CN113041213B

CN113041213B - Rectal suppository containing hyaluronic acid and tetrahydropyrimidine and preparation method thereof

Info

Publication number: CN113041213B
Application number: CN202110303090.1A
Authority: CN
Inventors: 王冠凤; 石艳丽; 董海光; 董艳美; 钱晓路; 周雪; 郭学平
Original assignee: Bloomage Biotech Co Ltd
Current assignee: Bloomage Biotech Co Ltd
Priority date: 2021-03-22
Filing date: 2021-03-22
Publication date: 2022-11-01
Anticipated expiration: 2041-03-22
Also published as: CN113041213A

Abstract

The invention provides a rectal suppository containing hyaluronic acid and tetrahydropyrimidine, which is characterized by comprising high molecular weight hyaluronic acid or salt thereof, low molecular weight hyaluronic acid or salt thereof, tetrahydropyrimidine or derivative thereof and gelatin. The invention also provides a preparation method of the rectal suppository containing hyaluronic acid and tetrahydropyrimidine, which comprises the following steps: preparing high molecular weight hyaluronic acid or salt thereof and gelatin into a matrix solution; adding low molecular weight hyaluronic acid or salt thereof and tetrahydropyrimidine or derivative thereof into the matrix solution, and uniformly mixing to obtain a rectal suppository solution; and preparing the rectal suppository solution into rectal suppositories. The rectal suppository prepared by the invention takes hyaluronic acid gelatin as a matrix, has good biocompatibility with a human body, is safe and mild, has no stimulation, and can reduce the stimulation of other medicine components through slow release.

Description

Rectal suppository containing hyaluronic acid and tetrahydropyrimidine and preparation method thereof

Technical Field

The invention belongs to the field of biological medicines, and particularly relates to a rectal suppository containing hyaluronic acid and tetrahydropyrimidine and a preparation method thereof.

Background

Constipation is a common clinical symptom. It is mainly manifested as hard stool. With the aging of society, the tension of modern life rhythm and the change of eating habits, constipation becomes one of the important factors influencing the quality of life of modern people. People who are prone to constipation are very wide, including children, pregnant women, the elderly, people who sit for a long time and move little, patients who lie in bed for a long time, and the like. Constipation affects the mood, and patients often develop melancholy and anxiety.

For constipation due to deficiency of body fluids caused by heat pathogen, strong purgative herbs should not be used. Enema is a common method for treating functional constipation, but most people reflect poor use experience and effect. The reason is that the opening end of the enema is hard and rough, so that the perianal mucosa is easily red, swollen and painful when in use, and even the rectal mucosa is damaged. Especially, when used by children, the feeling is not good and the coordination is not easy. In addition, the enema mainly stimulates the intestinal wall to cause defecation reaction in a reflex manner, so that the aim of relieving constipation is fulfilled. As often used, the intestinal wall becomes less and less sensitive to irritation, easily leading to poor results. But also dependence is generated by frequent use. Another reason why the enema is not suitable for pregnant women and children is that the enema may cause strong contraction of local tissues, cause transient ischemia in pregnant women and cause chronic inflammation. The stimulation of the enema may affect the normal function of the gastrointestinal tract in children due to the fragile intestinal mucosa.

The rectal suppository can avoid physical injury to the mucosa of the rectum caused by the enema, and can also avoid the side effect of the irritation on the intestinal wall and the dependence of the intestinal wall on the irritation caused by the enema.

Patent CN102114031B relates to a hyaluronic acid mixture for the treatment and prevention of inflammatory bowel diseases, comprising two or more hyaluronic acids with different molecular weights. The invention takes hyaluronic acid mixture as main component, is prepared according to the general pharmaceutical process, and can be prepared into rectal suppository by matching with proper excipient. Wherein the hyaluronic acid with different molecular weights comprises 50 to 150 million Da of hyaluronic acid and 150 to 500 million Da of hyaluronic acid, and the weight ratio of the two is 20:80 to 80:20, and the concentration of the hyaluronic acid mixture is regulated to be 0.5mg/ml to 50mg/ml. Patent CN106581073A discloses a Mongolian medicine rectal suppository for treating anorectal diseases and a preparation method thereof. Wherein the suppository matrix is polyethylene glycol honey matrix, namely 3-5.5 parts of polyethylene glycol are taken to be heated and melted in water bath, and then 0.8-1.5 parts of honey are added to be uniformly stirred. The invention indicates that the suppository prepared by using the pure polyethylene glycol as the matrix has good hardness, but the suppository is poor in toughness and easy to break, and the hardness is not influenced after the honey is added, so that the toughness can be increased, and the breakage can be reduced.

