CN113041235B - Venlafaxine hydrochloride sustained release agent, preparation method thereof, venlafaxine hydrochloride sustained release capsule and application thereof - Google Patents
Venlafaxine hydrochloride sustained release agent, preparation method thereof, venlafaxine hydrochloride sustained release capsule and application thereof Download PDFInfo
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- CN113041235B CN113041235B CN201911380655.5A CN201911380655A CN113041235B CN 113041235 B CN113041235 B CN 113041235B CN 201911380655 A CN201911380655 A CN 201911380655A CN 113041235 B CN113041235 B CN 113041235B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a venlafaxine hydrochloride sustained-release agent, a preparation method thereof, a venlafaxine hydrochloride sustained-release capsule and application thereof. It comprises the following steps: mixing venlafaxine hydrochloride raw medicine, an adhesive and a wetting agent, and sequentially granulating and drying to obtain a pill-carrying core; mixing the first coating film material with a first solvent to obtain a first coating liquid; coating the first coating liquid on the surface of the pill carrying core to obtain a pill carrying core containing an isolation layer; mixing the second coating film material, the pore-forming agent and the second solvent to obtain a second coating liquid; coating the second coating liquid on the surface of the isolation layer to obtain a pill carrying core containing the slow release layer and the isolation layer, wherein the thickness ratio of the pill carrying core, the isolation layer and the slow release layer is (0.85-1.25): (0.03-0.045) and (0.225-0.255). The method can greatly reduce the dumping speed of the venlafaxine hydrochloride sustained release agent in 60min under the ethanol environment, and has lower cost.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a venlafaxine hydrochloride sustained release agent, a preparation method thereof, a venlafaxine hydrochloride sustained release capsule and application thereof.
Background
Venlafaxine hydrochloride is an effective antidepressant and is known under the chemical name (R/S) -1- [2- (dimethylamine) -1- (4-methoxyphenyl) ethyl]Cyclohexenol hydrochloride, formula C 17 H 27 NO 2 HCl, molecular weight 313.87, structural formula:
the related technology of the existing venlafaxine hydrochloride sustained-release capsule preparation is a pellet coating technology, namely, pellets with a certain size are prepared as pellet cores, and then the pellets are coated. The prior literature provides a slow-release tablet of venlafaxine hydrochloride, which comprises a tablet core and a coating film, wherein the tablet core comprises a main medicine and a permeation enhancer, the coating film comprises 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-fast drug release (release degree is more than 60% in 60 min) in ethanol environment, which can cause abrupt dose release and further affect the medication safety of patients.
On the basis, it is necessary to provide a venlafaxine hydrochloride sustained-release agent which has a better sustained-release effect when being poured for 60 minutes in an ethanol environment.
Disclosure of Invention
The invention mainly aims to provide a venlafaxine hydrochloride sustained release agent, a preparation method thereof, a venlafaxine hydrochloride sustained release capsule and application thereof, so as to solve the problem that the release speed of the conventional venlafaxine hydrochloride sustained release agent is too high when the conventional venlafaxine hydrochloride sustained release agent is poured for 60min in an ethanol environment.
In order to achieve the above purpose, the present invention provides a method for preparing a venlafaxine hydrochloride sustained release preparation, the method comprising: preparing a pill carrying core; coating an isolation layer on the surface of the pill carrying 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 pill carrying core, the isolation layer and 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 includes: mixing the first coating film material with a first solvent to obtain a first coating liquid; coating the first coating liquid on the surface of the pill carrying core to obtain a pill carrying core containing an isolation layer; preferably, the first coating film material 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) (5-13).
Further, the preparation of the slow release layer includes: mixing the second coating film material, the pore-forming agent and the second solvent to obtain a second coating liquid; coating the second coating liquid on the surface of the isolation layer to obtain a venlafaxine hydrochloride sustained release agent; preferably, the second coating film material is selected from one or more of ethyl cellulose, hypromellose, polyethylene glycol and hypromellose, the pore-forming agent is selected from one or more of hypromellose, polyethylene glycol and hypromellose, and the second solvent is selected from one or more of dichloromethane, methanol, water and ethanol.
