CN110354093B

CN110354093B - Mosapride citrate pharmaceutical composition

Info

Publication number: CN110354093B
Application number: CN201910698839.XA
Authority: CN
Inventors: 樊继涛; 董礼; 杨宝海; 韩颜
Original assignee: Changzhou Hengbang Pharmaceutical Co ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co ltd
Priority date: 2019-07-31
Filing date: 2019-07-31
Publication date: 2021-09-17
Anticipated expiration: 2039-07-31
Also published as: CN110354093A

Abstract

The invention discloses a mosapride citrate pharmaceutical composition, which comprises mosapride citrate, a slow release agent, a diluent, a glidant, a lubricant and the like. The composition has advantages of slow release speed, no burst effect, good stability, improved patient compliance, high safety, and low adverse side effect.

Description

Mosapride citrate pharmaceutical composition

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition of mosapride citrate.

Background

Mosapride citrate (formula 1), chemical name (+/-) -4 chloro-amino-5-chloro-2-ethoxy-N- [ [4- (4-fluorobenzyl) -2-morpholinyl ] methyl ] benzamide dihydrate citrate, is a selective 5-hydroxytryptamine 4(5-HT4) receptor agonist, promotes the release of acetylcholine by exciting 5-HT4 receptors of cholinergic interneurons and internus muscularis, thereby enhancing gastrointestinal motility, improving gastrointestinal symptoms of patients with functional dyspepsia, and does not affect the secretion of gastric acid. The traditional Chinese medicine composition is clinically used for treating functional dyspepsia accompanied by digestive tract symptoms such as heartburn, eructation, nausea, vomiting, early satiety, epigastric distention and the like; it can also be used for treating gastroesophageal reflux disease, diabetic gastroparesis, and gastric dysfunction of patients with partial gastrectomy.

At present, many quick-release formulations of mosapride citrate have been developed at home and abroad, including tablets, capsules, dispersible tablets, oral solutions, granules, orally disintegrating tablets and the like. According to the pharmacokinetics research result of the quick-release preparation disclosed by PMDA, the half-life period (t1/2) of the preparation is 2 hours, the preparation needs to be administrated 3 times a day to maintain effective blood concentration, the compliance is poor, the preparation is not beneficial to the administration of patients with poor memory such as the old and the like, and meanwhile, the quick-release preparation has obvious high peak value and low valley value of the blood concentration and great side effect.

The patent with the publication number of CN102335154A discloses a mosapride citrate sustained-release tablet which has a sustained-release effect for 12 hours and consists of mosapride citrate, a sustained-release material, a diluent, an adhesive, a lubricant and a coating material, the repeatability of the release rate of the sustained-release tablet from a laboratory to mass production is good, and the release rate is basically kept unchanged after 6-month stability examination. However, the sustained-release tablet has poor chemical stability, and related substances are obviously increased in the long-term storage process.

The patent with the publication number of CN103356498B discloses a mosapride citrate sustained release tablet which has the sustained release effect of 12 hours and good chemical stability. The sustained-release tablet consists of mosapride citrate, a sustained-release material, a stabilizer, an adhesive, a lubricant and a coating material. According to IF (Interview form) documents published by PMDA, the medicine needs to take effect quickly and reaches a peak within 0.8 +/-0.1 hour, but the sustained-release tablet of the patent releases too slowly (only releases 5-9% within 1 hour) within 1 hour, the release amount within 1 hour is not enough to generate effective blood concentration, and the patient easily takes effect too slowly after taking the medicine, which is not beneficial to the exertion of the medicine effect.

Patent publication No. CN102548544A discloses a pharmaceutical composition having both immediate release and long-acting properties. The preparation process is divided into preparation of granules with long-acting characteristics and preparation of granules with quick-release characteristics, and the preparation method of the granules with long-acting characteristics is that a binder solution is sprayed on a mixture of an active pharmaceutical ingredient, a release control matrix and a pharmaceutically acceptable carrier, and two coatings are carried out, so that a sustained-release part with long-acting characteristics is prepared. Immediate release characteristics granules are prepared by spraying a binder solution onto an immediate release mixture to prepare immediate release granules. Adding excipient, disintegrant and lubricant into the two prepared granules, and tabletting to obtain the product with slow release and quick release properties. The preparation process disclosed by the patent is complicated, poor in reproducibility and high in energy consumption, does not conform to the current trend of energy conservation and environmental protection, and is not beneficial to commercial production. In addition, the product of the patent is easy to generate burst effect under the condition of existence of alcohol, and serious poor feedback can be caused.