The glycerin-gelatin matrix is one of the most common matrixes, is prepared from gelatin, glycerin and water, has elasticity, is not easy to break, does not melt at body temperature, but can be slowly dissolved in secretion to prolong the curative effect of the medicine. Although glycerin can prevent suppository from drying, glycerin may cause irritation to mucous membrane when its local concentration is too high.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a rectal suppository containing hyaluronic acid and tetrahydropyrimidine and a preparation method thereof.

Specifically, the present invention relates to the following aspects:

1. a rectal suppository comprising hyaluronic acid and tetrahydropyrimidine, wherein the rectal suppository comprises high molecular weight hyaluronic acid or a salt thereof, low molecular weight hyaluronic acid or a salt thereof, tetrahydropyrimidine or a derivative thereof, and gelatin.

2. A rectal suppository according to claim 1, characterised in that the high molecular weight hyaluronic acid or salt thereof has a molecular weight of 20-200 million Da, preferably 100-200 million Da.

3. The low molecular weight hyaluronic acid or salt thereof has a molecular weight in the range of 0.5 to 20 million Da, preferably 0.5 to 10 million Da.

4. The rectal suppository according to item 1, characterized in that the gelatin is 30-50 parts, the high molecular hyaluronic acid or salt thereof is 0.1-1 part, preferably 0.5-1 part, the low molecular hyaluronic acid or salt thereof is 0.1-1 part, preferably 0.5-1 part, and the tetrahydropyrimidine or derivative thereof is 1-5 parts, preferably 3-5 parts, by weight.

5. The rectal suppository according to item 1, characterized in that it further comprises other primary drug ingredients, which are selected from one or more of steroids, immunosuppressants, and anti-inflammatory drugs.

6. A method for preparing a rectal suppository comprising hyaluronic acid and tetrahydropyrimidine, the method comprising the steps of:

preparing high molecular weight hyaluronic acid or salt thereof and gelatin into a matrix solution;

adding low molecular weight hyaluronic acid or salt thereof and tetrahydropyrimidine or derivative thereof into the matrix solution, and uniformly mixing to obtain a rectal suppository solution;

and preparing the rectal suppository solution into rectal suppositories.

7. The production method according to item 6, wherein the high molecular weight hyaluronic acid or salt thereof has a molecular weight of 20 to 200 ten thousand Da, preferably 100 to 200 ten thousand Da.

8. The production method according to item 6, wherein the low-molecular-weight hyaluronic acid or a salt thereof has a molecular weight of 0.5 to 20 ten thousand Da, preferably 0.5 to 10 ten thousand Da.

9. The method according to item 6, wherein the gelatin is 30 to 50 parts by weight based on 100 parts by weight of the rectal suppository solution.

10. The method according to item 6, wherein the polymeric hyaluronic acid or a salt thereof is 0.1 to 1 part by weight, preferably 0.5 to 1 part by weight, based on 100 parts by weight of the rectal suppository solution.

11. The preparation method according to item 6, wherein the low molecular weight hyaluronic acid or a salt thereof is 0.1 to 1 part, preferably 0.5 to 1 part, based on 100 parts by weight of the rectal suppository solution.

12. The preparation method according to item 6, wherein the tetrahydropyrimidine or derivative thereof is 1 to 5 parts, preferably 3 to 5 parts, based on 100 parts by weight of the rectal suppository solution.

13. Use of a rectal suppository according to any one of claims 1 to 5 or a rectal suppository prepared by the preparation method according to any one of claims 6 to 12 for the manufacture of a medicament for repairing mucous membranes and/or relieving constipation.

The rectal suppository disclosed by the invention has the following beneficial effects:

(1) The rectal suppository prepared by the invention takes hyaluronic acid gelatin as a matrix, and compared with a glycerin gelatin matrix, the hyaluronic acid gelatin matrix is natural in source, good in biocompatibility with a human body, safe, mild and non-irritant, and can reduce irritation of other medicine components through a slow release effect.

