CN113041235A

CN113041235A - Venlafaxine hydrochloride sustained release preparation, preparation method thereof, venlafaxine hydrochloride sustained release capsule and application thereof

Info

Publication number: CN113041235A
Application number: CN201911380655.5A
Authority: CN
Inventors: 耿海明; 王锦刚; 刘敏; 林号天; 曹伟
Original assignee: Xi'an Grand Deten Pharmaceutical Co ltd
Current assignee: Xi'an Grand Deten Pharmaceutical Co ltd
Priority date: 2019-12-27
Filing date: 2019-12-27
Publication date: 2021-06-29
Anticipated expiration: 2039-12-27
Also published as: CN113041235B

Abstract

The invention provides a venlafaxine hydrochloride sustained release preparation, a preparation method thereof, a venlafaxine hydrochloride sustained release capsule and application. It includes: mixing a venlafaxine hydrochloride original drug, an adhesive and a wetting agent, and then sequentially performing granulation and drying steps to obtain a drug-loaded pill core; mixing the first coating film material with a first solvent to obtain a first coating solution; coating the first coating liquid on the surface of the drug-loaded pill core to obtain the drug-loaded pill core containing the isolation layer; mixing the second coating film material, a pore-forming agent and a second solvent to obtain a second coating solution; coating the second coating solution on the surface of the isolation layer to obtain a drug-loaded pill core containing a slow release layer and the isolation layer, wherein the thickness ratio of the drug-loaded pill core to the isolation layer to the slow release layer is (0.85-1.25): (0.03-0.045) and (0.225-0.255). The method can greatly reduce the pouring speed of the venlafaxine hydrochloride sustained release agent within 60min in an ethanol environment, and has low cost.

Description

Venlafaxine hydrochloride sustained release preparation, preparation method thereof, venlafaxine hydrochloride sustained release capsule and application thereof

Technical Field

The invention relates to the field of pharmacy, and in particular relates to a venlafaxine hydrochloride sustained release preparation, a preparation method thereof, a venlafaxine hydrochloride sustained release capsule and application thereof.

Background

Venlafaxine hydrochloride is an effective antidepressant drug with the chemical name (R/S) -1- [2- (dimethylamine) -1- (4-methoxyphenyl) ethyl]Cyclohexanol hydrochloride of formula C₁₇H₂₇NO₂HCl, molecular weight 313.87, structural formula:

the related technology for preparing the existing venlafaxine hydrochloride sustained-release capsule is a pellet coating technology, namely, pellets with a certain size are prepared to be used as pellet cores, and then the pellet cores are coated. The existing literature provides a venlafaxine hydrochloride sustained-release tablet which comprises a tablet core and a coating film, wherein the tablet core contains a main drug and a penetration enhancer, the coating film contains a film forming material and a pore-forming agent, the pore-forming agent accounts for 20-45% of the weight of the coating film, and the coating film accounts for 10-35% of the weight of the tablet core. The preparation has the defect of over-quick drug release (the release rate is more than 60 percent within 60 min) in an ethanol environment, which can cause the burst release of the dose and further influence the medication safety of patients.

On the basis, the venlafaxine hydrochloride sustained release preparation which has better sustained release effect when being poured for 60min in an ethanol environment needs to be provided.

Disclosure of Invention

The invention mainly aims to provide a venlafaxine hydrochloride sustained-release preparation, a preparation method thereof, a venlafaxine hydrochloride sustained-release capsule and application, so as to solve the problem that the release speed is too high when the existing venlafaxine hydrochloride sustained-release preparation is poured for 60min in an ethanol environment.

In order to achieve the above object, the present invention provides a method for preparing a venlafaxine hydrochloride sustained release formulation, the method comprising: preparing a drug-loaded pill core; coating an isolation layer on the surface of the drug-loaded pill core, and coating a slow release layer on the surface of the isolation layer to obtain the venlafaxine hydrochloride slow release agent, wherein the thickness ratio of the drug-loaded pill core to the isolation layer to the slow release layer is (0.85-1.25): (0.03-0.045) and (0.225-0.255).

