CN109200032B

CN109200032B - High drug-loading venlafaxine hydrochloride sustained-release pellet composition, sustained-release capsule and preparation method

Info

Publication number: CN109200032B
Application number: CN201811271188.8A
Authority: CN
Inventors: 侯奇伟; 李晓云; 后旻旸
Original assignee: Hunan Dongting Pharmaceutical Co Ltd
Current assignee: Hunan Dongting Pharmaceutical Co Ltd
Priority date: 2018-10-29
Filing date: 2018-10-29
Publication date: 2022-01-14
Anticipated expiration: 2038-10-29
Also published as: CN109200032A

Abstract

The invention relates to a venlafaxine hydrochloride sustained-release pellet composition with high drug-loading rate, a sustained-release capsule and a preparation method thereof. Specifically, the venlafaxine hydrochloride sustained-release pellet comprises a blank pellet core, a drug-carrying coating layer coated on the outer surface of the blank pellet core, and a sustained-release coating layer coated on the outer surface of the drug-carrying coating layer, wherein the drug-carrying coating layer contains venlafaxine hydrochloride serving as an active ingredient. The venlafaxine hydrochloride sustained-release pellet comprises 50-65% of venlafaxine hydrochloride as an active ingredient, and can pass through a 14-mesh sieve but not pass through a 30-mesh sieve; it can pass through a 16 mesh screen but not a 25 mesh screen; the dissolution amount is not more than 30% in 2h, 40-60% in 4h, 60-80% in 8h, 70-90% in 12h and not less than 85% in 24 h. The venlafaxine hydrochloride sustained-release pellets and sustained-release capsules of the invention have excellent pharmaceutical performance.

Description

High drug-loading venlafaxine hydrochloride sustained-release pellet composition, sustained-release capsule and preparation method

Technical Field

The invention belongs to the technical field of medicines, and relates to a venlafaxine oral pharmaceutical composition, in particular to a venlafaxine sustained-release capsule composition and a preparation method thereof, wherein the venlafaxine oral pharmaceutical composition is used for treating depression, generalized anxiety disorder, relapse prevention of depressive episode, social anxiety disorder, panic disorder and the like.

Background

Venlafaxine (venlafaxine), often used as its hydrochloride salt, has the formula: c₁₇H₂₇NO₂HCl, molecular weight: 313.86, CAS registry number: 99300-78-4, chemical name: (±) -1- [ alpha- [ (dimethylamino) methyl group]-p-methoxybenzyl]The concentration of cyclohexanol hydrochloride in the reaction mixture,

the sustained-release capsule is antidepressant drug of 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI). Animal experiments show that the medicine has antidepressant effect and no obvious affinity to muscarinic-like or histamine-like receptors. Therefore, the venlafaxine has no obvious adverse reaction characteristics caused by tricyclic antidepressants (TCAs) while having an antidepressant effect, and shows more unique pharmacological properties. Since 1994, the drug was successively approved by the U.S. food and drug administration for the treatment of depressive disorders, depressive disorders with anxiety symptoms, generalized anxiety disorder, and social anxiety disorder. In 2001, the general administration of food and drug administration in China has also successively approved indications of depression and generalized anxiety disorder, and until 7 months in 2012, the drug is the only novel antidepressant with the indications of generalized anxiety disorder on the market in China. Venlafaxine is a first-line treatment recommended by the guidelines for the prevention and treatment of depression and generalized anxiety disorder in countries such as canada and china.

Venlafaxine is a bicyclic family of phenethylamine compounds that selectively blocks reuptake of the 5-hydroxytryptamine (5-HT) transporter and the Norepinephrine (NE) transporter with approximately 8-fold higher affinity for 5-HT than NE. Venlafaxine blocks 5-HT reuptake only at low doses of 75mg/d to 100mg/d, and has dual monoamine reuptake inhibition on both NE and 5-HT at doses > 150 mg/d. In rodent depression-like model studies, venlafaxine exerts rapid beta-receptor desensitization, unlike other antidepressants, which require repeated doses to stimulate NE desensitization. The research on the action mechanism of venlafaxine on 5-HT1A receptors shows that the inhibition of forebrain 5-HT1A receptors generates antidepressant action, and the inhibition of intersomatic nucleus soma-dendritic autoreceptor can enhance the generation of analgesic action of a descending monoamine pain control system. The reuptake inhibition of Dopamine (DA) is very weak, with low or no affinity for muscarinic and histamine H1 receptors, as well as for α -adrenergic receptors. Has certain inhibitory effect on 5-HT neurons of dorsal suture nucleus and NE neurons of orchid plaques, and autoreceptors and heterogeneous receptors of soma-dendrites, thereby increasing the release of postsynaptic 5-HT and NE and accelerating the desensitization process of presynaptic membrane autoreceptors, and also explains the possible reason that SNRIs is superior to a selective 5-HT reuptake inhibitor (SSRI) in terms of anti-depression and anti-anxiety curative effect and onset time.

Venlafaxine is well absorbed in the gastrointestinal tract after oral administration, and when taken with food, it reduces its absorption rate without affecting its absorption degree. After first pass metabolism by the liver, the only active metabolite formed is ODV. After the common preparation is taken, the blood medicine peak concentration of venlafaxine is reached within 2h, and the peak concentration of ODV is reached within 3 h. The venlafaxine sustained release preparation has slower absorption than the common preparation, reaches the peak concentration of the blood drug for about 5.5 hours, and the ODV can reach the peak after 9 hours, thereby forming the blood drug concentration of low peak and valley and avoiding the defects of high peak and low valley of the common preparation. Both dosage forms are comparable in extent of absorption and bioavailability. After 3-4 days of treatment, the steady blood concentration can be achieved. When the dosage is in the range of 75mg/d to 450mg/d, the venlafaxine and the active metabolites thereof have linear pharmacokinetics. Venlafaxine and its metabolites are mainly excreted by the kidney. Venlafaxine has a half-life of 4h, and ODV clearance is slower than venlafaxine, with a half-life of 10 h. The sustained release dosage form has a bioavailability of 90% or more when administered 1 time per day, which is almost equal to that of a conventional dosage form administered 2 times per day. The sustained release preparation can be administered in the morning or evening, and can be administered with food without affecting bioavailability. Venlafaxine undergoes a number of metabolisms in the liver by the cytochrome P450 enzyme system, mainly the 2D6 enzyme, and since venlafaxine and its active metabolite ODV are pharmacologically equivalent, the direct consequences of inhibition of the 2D6 enzyme are clinically insignificant at least at therapeutic concentrations. Although venlafaxine is a substrate for the cytochrome P4502D 6 enzyme, it is one of the weakest inhibitory drugs for this enzyme in all novel antidepressants, and it is generally not necessary to adjust venlafaxine doses when combined with 2D6 enzyme inhibitors.

Venlafaxine is also used in the european union and the united states for relapse prevention of depressive episodes, social anxiety disorder, panic disorder, etc. the main indications for venlafaxine are depression, generalized anxiety disorder.

Venlafaxine is often used clinically in the form of its hydrochloride salt, and there are usually ordinary tablets, which are taken twice a day, sustained release tablets, and sustained release capsules, which are taken only once a day. There are many reports on the preparation method of venlafaxine sustained release capsules. For example, CN102772390A (chinese patent application No. 201210291863X, new commander) discloses a venlafaxine hydrochloride sustained release capsule and a preparation method thereof. The content of the sustained-release capsule is a sustained-release pellet which sequentially comprises a pellet core, an isolation layer and a sustained-release layer from inside to outside, wherein the pellet core is prepared from the following components in percentage by weight: 45-48% of venlafaxine hydrochloride, 15-18% of filler, 3-3.5% of disintegrant, 304-6% of povidone K, 24-26% of absolute ethyl alcohol and the balance of water; the isolating layer is prepared from the following components in percentage by weight: povidone K3011-13%, absolute ethyl alcohol 83-86% and the balance of talcum powder; the slow release layer is prepared from the following components in percentage by weight: 38-42% of ethyl cellulose suspension, 1.0% of polyethylene glycol-60000.1 and the balance of water, wherein the ethyl cellulose mass content of the ethyl cellulose suspension is 20-30%. The invention is believed to obtain the sustained-release capsule after preparing the pill core, coating the isolation layer, coating the sustained-release layer and filling the capsule. The invention is believed to adopt ethyl cellulose, has low flammability, small hygroscopicity, good film forming property, stable and easily controlled material quality, and is safer and more environment-friendly.

CN103054835A (Chinese patent application No. 2013100357601, as well as Xiaoming) discloses a venlafaxine sustained-release capsule and a preparation process thereof, wherein ethyl cellulose and enteric acrylic resin are compounded to be used as an adhesive, and an isolation layer is coated outside a blank pellet core, so that the pellet core is not released completely, the osmotic pressure in the sustained-release pellet is reduced, and the release speed of the medicine is slowed down; meanwhile, the adhesive is used for the drug-containing layer and the sustained-release protective layer, so that the venlafaxine drug is encapsulated in the sustained-release material layer by layer, the solubility of the pellet is further reduced, the stable release of the drug is ensured, and the standard requirement is met.

CN106955276A (Chinese patent application No. 2017101927278, Herui) discloses a venlafaxine hydrochloride sustained-release capsule composition, wherein the content of the sustained-release capsule composition is a sustained-release pellet consisting of 58-66 parts by weight of venlafaxine hydrochloride, 75-85 parts by weight of filler and 8-12 parts by weight of adhesive, and the sustained-release layer consists of 3.5-6 parts by weight of sustained-release coating material and 18-27 parts by weight of pore-forming agent, wherein the mass of the sustained-release layer is 14-17% of that of the drug-carrying layer. The invention also provides a preparation method of the venlafaxine hydrochloride sustained-release capsule composition, which prepares the drug-loaded pellets by using a fluidized bed and carries out sustained-release coating to prepare the sustained-release pellets. The venlafaxine hydrochloride sustained-release capsule composition prepared by the invention is believed to contain no auxiliary materials such as an anti-sticking agent, a plasticizer and the like, and the manufacturing conditions can be met by adjusting the fluidized bed process, so that the medicine with similar effect to the original medicine effect is obtained, the cost is saved, and the process difficulty is reduced.