The invention aims to solve the existing problems and provide the mosapride citrate composition which has the advantages of smooth release, stable chemical property, no burst effect, simple preparation process, improved patient compliance, improved medication safety and reduced toxic and side effects.

Disclosure of Invention

The invention provides a mosapride citrate pharmaceutical composition which is characterized by comprising a sustained-release agent consisting of a sustained-release framework and sustained-release components;

the sustained release agent is 5% to 85% (wt/wt) of the pharmaceutical composition, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, (wt/wt)%, of the pharmaceutical composition, 79%, 80%, 81%, 82%, 83%, 84%, 85%, etc.;

the slow release skeleton comprises one or more of xanthan gum, glyceryl behenate, chitosan, beeswax, carnauba wax, etc.;

the slow release component is a compound consisting of two or more substances, the compound comprises at least one of hydroxyethyl cellulose, povidone and polyvinyl alcohol, and the compound also comprises at least one of polyvinyl acetate, ethyl cellulose, cellulose acetate and stearic acid;

when the slow release component consists of two substances, the weight ratio of the slow release component is (1-10): (10-1), for example, may be 1: 10. 1.5: 10. 2: 10. 2.5: 10. 3: 10. 3.5: 10. 4: 10. 4.5: 10. 5: 10. 5.5: 10. 6: 10. 6.5: 10. 7: 10. 7.5: 10. 8: 10. 8.5: 10. 9: 10. 9.5: 10. 1: 1. 10: 9.5, 10: 9. 10: 8.5, 10: 8. 10: 7.5, 10: 7. 10: 6.5, 10: 6. 10: 5.5, 10: 5. 10: 4.5, 10: 4. 10: 3.5, 10: 3. 10: 2.5, 10: 2. 10: 1.5, 10:1, etc.;

the weight ratio of the slow release matrix to the slow release components is (0.1-10): (10-0.1); for example, it may be 0.1: 10. 0.5: 10. 1: 10. 1.5: 10. 2: 10. 2.5: 10. 3: 10. 3.5: 10. 4: 10. 4.5: 10. 5: 10. 5.5: 10. 6: 10. 6.5: 10. 7: 10. 7.5: 10. 8: 10. 8.5: 10. 9: 10. 9.5: 10. 1: 1. 10: 9.5, 10: 9. 10: 8.5, 10: 8. 10: 7.5, 10: 7. 10: 6.5, 10: 6. 10: 5.5, 10: 5. 10: 4.5, 10: 4. 10: 3.5, 10: 3. 10: 2.5, 10: 2. 10: 1.5, 10: 1. 10: 0.5, 10: 0.1, etc.;

in the pharmaceutical composition, the content of the mosapride citrate is 5-45%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% and the like;

the pharmaceutical composition may be a tablet, capsule, powder or dispersion;

the pharmaceutical composition can comprise a diluent, a glidant, a lubricant and the like besides a slow release agent and an active ingredient;

the diluent may be one or more of lactose, starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, or calcium hydrogen phosphate; 10-70% of the total weight of the pharmaceutical composition; for example, it may be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, etc.;

the glidant can be one or more of talcum powder and silicon dioxide; 0-5% by total weight of the pharmaceutical composition, e.g., can be 0.01%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%;

the lubricant can be one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and sodium lauryl sulfate; 0-5% of the total weight of the pharmaceutical composition; for example, it may be 0.01%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%;

in addition, the invention provides a preparation process of the mosapride citrate pharmaceutical tablet, which comprises the following steps:

firstly, pretreating raw and auxiliary materials;

② mixing the mosapride citrate with a slow release agent and a diluent;

thirdly, adding a flow aid and mixing;

adding lubricant and mixing;

tabletting the obtained granules;

sixthly, spraying the obtained tablet core with an Opadry solution to obtain a film-coated tablet.

