7 11.7 ± 1.6 11.8 ± 1.1 Number of animals in each group N = 10.

Table 4 Effect of drugs on colon contraction frequency of isolated rabbits (XiSD)

Drug dosage Frequency of contraction at different times before and after administration (times / minute)

(xlO— W / L) before administration 10 min 20min 30min

NS- 7.4 ± 1.1 7.5 JO.7 7.8 ^ 〇.9 7.8 ± 1.0 Metoclopramide 1 7.8¾.6 7.3 ^ 0.8 7.5 6 7.3 ^ 0.5

3 7.6 ± 1.0 8.1 ± 1.2 8.0 JO.9 7.9 ± 1.3

10 7.5¾.8 7.8 ± 1.0 7.8 JO.8 7.7 ± 1.2 Tegaserod 1 7.9¾.9 7.7 ± 1.9 7.9 ± 1.1 7.6 ± 1.3

3 7.7 ± 1.1 7.5¾.7 7.8 ± 1.0 7.9 ± 1.9

10 7.8 ^ 0.8 7.6 ± 1.4 7.8 ± 1.3 7.7 ^ 0.6 Mosapride 1 7.7 ± 1.5 7.5 ± 1.3 7.7 ± 1.4 8.0 ± 1.0

3 7.4 ± 1.1 7.3 ± 1.3 7.6 ± 1.2 7.5 ^ 0.7

10 7.5 8 7.7 ± 1.2 7.3 ± 1.0 7.6 JO.7 Cisapride 1 7.9 ± 1.5 7.6 ± 1.4 7.7 ± 1.1 7.8 ± 1.1

3 7.7 ^ 0.9 7.9 ± 1.1 7.8 ± 1.0 7.7 ± 1.1

10 7.6¾.6 7.5 ± 1.4 7.4 ± 1.5 7.5 ± 1.0 Reliable 1 8.1 ± 1.4 7.8 ± 1.2 7.9 ± 1.1 7.9 JO.9

3 8.0 7 8.2 ± 1.3 7.9 ± 1.3 8.0 ± 1.1

10 7.8 7 7.5 ± 1.1 7.6 ± 1.2 7.6 ± 1.2 Number of animals in each group N = 10. Above experimental results show that, compared with the control group, tegaserod at a concentration of ^{3, 10 xlO- 6 mol / L} , concentration of mosapride at 1, 3, 10 <10 " 6 mol / L At the concentration of 1, 3, 10 xlO " ⁶ mol / L, cisapride, at the concentration of 1, 3, 10 xlO- ⁶ mol / L, Etopril can significantly improve the duodenum and The contraction of the colon is dose-dependent. The effects of tegaserod, etobilide, and cisapride on the colon contractility of isolated rabbits were significantly stronger than those of mosapride, but tegaserod and Bili and cisapride have similar effects; while metoclopramide has no significant effect on the contractile amplitude of the duodenum and colon of isolated rabbits at concentrations of 1, 3, 10 xl (T ⁶ mol / L). Five drugs at a concentration of ^{3, 10 xlO- 6 mol / L} , had no significant effect on the contraction of rabbit duodenum and colon ex vivo frequency.

The above experimental results prove that the gastrointestinal motility drugs tegaserod, etopril, and cisapride can smoothly bind to the receptors on the smooth muscle of the colon through the colonic mucosa, and that the receptors on the colonic smooth muscle have a certain density to make the smooth muscles follow the drug concentration. Increase and increase contraction.

From the results of this test, it can be expected that the gastrointestinal motility drugs tegaserod, etopril, and cisapride can be designed as colon-targeted release preparations that enhance colonic contraction through local effects on the colon and are suitable for constipation. treatment. The results of the following clinical trials confirm this conjecture. Example 15 Effective data and methods of the colon-targeting pharmaceutical composition of the present invention General data Observation of a total of 40 cases, all of them were treated at the Medical Research Institute of the Chinese Academy of Textile Sciences, were unable to relieve constipation after repeated treatment with laxatives or strong laxatives Patients with chronic constipation. According to the randomized control method, it was divided into 3 groups, of which the 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. Formula: Etopril hydrochloride 50g, lactose 60g, starch 20g, microcrystalline cellulose 15g, carboxymethyl starch sodium 7.5g, magnesium stearate lg, and 1000 capsules of ordinary capsules after mixing well.) 12 cases, 4 males, 8 females, age 17 ~ 69 years old, with an average of 39.8 ± 1 2. 8 years old, with a course of August to 9 years, with an average of 3.45 ± 2.01 years; 13 cases of fruit guide film group (Group C, Tianjin Lisheng Pharmaceutical Factory, batch number 0101002) There were 5 males and 7 females, aged 17-68 years, with an average of 41.7 ± 14.64 years old. The course of disease was from June to 10 years, with an average of 3. 78 ± 2.09 years.