CN103181916A (Chinese patent application No. 201110452445X, large size) discloses venlafaxine hydrochloride sustained-release capsules and a preparation method thereof. The drug-containing core of the sustained-release capsule comprises venlafaxine hydrochloride, microcrystalline cellulose, fumed silica, tween-80 and hydroxypropyl methyl cellulose, and the sustained-release coating comprises polyacrylic resin, talcum powder, polyethylene glycol and sodium dodecyl sulfate. The invention changes the flow of the materials by adding the fumed silica and selects the slow-release coating, so that the production of the capsule realizes a pure water system. The venlafaxine hydrochloride sustained-release capsule prepared by the system has stable drug release, has effective sustained release time of 24 hours and only needs to be taken once a day. The method is simple in process, mild in condition, free of any organic solvent, low in equipment requirement and suitable for industrial production.

CN103893153A (Chinese patent application No. 2014101550047, Huaxin) discloses a venlafaxine hydrochloride sustained-release capsule and a preparation method thereof, belonging to the technical field of medicines. The venlafaxine hydrochloride sustained-release capsule consists of sustained-release contents and a capsule shell, wherein the sustained-release contents consist of a drug-loaded sucrose type medicinal pellet core and a sustained-release layer.

CN104873477A (chinese patent application No. 2015102600349, zhengda) discloses a venlafaxine hydrochloride sustained-release capsule and a preparation method thereof, wherein the sustained-release capsule consists of sustained-release pellets and a capsule shell. The slow release pellet uses inert pellet core as substrate, and the fluidized bed is coated with medicine layer, isolating layer and slow release layer separately.

CN103893151A (Chinese patent application No. 2012105838482, Zhongqi) discloses a venlafaxine hydrochloride sustained-release capsule, the content of the sustained-release capsule prepared by the invention is a sustained-release pellet, the pellet consists of a drug-containing pellet core and a sustained-release coating film, and the drug-containing pellet core contains venlafaxine hydrochloride, hydroxypropyl methylcellulose and microcrystalline cellulose. The venlafaxine hydrochloride sustained-release capsule prepared by the invention has the advantages of stable drug release, no organic solvent residue, safe product taking and friendly production environment. The invention also provides a preparation method of the venlafaxine hydrochloride sustained-release capsule, which is believed to have high production efficiency, simple process, convenient operation, low cost and easy industrialized production, saves the cost for pharmaceutical production enterprises and can generate considerable economic and social benefits.

CN106176679A (Chinese patent application No. 2016105481295, Dragon sea) discloses a venlafaxine hydrochloride sustained-release capsule and a preparation method thereof, belonging to the technical field of medicines. The venlafaxine hydrochloride sustained-release capsule consists of sustained-release contents and a capsule shell, wherein the sustained-release contents consist of a drug-loaded starch type medicinal pellet core and a sustained-release layer. The venlafaxine hydrochloride sustained-release capsule can be continuously released for 24 hours, and the release is stable without burst release. In addition, the preparation method of the venlafaxine hydrochloride sustained-release capsule is believed to have the advantages of high production efficiency, simple process, convenient operation, less auxiliary material types and dosage, easy industrial production, cost saving for pharmaceutical production enterprises and considerable economic and social benefits.

CN103191082A (Chinese patent application No. 2013101379063, Meihua) discloses a venlafaxine hydrochloride sustained-release capsule and a preparation method thereof. The existing method adopts aqueous dispersion to carry out coating, the venlafaxine hydrochloride migrates during coating due to the high water solubility of the venlafaxine hydrochloride, and the venlafaxine hydrochloride can become a pore agent under the condition of insufficient coating film thickness, so that the venlafaxine hydrochloride is released too fast. The venlafaxine hydrochloride sustained-release capsule is characterized in that the drug-containing pellet comprises a drug-containing pellet core, an isolation layer coated outside the drug-containing pellet core and a controlled-release layer coated outside the isolation layer, wherein the drug-containing pellet core is prepared from the following components in percentage by weight: 30-60% of venlafaxine hydrochloride, 30-80% of filler, 1-20% of slow-release framework material and 1-10% of adhesive. The invention is believed to thoroughly solve the technical problems of potential safety hazards to operators, high requirements on equipment and the like caused by the fact that organic solvents such as dichloromethane and ethanol are used as solvents for coating.

However, it is still expected to provide a method for preparing venlafaxine hydrochloride sustained-release pellets and sustained-release capsules with excellent performance, and also provide venlafaxine hydrochloride sustained-release pellets and sustained-release capsules with excellent performance.

Disclosure of Invention

The invention aims to provide a method for preparing venlafaxine hydrochloride sustained-release pellets and sustained-release capsules with excellent performance, and the invention also aims to provide venlafaxine hydrochloride sustained-release pellets and sustained-release capsules with excellent performance. It has been surprisingly found that venlafaxine hydrochloride sustained release pellets prepared using the formulation and process of the present invention exhibit superior properties and the present invention has been completed based on this finding.

Therefore, the first aspect of the invention provides a venlafaxine hydrochloride sustained-release pellet, which comprises a blank pellet core, a drug-carrying coating layer coated on the outer surface of the blank pellet core, and a sustained-release coating layer coated on the outer surface of the drug-carrying coating layer, wherein the drug-carrying coating layer contains venlafaxine hydrochloride as an active ingredient.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the invention, wherein the venlafaxine hydrochloride is 50 to 65%, such as 52 to 62%, such as 53 to 61% of the weight of the sustained-release pellet. It has been surprisingly found that the sustained release pellets prepared according to the present invention have a significantly higher drug loading than the prior art.

Venlafaxine hydrochloride sustained release pellets according to the first aspect of the invention, which pass through a 14 mesh screen but not a 30 mesh screen.

Venlafaxine hydrochloride sustained release pellets according to the first aspect of the invention, which pass through a 16 mesh screen but not a 25 mesh screen.

According to the venlafaxine hydrochloride sustained-release pellet of the first aspect of the invention, the dissolution amount is not more than 30% in 2h, 40-60% in 4h, 60-80% in 8h, 70-90% in 12h and not less than 85% in 24h, which are determined by a dissolution method.

The venlafaxine hydrochloride sustained release pellet according to the first aspect of the invention, wherein [ dissolution test ] comprises the following operations:

according to the specification of 0931 dissolution and release degree determination method in the four parts of the 2015 edition of Chinese pharmacopoeia, the amount of venlafaxine containing the active drug in each test sample is determined to be 50-250 mg (50-250 mg of venlafaxine can also be referred to as a test amount, for example, when the sample is a pellet, the pellet with the amount of 50-250 mg of venlafaxine is placed in a dissolution test basket for determination, and when the test sample is a capsule with the pellet in a hard capsule shell, the amount of the pellet in each capsule is 50-250 mg of venlafaxine);

dissolution medium: 900mL of water, and degassing;

the device comprises the following steps: blue method, rotation speed 100 rpm;

sampling time: sampling at 5 time points represented by an integer i of 1-5, wherein the sampling is respectively 2h, 4h, 8h, 12h and 24 h;

buffer solution: 10mL/L triethylamine water solution and phosphoric acid is used for adjusting the pH value to be 3.0;

flow sample: acetonitrile-buffer (20: 80);

standard solution: dissolving a proper amount of venlafaxine hydrochloride reference substances in a dissolution medium to prepare a standard solution, wherein the concentration of venlafaxine in the standard solution is equivalent to the theoretical concentration of venlafaxine in each dissolution cup of a dissolution test;

sample solution: centrifuging the test solution;

liquid chromatography system: an ultraviolet 226nm detector, a C18 column specification of 4.6mm multiplied by 15cm-5 μm, a flow rate of 2.5mL/min, a sample injection amount of 20 μ L, and a recording time of 1.5 times of a venlafaxine retention time;

the system applicability is as follows: the tailing factor is not more than 2.0 and the relative standard deviation is not more than 2.0 percent when the test is carried out by a standard solution;

and (3) determination:

the samples are standard solution and sample solution,

calculation of the concentration Ci (mg/mL) of venlafaxine (C17H27NO2) in the medium after time point i:

results i ═ rU/rS. times.CS × (Mr1/Mr2)

Wherein, rU is the peak response value of the sample solution, rS is the peak response value of the standard solution, CS is the concentration (mg/mL) of the venlafaxine hydrochloride control in the standard solution, Mr1 is the molecular weight of venlafaxine 277.40, Mr2 is the molecular weight of venlafaxine hydrochloride 313.86,

the percentage of marked amounts of venlafaxine (C17H27NO2) dissolved at each time point i was calculated as follows

Result 1 ═ C1 × V × (1/L) × 100

Result 2 { [ C2 × (V-VS) ] + [ C1 × VS ] } × (1/L) × 100

Result 3 { [ C3 × (V- (2 × VS)) ] + [ (C2+ C1) × VS ] } × (1/L) × 100

Result 4 { [ C4 × (V- (3 × VS)) ] + [ (C3+ C2+ C1) × VS ] } × (1/L) × 100

Result 5 { [ C5 × (V- (4 × VS)) ] + [ (C4+ C3+ C2+ C1) × VS ] } × (1/L) × 100

In the above formula, Ci is the venlafaxine concentration (mg/mL) in the sampled solution at time point i, V is 900mL of the dissolution medium volume, VS is the volume (mL) of the sample solution sucked from the dissolution medium, and L is the concentration test index (i.e., the theoretical amount of venlafaxine added in each dissolution cup, mg in the dissolution test; for example, the venlafaxine index, mg in each capsule in the dissolution test in the form of capsule).

