CN109718220A

CN109718220A - The preparation method of ML-4000 clathrate capsule

Info

Publication number: CN109718220A
Application number: CN201711021232.5A
Authority: CN
Inventors: 王彦竹; 张赫然; 董欣; 宋丽明; 王杏林
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2017-10-27
Filing date: 2017-10-27
Publication date: 2019-05-07

Abstract

The present invention relates to a kind of preparation methods of ML-4000 clathrate capsule, accommodate ML-4000 drug molecule, the result of extraction of Lai Tigao drug using the big hole in cyclodextrin molecular structure.This method comprises: inclusion compound is made using the cyclodextrin and anti-osteoarthritis new drug ML-4000 of proper proportion in (1).(2) inclusion compound prepared is mixed with pharmaceutical adjunct appropriate, stable capsule is made.The dissolution rate of ML-4000 clathrate capsule be improved significantly, while masking the bad smell of drug, increase the stability of drug, avoid illumination and the moist influence to principal component.

Description

The preparation method of ML-4000 clathrate capsule

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of ML-4000 clathrate capsule, it is main to wrap Include the preparation of ML-4000 inclusion compound and the prescription screening of clathrate capsule and preparation.

Background technique

Non-steroid anti-inflammatory drug (NSAID) is widely used in the treatment of various inflammation, but long-time service can generate serious stomach Enteron aisle side effect.The appearance and application of cyclooxygenase-2 (COX-2) inhibitor avoid non-steroid anti-inflammatory drug (NSAID) and make for a long time With brought gastrointestinal side effect, but there is adverse effect to cardiovascular system.Epoxidase/5- lipoxygenase (COX/5- LOX) double inhibitor be then by and meanwhile block the formation of inflammatory mediator Prostaglandins and Leukotrienes, generate the anti-inflammatory work of collaboration With the side effect for improving curative effect, while COX inhibitor being avoided to cause.

ML-4000 is anti-inflammatory new drug (the license notification number of Tianjin Inst. of Materia Medica independent research CN1005451662C), be using the double inhibitor ML-3000 of COX/5-LOX as parent, and in its structure introduce nitric acid fourth Ester and synthesize.This new compound can discharge ML-3000 and NO simultaneously in vivo, not only maintain antipyretic, the town of ML-3000 Pain and anti-inflammatory curative effect, and the NO that there is protective effect to cardiovascular, gastric mucosa is introduced, it has a good application prospect. But since ML-4000 molecular structure is novel, solubility in water is very poor, limits it as effective therapeutic agent Clinical application.To solve the above-mentioned problems, the present invention provides a kind of preparation sides of stable clathrate capsule convenient for operation Method.

Summary of the invention

Technical problem solved by the invention is to provide a kind of easy, stable method, is used to prepare ML-4000 inclusion compound Capsule.By the screening to cyclodextrin type and the control to inclusion condition, a kind of more stable ML-4000 inclusion is prepared Object, and clathrate capsule is made using specific auxiliary material mixed proportion, to significantly improve the dissolution rate of principal component ML-4000. To achieve the above object, this invention takes following technical schemes:

Using solution stirring method, using ethanol-water mixture as solvent, under heating conditions, by a certain proportion of ML- 4000 are reacted with cyclodextrin, and inclusion compound crude product is made, then a small amount of water and acetone elute surface, obtain ML-4000 inclusion compound. Inclusion powder obtained is crossed after 80 meshes and is mixed with auxiliary material appropriate, prescription screening is carried out, finally obtained ML-4000 inclusion Composite capsule.

Above-mentioned inclusion compound material includes beta-cyclodextrin (β-CD), hydroxypropylβ-cyclodextrin (HP- β-CD) and sulfobutyl ether- One or more of beta-cyclodextrin (SBE- β-CD), preferably SBE- β-CD.

Solvent needed for above-mentioned inclusion compound preparation includes 50%~100% alcohol-water (v/v) mixed solution, preferably pure Ethanol solution.

The condition heated needed for above-mentioned inclusion compound preparation process includes 30 DEG C -70 DEG C, preferably 50 DEG C.

Reaction time needed for above-mentioned inclusion compound preparation process includes 4h-12h, preferably 6h.

The feed ratio of host and guest's molecule needed for above-mentioned inclusion compound preparation process is respectively 1:1,1:2 and 1:3, preferably 1:3.

Auxiliary material needed for the preparation process of above-mentioned clathrate capsule includes lactose, microcrystalline cellulose and superfine silica gel powder, Prescription is preferably inclusion compound: lactose: the mass ratio of superfine silica gel powder is 100:50:0.3.

