CN109200032A - High drug load venlafaxine hydrochloride sustained-release pellet composition and spansule and preparation method - Google Patents

Abstract

The present invention relates to high drug load venlafaxine hydrochloride sustained-release pellet compositions and spansule and preparation method.Specifically, the venlafaxine hydrochloride sustained-release pellet includes blank capsule core, load medicine clothing layer, the sustained-release coating layer coated in the load medicine clothing layer outer surface coated in the blank capsule core outer surface, it include active ingredient hydrochloric acid Venlafaxine in the load medicine clothing layer.Active ingredient hydrochloric acid Venlafaxine accounts for the 50~65% of the sustained release pellet weight in the venlafaxine hydrochloride sustained-release pellet, the venlafaxine hydrochloride sustained-release pellet, can pass through 14 meshes but cannot pass through 30 meshes；It can pass through 16 meshes but cannot pass through 25 meshes；It is according to [dissolution method] measurement herein, and 2h the amount of dissolution is no more than 30%, 4h the amount of dissolution 40% -60%, and 8h the amount of dissolution 60% -80%, 12h the amount of dissolution 70% -90%, the amount of dissolution is not less than 85% for 24 hours.Excellent pharmacy performance is presented in venlafaxine hydrochloride sustained-release pellet of the present invention and spansule.

Description

High drug load venlafaxine hydrochloride sustained-release pellet composition and spansule and preparation method

Technical field

The invention belongs to pharmaceutical technology field, it is related to a kind of for treating depression, generalized anxiety disorder, paralepsyRecur the Venlafaxine combination of oral medication of prevention, social anxiety disorder, panic disorder etc., especially venlafaxine sustained-release glueCapsule composition and their preparation method.

Background technique

Venlafaxine (venlafaxine), often with the use of its hydrochloride, the molecular formula of VENLAFAXINE HCL: C₁₇H₂₇NO₂·HCl, molecular weight: 313.86, CAS registration numbers: 99300-78-4, chemical name: (±) -1- [α-[(dimethylamino) methyl]-p-Mehtoxybenzyl] cyclohexanol HCI,

Spansule is serotonin and norepinephrine reuptake inhibitors (serotonin andNoradrenaline reuptake inhibitor, SNRI) class antidepressant.Zoopery finds that the medical instrument has antidepressionEffect, while not having obvious affinity to muscarinic or histamine sample receptor.Therefore, Venlafaxine is in the same of antidepressant effectWhen, there is no adverse reaction feature caused by apparent tricyclic antidepressant (tricyclic antidepressant, TCA),It is demonstrated by more unique pharmacological properties.From 1994, which was ratified successively by United States Food and Drag Administration for pressing downStrongly fragrant obstacle, depressive disorder, generalized anxiety disorder and the treatment of social anxiety disorder with anxiety symptom.Over 2001, ChinaState food pharmaceuticals administration general bureau also has approved the idicatio of depression, generalized anxiety disorder in succession, until 2012 7Month, which is unique novel antidepressant that Discussion on Chinese Listed has generalized anxiety disorder idicatio.Venlafaxine becomes plus takesGreatly, the first-line treatment drug that the depression and generalized anxiety disorder guideline of prevention and treatment of the country such as China are recommended.

Venlafaxine is a kind of two ring class phenyl ethylamine compounds of group, can selective exclusion serotonin (5-HT) transporter andThe reuptake of norepinephrine (NE) transporter acts on, and to be higher by nearly 8 times to the affinity ratio NE of 5-HT.Venlafaxine existsWhen the low dosage of 75mg/d-100mg/d, only there is blocking effect to 5-HT reuptake, it is just right simultaneously as dosage > 150mg/dNE and 5-HT has dual monoamine-reuptake inhibiting effect.In rodent depression original mold type research, Venlafaxine is playedQuick beta receptor desensitization out needs repeat administration that could stimulate the hyposensitivity of NE rather than other antidepressants.TextThe pungent study on mechanism to 5-HT1A receptor of daraf(reciprocal of farad) is found, is blocked forebrain 5-HT1A receptor to generate antidepressant effect, is blocked seamBorder core cell space-dendron autoreceptor can enhance downlink monoamine Pain management system and generate analgesic activity.To taking the photograph again for dopamine (DA)Take inhibiting effect extremely weak, to the affinity of muscarinic sample choline receptor and histamine H1-receptor and alpha-2 adrenoceptor compared withLow or nothing.The NE neuronal synapse terminal and cell space-dendron autoreceptor of 5-HT neuron to dorsal raphe nucleus and blue spot andHeterogeneous receptor has certain inhibiting effect, to increase the release of postsynaptic 5-HT and NE and accelerate presynaptic membrane itself" desensitization " process of receptor, also partially explained from mechanism SNRIs antidepression and antianxiety curative effect, in terms of onset time it is excellentIt is former in the possibility of selective 5-HT reuptaking inhibitor (selective serotonin reuptake inhibitor } SSRI)Cause.