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the blank pellet core is a blank pellet core made of a base material selected from the group consisting of: sucrose, starch, microcrystalline cellulose, and combinations thereof. These empty cores may be made by the manufacturer or may be obtained commercially.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the blank pellet core is a blank pellet core made of sucrose. In one embodiment, the mean diameter of the empty pellet core is 0.3 to 0.6mm, preferably 0.35 to 0.5mm, preferably 0.35 to 0.45 mm. In the specific experiments described herein below, the empty pellet cores used were empty pellet cores made of sucrose and having an average diameter of 0.35 to 0.45mm, as not specifically mentioned.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the amount of the empty pellet core is 35 to 45 parts by weight, for example, 38 to 44 parts by weight, for example, 39 to 42 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

In the present invention, 84.86 parts by weight of venlafaxine hydrochloride corresponds to 75 parts by weight of venlafaxine.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the drug-loaded coating layer comprises, in addition to the active ingredient, a binder selected from the group consisting of: ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.

The venlafaxine hydrochloride sustained-release pellets according to the first aspect of the present invention, wherein the drug-loaded coating layer further comprises a binder selected from the group consisting of: ethyl cellulose, hydroxypropyl cellulose, and combinations thereof.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the invention, wherein the drug-carrying coating layer further comprises the following binders: ethyl cellulose, hydroxypropyl cellulose.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the amount of the binder is 10 to 15 parts by weight, for example 11 to 14 parts by weight, for example 12 to 13 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the invention, wherein the drug-carrying coating layer further comprises the following binders: ethyl cellulose and hydroxypropyl cellulose in an amount of 5 to 10 parts by weight, for example 6 to 9 parts by weight, for example 7 to 9 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the invention, wherein the drug-carrying coating layer further comprises the following binders: ethyl cellulose and hydroxypropyl cellulose in an amount of 3 to 7 parts by weight, for example 4 to 6 parts by weight, for example 4 to 5 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the sustained-release coating material in the sustained-release coating layer is selected from: ethyl acrylate and methyl methacrylate (2: 1) copolymers such as ewt NE30D, ethylcellulose, mixtures of ethylcellulose and hydroxypropylmethylcellulose, and the like; a preferred extended release coating material is a copolymer of ethyl acrylate and methyl methacrylate (2: 1) such as Ewing NE 30D.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the amount of the sustained-release coating material is 5 to 15 parts by weight, for example 6 to 12 parts by weight, for example 7 to 10 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride. The amount of the sustained-release coating material, as not specifically mentioned herein, is based on its dry matter.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the sustained-release coating layer further comprises an anti-sticking agent for preventing the sustained-release coating material from sticking during the coating process.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the anti-adhesion agent in the sustained-release coating layer is selected from the group consisting of: talc, colloidal silica, magnesium trisilicate, and the like, with talc being a preferred anti-adherent.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the anti-adhesion agent is present in an amount of 1 to 5 parts by weight, such as 1 to 3 parts by weight, such as 1 to 2 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride. One of the main functions of the anti-sticking agent is to prevent the slow release coating material from sticking during the coating process.

According to the venlafaxine hydrochloride sustained-release pellet of the first aspect of the invention, the drug-loaded coating layer is coated on the outer surface of the blank pellet core in the following way: the active ingredient and binder are dissolved and/or suspended in a first solvent and spray coated onto the surface of the blank pellet core, followed by drying the coated pellets to remove the first solvent. In one embodiment, the first solvent is selected from: water, ethanol, isopropanol, and combinations thereof, with the preferred first solvent being isopropanol.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the amount of the first solvent is such that the weight of solids in the obtained suspension is 20 to 40%, such as 25 to 35%, such as 28 to 32%.

According to the venlafaxine hydrochloride sustained-release pellet of the first aspect of the invention, the sustained-release coating layer is coated on the outer surface of the drug-carrying coating layer by the following method: the sustained release coating material and the anti-adhesive agent are dispersed and suspended in a second solvent and spray-coated onto the outer surface of the drug-loaded coating layer, followed by drying the coated pellets to remove the second solvent. In one embodiment, the second solvent is selected from: water, ethanol, isopropanol, and combinations thereof, with the preferred second solvent being water.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the amount of the second solvent is such that the weight of the solid in the obtained suspension is 20 to 35%, such as 25 to 30%, such as 25 to 28%.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the present invention, wherein the spraying of the drug-loaded coating layer onto the surface of the blank pellet core and the spraying of the sustained-release coating layer onto the outside of the drug-loaded coating layer are carried out in a fluidized bed coating apparatus. The solvent is removed during the process of coating the pellets, and both solvents used are easily removed to meet the requirements for pharmaceutical purposes.

The venlafaxine hydrochloride sustained-release pellet according to the first aspect of the invention is prepared according to a method comprising the following steps:

(1) providing blank pellet cores, and placing the blank pellet cores in a fluidized bed coating machine (for example, the temperature is 42-45 ℃) to enable the blank pellet cores to be in a fluidized state;

(2) dissolving the adhesive in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, uniformly mixing to obtain a suspension, spraying the suspension onto a blank pill core which is in a fluidized state in a fluidized bed coating machine through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain a drug-loaded pellet;

(3) uniformly dispersing the slow-release coating material and the anti-sticking agent in a second solvent, spraying the suspension onto the medicine-carrying pellets in a fluidized state in a fluidized bed coating machine through atomization, and continuously fluidizing until the solvent is removed after spraying to obtain the slow-release pellets;

(4) and (3) mixing the sustained-release pellets obtained in the last step with 0.2-0.5% of talcum powder, then placing the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets.

Furthermore, the invention provides a venlafaxine hydrochloride sustained-release capsule, which comprises a gelatin hollow capsule and a venlafaxine hydrochloride sustained-release pellet hermetically encapsulated in the gelatin hollow capsule.

A venlafaxine hydrochloride extended release capsule according to the second aspect of the invention, wherein the venlafaxine hydrochloride extended release pellet is as described in the first embodiment of the invention; or, for example, it comprises a blank pill core, a drug-carrying coating layer coated on the outer surface of the blank pill core, and a slow-release coating layer coated on the outer surface of the drug-carrying coating layer, wherein the drug-carrying coating layer contains venlafaxine hydrochloride as an active ingredient.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the venlafaxine hydrochloride sustained-release pellet contains 50 to 65% of venlafaxine hydrochloride as an active ingredient, such as 52 to 62% of the weight of the sustained-release pellet, such as 53 to 61% of the weight of the sustained-release pellet.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet can pass through a 14-mesh sieve but cannot pass through a 30-mesh sieve.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet can pass through a 16-mesh sieve but cannot pass through a 25-mesh sieve.

According to the venlafaxine hydrochloride sustained-release capsule of the second aspect of the invention, the dissolution amount in 2 hours is not more than 30%, the dissolution amount in 4 hours is 40% -60%, the dissolution amount in 8 hours is 60% -80%, the dissolution amount in 12 hours is 70% -90%, and the dissolution amount in 24 hours is not less than 85% as determined by [ dissolution determination method ].

dissolution medium: 900mL of water, and degassing;

the device comprises the following steps: blue method, rotation speed 100 rpm;

flow sample: acetonitrile-buffer (20: 80);

sample solution: centrifuging the test solution;

liquid chromatography system: an ultraviolet 226nm detector, a C18 column specification of 4.6mm multiplied by 15cm-5 μm, a flow rate of 2.5mL/min, a sample injection amount of 20 μ L,

recording time is 1.5 times of venlafaxine retention time;

and (3) determination:

the samples are standard solution and sample solution,

results i ═ rU/rS. times.CS × (Mr1/Mr2)

Result 1 ═ C1 × V × (1/L) × 100

Result 2 { [ C2 × (V-VS) ] + [ C1 × VS ] } × (1/L) × 100

Result 3 { [ C3 × (V- (2 × VS)) ] + [ (C2+ C1) × VS ] } × (1/L) × 100

Result 4 { [ C4 × (V- (3 × VS)) ] + [ (C3+ C2+ C1) × VS ] } × (1/L) × 100

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the blank pellet core in the venlafaxine hydrochloride sustained-release pellet is a blank pellet core made of a base material selected from the group consisting of: sucrose, starch, microcrystalline cellulose, and combinations thereof.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the blank pellet core in the venlafaxine hydrochloride sustained-release pellet is a blank pellet core made of sucrose. In one embodiment, the empty pellet core has an average diameter of 0.35 to 0.45 mm.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the venlafaxine hydrochloride sustained-release pellet has an amount of the empty pellet core of 35 to 45 parts by weight, for example, 38 to 44 parts by weight, for example, 39 to 42 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the drug-carrying coating layer of the venlafaxine hydrochloride sustained-release pellet comprises a binder selected from the following in addition to the active ingredients: ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the drug-loaded coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises a binder selected from the following: ethyl cellulose, hydroxypropyl cellulose, and combinations thereof.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the drug-carrying coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises the following binders: ethyl cellulose, hydroxypropyl cellulose.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the present invention, wherein the amount of the binder is 10 to 15 parts by weight, such as 11 to 14 parts by weight, such as 12 to 13 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride in the venlafaxine hydrochloride sustained-release pellet.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the drug-carrying coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises the following binders: ethyl cellulose and hydroxypropyl cellulose in an amount of 5 to 10 parts by weight, for example 6 to 9 parts by weight, for example 7 to 9 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the drug-carrying coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises the following binders: ethyl cellulose and hydroxypropyl cellulose in an amount of 3 to 7 parts by weight, for example 4 to 6 parts by weight, for example 4 to 5 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the sustained-release coating material in the sustained-release coating layer of the venlafaxine hydrochloride sustained-release pellet is selected from: ethyl acrylate and methyl methacrylate (2: 1) copolymers such as ewt NE30D, ethylcellulose, mixtures of ethylcellulose and hydroxypropylmethylcellulose, and the like; a preferred extended release coating material is a copolymer of ethyl acrylate and methyl methacrylate (2: 1) such as Ewing NE 30D.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the amount of the sustained-release coating material in the venlafaxine hydrochloride sustained-release pellet is 5 to 15 parts by weight, for example 6 to 12 parts by weight, for example 7 to 10 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the sustained-release coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises an anti-sticking agent for preventing the sustained-release coating material from sticking in the coating process.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the anti-sticking agent in the sustained-release coating layer of the venlafaxine hydrochloride sustained-release pellet is selected from: talc, colloidal silica, magnesium trisilicate, and the like, with talc being a preferred anti-adherent.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the present invention, wherein the amount of the anti-adhesion agent is 1 to 5 parts by weight, such as 1 to 3 parts by weight, such as 1 to 2 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride in the venlafaxine hydrochloride sustained-release pellet. One of the main functions of the anti-sticking agent is to prevent the slow release coating material from sticking during the coating process.