Further, the preparation of the isolation layer comprises: mixing the first coating film material with a first solvent to obtain a first coating solution; coating the first coating liquid on the surface of the drug-loaded pill core to obtain the drug-loaded pill core containing the isolation layer; preferably, the first coating film is selected from one or more of hypromellose E3, hypromellose E5, hypromellose E6 and hypromellose E15, and the first solvent is selected from one or more of dichloromethane, methanol, water and ethanol.

Further, the first coating film material is hydroxypropyl methylcellulose, the first solvent is a mixture of dichloromethane and methanol, and the weight ratio of the hydroxypropyl methylcellulose to the dichloromethane to the methanol is 1 (16-26) to (5-13).

Further, the preparation of the sustained-release layer comprises: mixing the second coating film material, a pore-forming agent and a second solvent to obtain a second coating solution; coating the second coating solution on the surface of the isolating layer to obtain the venlafaxine hydrochloride sustained release agent; preferably, the second coating film is selected from one or more of ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and hydroxypropyl cellulose, the pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol and hydroxypropyl cellulose, and the second solvent is selected from one or more of dichloromethane, methanol, water and ethanol.

Further, the second coating film is selected from a mixture of ethyl cellulose, polyethylene glycol and hydroxypropyl methylcellulose, the pore-forming agent is the hydroxypropyl methylcellulose, the second solvent is a mixture of dichloromethane and methanol, and the weight ratio of the ethyl cellulose to the hydroxypropyl methylcellulose to the polyethylene glycol to the dichloromethane to the methanol is 1 (0.1-0.7): (0.002-0.02): (19-28): 7-16)

Further, the preparation of the drug-loaded pill core comprises the following steps: mixing a venlafaxine hydrochloride original drug, an adhesive and a wetting agent, and then sequentially performing granulation and drying steps to obtain a drug-loaded pill core; preferably, the binder is selected from hypromellose and/or hyprolose, and the wetting agent is selected from water and/or ethanol.

Further, the preparation of the drug-loaded pill core also comprises the step of adding a lubricant and a filler in the preparation process of the drug-loaded pill core; preferably, the lubricant is selected from one or more of talc, magnesium stearate, stearic acid and sodium stearyl fumarate, and the filler is selected from microcrystalline cellulose and/or lactose.

Furthermore, the adhesive is hydroxypropyl cellulose, the wetting agent is water, the lubricant is selected from a mixture of talcum powder and magnesium stearate, the filler is microcrystalline cellulose, and the weight ratio of the venlafaxine hydrochloride raw drug, the hydroxypropyl cellulose, the water, the talcum powder, the magnesium stearate and the microcrystalline cellulose is (30-35): 0.5-4): 15-22): 0.2-8): 30-42.

Another aspect of the application also provides a venlafaxine hydrochloride sustained release agent, which is prepared by the preparation method.

The venlafaxine hydrochloride sustained-release capsule comprises a shell and a venlafaxine hydrochloride sustained-release agent filled in the shell, wherein the venlafaxine hydrochloride sustained-release agent comprises the venlafaxine hydrochloride sustained-release agent.

In another aspect of the application, the application also provides an application of the venlafaxine hydrochloride sustained release preparation in the preparation of antidepressant drugs.

By applying the technical scheme of the invention, the isolation layer is arranged between the drug-loaded pill core and the sustained-release layer, and the thickness of the isolation layer and the sustained-release layer is limited in the range, so that the sustained-release effect of the venlafaxine hydrochloride sustained-release agent poured for 60min in an ethanol environment is greatly improved. This is beneficial to improving the compliance of patients, keeping the blood concentration in a stable and lasting effective range, improving the safety of the medicine and reducing the administration frequency. In addition, the raw materials used by the preparation method also have the advantages of wide sources and low price, so the cost of the venlafaxine hydrochloride sustained release agent can be reduced by adopting the preparation method.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.