Using the present invention can obtain more stable ML-4000 inclusion compound, inclusion rate is higher, and method is simple and easy to operate, with Capsule dissolubility made from inclusion compound significantly improves, and facilitates the clinical application of ML-4000, good market prospect.

Specific embodiment

The following examples will make the present invention more specifically to explain, but the present invention is not limited only to these implementations Example, these same embodiments are not also limit the invention in any way.

Embodiment 1

Appropriate different types of cyclodextrin is weighed, is dissolved in 50% ethyl alcohol under magnetic stirring, is thrown by the molar ratio of 1:3 Material, a small amount of ML-4000 is dissolved in acetone, and under 60rpm stirring, ring paste is added dropwise in the acetone soln of ML-4000 In the solution of essence, 6h is persistently stirred in 50 DEG C of water-baths, solvent is removed with rotary evaporation, and dry for 24 hours at 50 DEG C, then a small amount of water Surface is eluted with acetone, does not include complete host and guest's molecule to clean in reaction, it is then, inclusion compound after purification is dry in 50 DEG C Dry 48h.The drugloading rate for measuring ML-4000 in different types of cyclodextrin inclusion compound respectively, as a result see the table below 1:

The drugloading rate measurement result of ML-4000 in the different types of cyclodextrin inclusion compound of table 1

Cyclodextrin type	β-CD	HP-β-CD	SBE-β-CD
				ML-4000 drugloading rate %	5.48	11.73	13.54

Embodiment 2

Appropriate SBE- β-CD is weighed, is dissolved in the ethanol-water solution of different proportion under magnetic stirring, by rubbing for 1:3 You feed intake at ratio, and a small amount of ML-4000 is dissolved in acetone, and under 60rpm stirring, the acetone soln of ML-4000 is added dropwise Enter in the solution of cyclodextrin, persistently stir 6h in 50 DEG C of water-baths, solvent is removed with rotary evaporation, and dry for 24 hours at 50 DEG C, then A small amount of water and acetone elute surface, do not include complete host and guest's molecule to clean in reaction, then, by inclusion compound after purification in 50 DEG C of dry 48h.The drugloading rate for measuring ML-4000 in inclusion compound respectively, as a result see the table below 2:

The drugloading rate measurement result of ML-4000 in the inclusion compound of the ethanol-water solution preparation of table 2 in varing proportions

Ethanol-water solution	50% ethyl alcohol	80% ethyl alcohol	100% ethyl alcohol
				ML-4000 drugloading rate %	13.54	16.73	20.38

Embodiment 3

Appropriate SBE- β-CD is weighed, is dissolved in ethanol solution under magnetic stirring, is fed intake by the molar ratio of 1:3, will be lacked ML-4000 dissolution is measured with acetone, under 60rpm stirring, the acetone soln of ML-4000 is added dropwise to the solution of cyclodextrin In, 6h is persistently stirred in 30 DEG C, 50 DEG C and 70 DEG C of water-bath respectively, solvent is removed with rotary evaporation, and in 50 DEG C of dryings For 24 hours, then a small amount of water and acetone elute surface, complete host and guest's molecule are not included to clean in reaction, then, by packet after purification Object is closed in 50 DEG C of dry 48h.The drugloading rate for measuring ML-4000 in inclusion compound respectively, as a result see the table below 3:

Table 3 presses the drugloading rate measurement result of ML-4000 in inclusion compound made from different reaction temperatures

Reaction temperature	30℃	50℃	70℃
				ML-4000 drugloading rate %	16.54	20.38	19.29

Embodiment 4

Appropriate SBE- β-CD is weighed, is dissolved in ethanol solution under magnetic stirring, is fed intake by the molar ratio of 1:3, will be lacked ML-4000 dissolution is measured with acetone, under 60rpm stirring, the acetone soln of ML-4000 is added dropwise to the solution of cyclodextrin In, 12h is persistently stirred in 50 DEG C of water-bath respectively, and remove respectively in 4h, 6h, 8h, 10h and 12h with rotary evaporation Solvent, obtains inclusion compound solid, and 50 DEG C it is dry for 24 hours, then a small amount of water and acetone elute surface, are not included with cleaning in reaction Complete host and guest's molecule, then, by inclusion compound after purification in 50 DEG C of dry 48h.The load of ML-4000 in inclusion compound is measured respectively As a result dose see the table below 4:

Table 4 presses the drugloading rate measurement result of ML-4000 in inclusion compound made from the different reaction time