Further, the second coating film material is selected from the mixture of ethyl cellulose, polyethylene glycol and hypromellose, the pore-forming agent is hypromellose, the second solvent is the mixture of dichloromethane and methanol, and the weight ratio of ethyl cellulose, hypromellose, polyethylene glycol, dichloromethane and methanol is 1 (0.1-0.7): (0.002-0.02): (19-28): (7-16)
Further, the preparation of the pill-carrying core comprises: mixing venlafaxine hydrochloride, an adhesive and a wetting agent, and sequentially granulating and drying to obtain a pill-carrying core; preferably, the binder is selected from hypromellose and/or hypromellose and the wetting agent is selected from water and/or ethanol.
Further, the preparation of the pill-carrying core further comprises adding a lubricant and a filler during the preparation of the pill-carrying 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.
Further, the adhesive is hydroxypropyl cellulose, the wetting agent is water, the lubricant is a mixture of talcum powder and magnesium stearate, the filler is microcrystalline cellulose, and the weight ratio of the raw material of Venlafaxine hydrochloride, 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.
The application also provides a slow release preparation of the venlafaxine hydrochloride, which is prepared by the preparation method.
Still another aspect of the present application provides a venlafaxine hydrochloride sustained-release capsule, which 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 yet another aspect, the application of the venlafaxine hydrochloride sustained release preparation in preparing antidepressant is provided.
By adopting the technical scheme of the invention, the sustained-release effect of the venlafaxine hydrochloride sustained-release agent in an ethanol environment is greatly improved by arranging the isolation layer between the pill carrying core and the sustained-release layer and limiting the thickness of the isolation layer and the sustained-release layer in the above range. This is beneficial to improving patient compliance, maintaining blood concentration within a relatively smooth and durable effective range, improving drug safety, and reducing frequency of administration. In addition, the raw materials used in the preparation method have the advantages of wide sources and low price, so that the preparation method can reduce the cost of the venlafaxine hydrochloride sustained-release agent.
Detailed Description
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present invention will be described in detail with reference to examples.
As described in the background art, the existing venlafaxine hydrochloride sustained release agent has the problem of over-high release speed when being poured for 60 minutes in an ethanol environment. In order to solve the technical problems, the application provides a preparation method of a venlafaxine hydrochloride sustained-release agent, which comprises the following steps: preparing a pill carrying core; coating an isolation layer on the surface of the pill carrying 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 pill carrying core, the isolation layer and the slow release layer is (0.85-1.25): (0.03-0.045) and (0.225-0.255).
The sustained release effect of the venlafaxine hydrochloride sustained release agent in an ethanol environment is greatly improved by arranging the isolation layer between the pill carrying core and the sustained release layer and limiting the thicknesses of the isolation layer and the sustained release layer in the above range. This is beneficial to improving patient compliance, maintaining blood concentration within a relatively smooth and durable effective range, improving drug safety, and reducing frequency of administration. In addition, the raw materials used in the preparation method have the advantages of wide sources and low price, so that the preparation method can reduce the cost of the venlafaxine hydrochloride sustained-release agent.
In order to better control the dosage of the user, in a preferred embodiment, the thicknesses of the pill carrying core, the isolation layer and the slow release layer in the venlafaxine hydrochloride slow release agent 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 methods commonly used in the art. In a preferred embodiment, the preparation of the barrier layer comprises: mixing the first coating film material with a first solvent to obtain a first coating liquid; and coating the first coating liquid on the surface of the pill-carrying core to obtain the pill-carrying core containing the isolation layer.
The first coating film and the first solvent may be of a type 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 methylene chloride, methanol, water, and ethanol. Compared with other materials, the first coating film material and the first solvent are favorable for improving the film forming efficiency, film forming property and drug release reproducibility of the isolating layer. More preferably, 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) (5-13).
The slow release layer may be prepared by methods commonly used in the art. In a preferred embodiment, the preparation of the slow release layer comprises: mixing the second coating film material, the pore-forming agent and the second solvent to obtain a second coating liquid; and coating the second coating liquid on the surface of the isolation layer to obtain the venlafaxine hydrochloride sustained release agent.