According to the venlafaxine hydrochloride sustained-release capsule of the second aspect of the invention, the drug-carrying coating layer in the venlafaxine hydrochloride sustained-release pellet is coated on the outer surface of the blank pellet core in the following way: the active ingredient and binder are dissolved and/or suspended in a first solvent and spray coated onto the surface of the blank pellet core, followed by drying the coated pellets to remove the first solvent. In one embodiment, the first solvent is selected from: water, ethanol, isopropanol, and combinations thereof, with the preferred first solvent being isopropanol.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the amount of the first solvent in the venlafaxine hydrochloride sustained-release pellet is such that the weight of the solid in the suspension is 20 to 40%, such as 25 to 35%, such as 28 to 32%.

According to the venlafaxine hydrochloride sustained-release capsule of the second aspect of the invention, the sustained-release coating layer in the venlafaxine hydrochloride sustained-release pellet is coated on the outer surface of the drug-carrying coating layer in the following way: the sustained release coating material and the anti-adhesive agent are dispersed and suspended in a second solvent and spray-coated onto the outer surface of the drug-loaded coating layer, followed by drying the coated pellets to remove the second solvent. In one embodiment, the second solvent is selected from: water, ethanol, isopropanol, and combinations thereof, with the preferred second solvent being water.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the invention, wherein the amount of the second solvent in the venlafaxine hydrochloride sustained-release pellet is such that the weight of the solid in the suspension is 20 to 35%, such as 25 to 30%, such as 25 to 28%.

According to the venlafaxine hydrochloride sustained-release capsule of the second aspect of the invention, in the venlafaxine hydrochloride sustained-release pellet, the spraying of the drug-carrying coating layer on the surface of the blank pellet core and the spraying of the sustained-release coating layer outside the drug-carrying coating layer are carried out in a fluidized bed coating device. The solvent is removed during the process of coating the pellets, and both solvents used are easily removed to meet the requirements for pharmaceutical purposes.

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet is prepared according to a method comprising the following steps:

The venlafaxine hydrochloride sustained-release capsule according to the second aspect of the present invention is prepared according to a method comprising the following steps:

(4) mixing the sustained-release pellets obtained in the previous step with 0.2-0.5% of talcum powder, then placing the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets; and filling the sustained-release pellets into gelatin hollow capsules, and sealing and encapsulating to obtain sustained-release capsules.

Further, the third aspect of the invention provides a method for preparing a venlafaxine hydrochloride sustained-release pellet, which comprises a blank pellet core, a drug-carrying coating layer coated on the outer surface of the blank pellet core, and a sustained-release coating layer coated on the outer surface of the drug-carrying coating layer, wherein the drug-carrying coating layer contains venlafaxine hydrochloride as an active ingredient, and the method comprises the following steps:

The method according to the third aspect of the present invention, wherein the venlafaxine hydrochloride sustained release pellet contains 50 to 65% by weight, such as 52 to 62% by weight, such as 53 to 61% by weight, of venlafaxine hydrochloride as the active ingredient.

The method according to the third aspect of the invention, wherein the venlafaxine hydrochloride sustained release pellets can pass through a 14-mesh sieve but cannot pass through a 30-mesh sieve.

The method according to the third aspect of the invention, wherein the venlafaxine hydrochloride sustained release pellets can pass through a 16 mesh sieve but cannot pass through a 25 mesh sieve.

According to the method of the third aspect of the invention, the venlafaxine hydrochloride sustained-release pellets have a dissolution amount of not more than 30% in 2 hours, 40% to 60% in 4 hours, 60% to 80% in 8 hours, 70% to 90% in 12 hours and not less than 85% in 24 hours, as determined by [ dissolution method ] herein.

The method according to the third aspect of the present invention, wherein said [ dissolution method ] comprises the following operations:

dissolution medium: 900mL of water, and degassing;

the device comprises the following steps: blue method, rotation speed 100 rpm;

flow sample: acetonitrile-buffer (20: 80);

sample solution: centrifuging the test solution;

and (3) determination:

the samples are standard solution and sample solution,

results i ═ rU/rS. times.CS × (Mr1/Mr2)

Result 1 ═ C1 × V × (1/L) × 100

Result 2 { [ C2 × (V-VS) ] + [ C1 × VS ] } × (1/L) × 100

Result 3 { [ C3 × (V- (2 × VS)) ] + [ (C2+ C1) × VS ] } × (1/L) × 100

Result 4 { [ C4 × (V- (3 × VS)) ] + [ (C3+ C2+ C1) × VS ] } × (1/L) × 100

The method according to the third aspect of the present invention, wherein the blank pellet core in the venlafaxine hydrochloride sustained-release pellet is a blank pellet core made of a base material selected from the group consisting of: sucrose, starch, microcrystalline cellulose, and combinations thereof.

The method according to the third aspect of the present invention, wherein the blank pellet core in the venlafaxine hydrochloride sustained-release pellet is a blank pellet core made of sucrose. In one embodiment, the empty pellet core has an average diameter of 0.35 to 0.45 mm.

The method according to the third aspect of the present invention, wherein the amount of the blank pellet core is 35 to 45 parts by weight, such as 38 to 44 parts by weight, such as 39 to 42 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride in the venlafaxine hydrochloride sustained release pellet.

The method according to the third aspect of the present invention, wherein the drug-loaded coating layer of the venlafaxine hydrochloride sustained-release pellet comprises a binder selected from the following group in addition to the active ingredient: ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.

The method according to the third aspect of the present invention, wherein the drug-loaded coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises a binder selected from the group consisting of: ethyl cellulose, hydroxypropyl cellulose, and combinations thereof.

The method according to the third aspect of the present invention, wherein the drug-loaded coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises the following binders: ethyl cellulose, hydroxypropyl cellulose.

The method according to the third aspect of the present invention, wherein the amount of the binder is 10 to 15 parts by weight, such as 11 to 14 parts by weight, such as 12 to 13 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride in the venlafaxine hydrochloride sustained release pellets.

The method according to the third aspect of the present invention, wherein the drug-loaded coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises the following binders: ethyl cellulose and hydroxypropyl cellulose in an amount of 5 to 10 parts by weight, for example 6 to 9 parts by weight, for example 7 to 9 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride.

The method according to the third aspect of the present invention, wherein the drug-loaded coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises the following binders: ethyl cellulose and hydroxypropyl cellulose in an amount of 3 to 7 parts by weight, for example 4 to 6 parts by weight, for example 4 to 5 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride.

The method according to the third aspect of the present invention, wherein the sustained-release coating material in the sustained-release coating layer of the venlafaxine hydrochloride sustained-release pellet is selected from the group consisting of: ethyl acrylate and methyl methacrylate (2: 1) copolymers such as ewt NE30D, ethylcellulose, mixtures of ethylcellulose and hydroxypropylmethylcellulose, and the like; a preferred extended release coating material is a copolymer of ethyl acrylate and methyl methacrylate (2: 1) such as Ewing NE 30D.

The method according to the third aspect of the present invention, wherein the amount of the sustained release coating material is 5 to 15 parts by weight, such as 6 to 12 parts by weight, such as 7 to 10 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride in the sustained release pellet of venlafaxine hydrochloride.

The method according to the third aspect of the present invention, wherein the sustained-release coating layer of the venlafaxine hydrochloride sustained-release pellet further comprises an anti-sticking agent for preventing the sustained-release coating material from sticking during the coating process.

The method according to the third aspect of the present invention, wherein the anti-sticking agent in the sustained-release coating layer is selected from the group consisting of: talc, colloidal silica, magnesium trisilicate, and the like, with talc being a preferred anti-adherent.

The method according to the third aspect of the present invention, wherein the amount of the anti-adhesion agent is 1 to 5 parts by weight, such as 1 to 3 parts by weight, such as 1 to 2 parts by weight, per 84.86 parts by weight of venlafaxine hydrochloride in the venlafaxine hydrochloride sustained release pellet. One of the main functions of the anti-sticking agent is to prevent the slow release coating material from sticking during the coating process.

According to the third aspect of the invention, the drug-loaded coating layer in the venlafaxine hydrochloride sustained-release pellet is coated on the outer surface of the blank pellet core in the following way: the active ingredient and binder are dissolved and/or suspended in a first solvent and spray coated onto the surface of the blank pellet core, followed by drying the coated pellets to remove the first solvent. In one embodiment, the first solvent is selected from: water, ethanol, isopropanol, and combinations thereof, with the preferred first solvent being isopropanol.

The method according to the third aspect of the present invention, wherein the amount of the first solvent in the venlafaxine hydrochloride sustained release pellet is such that the weight of the solids in the suspension is 20 to 40%, such as 25 to 35%, such as 28 to 32%.

According to the third aspect of the invention, the sustained-release coating layer in the venlafaxine hydrochloride sustained-release pellet is coated on the outer surface of the drug-carrying coating layer by the following method: the sustained release coating material and the anti-adhesive agent are dispersed and suspended in a second solvent and spray-coated onto the outer surface of the drug-loaded coating layer, followed by drying the coated pellets to remove the second solvent. In one embodiment, the second solvent is selected from: water, ethanol, isopropanol, and combinations thereof, with the preferred second solvent being water.