Reaction time	4h	6h	8h	10h	12h
						ML-4000 drugloading rate %	18.47	20.38	19.93	20.74	21.38

Embodiment 5

Appropriate SBE- β-CD is weighed, is dissolved in ethanol solution under magnetic stirring, by the molar ratio of 1:1,1:2 and 1:3 It feeds intake, by a small amount of ML-4000 dissolution with acetone, under 60rpm stirring, ring is added dropwise in the acetone soln of ML-4000 In the solution of dextrin, 6h is persistently stirred in 50 DEG C of water-bath respectively, solvent is removed with rotary evaporation, it is solid to obtain inclusion compound Body, and dried for 24 hours at 50 DEG C, then a small amount of water and acetone elute surface, do not include complete host and guest's molecule to clean in reaction, so Afterwards, by inclusion compound after purification in 50 DEG C of dry 48h.Again to feed intake by host and guest's molecule molar ratio of 1:1,1:2 and 1:3, preparation Physical mixture.The 30min dissolution rate for measuring ML-4000 in inclusion compound and physical mixture respectively, as a result see the table below 5:

Table 5 presses the 30min dissolution determination result of ML-4000 in inclusion compound made from different feed ratios

Embodiment 6

Appropriate SBE- β-CD is weighed, is dissolved in ethanol solution under magnetic stirring, is fed intake by the molar ratio of 1:3, will be lacked Amount ML-4000 is dissolved in acetone, and under 60rpm stirring, the acetone soln of ML-4000 is added dropwise to the solution of cyclodextrin In, 6h is persistently stirred in 50 DEG C of water-bath respectively, solvent is removed with rotary evaporation, obtains inclusion compound solid, and at 50 DEG C It dries for 24 hours, then a small amount of water and acetone elute surface, do not include complete host and guest's molecule to clean in reaction, it then, will after purification Inclusion compound in 50 DEG C of dry 48h.

It weighs the SBE- beta-CD inclusion prepared in right amount and crosses 80 meshes, select different auxiliary material and inclusion compound peace recipe quantity mixed It closes, and measures angle of repose.Then the filling for carrying out capsule, measures dissolution of the ML-4000 in 30min in clathrate capsule respectively Degree, composition and measurement result see the table below 6.

6 clathrate capsule composition of table and angle of repose and dissolution determination result

In conclusion this method is easy to operate, the dissolution rate of the ML-4000 inclusion compound of preparation is compared compared with its physical mixture It is significantly improved, the prescription of clathrate capsule is simple, is readily produced, and dissolution rate is good, establishes for the clinical application of new drug ML-4000 Basis is determined.

All contents without departing from technical solution of the present invention, technical spirit is made to the above embodiment any according to the present invention Simple modification and modification are all fallen in the range of technical solution of the present invention protects.

Claims

1. a kind of preparation method of ML-4000 clathrate capsule, it is characterised in that: use solution stirring method, mixed with alcohol-water Liquid is solvent, and under heating conditions, a certain proportion of ML-4000 is reacted with cyclodextrin, and inclusion compound crude product is made, few It measures water and acetone elutes surface, obtain ML-4000 inclusion compound；By inclusion powder obtained cross after 80 meshes with auxiliary material appropriate Mixing carries out prescription screening, finally obtained ML-4000 clathrate capsule.

2. preparation method according to claim 1, it is characterised in that: the inclusion compound material is selected from beta-cyclodextrin, hydroxyl One or more of propyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin；It is preferred that sulfobutyl ether-beta-cyclodextrin.

3. preparation method according to claim 1, it is characterised in that: solvent needed for the inclusion compound preparation is 50% ~100% alcohol-water mixed solution；It is preferred that straight alcohol solution.

4. preparation method according to claim 1, it is characterised in that: the item heated needed for the inclusion compound preparation process Part is 30 DEG C -70 DEG C；It is preferred that 50 DEG C.

5. preparation method according to claim 1, it is characterised in that: when reaction needed for the inclusion compound preparation process Between be 4h-12h；It is preferred that 6h.

6. preparation method according to claim 1, it is characterised in that: host and guest's molecule in the inclusion compound preparation process Feed ratio is respectively 1:1,1:2 or 1:3；It is preferred that 1:3.

7. preparation method according to claim 1, it is characterised in that: needed in the preparation process of the clathrate capsule Auxiliary material be selected from lactose, microcrystalline cellulose or superfine silica gel powder.

8. preparation method according to claim 1, it is characterised in that: the clathrate capsule prescription preferably includes Object: lactose: the mass ratio of superfine silica gel powder is 100:50:0.3.