The second coating film and the second solvent may be of a type commonly used in the art. In a preferred embodiment, the second coating film comprises, but is not limited to, one or more of ethylcellulose, hypromellose, polyethylene glycol, and hypromellose, the porogen comprises, but is not limited to, one or more of hypromellose, polyethylene glycol, and hypromellose, and the second solvent comprises, but is not limited to, one or more of methylene chloride, methanol, ethanol, and water. Compared with other materials, the coating material and the solvent are selected to be favorable for improving the uniform stability of the slow-release layer. The pore-forming agent can form a drug release channel on the surface of the slow-release layer, and can better regulate the release efficiency of the drug. In order to better control the slow release efficiency of the medicine, more preferably, the second coating film material is a mixture of ethyl cellulose, polyethylene glycol and hypromellose, the pore-forming agent is hypromellose, the second solvent is a mixture of methylene dichloride and methanol, and the weight ratio of the ethyl cellulose to the hypromellose to the polyethylene glycol to the methylene dichloride to the methanol is 1 (0.1-0.7) (0.002-0.02) (19-28) (7-16).
The pill-carrying cores may be prepared by methods commonly used in the art. In a preferred embodiment, the preparation of the pill-carrying core comprises: mixing venlafaxine hydrochloride, binder and wetting agent, granulating and drying to obtain pill core. More preferably, the binder includes, but is not limited to, hypromellose and/or hypromellose, and the wetting agent includes, but is not limited to, water and/or ethanol. The use of the several binders and wetting agents described above allows for better shaping of the pellet-carrying cores than other binders and wetting agents.
In order to improve the processability of the pill-carrying core, the preparation of the pill-carrying core further comprises adding lubricants and fillers during the preparation of the pill-carrying 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. The addition of the above types is advantageous in further reducing the tackiness of the pellet-carrying core and in improving the rounding of the pellets compared to other lubricants and fillers. More preferably, the binder is hydroxypropyl cellulose, the wetting agent is water, the lubricant includes, but is not limited to, a mixture of talc and magnesium stearate, the filler is microcrystalline cellulose, and the weight ratio of venlafaxine hydrochloride, hydroxypropyl cellulose, water, talc, magnesium stearate and microcrystalline cellulose is (30-35): 0.5-4): 15-22): 0.2-8: 30-42.
Preferably, the venlafaxine hydrochloride sustained release agent is prepared by adopting an extrusion and spheronization process.
It should be noted that: the solvent and the wetting agent added in the preparation process volatilize in the drying process, so that the addition of the two substances does not influence the weight of the slow release of the venlafaxine hydrochloride formed later.
The application also provides a slow release preparation of the venlafaxine hydrochloride, which is prepared by adopting the preparation method.
The sustained release effect of the venlafaxine hydrochloride sustained release agent in an ethanol environment is greatly improved by arranging the isolation layer between the pill carrying core and the sustained release layer and limiting the thicknesses of the isolation layer and the sustained release layer in the above range. This is beneficial to improving patient compliance, maintaining blood concentration within a relatively smooth and durable effective range, improving drug safety, and reducing frequency of administration. In addition, the raw materials used in the preparation method have the advantages of wide sources and low price, so that the preparation method can reduce the cost of the venlafaxine hydrochloride sustained-release agent. Meanwhile, the sustained release agent has the advantage of non-pH dependence. On the basis, the venlafaxine hydrochloride sustained-release preparation prepared by the preparation method has the advantages of non-pH dependence, good sustained-release effect, low cost, high medication safety and the like.
Still another aspect of the present application provides a venlafaxine hydrochloride sustained-release capsule, which 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.
The venlafaxine hydrochloride sustained release agent prepared by the preparation method has the advantages of non-pH dependence, good sustained release effect, low cost, high medication safety and the like. The sustained-release capsule containing the same has good sustained-release effect under different use pH values, and has the characteristics of low cost and safety in ethanol environment.
In another aspect, the application also provides an application of the venlafaxine hydrochloride sustained-release preparation in preparation of antidepressant drugs.
The venlafaxine hydrochloride sustained release agent prepared by the preparation method has the advantages of non-pH dependence, good sustained release effect, low cost, high medication safety and the like. Therefore, the sustained release agent has wider application prospect and economic value in the field of antidepressant drugs.
The present application is described in further detail below in conjunction with specific embodiments, which should not be construed as limiting the scope of the claims.
The manufacturers of the raw materials used in the examples are shown in Table 1.