As described in the background art, the existing venlafaxine hydrochloride sustained release preparation has the problem of too fast release speed when being poured for 60min under the ethanol environment. In order to solve the technical problem, the application provides a preparation method of a venlafaxine hydrochloride sustained release preparation, which comprises the following steps: preparing a drug-loaded pill core; coating an isolation layer on the surface of the drug-loaded pill core, and coating a slow release layer on the surface of the isolation layer to obtain the venlafaxine hydrochloride slow release agent, wherein the thickness ratio of the drug-loaded pill core to the isolation layer to the slow release layer is (0.85-1.25): (0.03-0.045) and (0.225-0.255).

The isolation layer is arranged between the drug-loaded pill core and the sustained-release layer, and the thickness of the isolation layer and the sustained-release layer is limited in the range, so that the sustained-release effect of the venlafaxine hydrochloride sustained-release agent poured for 60min in an ethanol environment is greatly improved. This is beneficial to improving the compliance of patients, keeping the blood concentration in a stable and lasting effective range, improving the safety of the medicine and reducing the administration frequency. In addition, the raw materials used by the preparation method also have the advantages of wide sources and low price, so the cost of the venlafaxine hydrochloride sustained release agent can be reduced by adopting the preparation method.

In order to better control the dosage of the venlafaxine hydrochloride, in a preferred embodiment, the thicknesses of the drug-loaded pill core, the isolating layer and the sustained-release layer in the venlafaxine hydrochloride sustained-release preparation are 0.85-1.25 mm, 0.03-0.045 mm and 0.225-0.255 mm in sequence.

The isolation layer may be prepared by a method commonly used in the art. In a preferred embodiment, the preparation of the isolation layer comprises: mixing the first coating film material with a first solvent to obtain a first coating solution; and coating the first coating liquid on the surface of the drug-loaded pill core to obtain the drug-loaded pill core containing the isolation layer.

The first coating film and the first solvent may be selected from those commonly used in the art. In a preferred embodiment, the first coating film includes, but is not limited to, one or more of hypromellose E3, hypromellose E5, hypromellose E6, and hypromellose E15, and the first solvent includes, but is not limited to, one or more of dichloromethane, methanol, water, and ethanol. Compared with other materials, the first coating film material and the first solvent in the above types are beneficial to improving the film forming efficiency and film forming property of the isolation layer and the release reproducibility of the medicine. More preferably, the first coating film material is hydroxypropyl methylcellulose, the first solvent is a mixture of dichloromethane and methanol, and the weight ratio of the hydroxypropyl methylcellulose to the dichloromethane to the methanol is 1 (16-26) to (5-13).

The sustained-release layer can be prepared by a method commonly used in the art. In a preferred embodiment, the preparation of the sustained release layer comprises: mixing the second coating film material, a pore-forming agent and a second solvent to obtain a second coating solution; and coating the second coating solution on the surface of the isolating layer to obtain the venlafaxine hydrochloride sustained release agent.

The second coating film material and the second solvent may be selected from those commonly used in the art. In a preferred embodiment, the second coating film includes, but is not limited to, one or more of ethyl cellulose, hypromellose, polyethylene glycol, and hypromellose, the pore-forming agent includes, but is not limited to, one or more of hypromellose, polyethylene glycol, and hypromellose, and the second solvent includes, but is not limited to, one or more of dichloromethane, methanol, ethanol, and water. The coating material and solvent are selected to facilitate improved uniform stability of the sustained release layer compared to other materials. The pore-forming agent is selected to form a drug release channel on the surface of the sustained release layer, and the release efficiency of the drug can be better adjusted. In order to better control the slow release efficiency of the drug, it is more preferable that the second coating film material is a mixture of ethyl cellulose, polyethylene glycol and hydroxypropyl methylcellulose, the pore-forming agent is hydroxypropyl methylcellulose, the second solvent is a mixture of dichloromethane and methanol, and the weight ratio of ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, dichloromethane and methanol is 1 (0.1-0.7): (0.002-0.02): (19-28): 7-16.