It is absorbed well after Venlafaxine is oral in gastrointestinal tract, its infiltration rate can be reduced by taking simultaneously with food, but not shadowRing degree of absorption.After liver carries out first-pass metabolism, forming unique active metabolite is ODV.It takes after general formulation in 2hReach the blood peak concentration of drug of Venlafaxine, 3h reaches the Cmax of ODV.The absorptance general formulation of Effexor ER type is slowSlowly, reach blood peak concentration of drug about 5.5h, ODV then needs 9h that could thus form the blood concentration of ebb Gao Gu up to peak and avoidThe peak and low valley defect of general formulation.Two kinds of dosage forms are all comparable in terms of degree of absorption and bioavilability.TreatmentIt can reach steady state plasma concentration after 3-4d afterwards.Dosage range is in 75mg/d-450mg/d, Venlafaxine and its active metabolismThe linear medicine of product is for feature.Venlafaxine and its metabolite are mainly through kidney excretion.Venlafaxine half-life period is 4h, ODVRemove, half-life period 10h slower than Venlafaxine.The bioavilability that sustained-release dosage type is administered 1 time a day is 90% or more, and everyThe general formulation of it 2 times administrations is almost equal.Sustained-release dosage type no matter morning or at night can be administered, when being taken simultaneously with food,Bioavilability is simultaneously unaffected.Venlafaxine carries out a variety of metabolism by cytochrome P 450 Enzyme system in liver, with 2D6 enzymeBased on, since Venlafaxine and its active metabolite ODV pharmacologically have equivalence, at least in treatment concentration, suppressionDirect result caused by after 2D6 enzyme processed has no clinical meaning.Although Venlafaxine is the substrate of Cytochrome P450 2D6 enzyme,It is one of drug most weak to the enzyme inhibition in all novel antidepressants, usually when being shared with 2D6 enzyme inhibitor,Adjustment venlafaxine dosages are not needed.

The main adaptation disease of Venlafaxine is depression, generalized anxiety disorder, and in European Union and the U.S., Venlafaxine is also used toThe recurrence prevention of paralepsy, social anxiety disorder, panic disorder etc..

Venlafaxine often in the form of the hydrochloride salt for clinic, usually there is conventional tablet, sustained-release tablet and spansuleAgent is taken twice for conventional tablet one day, and sustained release preparation only needs to take daily once.Have many related venlafaxine sustained-releasesThe document report of capsule preparation method thereof.For example, CN102772390A (Chinese Patent Application No. 201210291863X, new coachGram) disclose a kind of venlafaxine hydrochloride slow-release capsule and preparation method thereof.The content of the spansule is sustained release pellet, is delayedIt releases pellet and is followed successively by capsule core, separation layer, slow release layer from the inside to the outside, capsule core is made of the ingredient of following weight percent: hydrochloric acidVenlafaxine 45-48%, filler 15-18%, disintegrating agent 3-3.5%, PVP K30 4-6%, dehydrated alcohol 24-26%, it is remainingAmount is water；Separation layer is made of the ingredient of following weight percent: PVP K30 11-13%, dehydrated alcohol 83-86%, remainingAmount is talcum powder；Slow release layer is made of the ingredient of following weight percent: ethylcellulose mixed suspension liquid 38-42%, poly- second twoAlcohol -60000.1-1.0%, surplus are water, and the ethyl cellulose mass content of the ethylcellulose mixed suspension liquid is 20-30%.It is believed that the invention obtains spansule after preparation capsule core, packet separation layer, packet slow release layer, filling capsule.It is believed that the invention usesEthyl cellulose, flammable low, hygroscopicity is small, has good film forming, stable material quality is easy to control, safer and environmentally friendly.

CN103054835A (Chinese Patent Application No. 2013100357601 is known bright) discloses a kind of venlafaxine sustained-releaseCapsule and its preparation process, using ethyl cellulose and enteric acrylate's resin compounded as adhesive, outside blank capsule coreSeparation layer is wrapped, discharges capsule core not completely, reduces the osmotic pressure inside sustained release pellet, slows down the rate of release of drug；Adhesive is used for medicated layer and sustained release protective layer simultaneously, is encapsulated in Venlafaxine drug in slow-release material layer by layer, so that micro-The dissolubility of ball further decreases, it is ensured that drug steadily discharges, and has reached standard requirements.