The mosapride citrate pharmaceutical composition prepared by the invention has the advantages of smooth release, good stability, no burst release phenomenon, simple preparation process, low energy consumption, good reproducibility and suitability for commercial production, and can effectively improve the compliance and safety of the medication of patients.

Drawings

FIG. 1 is a graph of blood levels in beagle dogs at various times as prescribed in example 1.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The excipients in the following examples can be replaced by pharmaceutically acceptable excipients, or increased or decreased.

Example 1

(1) Prescription

Composition (I)	Ratio of occupation of
		Mosapride citrate	20.21％
Xanthan gum	18％
		Polyvinyl acetate	9％
Hydroxyethyl cellulose	8％
		Mannitol	42.79％
Silicon dioxide	1％
		Talcum powder	1％

(2) Preparation of

The preparation method comprises the steps of carrying out airflow crushing treatment on mosapride citrate, carrying out wet granulation and drying treatment on polyvinyl acetate and hydroxyethyl cellulose, adding the treated mosapride citrate, a wet granulation drying product, xanthan gum and mannitol into a hopper mixer, mixing at 15rpm for 40min, adding silicon dioxide, mixing at 15rpm for 10min, adding talcum powder, mixing for 5min, tabletting according to the controlled content, and coating with Opadry.

Example 2

(1) Prescription

(2) Preparation of

Carrying out jet milling on mosapride citrate, carrying out spray drying on polyvinyl acetate and povidone, adding the processed mosapride citrate, a product obtained by spray drying, glyceryl behenate and lactose into a hopper mixer, mixing at 15rpm for 40min, adding silicon dioxide, mixing at 15rpm for 10min, adding sodium dodecyl sulfate, mixing for 5min, tabletting according to the controlled content, coating with Opadry, and increasing the weight by 2%.

Example 3

(1) Prescription

(2) Preparation of

Carrying out jet milling on mosapride citrate, carrying out spray drying on polyvinyl acetate and polyvinyl alcohol, adding the processed mosapride citrate and a product obtained by spray drying, chitosan and lactose into a hopper mixer, mixing at 15rpm for 40min, adding silicon dioxide, mixing at 15rpm for 10min, adding magnesium stearate, mixing for 5min, tabletting according to the controlled content, coating with Opadry, and increasing the weight by 2%.

Example 4

(1) Prescription

Composition (I)	Ratio of occupation of
		Mosapride citrate	25％
Beeswax (Cera flava)	25％
		Polyvinyl acetate
	6％
		Povidone	7％
Pregelatinized starch	35％
		Silicon dioxide	1％
Stearic acid sodium fumarate	1％

(2) Preparation of

Carrying out airflow crushing treatment on mosapride citrate, carrying out wet granulation and drying on polyvinyl acetate and povidone, heating beeswax in a water bath at 80 ℃ to melt, adding the treated mosapride citrate, stirring to uniformly disperse, cooling, crushing and sieving, adding the wet granulation dried product, the crushed and sieved mosapride citrate, a waxy material and pregelatinized starch into a hopper mixer, mixing at 15rpm for 40min, adding silicon dioxide, mixing at 15rpm for 10min, adding sodium stearyl fumarate, mixing for 5min, tabletting according to the controlled content, and coating with opadry.

Comparative example 1

(1) Prescription

Composition (I)	Ratio of occupation of
		Mosapride citrate	15％
Hydroxypropyl methylcellulose	20％
		Polyvinyl acetate
	10％
		Lactose	53％
Silicon dioxide	1％
		Magnesium stearate	1％

(2) Preparation of

Carrying out airflow crushing treatment on the mosapride citrate, adding the treated mosapride citrate, polyvinyl acetate, hydroxypropyl methylcellulose and lactose into a hopper mixer, mixing at 15rpm for 40min, adding silicon dioxide, mixing at 15rpm for 10min, adding magnesium stearate, mixing for 5min, tabletting according to the controlled content, coating with Opadry, and increasing the weight by 2%.