TABLE 1
| Raw materials | Manufacturer' s |
| Venlafaxine hydrochloride | GUILIN HUAXIN PHARMACEUTICAL Co.,Ltd. |
| Microcrystalline cellulose pH101 | German JRS pharmaceutical excipients Co |
| Talc powder | GUANGXI LONGSHENG HUAMEI TALC DEVELOPMENT Co.,Ltd. |
| Magnesium stearate | ANHUI SUNHERE PHARMACEUTICAL EXCIPIENTS Co.,Ltd. |
| Hydroxypropyl methylcellulose E6 | American Dow chemical |
| Dichloromethane (dichloromethane) | Komio Europe |
| Methanol | "Bailingwei |
| Ethylcellulose 20cp | American Dow chemical |
| 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) Preparation of the pill-carrying core:
the ingredients are as follows:
84.92 parts by weight of venlafaxine hydrochloride, 101.28 parts by weight of microcrystalline cellulose pH101, 11.00 parts by weight of talcum powder, 11.00 parts by weight of magnesium stearate, 1.80 parts by weight of hypromellose E6 and 51.50 parts by weight of water.
Sieving the raw materials, hypromellose and microcrystalline cellulose with 40 mesh sieve respectively, sieving the materials together, and sieving pulvis Talci and magnesium stearate with 60 mesh sieve respectively. The materials are placed in a wet granulator and mixed uniformly. Then adding wetting agent (water) to make soft material.
Adding the soft material into an extruder, extruding the soft material from the extruder by using a sieve plate with the aperture of 0.8mm, and then putting the extruded strip-shaped object into a rounding machine to prepare round pellets; and then placing the pellets in a fluidized bed for drying, controlling the moisture content of the pellets to be less than 2%, and finally screening by using a 16-mesh and 25-mesh oscillating screen, and selecting the pellets passing through the 16-mesh and 25-mesh screen as final target pellets.
(2) Preparation of the isolation layer
The ingredients are as follows:
6.30 parts by weight of hypromellose E6, 121.59 parts by weight of methylene chloride and 51.11 parts by weight of methanol.
Hypromellose E6 was dispersed in methanol, and then methylene chloride was added thereto with stirring. Stirring is carried out for at least 30 minutes. The polymer concentration of the coating liquid is 3.5%, and the coating weight gain is 3.0%.
And respectively coating the two pill-carrying cores by using a fluidized bed to obtain two pill-carrying cores containing the 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 a sustained release layer
The ingredients are as follows:
30.34 parts by weight of ethylcellulose (Brookfield viscosity 20 cP), 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 with stirring, then dichloromethane was added, and stirring was continued for at least 60 minutes until a clear solution was obtained.
And (3) adopting a fluidized bed to carry out slow release layer coating on the two pill-carrying cores containing the isolation layers, controlling the material temperature to be 25+/-2 ℃ in the coating process, controlling the moisture in the pellets to be less than 2% after coating, controlling the coating weight to be 17%, controlling the thickness of the slow release layer to be 0.225-0.255 mm, drying, and passing the pellets through a 14-mesh and 25-mesh sieve correspondingly to obtain the required slow release agent.
(4) Capsule filling
And (3) installing a No. 1 die on a filling machine, filling the slow-release agent into a hopper, adjusting filling quantity starting equipment, and checking the filling quantity difference every 15 minutes to obtain the slow-release capsule.
The release properties of the venlafaxine hydrochloride sustained-release capsules prepared in example 1 at different pH values were tested by the method of USP1 method: basket method, rotational speed: 100 revolutions, 900ml of medium and 4 mediums respectively: purified water, 0.1N HCI, acetate buffer, phosphate buffer, sampling time points were respectively: 0.2, 4, 8, 12, 20 hours.
The dissolution results of samples (the thicknesses of the pellet core, the isolation layer and the sustained release layer are sequentially 1.0mm, 0.03mm and 0.250 mm) of the venlafaxine hydrochloride sustained release capsule prepared in example 1 are shown in Table 2.
The dissolution data of the commercial venlafaxine hydrochloride sustained release capsules at different pH are shown in table 3. The limit criteria for each time point of detection of the dissolution rate in the standard medium (aqueous medium) are shown in table 4.