(2) The hyaluronic acid in the rectal suppository prepared by the invention can form a layer of protective film on the surfaces of contacted anal canal and rectal mucosa, and plays a role in protecting and repairing damaged or inflamed mucosa.

(3) The hyaluronic acid in the rectal suppository prepared by the invention has a lubricating effect, and more water enters a rectal cavity by utilizing the hypertonic effect of the tetrahydropyrimidine, so that excrement is softened, the excrement can be easily discharged, and constipation is relieved.

(4) The rectal suppository prepared by the invention has the combined action of the low molecular weight hyaluronic acid and the tetrahydropyrimidine, and can play the roles of relieving congestion and inflammation of anorectal, astringing and promoting healing. Therefore, the composition can also be used for symptomatic treatment of pain, swelling and bleeding caused by hemorrhoids, anal fissure and other anal diseases, and can also be used for relieving discomfort after local anal operation.

(5) The rectal suppository prepared by the invention can not cause the intestinal wall to generate dependence on the medicament after long-term use. The convenient defecation device is suitable for people with long-term constipation, has the effects of dredging without diarrhea and defecating without deficiency, enables defecating to be smooth and natural, can protect rectal mucosa and capillary vessels, and recovers the normal state of tissues in the anorectal region without any side effect.

Detailed Description

The present invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not intended to be limiting.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or experimental applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control, and the materials, methods, and examples are illustrative only and not intended to be limiting. The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

The suppository is a solid preparation which is prepared from the medicine and a proper matrix and has a certain shape for cavity administration. The suppository is solid at normal temperature, and can be rapidly softened, melted or dissolved in secretion at body temperature after being inserted into human body cavity, and gradually releases medicine to produce local or systemic effect. The rectal suppository is the most common, and compared with oral gastrointestinal administration, rectal administration has the advantages that the absorption of the medicament by the body is more regular, the damage of gastrointestinal digestive juice and enzymes to the medicament can be avoided, and the adverse stimulation reaction of the medicament to the gastrointestinal tract can be avoided. Rectal suppositories may be used for infants, children, patients with vomiting, inability or reluctance to take oral medication.

The rectal suppository has many local effects, can play a role in catharsis and lubrication, and can relieve constipation; treating anal diseases such as hemorrhoid and anal fissure; treating rectal mucosal injury; has local antiinflammatory effect on rectal inflammation and other rectal diseases.

The invention provides a rectal suppository containing hyaluronic acid and tetrahydropyrimidine, which comprises high molecular weight hyaluronic acid or salt thereof, low molecular weight hyaluronic acid or salt thereof, tetrahydropyrimidine or derivative thereof and gelatin.

In a specific embodiment, the high molecular weight hyaluronic acid or salt thereof has a molecular weight of 20-200 million Da, for example 20-30 million Da, 40-million Da, 50-million Da, 60-million Da, 70-million Da, 80-million Da, 90-million Da, 100-million Da, 110-million Da, 120-million Da, 130-million Da, 140-million Da, 150-million Da, 160-million Da, 170-million Da, 180-million Da, 190-million Da, 200-million Da, preferably 100-200-million Da, and the low molecular weight hyaluronic acid or salt thereof has a molecular weight of 0.5-20-million Da, for example 0.5-million Da, 1-million Da, 2-million Da, 3-million Da, 4-million Da, 5-Da, 6-million Da, 7-Da, 8-million Da, 9-Da, 10-million Da, 11-million Da, 12-million Da, 13-million Da, 14-million Da, 15-million Da, 16-million Da, 17-million Da, 18-million Da, 19-million-Da, preferably 0.5-million-10-million Da.

Among them, hyaluronic acid is an acidic mucopolysaccharide, and is present in a high content of hyaluronic acid in soft connective tissues of mammals, such as skin, vitreous body of eye, synovial fluid, umbilical cord and cartilage tissue. Hyaluronic acid in the human body plays roles in adhesion, lubrication and protection. Hyaluronic acid also has a remarkable water retention effect, and is an ideal natural moisturizing factor. The hyaluronate comprises sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, etc.