The method according to the third aspect of the present invention, wherein the amount of the second solvent in the venlafaxine hydrochloride sustained release pellet is such that the weight of the solids in the suspension is 20 to 35%, such as 25 to 30%, such as 25 to 28%.

The process according to the third aspect of the present invention, wherein the spraying of the drug-loaded coating layer onto the surface of the blank pellet core and the spraying of the slow-release coating layer onto the outside of the drug-loaded coating layer are carried out in a fluidized bed coating apparatus. The solvent is removed during the process of coating the pellets, and both solvents used are easily removed to meet the requirements for pharmaceutical purposes.

The method according to the third aspect of the invention further comprises the step of filling the venlafaxine hydrochloride sustained-release pellets into gelatin hollow capsules, and sealing and encapsulating the gelatin hollow capsules to obtain sustained-release capsules.

Further, the invention provides, in a fourth aspect, a use of the venlafaxine hydrochloride sustained-release pellet of any one of the embodiments of the first aspect of the invention or the venlafaxine hydrochloride sustained-release capsule of any one of the embodiments of the second aspect of the invention for preparing a medicament for treating or preventing depression, generalized anxiety disorder, relapse prevention of depressive episodes, social anxiety disorder, and panic disorder.

Further, the fifth aspect of the present invention provides a method for determining the dissolution rate of the venlafaxine hydrochloride sustained-release pellet of the first aspect of the present invention or the venlafaxine hydrochloride sustained-release capsule of the second aspect of the present invention, comprising the following operations:

dissolution medium: 900mL of water, and degassing;

the device comprises the following steps: blue method, rotation speed 100 rpm;

flow sample: acetonitrile-buffer (20: 80);

sample solution: centrifuging the test solution;

and (3) determination:

the samples are standard solution and sample solution,

results i ═ rU/rS. times.CS × (Mr1/Mr2)

Result 1 ═ C1 × V × (1/L) × 100

Result 2 { [ C2 × (V-VS) ] + [ C1 × VS ] } × (1/L) × 100

Result 3 { [ C3 × (V- (2 × VS)) ] + [ (C2+ C1) × VS ] } × (1/L) × 100

Result 4 { [ C4 × (V- (3 × VS)) ] + [ (C3+ C2+ C1) × VS ] } × (1/L) × 100

According to any aspect of the present invention, the venlafaxine hydrochloride sustained release capsule may contain venlafaxine hydrochloride in an amount of 50 to 500mg, such as 50 to 400mg, such as 50 to 300mg, such as 50mg, 100mg, 150mg, 20mg, 250mg, 300mg, calculated as venlafaxine.

According to any aspect of the invention, in the process of preparing the venlafaxine hydrochloride sustained-release pellet, the drug-loaded coating layer is coated in the following way: dissolving ethyl cellulose and 4/5 amount of hydroxypropyl cellulose in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, and uniformly mixing to obtain a suspension; dissolving 1/5 amounts of hydroxypropyl cellulose in the first solvent, wherein the concentration of the solid matter is the same as that of the previous suspension, so as to obtain a solution; and spraying the suspension and the solution onto a blank pill core in a fluidized state in a fluidized bed coating machine in sequence through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain the drug-loaded pellets. It has been surprisingly found that a small portion of hydroxypropylcellulose is coated onto the pellets separately after dosing, and the resulting pellets exhibit significantly better dissolution stability.

In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

The venlafaxine hydrochloride sustained-release capsule is taken with food at the same time in a fixed time in the morning or at night, and is taken once a day. The capsule should be taken as a whole to avoid taking it separately, crushed, chewed or dissolved, or the capsule may be opened carefully to place the contents in a spoon of applesauce, and the drug/food mixture should be swallowed soon without chewing, followed by drinking a glass of water to ensure complete consumption.

The venlafaxine hydrochloride sustained-release capsule of the invention is used for the initial treatment of various depression. For most patients, a starting dose of 75mg per day, single dose, of venlafaxine hydrochloride sustained release capsules is recommended. In a clinical study of venlafaxine hydrochloride extended release capsules for the treatment of outpatient moderate depression, the initial dose was 75mg per day. For some new-onset patients, 37.5mg per day of initial treatment may be more appropriate for 4 to 7 days before adjusting the dosage to 75mg per day. Although the relationship between dose and antidepressant effect is not fully explored, some patients who do not respond to a dose of 75mg per day may be effective at doses up to about 225mg per day because in most patients venlafaxine and major metabolites reach steady state concentrations by day 4, and may be dosed in increments of up to 75 mg/day at intervals of 4 days or more, if necessary. In studies evaluating efficacy, titration of the drug is allowed at intervals of 2 weeks or more, with an average dose of about 140-180 mg per day.

The venlafaxine hydrochloride sustained-release capsule is used for treating generalized anxiety disorder. For most patients, a starting dose of 75mg per day, single dose, of venlafaxine hydrochloride sustained release capsules is recommended. In clinical studies of the efficacy of venlafaxine hydrochloride sustained release capsules for the treatment of outpatient generalized anxiety disorder, the initial dose was 75mg per day and the maximum dose was 225mg per day. For some new-onset patients, 37.5mg per day of initial treatment may be more appropriate for 4 to 7 days before adjusting the dosage to 75mg per day. Although dose-response relationships for treating GAD have not been clearly demonstrated in fixed-dose studies, some patients who do not respond to a dose of 75mg per day may be effective when the dose is increased to about 225mg per day, if necessary, by adding doses in increments of up to 75 mg/day at intervals of 4 days or more

Under the condition that the venlafaxine hydrochloride sustained-release tablets are replaced by sustained-release capsules, the current depression patients treated by the venlafaxine hydrochloride sustained-release tablets can be replaced by sustained-release capsules with almost equal daily treatment dosage, for example, the patients take 37.5mg of venlafaxine twice a day, and can be replaced by 75mg of sustained-release capsules once a day. If necessary, it is adjusted according to the individual condition of the patient.

In the case of the sustained release venlafaxine hydrochloride capsule used for maintenance therapy, no positive evidence from a control study indicates how long the venlafaxine hydrochloride sustained release capsule needs to be treated for depression and GAD. It is generally accepted that drug consolidation treatment is required for months or longer after the treatment of the acute symptoms of depression is effective. In study 1, patients treated with venlafaxine hydrochloride extended release capsules for 8 weeks were randomized to placebo treatment and venlafaxine hydrochloride extended release capsules (75, 150, or 225mg per morning) at the same dose as the previous treatment, and the long-term efficacy of venlafaxine hydrochloride extended release capsules was confirmed for 26 weeks of maintenance treatment. Based on these limited data, it is not known whether the sustained release capsule of venlafaxine hydrochloride should be maintained at a therapeutic dose equal to the initial therapeutically effective dose. The necessity and proper dosage of maintenance therapy should be re-evaluated periodically during treatment. Venlafaxine hydrochloride sustained release capsules have been shown to be therapeutically effective in patients with GAD in a clinical study over a period of 6 months. The necessity for continued administration to GAD patients who are therapeutically effective with venlafaxine hydrochloride extended release capsules should be re-evaluated at regular intervals.

In the case of withdrawal of venlafaxine hydrochloride extended release capsules, other SNRIs and SSRIs withdrawal-related symptoms have been reported. Care should be taken to monitor these symptoms when the patient stops taking the medication, with gradual reductions rather than sudden stops being recommended as much as possible. If venlafaxine is used for more than 6 weeks, it is recommended that the tapering time be at least more than two weeks. If an intolerant response occurs during a drug withdrawal or withdrawal, a return to the previously prescribed dose may be considered, after which the physician may again withdraw the drug at a slower rate. In clinical studies of venlafaxine hydrochloride sustained-release capsules, the daily dose is usually reduced by 75mg every 1 week, and the time of gradual reduction can be determined clinically according to the dose, the treatment course and individual differences of patients.

To replace the MAOI inhibitor, the extended release venlafaxine hydrochloride capsule is stopped for at least 14 days before the MAOI is administered, and the MAOI treatment is stopped 7 days after the extended release venlafaxine hydrochloride capsule is administered.

Clinical trial

Various types of depression:

the completed 2 venlafaxine hydrochloride sustained release capsules were evaluated for efficacy in treating depression in an adult outpatient depression study with placebo-controlled, adjustable dose short-term clinical study, subject to DSM-III-R or DSM-IV diagnostic criteria. 1 study in 12 weeks uses venlafaxine hydrochloride sustained-release capsules in a dosage range of 75-150 mg/day (average dose for subjects completing the test is 136 mg/day), and 1 study in 8 weeks uses venlafaxine hydrochloride sustained-release capsules in a dosage range of 75-225 mg/day (average dose for subjects completing the test is 177 mg/day), and 2 studies prove that venlafaxine hydrochloride sustained-release capsules are superior to placebo in terms of HAM-D total score, HAM-D depressed mood factor, MADRS total score, clinical global impression scale (CGI) disease severity and improvement degree; meanwhile, the venlafaxine hydrochloride sustained-release capsule has the obvious advantage over placebo in improving the contents of specific factors such as anxiety, somatization, cognition, retardation and anxiety factors in the HAM-D scale.

A clinical trial of 4-week-old hospitalized patients (meeting DSM-III-R criteria for depression) treated with venlafaxine hydrochloride extended release capsules (normally released) (150-375 mg/day, three times a day) demonstrated that venlafaxine hydrochloride extended release capsules outperform placebo. The average dose for patients who completed the trial was 350 mg/day. The curative effect of male and female patients is not different.