The drug-loaded pellet core can adopt the preparation method commonly used in the field. In a preferred embodiment, the preparation of the drag-loaded pellet core comprises: mixing the venlafaxine hydrochloride technical product, the adhesive and the wetting agent, and then sequentially carrying out granulation and drying steps to obtain the drug-loaded pill core. More preferably, the binder includes, but is not limited to, hypromellose and/or hyprolose, and the wetting agent includes, but is not limited to, water and/or ethanol. Compared with other adhesives and wetting agents, the adhesive and wetting agent can enable the medicine-carrying pill core to be better formed.

In order to improve the processing performance of the drug-loaded pill core, the preparation of the drug-loaded pill core also comprises the addition of a lubricant and a filler in the preparation process of the drug-loaded pill core. Preferably, the lubricant includes, but is not limited to, one or more of talc, magnesium stearate, stearic acid, and sodium stearyl fumarate, and the filler includes, but is not limited to, microcrystalline cellulose and/or lactose. Compared with other lubricants and fillers, the addition of the above-mentioned substances is beneficial to further reducing the viscosity of the drug-loaded pill core and improving the roundness of the granules. More preferably, the adhesive is hydroxypropyl cellulose, the wetting agent is water, the lubricant comprises but is not limited to a mixture of talcum powder and magnesium stearate, the filler is microcrystalline cellulose, and the weight ratio of the venlafaxine hydrochloride raw drug, the hydroxypropyl cellulose, the water, the talcum powder, the magnesium stearate and the microcrystalline cellulose is (30-35): 0.5-4): 15-22): 0.2-8): 30-42.

Preferably, the venlafaxine hydrochloride sustained release preparation is prepared by adopting an extrusion spheronization process.

It should be noted that: the solvent and the wetting agent added in the preparation process can volatilize in the drying process, so the addition of the two substances does not influence the weight of the subsequently formed venlafaxine hydrochloride sustained release.

Another aspect of the application also provides a venlafaxine hydrochloride sustained release preparation, which is prepared by adopting the preparation method.

The isolation layer is arranged between the drug-loaded pill core and the sustained-release layer, and the thickness of the isolation layer and the sustained-release layer is limited in the range, so that the sustained-release effect of the venlafaxine hydrochloride sustained-release agent poured for 60min in an ethanol environment is greatly improved. This is beneficial to improving the compliance of patients, keeping the blood concentration in a stable and lasting effective range, improving the safety of the medicine and reducing the administration frequency. In addition, the raw materials used by the preparation method also have the advantages of wide sources and low price, so the cost of the venlafaxine hydrochloride sustained release agent can be reduced by adopting the preparation method. Meanwhile, the sustained release agent also has the advantage of being independent of pH. On the basis, the venlafaxine hydrochloride sustained release preparation prepared by the preparation method has the advantages of no pH dependence, good sustained release effect, low cost, high medication safety and the like.

The venlafaxine hydrochloride sustained release preparation prepared by the preparation method has the advantages of no pH dependence, good sustained release effect, low cost, high medication safety and the like. The sustained-release capsule containing the compound also has good sustained-release effect under different use pH values, and has the characteristics of low cost and safety in an ethanol environment.

The application also provides an application of the venlafaxine hydrochloride sustained release preparation in preparation of antidepressant drugs.

The venlafaxine hydrochloride sustained release preparation prepared by the preparation method has the advantages of no pH dependence, good sustained release effect, low cost, high medication safety and the like. Therefore, the sustained release agent has wide application prospect and economic value when being applied to the field of antidepressant drugs.

The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.

The manufacturers of the raw materials used in the examples are shown in Table 1.

TABLE 1

Raw materials	Manufacturer of the product
		Venlafaxine hydrochloride	GUILIN HUAXIN PHARMACEUTICAL Co.,Ltd.
Microcrystalline cellulose pH101	Germany JRS pharmaceutical excipients
		Talcum powder	GUANGXI LONGSHENG HUAMEI TALC DEVELOPMENT Co.,Ltd.
Magnesium stearate	ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd.
		Hydroxypropyl methylcellulose E6	Dow chemical of America
Methylene dichloride	Koimeu tea
		Methanol	Bailingwei-medicine
Ethyl cellulose 20cp	Dow chemical of America
		Polyethylene glycol 6000	Hunan Er-Kang Pharmaceutical Co.,Ltd.
Venlafaxine hydrochloride sustained-release capsule	Pfizer Pharmaceuticals Ltd.