Comparative example 2

(1) Prescription

(2) Preparation of

Performing jet milling on the mosapride citrate, performing spray drying on polyvinyl acetate and polyvinyl alcohol, adding the processed mosapride citrate, a spray-dried product and mannitol into a hopper mixer, mixing at 15rpm for 40min, adding silicon dioxide, mixing at 15rpm for 10min, adding magnesium stearate, mixing for 5min, tabletting according to the controlled content, coating with Opadry, and increasing the weight by 2%.

Product detection

First, stability investigation

The samples of examples 1-4 were subjected to accelerated conditions at 40 ℃ and 75% humidity and the results were as follows:

second, release degree investigation

1. Method for measuring release:

a sample is taken, 900ml of 0.1mol/L hydrochloric acid solution is taken as a dissolution medium according to a dissolution determination method (second method of 0931 appendix in the four parts of the national pharmacopoeia 2015 year edition), the rotating speed is 75rpm, the method is operated, 10ml of solution is taken after 1, 2, 4, 6, 8 and 12 hours, and the filtrate is taken as a sample solution. Meanwhile, 10ml of 0.1mol/L hydrochloric acid solution was supplemented. And precisely weighing 65mg of mosapride citrate as a reference substance, placing the reference substance in a 100ml volumetric flask, adding methanol for diluting to a constant volume, precisely transferring 5ml of solution to the 100ml volumetric flask by using a pipette, adding methanol for diluting to a constant volume, precisely transferring 5ml of solution to a 10ml volumetric flask by using the pipette, adding methanol for diluting to a constant volume, and shaking up to obtain a reference substance solution. The two solutions are taken and detected by HPLC, and the cumulative release degree of each tablet is calculated and is in accordance with the specification.

(1) The release results were as follows:

2. alcohol burst test:

taking a sample, taking 0.1mol/L hydrochloric acid containing 0%, 5%, 20% and 40% alcohol solution as release medium respectively according to the release degree determination term, taking 10ml of solution at 15min, 30min, 45min, 60min, 90min and 120min, filtering, and taking the filtrate as a sample solution. The corresponding solution was supplemented with 10 ml. The control formulation was identical to the formulation used in the release measurements. The two solutions are taken and detected by HPLC, and the cumulative release degree of each tablet is calculated and is in accordance with the specification.

Example 1 results:

example 2 results:

example 3 results:

example 4 results:

comparative example 1 results:

comparative example 2 results:

the test results show that the mosapride citrate composition has stable property, good slow release effect, no influence of alcohol content and no burst release phenomenon, and can effectively improve the compliance and safety of the medication of patients.

Third, blood concentration determination in beagle dog

In order to study the sustained release effect of the product, the blood concentration of the beagle dog at different times is measured for the samples prepared in example 1, and the results are shown in the following table and fig. 1, which show that the product is released smoothly in the beagle dog and has good sustained release effect.

Time/h	Blood concentration mu g/ml
		0	0
0.5	3.1
		1	4.6
2	4.8
		3	4.7
4	4.5
		5	4.6
6	4.3
		8	4.4
10	4.2
		12	4.1
14	3.4
		16	2.4
18	1.1
		24	0.3

Claims

1. The mosapride citrate pharmaceutical composition is characterized by comprising a sustained-release agent, wherein the sustained-release agent consists of a sustained-release framework and a sustained-release component, the sustained-release component is a compound consisting of two substances, the sustained-release component comprises one of hydroxyethyl cellulose, povidone and polyvinyl alcohol, the sustained-release component further comprises one of polyvinyl acetate, ethyl cellulose and cellulose acetate, the sustained-release framework comprises one or more of xanthan gum, glyceryl behenate, chitosan, beeswax and carnauba wax, the weight ratio of the two substances in the sustained-release component is 1-10:10-1, and the weight ratio of the sustained-release framework to the sustained-release component is 0.1-10: 10-0.1.

2. The pharmaceutical composition of claim 1, wherein the sustained release agent is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77% by weight of the pharmaceutical composition, 78%, 79%, 80%, 81%, 82%, 83%, 84% or 85%.