Gelatin is a macromolecular hydrocolloid that is the product of partial hydrolysis of collagen. The raw materials for producing gelatin mainly comprise skins and bones of animals, leather-making waste materials and the like, common gelatin in the market is prepared by taking cow leather bones or pig skins as raw materials, and in recent years, due to the emergence of mad cow diseases and foot and mouth diseases, many gelatin manufacturers turn to the preparation of gelatin by taking fish skins, fish scales and chicken skins as raw materials. It can be classified into photographic gelatin, edible gelatin and industrial gelatin according to its properties and uses. The quality requirements for gelatin vary according to the application. When used as an adhesive, the adhesive strength is mainly required. When the method is used in the fields of photography, food, medicine and the like, the purity of the product is emphasized.

Hyaluronic acid has different molecular weights and different effects. The suppository matrix formed by compounding the high molecular weight hyaluronic acid and the gelatin has good elasticity and toughness, and cannot be easily broken when in use; meanwhile, hyaluronic acid and gelatin are safe natural components for human bodies, have high biocompatibility and biodegradability, and do not generate other byproducts after in vivo degradation, so that irritation to the rectal mucosa is avoided; the hyaluronic acid with high molecular weight released by slowly dissolving in body fluid in the cavity can play a lubricating role and can easily discharge excrement; the water retention property of the dissolved hyaluronic acid is utilized, and the constipation and dry stool symptoms can be relieved; in addition, the low molecular weight hyaluronic acid can play a role in repairing rectal mucosa; it also has effects of eliminating inflammation, promoting wound healing, and relieving discomfort of anal canal and rectum.

The tetrahydropyrimidine is a micromolecule cyclic amino acid derivative, is an osmotic pressure compensation solute synthesized by extreme environment microorganisms under osmotic pressure stress, is compatible with metabolism in cells, and has good protection effect on cells and biological macromolecules under the stimulation of adverse environments such as high temperature, high salt, freezing, drying, radiation and the like. The rectal suppository prepared by the invention utilizes the hypertonic action brought by the tetrahydropyrimidine to ensure that more water enters the rectal cavity, thereby softening the excrement and facilitating the discharge. The tetrahydropyrimidine can also protect rectal mucosa and maintain the stability of the rectal mucosa; the tetrahydropyrimidine and low molecular weight hyaluronic acid can also accelerate tissue and cell repair together, so that the damage of mucous membrane and muscular layer is repaired. By repairing capillary walls, tetrahydropyrimidine can also inhibit hematochezia caused by hemorrhoids or anal fissure and the like.

In a specific embodiment, in the rectal suppository, the gelatin is 30 to 50 parts, the high molecular hyaluronic acid or the salt thereof is 0.1 to 1 part, preferably 0.5 to 1 part, the low molecular hyaluronic acid or the salt thereof is 0.1 to 1 part, preferably 0.5 to 1 part, and the tetrahydropyrimidine or the derivative thereof is 1 to 5 parts, preferably 3 to 5 parts by weight.

Wherein, in the rectal suppository, the components in parts by weight are added in the parts by weight respectively when the rectal suppository is prepared, and are finally present in the rectal suppository in the parts by weight.

Furthermore, the rectal suppository can also comprise other main drug components, wherein the main drug refers to an active component playing a therapeutic role. Wherein the other main medicine components are selected from one or more of steroid, immunosuppressant and anti-inflammatory medicine. When the main medicine is a fat-soluble component, a surfactant is required to be added into the rectal suppository. Preferably, the surfactant is a biosurfactant.

The invention also provides a rectal suppository containing hyaluronic acid and tetrahydropyrimidine, which is composed of high molecular weight hyaluronic acid or salt thereof, low molecular weight hyaluronic acid or salt thereof, tetrahydropyrimidine or derivative thereof and gelatin. Wherein, the ratio of the high molecular weight hyaluronic acid or salt thereof, the low molecular weight hyaluronic acid or salt thereof, the tetrahydropyrimidine or derivative thereof and the gelatin, and the molecular weight of the high molecular weight hyaluronic acid or salt thereof and the low molecular weight hyaluronic acid or salt thereof are as described above.

The invention also provides a preparation method of the rectal suppository containing hyaluronic acid and tetrahydropyrimidine, which comprises the following steps:

preparing the rectal suppository solution into rectal suppositories.