After completion of an 8-week open clinical study with venlafaxine hydrochloride extended release capsules (75, 150, or 225mg, qAM), outpatients in which treatment was efficacious and which met DSM-IV criteria for depression were randomized for follow-up study (same dose of venlafaxine hydrochloride extended release capsules or placebo). Disease recurrence was continued for 26 weeks. Treatment efficacy in the open phase was defined as a CGI disease severity score of 3 or less and a HAM-D-21 total score of 10 or less on day 56 of evaluation. Recurrence in the double-blind stage was defined as: (1) recurrence of depression was defined as meeting DSMIV diagnostic criteria and CGI disease severity score ≧ 4 (moderate disease), (2) CGI disease severity score ≧ 4 for 2 consecutive visits, or (3) a final CGI disease severity score ≧ 4 for any patient withdrawal from the trial for a variety of reasons. Patients who continued to use the venlafaxine hydrochloride extended release capsule for 26 weeks had significantly lower disease recurrence rates compared to placebo.

In another follow-up study, therapeutically effective patients were randomized to the same dose of venlafaxine hydrochloride extended release capsules or placebo (outpatient depression, DSM-III-R diagnostic criteria met, relapse, therapeutically effective (HAM-D-21 score ≦ 12 at day 56 evaluation) and continued to progress [ defined as criteria for (1) no HAM-D-21 score ≧ 20, (2) no more than 2 visits with HAM-D-21 score ≧ 10 for day 56 to 180 days and (3) randomized use of venlafaxine hydrochloride extended release capsules (released) for the first 26 weeks [100 + 200 mg/day, twice daily ] no single CGI disease severity score ≧ 4 (moderate disease) ]. Patients were observed for relapse in the following 52 weeks, with relapse defined as a CGI disease severity score of 4 or more. Patients who continued to receive venlafaxine hydrochloride extended release capsule therapy for the subsequent 52 weeks had significantly lower disease recurrence rates compared to placebo.

Generalized anxiety disorder:

clinical studies on the efficacy of venlafaxine hydrochloride extended release capsules for the treatment of Generalized Anxiety Disorder (GAD) have been completed including: phase 2 was a placebo-controlled, fixed dose study for 8 weeks, phase 1 was a 6-month placebo-controlled, fixed dose study and phase 1 was a 6-month placebo-controlled variable dose study for adult outpatients meeting DSM-IV GAD diagnostic criteria.

1 study of 8 weeks duration evaluating the efficacy of 75, 150 and 225 mg/day venlafaxine hydrochloride extended release capsules and placebo on GAD, found that the improvements in HAM-A scale total score, HAM-A anxiety and stress factor score and CGI score for 225 mg/day venlafaxine hydrochloride extended release capsules were significantly better than placebo, while the efficacy of 75 and 150 mg/day venlafaxine hydrochloride extended release capsules was also better than placebo, except that the efficacy of the lower dose of drug was not as sustained as the efficacy of the higher dose of drug. The study of phase 2, 8 weeks, evaluated the efficacy of the venlafaxine hydrochloride extended release capsules 75, 150 mg/day and placebo on GAD, and the results showed that the efficacy of the 2 doses of venlafaxine hydrochloride extended release capsules was superior to placebo, however, patients treated with the 75 mg/day drug had efficacy superior to those of 150 mg/day. When GAD patients are treated, the correlation between the curative effect and the dosage of the GAD patients cannot be established within the dosage range of 75-225 mg/day.

In the study of 2 months, 1 of the studies evaluates 37.5 mg/day, 75 mg/day and 150 mg/day of venlafaxine hydrochloride sustained-release capsules, and the other 1 evaluates the curative effect of the venlafaxine hydrochloride sustained-release capsules of 75-225 mg/day on GAD, and the improvement of the total HAM-A scale score, the HAM-A anxiety and stress factor score and the CGI score is obviously better than that of a placebo after the venlafaxine hydrochloride sustained-release capsules are treated for 6 months at 75 mg/day or more than 75 mg/day. There is also evidence that the 37.5 mg/day drug is more efficacious than placebo, but the efficacy of this dose is not as consistently efficacious as the high dose drug. The curative effect of patients with different sexes is analyzed, and no difference in curative effect is found.

Pharmacology and toxicology

The pharmacological action is as follows: non-clinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine, are strong inhibitors of 5-HT, NE reuptake and weak inhibitors of dopamine. In vitro experiments show that venlafaxine and O-desmethylvenlafaxine have no obvious affinity to M choline receptor, H1 histamine receptor and alpha 1-adrenergic receptor. Venlafaxine and O-desmethylvenlafaxine have no MAO inhibitory activity.

Toxicology studies, genotoxicity: the results of venlafaxine, O-desmethylvenlafaxine Ames test and CHO/HGPRT mammalian cell forward gene mutation test are negative. Venlafaxine BALB/c-3T3 mouse cell transformation test, CHO cell sister chromosome exchange test and rat micronucleus test results are all negative. The result of the O-desmethylvenlafaxine CHO chromosome aberration test is negative, and the result of the rat micronucleus test is positive. Reproductive toxicity: when the dose of the drug administered orally to male rats was 2 times the Maximum Recommended Human Dose (MRHD), no effect on fertility was observed, as estimated by mg/m2 (the same applies hereinafter). When the oral administration is carried out during the pregnancy and lactation period of rats and rabbits, the dosage is 2.5 times and 4 times of the maximum recommended daily dosage of people, deformity is not seen, but the weight loss of rat pups, the death rate is increased, and the number of death pups is increased 5 days before lactation. The cause of death in animals is unknown and the dose that does not affect death in young animals is 0.25 times the maximum recommended daily dose for humans. In addition, in a single oral administration of O-desmethylvenlafaxine succinate 30, 100, 300mg/kg in male and female SD rats, it was seen that there was a disturbance of the estrogenic cycle and a prolonged mating time in each dose group; fertility is seen to decrease in the medium and high dose groups, pre-implantation mortality increases in the high dose groups, and litter size decreases. The exposure of O-desmethylvenlafaxine at a dose of 100mg/kg (corresponding to 4.5 times the MRHD of venlafaxine) is about 2-3 times the dose of 225 mg/day used by venlafaxine. Carcinogenicity: when mice are orally administered venlafaxine with dosage of 120 mg/kg/day (1.7 times of the maximum recommended dose) for 18 months, and rats are orally administered venlafaxine with dosage of 120 mg/kg/day for 24 months (the venlafaxine blood concentrations of male rats and female rats are respectively 1 time and 6 times of the human blood concentration at the maximum recommended human dose, but the O-desmethylvenlafaxine level is lower than that of the human body), no increase of tumor incidence rate is seen after 24 months.

Pharmacokinetics

By multiple oral administrations venlafaxine and ODV reach steady state plasma concentrations within 3 days. The venlafaxine and ODV belong to linear pharmacokinetic models within the dosage range of 75-450 mg/day, the mean steady state plasma clearance rates are respectively 1.3 +/-0.6 and 0.4 +/-0.2L/h/kg, the apparent clearance half-lives are respectively 5 +/-2 and 11 +/-2 h, and the apparent (steady state) distribution volumes are respectively 7.5 +/-3.7 and 5.7 +/-1.8L/kg. Venlafaxine and ODV bind less to plasma proteins at therapeutic plasma concentrations, 27% and 30%, respectively. Absorption: venlafaxine is readily absorbed and is metabolized primarily in the liver, with ODV being its major active metabolite. At least 92% is absorbed after a single oral administration of venlafaxine. The absolute bioavailability of venlafaxine is about 45%. The administration of venlafaxine hydrochloride sustained release capsules (150mg, q24h) generally had lower peak concentrations (150 ng/mL and 260ng/mL for venlafaxine and ODV, respectively) and later peak times (5.5 h and 9h for venlafaxine and ODV, respectively). When the venlafaxine is taken every day at the same dose, the fluctuation of the blood concentration of the patient taking the venlafaxine hydrochloride sustained-release capsule is obviously lower. Therefore, the venlafaxine hydrochloride sustained release capsule absorbs slowly compared with the normal release tablet, but the total amount of the absorbed medicine is the same. When 75mg of venlafaxine hydrochloride sustained-release capsules are used, food has no influence on the bioavailability of venlafaxine and its active metabolite ODV, and the difference of the taking time (in the morning or in the afternoon) does not influence the drug metabolism of venlafaxine and ODV. Metabolism and excretion: venlafaxine undergoes first-pass metabolism in the liver after absorption, and the main metabolite is ODV, which includes N-desmethylvenlafaxine, N, O-desmethylvenlafaxine and other minor metabolites. In vitro studies have shown that ODV is produced by the metabolism of CYP2D6 enzymes, and clinical studies have also demonstrated that patients with low CYP2D6 activity (slow metabolism) have higher venlafaxine and lower ODV drug concentrations than patients with normal CYP2D6 activity. Since the total amount of venlafaxine and ODV were close in the 2 groups of patients with different CYP2D6 activities and ODV had similar pharmacological effects and potency to venlafaxine, this difference in metabolic capacity was not clinically significant.

About 87% of the drug was excreted in the urine 48 hours after venlafaxine administration, which included 5% of the proto-drug, 29% unbound ODV, 26% bound ODV and 27% inactive metabolites. Thus, venlafaxine and its metabolites are mainly excreted through the kidney.

The venlafaxine hydrochloride sustained-release pellet composition and sustained-release capsule prepared by the method have excellent preparation performance

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.

The following preparation steps are given for the purpose of illustration and are based on the comparative description of the respective examples and the person skilled in the art is fully enabled to generalize the process for preparing the compositions according to the invention from the prior knowledge. In the following various compositions according to the invention were prepared, the batch was prepared in 5kg charges, as not otherwise specified. However, when listing the formulation and preparation process, the formulation and preparation process are illustrated for pellets with a composition of 75mg of venlafaxine per venlafaxine hydrochloride (corresponding to 84.86mg of venlafaxine hydrochloride), and when actually encapsulating, 75m or 150mg of venlafaxine per capsule is filled. As not specifically mentioned, in the preparation, each material was previously pulverized and sieved through a 120-mesh sieve before the preparation. Unless otherwise specified, the venlafaxine hydrochloride raw material used in the preparation is the same batch.