Example 1

The preparation process of the venlafaxine hydrochloride sustained-release capsule comprises the following steps:

(1) preparing a drug-loaded pill core:

the materials are prepared according to the following parts by weight:

84.92 parts of venlafaxine hydrochloride raw drug, 101.28 parts of microcrystalline cellulose pH101, 11.00 parts of talcum powder, 11.00 parts of magnesium stearate, 1.80 parts of hydroxypropyl methylcellulose E6 and 51.50 parts of water.

The raw material medicines, the hydroxypropyl methylcellulose and the microcrystalline cellulose are respectively sieved by a 40-mesh sieve, the materials are sieved together, and the talcum powder and the magnesium stearate are respectively sieved by a 60-mesh sieve. The materials are placed in a wet granulator and mixed evenly. Then adding wetting agent (water) to make soft material.

Adding the soft material into an extruder, extruding the soft material out of the extruder by using a sieve plate with the aperture of 0.8mm, and putting the extruded strip-shaped objects into a rounding machine to prepare round pellets; and then placing the pellets in a fluidized bed for drying, controlling the moisture of the pellets to be less than 2%, finally screening by using 16-mesh and 25-mesh vibrating screens, and selecting the pellets passing through the 16-mesh and 25-mesh screens as final target pellets.

(2) Preparation of the isolating layer

The materials are prepared according to the following parts by weight:

6.30 parts by weight of hypromellose E6, 121.59 parts by weight of dichloromethane and 51.11 parts by weight of methanol.

Hypromellose E6 was dispersed in methanol, and dichloromethane was then added thereto under stirring. Stirring for at least 30 minutes. The concentration of the coating solution polymer is 3.5%, and the weight of the coating is increased by 3.0%.

And (3) respectively carrying out isolation layer coating on the two drug-loaded pill cores by adopting a fluidized bed to correspondingly obtain two drug-loaded pill cores containing isolation layers, wherein the material temperature is controlled to be 25 +/-2 ℃ in the coating process, and the thickness of the isolation layers is 0.03-0.045 mm.

(3) Preparation of sustained-release layer

The materials are prepared according to the following parts by weight:

30.34 parts by weight of ethyl cellulose (Brookfield viscosity 20cP), 6.44 parts by weight of hypromellose E6, 0.18 part by weight of polyethylene glycol 6000, 713.23 parts by weight of methylene chloride and 305.67 parts by weight of methanol.

Polyethylene glycol 6000, hypromellose E6, and ethylcellulose 20cp were dispersed in methanol in this order under stirring, followed by addition of dichloromethane and stirring for at least 60 minutes until a clear solution was obtained.

And (3) performing slow-release layer coating on the two drug-loaded pellet cores containing the isolating layers by adopting a fluidized bed, controlling the material temperature to be 25 +/-2 ℃ in the coating process, controlling the water content in the pellets to be less than 2% after coating, controlling the weight gain of the coating to be 17%, and controlling the thickness of the slow-release layer to be 0.225-0.255 mm, and sieving the pellets correspondingly through 14-mesh and 25-mesh sieves after drying to obtain the required slow-release agent.

(4) Capsule filling

And installing a No. 1 mold on a filling machine, filling the sustained-release agent into a hopper, adjusting filling amount starting equipment, and checking the filling amount difference every 15 minutes to obtain the sustained-release capsule.

The venlafaxine hydrochloride sustained release capsules prepared in example 1 were tested for release properties at different pH, see USP1 method: basket method, rotational speed: 100 turns, the dosage of the medium is 900ml, and the 4 media are respectively: purified water, 0.1N HCI, acetate buffer solution and phosphate buffer solution, wherein the sampling time points are respectively as follows: 0.2, 4, 8, 12 and 20 hours.