TABLE 2
TABLE 3 Table 3
TABLE 4 Table 4
| Time (h) | Release of drug (%) |
| 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 non-constant release. Meanwhile, compared with the existing commercial products, the venlafaxine hydrochloride sustained-release preparation prepared by the application can achieve the same sustained-release effect as can be seen by comparing the data in tables 2 to 4.
The release performance of the venlafaxine hydrochloride sustained-release capsule prepared in example 1 in ethanol was tested as follows: 5 samples are selected, the thickness ratio of sample 1 (the thicknesses of the pill core, the isolation layer and the slow release layer are sequentially 1.0mm, 0.03mm and 0.250 mm), the thickness ratio of sample 2 (the thicknesses of the pill core, the isolation layer and the slow release layer are sequentially 1.0mm, 0.04mm and 0.250 mm), the thickness ratio of sample 3 (the thicknesses of the pill core, the isolation layer and the slow release layer are sequentially 1.0mm, 0.03mm and 0.235 mm), the thickness ratio of sample 4 (the thicknesses of the pill core, the isolation layer and the slow release layer are sequentially 1.0mm, 0.03mm and 0.250 mm), and the thickness ratio of sample 5 (the thicknesses of the pill core, the isolation layer and the slow release layer are sequentially 1.0mm, 0.03mm and 0.255 mm).
And the samples were placed in 0.1N HCI medium with 40% ethanol added to detect release of the samples, and samples were taken 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 venlafaxine hydrochloride sustained release agent prepared by the method has a better sustained release effect in the process of pouring for 60min in the ethanol environment compared with the conventional venlafaxine hydrochloride Xin Zhiji in the prior art (the sustained release degree of pouring for 60min in the ethanol environment is more than 60 percent) because the release degree of samples 1 to 5 is 21 to 32 percent in the ethanol environment. Meanwhile, as can be seen from comparing the data of table 5, which are poured for 0-60 min under the ethanol environment, the release degree of venlafaxine hydrochloride prepared by the method provided by the application is lower than that of the commercial products. Compared with the existing commercial products, the venlafaxine hydrochloride sustained release agent prepared by the preparation method has better sustained release effect in the process of pouring for 60 minutes in an ethanol environment. (the preparation method and structure of the commercial venlafaxine hydrochloride sustained-release capsule used in the examples of the present application are not disclosed).
Example 2
The difference from example 1 is that: in the preparation process of the isolation layer, the weight ratio of the hypromellose E6 to the dichloromethane to the methanol in the first coating film material is 1:16:13, wherein the weight ratio of the hypromellose E6 to the dichloromethane is 6.30.
Example 3
The difference from example 1 is that: in the preparation process of the isolation layer, 6.30 parts by weight of hypromellose E6 is in the first coating film material, and the weight ratio of the hypromellose 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, 6.30 parts by weight of hypromellose E6 is in the first coating film material, and the weight ratio of the hypromellose 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 to the hydroxypropyl methylcellulose to the polyethylene glycol to the methylene dichloride to 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 to the hydroxypropyl methylcellulose to the polyethylene glycol to the methylene dichloride to 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 to the hydroxypropyl methylcellulose to the polyethylene glycol to the methylene dichloride to 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 pill-carrying core, the dosage of the venlafaxine hydrochloride raw medicine is 84.92 parts by weight, and the weight ratio of the venlafaxine hydrochloride raw medicine to the hydroxypropyl cellulose to the water to the talcum 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 pill-carrying core, the dosage of the venlafaxine hydrochloride raw medicine is 84.92 parts by weight, and the weight ratio of the venlafaxine hydrochloride raw medicine to the hydroxypropyl cellulose to the water to the talcum 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 8.0mm.
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 3.0mm.
The release properties of the venlafaxine hydrochloride sustained-release capsules prepared in examples 2 to 9 and comparative examples 1 to 2 at pure water ph=7 were tested, the test method was the same as in example 1, and the test results are shown in table 6.