The sucrose medicinal pellet core used in the invention is a commercial preparation intermediate product, and meets Shanghai pharmaceutical standard Shanghai Hu Q/WS-1-2274-2001; the Eudragit NE30D used in the invention is a commercial auxiliary material product sold in the market, and meets the registration standard JX20020019 of imported drugs.

First, example section for preparation of pellets and capsules

Example 1: preparation of venlafaxine hydrochloride sustained-release pellets and sustained-release capsules

The formula is as follows:

the preparation method comprises the following steps:

(1) providing blank pill cores, and placing the blank pill cores in a fluidized bed coating machine (the temperature is 42-45 ℃) to enable the blank pill cores to be in a fluidized state;

(2) coating a drug-loaded coating layer: dissolving the adhesive in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, uniformly mixing to obtain a suspension, spraying the suspension onto a blank pill core which is in a fluidized state in a fluidized bed coating machine through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain a drug-loaded pellet; [ the residual amount of the first solvent is detected to be less than 500ppm, far below the limits generally required in the art ]

(3) Coating a slow release coating layer: uniformly dispersing the slow-release coating material and the anti-sticking agent in a second solvent, spraying the suspension onto the medicine-carrying pellets in a fluidized state in a fluidized bed coating machine through atomization, and continuously fluidizing until the solvent is removed after spraying to obtain the slow-release pellets; [ the water content of the obtained sustained-release pellets is detected to be less than 1 percent and lower than the general requirement limit in the field ]

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.35% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets. [ measuring the content of active ingredients in the obtained sustained-release pellets, and calculating the weight of the sustained-release pellets corresponding to 75mg of venlafaxine ]

(5) And (3) filling the sustained-release pellets obtained in the last step into gelatin hollow capsules, wherein the amount of the pellets filled in each capsule is equivalent to 75mg of venlafaxine or 150mg of venlafaxine, and obtaining the venlafaxine hydrochloride sustained-release capsules.

Example 2: preparation of venlafaxine hydrochloride sustained-release pellets and sustained-release capsules

The formula is as follows:

the preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.2% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets. [ measuring the content of active ingredients in the obtained sustained-release pellets, and calculating the weight of the sustained-release pellets corresponding to 75mg of venlafaxine ]

Example 3: preparation of venlafaxine hydrochloride sustained-release pellets and sustained-release capsules

The formula is as follows:

the preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.5% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets. [ measuring the content of active ingredients in the obtained sustained-release pellets, and calculating the weight of the sustained-release pellets corresponding to 75mg of venlafaxine ]

Example 4: preparation of venlafaxine hydrochloride sustained-release pellets and sustained-release capsules

The formula is as follows:

the preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.4% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets. [ measuring the content of active ingredients in the obtained sustained-release pellets, and calculating the weight of the sustained-release pellets corresponding to 75mg of venlafaxine ]

Example 5: preparation of venlafaxine hydrochloride sustained-release pellets and sustained-release capsules

The formula is as follows:

blank pellet cores:	composition of	Dosage (in mg proportion)
				Medicinal pellet core	39
A drug-loaded coating layer:
				venlafaxine hydrochloride	84.86
	Ethyl cellulose	9
				Hydroxypropyl cellulose	5
	First solvent (isopropanol)	Proper amount until the solid concentration is 28% (finally removed)
			A slow-release coating layer:
	unitrech NE30D	7
				Talcum powder	1.5
	Second solvent (purified water)	Proper amount until the solid concentration is 28% (finally removed)

The preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.25% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets. [ measuring the content of active ingredients in the obtained sustained-release pellets, and calculating the weight of the sustained-release pellets corresponding to 75mg of venlafaxine ]

Example 6: preparation of venlafaxine hydrochloride sustained-release pellets and sustained-release capsules

Referring to the methods of examples 1 to 5, respectively, except that the step (2) is changed to the following operation:

(2) coating a drug-loaded coating layer: dissolving ethyl cellulose and 4/5 amount of hydroxypropyl cellulose in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, and uniformly mixing to obtain a suspension; dissolving 1/5 amounts of hydroxypropyl cellulose in the first solvent, wherein the concentration of the solid matter is the same as that of the previous suspension, so as to obtain a solution; and spraying the suspension and the solution onto a blank pellet core in a fluidized state in a fluidized bed coating machine in sequence through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain 5 batches of drug-loaded pellets.

Example 7: referring to the methods of examples 1-5, respectively, except that hydroxypropyl cellulose was replaced with equal amount of hydroxypropyl methylcellulose to obtain 5 batches of sustained-release pellets and sustained-release capsules.

Example 8: reference is made to the procedures of examples 1 to 5, respectively, except that ethyl cellulose in the pellet is replaced by the same amount of methyl cellulose to obtain 5 batches of sustained-release pellets and sustained-release capsules.

Example 9: referring to the methods of examples 1-5, except that the first solvent was changed to ethanol with the same amount, 5 batches of sustained-release pellets and sustained-release capsules were obtained.

Second, test example of formulation Performance test

Test example 1: pellet size

The granularity of the blank pellet core used in each experiment is 0.35-0.45 mm in average diameter. The final sustained release pellets obtained in each example were sieved using a 14-mesh standard sieve, a 16-mesh standard sieve, a 25-mesh standard sieve, and a 30-mesh standard sieve. As a result: all batches of the slow-release pellets can pass through the 14-mesh standard sieve, all batches of the slow-release pellets can pass through the 16-mesh standard sieve, all batches of the slow-release pellets cannot pass through the 30-mesh standard sieve, more than 98% of all batches of the slow-release pellets cannot pass through the 25-mesh standard sieve, for example, all the slow-release pellets of all the batches of examples 1 to 6 can pass through the 16-mesh standard sieve but cannot pass through the 30-mesh standard sieve. Supplementary example 10 samples: sustained-release pellets and sustained-release capsules (75 mg/capsule) were prepared by the method of example 1 with reference to [0056] to [0067] of CN103054835B, wherein the blank pellet core used was the blank pellet core of the present invention.

Test example 2: dissolution determination

Each batch of venlafaxine hydrochloride sustained-release capsules prepared by the method (75mg calculated by venlafaxine) and imported control venlafaxine hydrochloride sustained-release capsules Yinuosi (75mg calculated by venlafaxine, Chinese medicine standard character J20160078) are tested.

[ dissolution assay ]:

dissolution medium: 900mL of water, and degassing;

the device comprises the following steps: blue method, rotation speed 100 rpm;

flow sample: acetonitrile-buffer (20: 80);

sample solution: centrifuging the test solution;

and (3) determination:

the samples are standard solution and sample solution,

results i ═ rU/rS. times.CS × (Mr1/Mr2)

Result 1 ═ C1 × V × (1/L) × 100

Result 2 { [ C2 × (V-VS) ] + [ C1 × VS ] } × (1/L) × 100

Result 3 { [ C3 × (V- (2 × VS)) ] + [ (C2+ C1) × VS ] } × (1/L) × 100

Result 4 { [ C4 × (V- (3 × VS)) ] + [ (C3+ C2+ C1) × VS ] } × (1/L) × 100

And (3) measuring results:

(1) with the dissolution determination method, for all samples of examples 1 to 9, the samples were put into hard gelatin hollow capsules or directly determined by sustained-release pellets, and no difference in dissolution was observed between the samples, which indicates that the hard gelatin hollow capsules have no influence on the dissolution performance of the sustained-release pellets, and the capsule shells are completely dissolved within 3 minutes when the dissolution is performed.

(2) In the above [ dissolution test method ], 75mg, 150mg and 300mg venlafaxine were filled in the hard gelatin empty capsules for all the samples of examples 1 to 9, and it was found that the capsule filling amount did not affect the dissolution performance to some extent, and the dissolution curves of the same sample at three filling amounts were consistent.

(3) With the above [ dissolution test ], the general requirements for dissolution test results are: the dissolution amount is not more than 30% in 2h, 40-60% in 4h, 60-80% in 8h, 70-90% in 12h and not less than 85% in 24h, and the determination shows that:

yinuesi: the leaching amount is 11-14% in 2h, 48-51% in 4h, 67-69% in 8h, 79-82% in 12h and 94-96% in 24 h;

examples 1-6 all samples: the leaching amount is 9-16% in 2h, 47-53% in 4h, 65-71% in 8h, 77-84% in 12h and 91-97% in 24 h; the similarity f2 between the dissolution release curves of the samples of each example and Yinousi was calculated (f 2 is generally acceptable and more than 80% is preferred) and the results show that f2 of all the samples of examples 1 to 5 is between 89 and 93% and f2 of all the samples of example 6 is between 92 and 94%, indicating that all the samples of examples 1 to 6 have excellent dissolution release curve consistency with the original product sold in the market.

Examples 7-9 all samples: the dissolution amount is 26-37% in 2h, 56-74% in 4h, 84-90% in 8h, more than 95% in 12h and more than 95% in 24 h; the similarity f2 between the dissolution release curves of the samples of the examples and Yinousi is calculated, and the results show that f2 of all the samples of the examples 7 to 9 is 31 to 38 percent, which shows that the dissolution release curves of the samples and the original ground commercial products are obviously not consistent and unacceptable. Example 10 samples: the dissolution amount of 24% in 2h, 55% in 4h, 78% in 8h and more than 89% in 12h, the dissolution amount of 97% in 24h and 76% in f2 were all acceptable basically in similarity with the dissolution release curve of the original ground product.

Dissolution stability test: all the capsules obtained in examples 1 to 6 and example 10 and dinotefuran were placed in a sealed state at 40 ℃ for 6 months, and the dissolution and release profiles of the tablets in each lot at 6 months were measured, and the results were compared with the data at 0 month of the same sample for each lot, with the similarity f2, and the results were: 99.6% of f2 in dinotefuran, 79.6% of f2 in example 10, 88.3% of f2 in example 1, 86 to 90% of f2 in examples 2 to 5, 99.1% of f2 in example 6 with reference to example 1, and 98.4 to 99.8% of f2 in example 6 with reference to examples 2 to 5. This indicates that some of the sustained-release capsules prepared by the present invention exhibited excellent dissolution stability.