Dissolution results of samples of the venlafaxine hydrochloride sustained-release capsules prepared in example 1 (pellet core, isolation layer, and sustained-release layer having thicknesses of 1.0mm, 0.03mm, and 0.250mm in this order) are shown in table 2.

Dissolution data for commercially available venlafaxine hydrochloride sustained release capsules at different pH are shown in table 3. The limit criteria for the dissolution in the standard medium (aqueous medium) for each test time point are shown in Table 4.

TABLE 2

TABLE 3

TABLE 4

Time (h)	Degree of drug Release (%)
		2	10～30
4	33～53
		8	58～78
12	68～88
		20	Greater than 80

As can be seen from Table 2: the medicine prepared by the preparation method is pH-independent and can realize the purpose of slow and non-constant-speed release. Meanwhile, as can be seen from comparison of data in tables 2 to 4, compared with the existing commercially available product, the venlafaxine hydrochloride sustained release agent prepared by the method can achieve the same sustained release effect.

The venlafaxine hydrochloride sustained-release capsules prepared in example 1 were tested for their release properties in ethanol by the following test methods: selecting 5 samples, wherein the thickness ratio of a sample 1 (the thicknesses of the pill core, the isolation layer and the slow release layer are 1.0mm, 0.03mm and 0.250mm in sequence), the thickness ratio of a sample 2 (the thicknesses of the pill core, the isolation layer and the slow release layer are 1.0mm, 0.04mm and 0.250mm in sequence), the thickness ratio of a sample 3 (the thicknesses of the pill core, the isolation layer and the slow release layer are 1.0mm, 0.03mm and 0.235mm in sequence), the thickness ratio of a sample 4 (the thicknesses of the pill core, the isolation layer and the slow release layer are 1.0mm, 0.03mm and 0.250mm in sequence), and the thickness ratio of a sample 5 (the thicknesses of the pill core, the isolation layer and the slow release layer are 1.0mm, 0.03mm and 0.255mm in sequence).

And the samples were placed in 0.1N HCI medium with 40% ethanol added to detect the release of the samples, sampling every 15 minutes until the end of 2 hours. The test results are shown in Table 5.

TABLE 5

As can be seen from Table 5: the release degree of samples 1 to 5 is 21 to 32 percent after the samples are poured for 60min in an ethanol environment, so that compared with the existing venlafaxine hydrochloride preparation in the background technology (the release degree of the samples poured for 60min in the ethanol environment is more than 60 percent), the venlafaxine hydrochloride sustained release agent prepared by the method provided by the application has better sustained release effect in the process of pouring for 60min in the ethanol environment. Meanwhile, by comparing the data of 0-60 min of pouring in the ethanol environment in the table 5, the release degree of the venlafaxine hydrochloride prepared by the method provided by the application is lower than that of the venlafaxine hydrochloride sold in the market. Therefore, compared with the existing products sold on the market, the venlafaxine hydrochloride sustained release agent prepared by the preparation method has better sustained release effect in the process of pouring for 60min under the ethanol environment. (the preparation method and structure of the commercially available venlafaxine hydrochloride sustained release capsule used in the examples of this application are not disclosed).

Example 2

The difference from example 1 is that: in the preparation process of the isolation layer, the hydroxypropyl methylcellulose E6 in the first coating film material is 6.30 parts by weight, and the weight ratio of the hydroxypropyl methylcellulose E6 to the dichloromethane to the methanol is 1:16: 13.

Example 3

The difference from example 1 is that: in the preparation process of the isolation layer, the hydroxypropyl methylcellulose E6 in the first coating film material is 6.30 parts by weight, and the weight ratio of the hydroxypropyl methylcellulose to the dichloromethane to the methanol is 1:13: 16.

Example 4

The difference from example 1 is that: in the preparation process of the isolation layer, the hydroxypropyl methylcellulose E6 in the first coating film material is 6.30 parts by weight, and the weight ratio of the hydroxypropyl methylcellulose to the dichloromethane to the methanol is 1:26: 5.