CN106955276A (Chinese Patent Application No. 2017101927278 is closed auspicious) discloses a kind of VENLAFAXINE HCLSpansule composition, the content of the spansule composition are the sustained release pellet being made of load medicine pellet and slow release layer,Carry VENLAFAXINE HCL of the medicine pellet by 58~66 parts by weight, the filler of 75~85 parts by weight, the adhesive of 8~12 parts by weightComposition, slow release layer are made of the Sustained release coating materials of 3.5~6 parts by weight and the pore-foaming agent of 18~27 parts by weight, wherein slow release layerQuality be drug-loaded layer quality 14~17%.The invention additionally provides the preparation side of venlafaxine hydrochloride slow-release capsule compositionMethod is made using fluidized bed and carries medicine pellet and carry out the obtained sustained release pellet of slow release layer coating.It is believed that hydrochloric acid made from the inventionFor Venlafaxine sustained-release capsule composition without auxiliary materials such as antiplastering aid, plasticizer, manufacturing condition can be met by adjusting fluidized-bed process,It obtains grinding drug similar in drug effect fruit with original, saves cost, reduce technology difficulty.

CN103181916A (Chinese Patent Application No. 201110452445X, product are big) discloses venlafaxine hydrochloride sustained-releaseCapsule and preparation method thereof.The pellet core of the spansule includes VENLAFAXINE HCL, microcrystalline cellulose, gas phase titanium dioxideSilicon, Tween-80 and hypromellose, sustained release coating include polyacrylic resin, talcum powder, polyethylene glycol and dodecylSodium sulphate.The invention changes the flowing of material, and the selection to sustained release coating by addition fumed silica, makes the capsuleProduction realize pure aquatic system.The venlafaxine hydrochloride slow-release capsule drug release being prepared by the system is steady, effectively holdsContinuous release time is 24 hours, is taken only once a day.It is believed that this method simple process, mild condition have without using anySolvent, it is low for equipment requirements, it is suitble to industrialized production.

CN103893153A (Chinese Patent Application No. 2014101550047, Hua Xin) discloses a kind of VENLAFAXINE HCLSpansule and preparation method thereof belongs to pharmaceutical technology field.The venlafaxine hydrochloride slow-release capsule, by sustained release content withCapsule shells composition, the sustained release content are made of load medicine cane sugar type medicinal fine pellet core and slow release layer, it is believed that the hydrochloric acid text is drawnThe pungent spansule of method have it is easy to use, biddability is high, adverse reaction is few, and blood concentration is steady, the good feature of therapeutic effect.

CN104873477A (Chinese Patent Application No. 2015102600349, honest) discloses a kind of VENLAFAXINE HCLSpansule and preparation method thereof, wherein spansule is made of slow-release pill and capsule shells.Slow-release pill is with inertia capsule coreSubstrate, fluidized bed packet medicine layer, separation layer, slow release layer respectively, compared to the round as a ball extrusion molding of tradition, it is believed that preparation process letterIt is single, simultaneously because the optimum choice of coating layer material, so that drug can be realized sustained release.

CN103893151A (Chinese Patent Application No. 2012105838482, middle surprise) discloses a kind of VENLAFAXINE HCLSpansule, spansule content prepared by the present invention are sustained release pellet, and the pellet is by pellet core and sustained release clothing film groupAt pellet core contains VENLAFAXINE HCL, hypromellose and microcrystalline cellulose.The hydrochloric acid text daraf(reciprocal of farad) of invention preparationPungent spansule drug release is steady, and organic solvent-free residue problem, product takes safety, and production environment is friendly.The invention also providesA kind of venlafaxine hydrochloride slow-release capsule preparation method, it is believed that this method high production efficiency, simple process, easy to operate, costIt is low, be easy to industrialization production, saved cost for pharmaceutical producing enterprise, and considerable economic and social benefit can be generated.

CN106176679A (Chinese Patent Application No. 2016105481295, Longhai City) discloses a kind of VENLAFAXINE HCLSpansule and preparation method thereof belongs to pharmaceutical technology field.The venlafaxine hydrochloride slow-release capsule is by sustained release content and glueSoftgel shell composition, the sustained release content are made of load medicine starch type medicinal fine pellet core and slow release layer.It is believed that described in the inventionVenlafaxine hydrochloride slow-release capsule can be sustained release 24 hours, and discharge steadily without burst release.It is also believed that described in the inventionThe preparation method of venlafaxine hydrochloride slow-release capsule, high production efficiency, simple process, easy to operate, supplementary product kind and dosage it is few,It is easy to industrialization production, has saved cost for pharmaceutical producing enterprise, and considerable economic and social benefit can be generated.