The spirit of the present invention is described in detail by the preferred embodiments of the present invention. It will be understood by those skilled in the art that any modification, equivalent change and modification made to the above embodiments in accordance with the technical spirit of the present invention fall within the scope of the present invention.

Claims

1. A venlafaxine hydrochloride sustained-release pellet comprises a blank pellet core, a drug-loaded coating layer coated on the outer surface of the blank pellet core and a sustained-release coating layer coated on the outer surface of the drug-loaded coating layer; wherein:

the venlafaxine hydrochloride accounts for 50-65% of the weight of the sustained-release pellet;

the blank pellet core is made of cane sugar, and the average diameter of the blank pellet core is 0.3-0.6 mm;

the drug-carrying coating layer consists of venlafaxine hydrochloride, ethyl cellulose and hydroxypropyl cellulose, wherein the amount of the ethyl cellulose is 5-10 parts by weight and the amount of the hydroxypropyl cellulose is 3-7 parts by weight based on 84.86 parts by weight of venlafaxine hydrochloride;

the slow-release coating materials in the slow-release coating layer are ethyl acrylate and methyl methacrylate 2: 1, the amount of the slow-release coating material is 5-15 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride;

the slow release coating layer further comprises an anti-sticking agent selected from the group consisting of: talc powder, colloidal silica and magnesium trisilicate, wherein the anti-sticking agent is 1-5 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride;

in the process of preparing the sustained-release pellet, when a drug-carrying coating layer is coated, the following steps are carried out: dissolving ethyl cellulose and 4/5 amount of hydroxypropyl cellulose in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, and uniformly mixing to obtain a suspension; dissolving 1/5 amounts of hydroxypropyl cellulose in the first solvent, wherein the concentration of the solid matter is the same as that of the previous suspension, so as to obtain a solution; spraying the suspension and the solution on a blank pill core in a fluidized state in a fluidized bed coating machine in sequence through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain a medicine-carrying pellet;

the first solvent is isopropanol;

the slow release coating layer is coated on the outer surface of the drug-carrying coating layer in the following way: dispersing the sustained release coating material and the anti-sticking agent in a second solvent, spraying the suspension on the outer surface of the drug-loaded coating layer, and drying the coated pellets to remove the second solvent; the second solvent is water; the amount of the second solvent is such that the weight of solids in the resulting suspension is 20-35%.

2. Venlafaxine hydrochloride sustained-release pellets according to claim 1, which pass through a 14 mesh screen but not a 30 mesh screen.

3. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the dissolution amount is not more than 30% in 2 hours, 40% to 60% in 4 hours, 60% to 80% in 8 hours, 70% to 90% in 12 hours, and not less than 85% in 24 hours, as measured by the dissolution method described in the specification.

4. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the average diameter of the blank pellet core is 0.35-0.5 mm.

5. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the amount of the empty pellet core is 35 to 45 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride.

6. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the amount of the ethylcellulose is 6 to 9 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride.

7. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the amount of the hydroxypropylcellulose is 4 to 6 parts by weight per 84.86 parts by weight of venlafaxine hydrochloride.

8. The venlafaxine hydrochloride sustained release pellet according to claim 1, wherein the sustained release coating material in the sustained release coating layer is Eudragit NE 30D.

9. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the amount of the first solvent is such that the weight of solids in the resulting suspension is 20 to 40%.

10. The venlafaxine hydrochloride sustained-release pellet according to claim 1, wherein the spraying of the drug-loaded coating layer onto the surface of the blank pellet core and the spraying of the sustained-release coating layer onto the outside of the drug-loaded coating layer are carried out in a fluidized bed coating apparatus.

11. Venlafaxine hydrochloride sustained-release pellets according to claim 1, prepared according to a process comprising the following steps:

(1) providing blank pill cores, placing the blank pill cores in a fluidized bed coating machine, and keeping the blank pill cores in a fluidized state at the temperature of 42-45 ℃;

(2) dissolving ethyl cellulose and 4/5 amount of hydroxypropyl cellulose in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, and uniformly mixing to obtain a suspension; dissolving 1/5 amounts of hydroxypropyl cellulose in the first solvent, wherein the concentration of the solid matter is the same as that of the previous suspension, so as to obtain a solution; spraying the suspension and the solution on a blank pill core in a fluidized state in a fluidized bed coating machine in sequence through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain a medicine-carrying pellet;

12. Venlafaxine hydrochloride sustained-release pellets according to claim 1, prepared according to the following formulation and preparation method:

the formula is as follows:

blank pellet cores: 40.5mg of medicinal pellet core,

a drug-loaded coating layer: 84.86mg of venlafaxine hydrochloride, 8mg of ethyl cellulose, 4.5mg of hydroxypropyl cellulose and a proper amount of first solvent isopropanol till the solid concentration is 30 percent and finally removed,

a slow-release coating layer: 8.5mg of Eudragit NE30D, 1.5mg of talcum powder, and a proper amount of purified water of a second solvent until the solid concentration is 26.5 percent, and finally removed;

the preparation method comprises the following steps:

(2) coating a drug-loaded coating layer: dissolving ethyl cellulose and 4/5 amount of hydroxypropyl cellulose in the first solvent, adding venlafaxine hydrochloride which is pre-crushed to pass through a 150-mesh sieve, and uniformly mixing to obtain a suspension; dissolving 1/5 amounts of hydroxypropyl cellulose in the first solvent, wherein the concentration of the solid matter is the same as that of the previous suspension, so as to obtain a solution; spraying the suspension and the solution on a blank pill core in a fluidized state in a fluidized bed coating machine in sequence through atomization, and continuously fluidizing until the solvent is removed after the spraying is finished to obtain a medicine-carrying pellet;

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.35% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets.

13. Venlafaxine hydrochloride sustained-release pellets according to claim 1, prepared according to the following formulation and preparation method:

the formula is as follows:

blank pellet cores: 38mg of a medicinal pellet core of the pellet,

a drug-loaded coating layer: 84.86mg of venlafaxine hydrochloride, 8.5mg of ethyl cellulose, 4mg of hydroxypropyl cellulose and a proper amount of first solvent isopropanol till the solid concentration is 35 percent and finally removed,

a slow-release coating layer: 6mg of Extension NE30D, 1mg of talcum powder, and a proper amount of purified water of a second solvent until the solid concentration is 29%, and finally removing the purified water;

the preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.2% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets.

14. Venlafaxine hydrochloride sustained-release pellets according to claim 1, prepared according to the following formulation and preparation method:

the formula is as follows:

blank pellet cores: the core of the medicinal pellet is 44mg,

a drug-loaded coating layer: 84.86mg of venlafaxine hydrochloride, 6mg of ethyl cellulose, 6mg of hydroxypropyl cellulose and a proper amount of isopropanol as a first solvent are removed till the solid concentration is 25 percent,

a slow-release coating layer: 12mg of eucalyptus NE30D, 3mg of talc, and a suitable amount of purified water as a second solvent to a solid concentration of 30% and finally removed;

the preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.5% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets.

15. Venlafaxine hydrochloride sustained-release pellets according to claim 1, prepared according to the following formulation and preparation method:

the formula is as follows:

blank pellet cores: 42mg of medicinal pellet core of the pellet,

a drug-loaded coating layer: 84.86mg of venlafaxine hydrochloride, 7mg of ethyl cellulose, 4.5mg of hydroxypropyl cellulose and a proper amount of first solvent isopropanol till the solid concentration is 32 percent and finally removed,

a slow-release coating layer: 10mg of eucalyptus NE30D, 2mg of talc, and a suitable amount of purified water as a second solvent to a solid concentration of 25% and finally removed;

the preparation method comprises the following steps:

(4) Aging: mixing the sustained-release pellets obtained in the last step with 0.4% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets.

16. Venlafaxine hydrochloride sustained-release pellets according to claim 1, prepared according to the following formulation and preparation method:

the formula is as follows:

blank pellet cores: the core of the medicinal pellet is 39mg,

a drug-loaded coating layer: 84.86mg of venlafaxine hydrochloride, 9mg of ethyl cellulose, 5mg of hydroxypropyl cellulose and a proper amount of isopropanol as a first solvent are removed till the solid concentration is 28 percent,

a slow-release coating layer: 7mg of eucalyptus NE30D, 1.5mg of talcum powder, and a proper amount of purified water as a second solvent until the solid concentration is 28% and finally removed;

the preparation method comprises the following steps:

(3) coating a slow release coating layer: uniformly dispersing the slow-release coating material and the anti-sticking agent in a second solvent, spraying the suspension onto the medicine-carrying pellets in a fluidized state in a fluidized bed coating machine through atomization, and continuously fluidizing until the solvent is removed after spraying to obtain the slow-release pellets;

(4) aging: mixing the sustained-release pellets obtained in the last step with 0.25% of talcum powder, then putting the mixture into a hot air circulation oven, aging the mixture for 24 hours at the temperature of 52 +/-4 ℃, and screening out the talcum powder to obtain the sustained-release pellets.

17. A venlafaxine hydrochloride sustained-release capsule comprising a gelatin hollow capsule and venlafaxine hydrochloride sustained-release pellets hermetically encapsulated in the gelatin hollow capsule, wherein the venlafaxine hydrochloride sustained-release pellets are as claimed in any one of claims 1 to 16.

18. A process for preparing a venlafaxine hydrochloride sustained release pellet according to any one of claims 1 to 16, comprising the steps of:

(1) providing blank pill cores, and placing the blank pill cores in a fluidized bed coating machine with the temperature of 42-45 ℃ to enable the blank pill cores to be in a fluidized state;