Example 5

The difference from example 1 is that: in the preparation process of the slow release layer, the dosage of the ethyl cellulose in the second coating film material is 30.34 parts by weight, and the weight ratio of the ethyl cellulose, the hydroxypropyl methylcellulose, the polyethylene glycol, the dichloromethane and the methanol is 1:0.1:0.002: 19: 16.

Example 6

The difference from example 1 is that: in the preparation process of the slow release layer, the dosage of the ethyl cellulose in the second coating film material is 30.34 parts by weight, and the weight ratio of the ethyl cellulose, the hydroxypropyl methylcellulose, the polyethylene glycol, the dichloromethane and the methanol is 1:0.7:0.02:28: 7.

Example 7

The difference from example 1 is that: in the preparation process of the slow release layer, the dosage of the ethyl cellulose in the second coating film material is 30.34 parts by weight, and the weight ratio of the ethyl cellulose, the hydroxypropyl methylcellulose, the polyethylene glycol, the dichloromethane and the methanol is 1:0.9:0.04:15: 5.

Example 8

The difference from example 1 is that: in the preparation process of the drug-loaded pill core, the dosage of the venlafaxine hydrochloride raw drug is 84.92 parts by weight, and the weight ratio of the venlafaxine hydrochloride raw drug to the hydroxypropyl cellulose to the water to the talc powder to the magnesium stearate to the microcrystalline cellulose is 30:4:15: 8:0.2: 30.

Example 9

The difference from example 1 is that: in the preparation process of the drug-loaded pill core, the dosage of the venlafaxine hydrochloride raw drug is 84.92 parts by weight, and the weight ratio of the venlafaxine hydrochloride raw drug to the hydroxypropyl cellulose to the water to the talc powder to the magnesium stearate to the microcrystalline cellulose is 30:5:30: 0.5:0.5: 25.

Comparative example 1

The difference from example 3 is that: the thickness of the pill core is 1.0mm, the thickness of the isolation layer is 1.0mm, and the thickness of the slow release layer is 8.0 mm.

Comparative example 2

The difference from example 3 is that: the thickness of the pill core is 1.0mm, the thickness of the isolation layer is 1.0mm, and the thickness of the slow release layer is 3.0 mm.

The venlafaxine hydrochloride sustained release capsules prepared in examples 2 to 9 and comparative examples 1 to 2 were tested for their release properties at pH 7 in pure water, in the same manner as in example 1, and the test results are shown in table 6.

The venlafaxine hydrochloride sustained release capsules prepared in examples 2 to 9 and comparative examples 1 to 2 were tested for their release properties in ethanol in the same manner as in example 1, and the test results are shown in table 7.

TABLE 6

TABLE 7

As can be seen from table 6, the venlafaxine hydrochloride sustained release agents prepared in examples 2 to 9 all have a good sustained release effect in a pure water environment; compared with comparative examples 1 to 2, the preparation method provided by the application can obtain better sustained-release effect. As can be seen from tables 5 and 7, the venlafaxine hydrochloride sustained release agents in examples 2 to 9, which are poured in an ethanol environment for 60min, have a release degree of 28 to 32%, and thus compared with the existing venlafaxine hydrochloride preparations in the background art (the release degree of 60min poured in an ethanol environment is greater than 60%), the venlafaxine hydrochloride sustained release agent prepared by the method provided by the present application has a better sustained release effect in the process of 60min pouring in an ethanol environment; compared with the commercially available product and the comparative example 2, the sustained-release agent prepared by the preparation method of the application can obtain better sustained-release effect which is equivalent to the sustained-release effect of the comparative example 1, but the sustained-release layer of the sustained-release agent prepared in the comparative example 1 is too thick, so that the volume of the sustained-release agent is too large, and the industrial production is not convenient.