In one embodiment, the step of formulating the matrix solution comprises: weighing a proper amount of gelatin, soaking the gelatin in distilled water, heating the gelatin in a water bath, stirring the gelatin until the gelatin is dissolved, and then adding hyaluronic acid with high molecular weight while stirring to fully dissolve the hyaluronic acid.

The step of forming the rectal suppository comprises: pouring the rectal suppository solution into the suppository mold while the solution is hot until the solution slightly overflows from the mold opening, cooling, scraping the overflowing part after the solution is completely solidified, demolding, airing and packaging.

The rectal suppository comprises hyaluronic acid and tetrahydropyrimidine, has good hardness and elasticity, is easy to enter a human cavity and is not easy to break. The suppository takes high molecular weight hyaluronic acid and gelatin as matrixes, compared with the suppository matrix formed by traditional glycerin and gelatin, hyaluronic acid can form a layer of protective film on the surfaces of anal canal and rectal mucosa which are in contact with each other, so that the protective film has the functions of protecting and repairing damaged or inflamed mucosa, and meanwhile, by utilizing the hypertonic action of tetrahydropyrimidine, more water enters a rectal cavity, stool is softened, excrement can be easily discharged, and constipation is relieved; the hyaluronic acid gelatin matrix is natural in source, good in biocompatibility with a human body, safe, mild and non-irritant, and can reduce irritation of other medicine components through a slow release effect.

Examples

Example 1

Weighing 30g of gelatin, soaking in appropriate amount of distilled water, heating in water bath, stirring until the gelatin is dissolved, adding 0.5g of high molecular weight sodium hyaluronate (molecular weight of 150 ten thousand Da), and stirring while adding to dissolve completely; then 0.5g of low molecular weight sodium hyaluronate (molecular weight of 1 ten thousand Da) and 3g of tetrahydropyrimidine are respectively weighed and added into the matrix solution, and the mixture is uniformly mixed; and finally, supplementing 100g of distilled water, pouring the hot distilled water into the suppository mold until the distilled water slightly overflows from the mold opening, cooling, scraping the overflowing part after the distilled water is completely solidified, demolding, airing and packaging to obtain the rectal suppository.

Example 2

The only difference from example 1 is that the amount of gelatin used was 40g.

Example 3

The only difference from example 1 is that 50g of gelatin was used.

Example 4

The only difference from example 2 is that the high molecular weight sodium hyaluronate has a molecular weight of 250 ten thousand Da.

Example 5

The only difference from example 2 is that the high molecular weight sodium hyaluronate has a molecular weight of 200 ten thousand Da.

Example 6

The only difference from example 2 is that the high molecular weight sodium hyaluronate has a molecular weight of 100 ten thousand Da.

Example 7

The only difference from example 2 is that the high molecular weight sodium hyaluronate has a molecular weight of 50 ten thousand Da.

Example 8

The only difference from example 2 is that the high molecular weight sodium hyaluronate has a molecular weight of 20 ten thousand Da.

Example 9

The only difference from example 2 is that the amount of high molecular weight sodium hyaluronate used was 1.5g.

Example 10

The only difference from example 2 is that the amount of high molecular weight sodium hyaluronate used was 1g.

Example 11

The only difference from example 2 is that the amount of high molecular weight sodium hyaluronate used was 0.1g.

Example 12

The only difference from example 2 is that the molecular weight of the low molecular weight sodium hyaluronate is 0.5 ten thousand Da.

Example 13

The only difference from example 2 is that the low molecular weight sodium hyaluronate has a molecular weight of 10 ten thousand Da.

Example 14

The only difference from example 2 is that the low molecular weight sodium hyaluronate has a molecular weight of 20 ten thousand Da.

Example 15

The only difference from example 2 is that the amount of low molecular weight sodium hyaluronate used was 0.1g.

Example 16

The only difference from example 2 is that the amount of low molecular weight sodium hyaluronate used was 1.0g.

Example 17

The only difference from example 2 is that tetrahydropyrimidine is used in an amount of 1.0g.

Example 18

The only difference from example 2 is that tetrahydropyrimidine was used in an amount of 2.0g.

Example 19

The only difference from example 2 is that tetrahydropyrimidine was used in an amount of 4.0g.