The release properties of the venlafaxine hydrochloride sustained-release capsules prepared in examples 2 to 9 and comparative examples 1 to 2 in ethanol were tested 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 have good sustained release effect in pure water environment; and compared with comparative examples 1 to 2, a better sustained-release effect can be obtained by adopting the preparation method provided by the application. As can be seen from tables 5 and 7, the release rate of venlafaxine hydrochloride sustained release agent in examples 2 to 9 is 28-32% when the venlafaxine hydrochloride sustained release agent is poured in an ethanol environment for 60min, so that compared with the conventional venlafaxine hydrochloride Xin Zhiji in the prior art (the release rate of the venlafaxine hydrochloride sustained release agent is more than 60% when the venlafaxine hydrochloride sustained release agent is poured in the ethanol environment for 60 min), the venlafaxine hydrochloride sustained release agent prepared by the method provided by the application has a better sustained release effect when the venlafaxine hydrochloride sustained release agent is poured in the ethanol environment for 60 min; compared with the commercial products 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 that of the sustained-release agent in the comparative example 1, but the sustained-release agent prepared in the comparative example 1 has too thick sustained-release layer, so that the volume of the sustained-release agent is too large, and the sustained-release agent is inconvenient for industrial production.
From the above description, it can be seen that the above 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 peak-valley phenomenon of blood concentration presented by common dosage form administration, improving the compliance of patients, keeping the blood concentration in a stable and durable effective range, improving the safety of the medicament 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 same 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 of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The preparation method of the venlafaxine hydrochloride sustained-release agent is characterized by comprising the following steps:
preparing a pill carrying core;
coating an isolation layer on the surface of the pill carrying 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 pill carrying core, the isolation layer and the slow release layer is (0.85-1.25): (0.03-0.045) (0.225-0.255);
the preparation of the isolation layer comprises the following steps: mixing the first coating film material with a first solvent to obtain a first coating liquid; coating the first coating liquid on the surface of the pill carrying core to obtain a pill carrying core containing the isolation layer; 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) (5-13);
the preparation of the slow release layer comprises the following steps: mixing the second coating film material, the pore-forming agent and the second solvent to obtain a second coating liquid; coating the second coating liquid on the surface of the isolation layer to obtain the venlafaxine hydrochloride sustained-release agent;
the second coating film material is selected from a mixture of ethyl cellulose, polyethylene glycol and hypromellose, the pore-forming agent is hypromellose, the second solvent is a mixture of dichloromethane and methanol, and the weight ratio of the ethyl cellulose to the hypromellose to the polyethylene glycol to the dichloromethane to the methanol is 1 (0.1-0.7) (0.002-0.02) (19-28) (7-16).
2. The method of preparing as claimed in claim 1, wherein the preparation of the pill-carrying core comprises: mixing venlafaxine hydrochloride, adhesive and wetting agent, granulating and drying to obtain the pill-carrying core.
3. The preparation method according to claim 2, wherein the binder is selected from hypromellose and/or hypromellose, and the wetting agent is selected from water and/or ethanol.
4. The method of preparing according to claim 2, wherein the preparation of the pill-carrying core further comprises adding lubricants and fillers during the preparation of the pill-carrying core.
5. The method according to claim 4, wherein the lubricant is one or more selected from the group consisting of talc, magnesium stearate, stearic acid and sodium stearyl fumarate, and the filler is one or more selected from the group consisting of microcrystalline cellulose and lactose.
6. The preparation method according to claim 5, wherein the binder 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 venlafaxine hydrochloride raw medicine, hydroxypropyl cellulose, water, talcum powder, magnesium stearate and microcrystalline cellulose is (30-35): 0.5-4): 15-22): 0.2-8: 30-42.
7. A venlafaxine hydrochloride sustained release preparation, which is characterized in that the venlafaxine hydrochloride sustained release preparation is prepared by the preparation method of any one of claims 1 to 6.
8. A venlafaxine hydrochloride sustained-release capsule comprising 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 of claim 7.
9. Use of venlafaxine hydrochloride sustained release formulation according to claim 7 in the manufacture of an antidepressant.
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| CN103191082A (en) * | 2013-04-19 | 2013-07-10 | 浙江美华鼎昌医药科技有限公司 | Venlafaxine hydrochloride spansule and preparation method thereof |
| CN109846858A (en) * | 2018-12-18 | 2019-06-07 | 杭州和康药业有限公司 | A kind of Memantine hydrochloride sustained-release capsule and preparation method thereof |
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