The gender, age, and course of disease of the three groups of cases were balanced (P> 0.05), and were comparable.

The diagnostic criteria refer to the 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.

Symptom classification criteria

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.

Bloating Index Grade 0: No bloating. Level 1: Slight abdominal distension, which is reduced or disappeared within half an hour, without affecting life. Grade 2: Discomfort of abdominal distension, which worsens after eating, partially affecting normal life. Grade 3: Abdominal discomfort is extremely uncomfortable, and does not resolve when fasting, and life is affected.

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.

Treatment results

The comparison of curative effect is shown in Table 5. It can be seen from Table 5 that the total effective rate of group A is higher than that of groups B and C. After statistical processing, there is a significant difference between group A and group B (P <0.01), and the difference between group A and group C is not significant. (P> 0.05).

Table 5 Comparison of treatment results in each group (%) Number of groups in clinical cure markedly effective effective ineffective total effective rate (%)

Group A 15 6 (40.0) 5 (33.3) 3 (20.0) 1 (6.7) 93.3 *

Group B 12 1 (8.3) 2 (16.7) 4 (33.3) 5 (41.7) 58.3

Group C 13 3 (23.1) 4 (30.7) 4 (30.7) 2 (15.5) 84.5

* Compared with group B, P <0.01

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). After treatment in group A, 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). Table 6 Comparison of improvement of symptom score before and after treatment in each group (X: * SD) (unit: points) Symptom index group A (n = 15 cases) Group B (n = 12 cases) Group C (n = 13 cases)

Before treatment After treatment Before treatment After treatment After treatment Before treatment After treatment ii ft interval 2.47 * .50 0.85 J0.52 * ▲ 2.49 JO.53 1.65 ¾) .52 2.44¾.55 0.98 JO.49 * Fecal properties .61 "1.76 JO.58 1.17 JO.67 1.87 JO.51 0.65 JO.63 *

# & Effort 1.97 67 0.66 65 * A 1.89 JO.61 1.35 JO.74 1.91 JO.63 0.64 JO.55 * abdominal pain 0.86¾). 61 0.35 JO.29 * 0.83 JO.57 0.55 JO.39 0.90 ^ 0.61 0. 1 27 * m ~ 0.78 ¾). 69 0.37 JO.32 * 0.88 ^ 0.66 0.57 33 0.83 65 0.39 29 *

* Before treatment and after treatment, P <0.05; AA group compared with group B, P <0.05 and above The clinical research results have preliminary proved that the gastrointestinal motility drug colon-specific preparation is superior to gastrointestinal motility when used to treat constipation It is a common drug preparation, and is better than the commonly used drugs for treating constipation.

Claims

Rights request

1. A colon-locating pharmaceutical composition for treating constipation, comprising a colon-locating material and a dosage unit containing a clinically effective amount of gastrointestinal motility drugs and medicinal excipients, said colon-locating material is wrapped in said dosage unit Outer coating or colonic enteric-coated hollow capsules.

2. The colon-locating pharmaceutical composition of claim 1, wherein said colon-locating material coating comprises an acrylic resin.

3. The colon-locating pharmaceutical composition of claim 1, wherein said colon-locating material coating comprises cellulose acetate phenolphthalein.

4. The colon-locating pharmaceutical composition of claim 1, wherein the colon-locating material coating comprises pectin calcium, pectin iron, or pectin zinc, or a mixture thereof.

5. The colon-targeting pharmaceutical composition according to claim 1, characterized in that said gastrointestinal motility drug is domperidone, metoclopramide, etopril, cisapride, mosapride, pupapride, and tega One of the theros.

6. The colon-targeting pharmaceutical composition according to claim 5, wherein said gastrointestinal motility drug is etorib.

7. The colon-targeting pharmaceutical composition according to claim 1, characterized in that said gastrointestinal power drug accounts for 0.1% to 90% of said dosage unit weight.

8. The colon-targeting pharmaceutical composition according to claim 7, characterized in that said gastrointestinal motility drug accounts for 0.3% ~ 5% of said dosage unit weight.

The colon-locating pharmaceutical composition according to claim 1, characterized in that said colon-locating material is a coating wrapped on the outer layer of a dosage unit, wherein the dosage unit is in the form of a common capsule, tablet or pellet.

10. Use of a colon-specific pharmaceutical composition according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of constipation.