Example 20

The only difference from example 2 is that tetrahydropyrimidine was used in an amount of 5.0g.

Comparative example 1

Only in contrast to example 2, no high molecular weight sodium hyaluronate and no low molecular weight sodium hyaluronate were added.

Comparative example 2

Only in contrast to example 2, no high molecular weight sodium hyaluronate was added.

Comparative example 3

The only difference from example 2 is that no tetrahydropyrimidine was added.

Comparative example 4

Weighing 20g of gelatin, soaking in appropriate amount of distilled water, swelling and softening the gelatin, draining off excessive water, adding 70g of glycerol, heating in water bath, stirring until the gelatin is dissolved, and heating to make the content weight reach 97g to obtain glycerol-gelatin matrix. Then 3g of tetrahydropyrimidine is weighed and added into the glycerol gelatin matrix solution, and the mixture is uniformly mixed; and finally, pouring the mixture into the plug die while the mixture is hot until the mixture slightly overflows from a die opening, cooling the mixture, scraping the overflowing part after the mixture is completely solidified, demolding, airing and packaging.

TABLE 1

Experimental example 1 suppository hardness and elasticity measurement

Suppository hardness and elasticity were measured at room temperature using a Universal TA research texture analyzer. The test mode is full texture TPA, the probe is a P/36R cylindrical probe, the suppository is placed right above the cylindrical probe, the speed before measurement, the speed after measurement and the speed after measurement are all 1.0mm/s, the trigger force is 8g, the deformation is 50%, the time is 5s, and the data recording rate is 200pps. The hardness is the peak value generated at the 1 st compression. Elasticity is the ratio of the heights detected by the two compressions, and represents the degree of elastic recovery after deformation during the 1 st compression.

Experimental example 2 measurement of melting time limit

The melting time limit is a time for examining melting, softening or dissolving of a solid preparation such as a suppository or a vaginal tablet under a predetermined condition [ generally, body temperature (37 ℃. + -. 0.5 ℃). Referring to the examination method of the melting time limit of 0922 in the general guidelines of the chinese pharmacopoeia of the 2015 edition, the melting time limit of the rectal suppository prepared in the above examples and comparative examples is determined, and the specific steps are as follows: taking 3 different suppositories, standing at room temperature for 1 hr, placing on the lower round plates of 3 metal racks, placing into the sleeves, and fixing with hooks. The devices are respectively and vertically immersed into a container containing not less than 4L of water with the temperature of 37.0 +/-0.5 ℃, and the upper end of the device is 90mm below the water surface. The device was inverted in solution every 10 minutes. The results are shown in Table 2.

TABLE 2 measurement results of hardness, elasticity and melting time limit of rectal suppository based on different samples

The suppository should have suitable hardness and elasticity, and is easy to enter human body cavity and not easy to break.

The Chinese pharmacopoeia stipulates that 3 suppositories made of the water-soluble matrix should be completely dissolved in 60 minutes (dissolved in water at 37 ℃). The rectal suppository prepared by the embodiment has melting time limit of less than 60 minutes and meets the requirements of Chinese pharmacopoeia. Meanwhile, the results show that the larger the amount of gelatin used, the greater the hardness, the lower the elasticity, and the longer the melting time limit of the suppository.

When a plurality of air bubbles form gaps in the suppository, the suppository is easy to break under external force, the deformation bearing capacity is weakened, and the elasticity of the suppository is deteriorated. The result shows that the molecular weight of the high molecular hyaluronic acid exceeds 200 ten thousand Da, and a large amount of bubbles can be generated in the suppository preparation process, so that the hardness of the suppository is poor and the suppository is easy to break; the low molecular weight, low hardness and elasticity ratio of the suppository are not beneficial to the use of the suppository; therefore, the molecular weight of the high molecular weight hyaluronic acid is preferably 100 to 200 ten thousand Da. When the dosage of the high molecular hyaluronic acid exceeds 1 part, a large amount of bubbles are generated in the suppository preparation process, so that the hardness and the elasticity of the suppository are deteriorated; the dosage is low, and the suppository hardness and elasticity ratio are low; therefore, the amount of the polymeric hyaluronic acid is preferably 0.5 to 1 part.