From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:

the sustained release agent prepared by the method has better sustained release effect under different pH values, thereby reducing the peak valley phenomenon of the blood concentration presented by the administration of common dosage forms, improving the compliance of patients, keeping the blood concentration in a more stable and lasting effective range, improving the safety of the medicine and reducing the administration frequency. In addition, the sustained release agent prepared by the method has a proper release rate in an ethanol environment, so that the medication safety in the ethanol environment can be improved. On the basis, the sustained-release capsule containing the compound also has better sustained-release effect under different use pH values and also has better release rate in an ethanol environment.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of venlafaxine hydrochloride sustained release preparation is characterized by comprising the following steps:

preparing a drug-loaded pill core;

coating an isolation layer on the surface of the drug-loaded pill core, and coating a slow release layer on the surface of the isolation layer to obtain the venlafaxine hydrochloride slow release agent, wherein the thickness ratio of the drug-loaded pill core to the isolation layer to the slow release layer is (0.85-1.25): (0.03-0.045) and (0.225-0.255).

2. The method of manufacturing according to claim 1, wherein the preparation of the separation layer includes: mixing the first coating film material with a first solvent to obtain a first coating solution; coating the first coating liquid on the surface of the drug-loaded pill core to obtain the drug-loaded pill core containing the isolating layer;

preferably, the first coating film is selected from one or more of hypromellose E3, hypromellose E5, hypromellose E6 and hypromellose E15, and the first solvent is selected from one or more of dichloromethane, methanol, water and ethanol.

3. The preparation method of claim 2, wherein the first coating film material is hypromellose, the first solvent is a mixture of dichloromethane and methanol, and the weight ratio of the hypromellose to the dichloromethane to the methanol is 1 (16-26) to (5-13).

4. The production method according to claim 2 or 3, wherein the production of the sustained-release layer comprises: mixing the second coating film material, a pore-forming agent and a second solvent to obtain a second coating solution; coating the second coating solution on the surface of the isolation layer to obtain the venlafaxine hydrochloride sustained release agent;

preferably, the second coating film is selected from one or more of ethyl cellulose, hypromellose, polyethylene glycol and hyprolose, the pore-forming agent is selected from one or more of hypromellose, polyethylene glycol and hyprolose, and the second solvent is selected from one or more of dichloromethane, methanol, water and ethanol.

5. The preparation method of claim 4, wherein the second coating film is selected from a mixture of ethyl cellulose, polyethylene glycol and hydroxypropyl methylcellulose, the pore-forming agent is hydroxypropyl methylcellulose, the second solvent is a mixture of dichloromethane and methanol, and the weight ratio of ethyl cellulose to hydroxypropyl methylcellulose to polyethylene glycol to dichloromethane to methanol is 1 (0.1-0.7): (0.002-0.02): (19-28): 7-16).

6. The method of any one of claims 1-5, wherein the preparation of the drag-loaded pellet core comprises: mixing a venlafaxine hydrochloride original drug, an adhesive and a wetting agent, and then sequentially performing granulation and drying steps to obtain the drug-loaded pill core;

preferably, the adhesive is selected from hypromellose and/or hyprolose, and the wetting agent is selected from water and/or ethanol.

7. The method of claim 6, wherein the preparation of the pre-pellet core further comprises adding a lubricant and a filler during the preparation of the pre-pellet core;

preferably, the lubricant is selected from one or more of talc, magnesium stearate, stearic acid and sodium stearyl fumarate, and the filler is selected from microcrystalline cellulose and/or lactose.

8. The preparation method of claim 7, wherein the binder is hydroxypropyl cellulose, the wetting agent is water, the lubricant is selected from a mixture of talc powder and magnesium stearate, the filler is microcrystalline cellulose, and the weight ratio of the venlafaxine hydrochloride technical product, the hydroxypropyl cellulose, the water, the talc powder, the magnesium stearate and the microcrystalline cellulose is (30-35): (0.5-4): (15-22): (0.2-8): (30-42).

9. A venlafaxine hydrochloride sustained release formulation characterized in that it is prepared by the preparation method according to any one of claims 1 to 8.

10. A venlafaxine hydrochloride sustained release capsule comprising a shell and a venlafaxine hydrochloride sustained release agent filled inside the shell, wherein the venlafaxine hydrochloride sustained release agent comprises the venlafaxine hydrochloride sustained release agent of claim 9.

11. The use of a venlafaxine hydrochloride sustained release formulation according to claim 9 in the preparation of an antidepressant.