3. The pharmaceutical composition of claim 1, wherein the weight ratio of the two substances in the sustained release component is 1: 10. 1.5: 10. 2: 10. 2.5: 10. 3: 10. 3.5: 10. 4: 10. 4.5: 10. 5: 10. 5.5: 10. 6: 10. 6.5: 10. 7: 10. 7.5: 10. 8: 10. 8.5: 10. 9: 10. 9.5: 10. 1: 1. 10: 9.5, 10: 9. 10: 8.5, 10: 8. 10: 7.5, 10: 7. 10: 6.5, 10: 6. 10: 5.5, 10: 5. 10: 4.5, 10: 4. 10: 3.5, 10: 3. 10: 2.5, 10: 2. 10: 1.5 or 10: 1.

4. the pharmaceutical composition of claim 1, wherein the weight ratio of the sustained-release matrix to the sustained-release component is 0.1: 10. 0.5: 10. 1: 10. 1.5: 10. 2: 10. 2.5: 10. 3: 10. 3.5: 10. 4: 10. 4.5: 10. 5: 10. 5.5: 10. 6: 10. 6.5: 10. 7: 10. 7.5: 10. 8: 10. 8.5: 10. 9: 10. 9.5: 10. 1: 1. 10: 9.5, 10: 9. 10: 8.5, 10: 8. 10: 7.5, 10: 7. 10: 6.5, 10: 6. 10: 5.5, 10: 5. 10: 4.5, 10: 4. 10: 3.5, 10: 3. 10: 2.5, 10: 2. 10: 1.5, 10: 1. 10: 0.5 or 10: 0.1.

5. the pharmaceutical composition of claim 1, wherein the mosapride citrate is present in an amount of from 5% to 45% by weight of the total pharmaceutical composition.

6. The pharmaceutical composition of claim 5, wherein the mosapride citrate comprises 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% of the total weight of the composition.

7. The pharmaceutical composition of claim 1, wherein the composition comprises a diluent, a glidant, and a lubricant in addition to the sustained release agent.

8. The pharmaceutical composition of claim 7, wherein the diluent comprises one or more of lactose, starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, or dibasic calcium phosphate.

9. The pharmaceutical composition according to any one of claims 7 to 8, wherein the diluent comprises 10 to 70% by weight of the total pharmaceutical composition.

10. The pharmaceutical composition of claim 9, wherein the diluent comprises 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the total weight of the pharmaceutical composition.

11. The pharmaceutical composition of claim 7, wherein the glidant comprises one or more of talc and silicon dioxide.

12. The pharmaceutical composition of claim 7 or claim 11, wherein the glidant comprises 0-5% of the total weight of the pharmaceutical composition.

13. The pharmaceutical composition of claim 12, wherein the glidant comprises 0.01, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 weight percent of the total weight of the pharmaceutical composition.

14. The pharmaceutical composition of claim 7, wherein the lubricant comprises one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, sodium lauryl sulfate.

15. The pharmaceutical composition of claim 7 or claim 14, wherein the lubricant comprises 0-5% by weight of the total pharmaceutical composition.

16. The pharmaceutical composition of claim 15, wherein the lubricant comprises 0.01%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the total weight of the pharmaceutical composition.

17. The pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

18. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

19. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

20. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

21. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

22. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

23. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

24. the pharmaceutical composition according to any one of claims 1 to 8, 10 to 11, 13 to 14 and 16, wherein the composition comprises:

25. the pharmaceutical composition of any one of claims 1-8, 10-11, 13-14, 16, wherein the composition is a tablet, capsule, powder or dispersion.

26. The pharmaceutical composition of claim 25, wherein the composition is a tablet and the tablet is coated with a gastric coating.

27. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 26, comprising the steps of: (1) pretreating the raw materials and the auxiliary materials; (2) mixing the mosapride citrate with a slow release agent and a diluent; (3) adding a flow aid and mixing; (4) adding a lubricant for total mixing; (5) tabletting the obtained granules; (6) and (3) spraying the obtained tablet core with an Opadry solution to obtain a film-coated tablet.