Experimental example 3 mucous membrane repairing Effect test

Adult male rats of SPF grade were selected and randomly divided into model and experimental groups of 5 rats each. The model group and experimental group rats are subjected to inflammatory enteritis modeling, and the method comprises the following steps: rats were fasted for 24 hours prior to the trial and then anesthetized and given 1mL TNBS (50 mg/mL) via anus, which induces inflammatory enteritis in the rats. The experimental groups were then administered via anus to the corresponding rectal suppositories prepared in the examples of the present invention or comparative examples, respectively, from day 2 to day 4. All rats were sacrificed on day 5 and colorectal sites were taken for clinical lesion visualization.

TABLE 3 rat colorectal clinical lesion results

Grouping	Average value of inflammation range (cm)	Ulcer focus
			Model set	4.5	3
Example 12	1.5	0
			Example 13	3.0	0
Example 14	3.5	1
			Example 15	3.5	1
Example 16	1.0	0
			Example 17	3.0	1
Example 18	2.5	0
			Example 19	1.5	0
Example 20	1.0	0
			Comparative example 1	4.0	2
Comparative example 2	2.5	1
			Comparative example 3	4.0	2
Comparative example 4	3.0	1

TNBS is used for inducing inflammatory enteritis of rats, and whether the rectal suppository has the effect of repairing mucous membranes is evaluated. The results show that the average value of the inflammation range of the model group is 4.5cm, which indicates that the modeling of inflammatory enteritis is successful. The sample group and the control group have certain effects of repairing mucous membrane and reducing inflammation.

The results show that the lower the molecular weight and the higher the dosage of the low-molecular hyaluronic acid, the more obvious the mucous membrane repairing effect is, the molecular weight is preferably 0.5-10 ten thousand Da, and the dosage is preferably 0.5-1 part. Comparative example 1 (containing no hyaluronic acid and only tetrahydropyrimidine) and comparative example 3 (containing no tetrahydropyrimidine and only hyaluronic acid) show that the mucosa repair effect is not obvious when only hyaluronic acid or tetrahydropyrimidine is contained, and only rectal suppository with both has obvious synergistic effect on repairing colorectal mucosa.

The results show that the higher the consumption of the tetrahydropyrimidine, the more obvious the mucous membrane repairing effect is, and the consumption is preferably 3-5 parts.

Experimental example 4 Constipation-relieving Effect test

Healthy adult mice of SPF grade were selected and randomly divided into a blank group, a model group and an experimental group, with 5 mice per group. Wherein the model group and experimental group mice were administered compound diphenoxylate (10 mg/kg) by gavage, and the blank group mice were administered the same volume of distilled water. After the gavage, the model group and the experimental group observe that the mouse activity is reduced, the number of the defecation grains is obviously reduced, the defecation is dry and beaded, and the water content is reduced to 30-40 percent from the normal average value of 60-70 percent. From day 4 on, the experimental groups were administered the corresponding rectal suppositories prepared according to the examples of the present invention or comparative examples, respectively, via anus. Rectal administration was performed 1 time per day for 3 consecutive days. The number of the stools in 8 hours of the mice was observed on day 7, and the water content of the stools was measured.

TABLE 4 influence of rectal suppositories on the laxative function of mice

Grouping	Average value of stool Water content (%)	Average number of defecation granules
			Blank group	71.61±2.10	35.08±4.53
Model set	35.07±7.36	9.63±1.58
			Example 12	65.43±4.95	35.47±5.78
Example 13	65.76±5.78	34.39±5.45
			Example 14	67.69±6.96	31.59±8.20
Example 15	51.14±6.52	20.50±4.82
			Example 16	68.89±1.31	33.88±5.06
Example 17	57.50±7.10	27.10±7.37
			Example 18	62.05±1.27	29.85±7.50
Example 19	67.78±1.59	32.03±5.02
			Example 20	70.51±7.93	35.07±2.71
Comparative example 1	40.55±6.19	12.03±9.46
			Comparative example 2	48.89±8.22	18.68±4.35
Comparative example 3	42.43±5.54	17.95±8.03
			Comparative example 4	46.65±6.05	18.03±2.96

In the test process, the feces of the mice in the blank group, the sample group and the control group are normal oval granular feces, the feces of the mice in the model group are dry and hard round-bead shaped feces, and the water content and the number of the feces grains are obviously lower than those in the blank group, which indicates that the constipation model of the mice is successfully modeled. Compared with the model group, the defecation state of the mice in the sample group and the control group tends to be normal, and the feces become wet and soft obviously and the water content is increased obviously. The results show that the higher the dosage of the low molecular weight hyaluronic acid is, the more obvious the effect of relieving constipation is, and the dosage is preferably 0.5-1 part; under the same dosage, the molecular weight of the low molecular hyaluronic acid is in the range of 0.5-20 ten thousand Da, and the effect of relieving constipation is not obviously influenced. Comparative example 1 (containing no hyaluronic acid and only tetrahydropyrimidine) and comparative example 3 (containing no tetrahydropyrimidine and only hyaluronic acid) show that the constipation relieving effect of the rectal suppository containing hyaluronic acid or tetrahydropyrimidine alone is not obvious, and the constipation relieving effect of the rectal suppository containing hyaluronic acid or tetrahydropyrimidine has obvious synergistic effect. The results of comparative example 2 (without polymeric hyaluronic acid) show that the addition of polymeric hyaluronic acid to rectal suppositories can effectively alleviate constipation.

The above results indicate that the higher the amount of tetrahydropyrimidine used, the more remarkable the effect of relieving constipation, and the amount is preferably 3 to 5 parts.

Claims

1. A rectal suppository comprising hyaluronic acid and tetrahydropyrimidine, wherein the rectal suppository comprises high molecular weight hyaluronic acid or a salt thereof, low molecular weight hyaluronic acid or a salt thereof, tetrahydropyrimidine and gelatin, the high molecular weight hyaluronic acid or a salt thereof having a molecular weight of 50-200 ten thousand Da, and the low molecular weight hyaluronic acid or a salt thereof having a molecular weight of 0.5-10 ten thousand Da; according to parts by weight, 0.5-1 part of the high molecular hyaluronic acid or the salt thereof, 0.5-1 part of the low molecular hyaluronic acid or the salt thereof and 1-5 parts of the tetrahydropyrimidine.

2. A rectal suppository according to claim 1, characterized in that the high molecular weight hyaluronic acid or salt thereof has a molecular weight of 100-200 ten thousand Da.

3. A rectal suppository according to claim 1, characterized in that the gelatin is 30-50 parts, the high molecular hyaluronic acid or salt thereof is 0.5-1 part, the low molecular hyaluronic acid or salt thereof is 0.5-1 part, and the tetrahydropyrimidine is 3-5 parts by weight.

4. A rectal suppository as claimed in claim 1, characterised in that it further comprises other primary drug ingredients, selected from one or more of steroids, immunosuppressants and anti-inflammatory drugs.

5. A method for preparing a rectal suppository comprising hyaluronic acid and tetrahydropyrimidine, the method comprising the steps of:

adding low molecular weight hyaluronic acid or salt thereof and tetrahydropyrimidine into the matrix solution, and uniformly mixing to obtain a rectal suppository solution;

preparing the rectal suppository solution into rectal suppositories;

the molecular weight of the high molecular weight hyaluronic acid or the salt thereof is 50-200 ten thousand Da, and the molecular weight of the low molecular weight hyaluronic acid or the salt thereof is 0.5-10 ten thousand Da; according to 100 parts by weight of the rectal suppository solution, 0.5-1 part of the high molecular hyaluronic acid or the salt thereof, 0.5-1 part of the low molecular hyaluronic acid or the salt thereof and 1-5 parts of tetrahydropyrimidine are used.

6. The method according to claim 5, wherein the high molecular weight hyaluronic acid or salt thereof has a molecular weight of 100-200 ten thousand Da.

7. The method of claim 5, wherein the gelatin is present in an amount of 30 to 50 parts per 100 parts by weight of the rectal suppository solution.

8. The method of claim 5, wherein the tetrahydropyrimidine is present in an amount of 3 to 5 parts by weight based on 100 parts by weight of the rectal suppository solution.

9. Use of a rectal suppository according to any one of claims 1 to 4 or prepared by a method according to any one of claims 5 to 8 for the manufacture of a medicament for repairing mucous membranes and/or relieving constipation.