CN103191082A (Chinese Patent Application No. 2013101379063, U.S. China) discloses a kind of VENLAFAXINE HCLSpansule and preparation method thereof.Existing method is coated using aqueous dispersion, since the height of VENLAFAXINE HCL is water-solubleProperty, cause VENLAFAXINE HCL to migrate in coating, in the case where coating membrane thickness low LCL, VENLAFAXINE HCL mayAs to hole agent, cause the release of VENLAFAXINE HCL too fast.Venlafaxine hydrochloride slow-release capsule of the present invention, it is characterised in that instituteThe medicated pellet stated includes the controlled release layer of separation layer and packet outside separation layer of pellet core, packet outside pellet core, describedPellet core is made of the component of following weight percentage: VENLAFAXINE HCL 30-60%, filler 30-80%, sustained-release matrixMaterial 1-20%, adhesive 1-10%.It is believed that the invention thoroughly solve it is original done using organic solvent dichloromethane, ethyl alcohol it is moltenAgent is coated, and causes that there are the high technical problems of the requirement of security risk and equipment to operator.

However, this field still expect to provide a kind of venlafaxine hydrochloride sustained-release pellet prepared with excellent performance and itsThe method of spansule, it is same to be to provide a kind of venlafaxine hydrochloride sustained-release pellet and its spansule with excellent performance.

Summary of the invention

The purpose of the present invention is to provide a kind of venlafaxine hydrochloride sustained-release pellet prepared with excellent performance and its delayThe method for releasing capsule, the venlafaxine hydrochloride sustained-release pellet that it is a further object of the present invention to provide a kind of with excellent performance and itsSpansule.It has been unexpectedly discovered that the venlafaxine hydrochloride sustained-release pellet prepared using inventive formulation and preparation method,Excellent performance is presented, is accomplished the present invention is based on this discovery.

For this purpose, first aspect present invention provides a kind of venlafaxine hydrochloride sustained-release pellet comprising blank capsule core, coatingLoad medicine clothing layer, the sustained-release coating layer coated in the load medicine clothing layer outer surface in the blank capsule core outer surface, in the load medicine clothing layerInclude active ingredient hydrochloric acid Venlafaxine.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein active ingredient hydrochloric acid Venlafaxine accounts for thisThe 50~65% of sustained release pellet weight, such as 52~62%, such as 53~61%.It has been unexpectedly discovered that system of the present inventionSustained release pellet have than it in the significantly higher drugloading rate of the prior art.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention can pass through 14 meshes but cannot pass through 30 meshSieve.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention can pass through 16 meshes but cannot pass through 25 meshSieve.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention is measured according to [dissolution method] herein,2h the amount of dissolution be no more than 30%, 4h the amount of dissolution 40% -60%, 8h the amount of dissolution 60% -80%, 12h the amount of dissolution 70% -90%, for 24 hoursThe amount of dissolution is not less than 85%.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, [dissolution method] include following behaviourMake:

It is carried out according to Chinese Pharmacopoeia 2015 version four " 0931 dissolution rate and drug release determination method " specifications, with every part of test specimensProduct include that the amount of active medicine Venlafaxine is that (50~250mg of the Venlafaxine is also referred to as herein for 50~250mg measurementTest volume, such as when sample is piller, takes the piller for being equivalent to 50~250mg amount containing Venlafaxine to be placed in dissolution test and turn indigo plantIn be measured；When test sample is capsule of the piller in hard capsule case, the amount phase of the piller in every capsuleWhen in 50~250mg containing Venlafaxine)；

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

Sample time: with i be 1~5 integer representation 5 point in time sampling, respectively be 2h, 4h, 8h, 12h,24h；

Buffer: 10mL/L triethylamine aqueous solution simultaneously adjusts pH=3.0 with phosphoric acid；

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

Standard solution: take VENLAFAXINE HCL reference substance that standard solution is made with dissolution medium dissolution in right amount, in the standardIn solution, Venlafaxine concentration is suitable with each stripping rotor Venlafaxine theoretical concentration of Dissolution Rate Testing；

Sample solution: testing liquid centrifugation；

Liquid chromatographic system: ultraviolet 226nm detector, 4.6mm × 15cm-5 μm of specification of C18 column, flow velocity 2.5mL/min,20 μ L of sample volume, record time are 1.5 times of Venlafaxine retention time；

System suitability: being tested with standard solution, and tailing factor is no more than 2.0, and relative standard deviation is no more than 2.0%；

Measurement:

Sample be standard solution and sample solution,

The calculating of medium Venlafaxine (C17H27NO2) concentration C i (mg/mL) after time point i:

As a result i=(rU/rS) × CS × (Mr1/Mr2)

In formula, the peak response value of rU=sample solution, the peak response value of rS=standard solution, hydrochloric acid in CS=standard solutionThe concentration (mg/mL) of Venlafaxine reference substance, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight313.86

The percentage of Venlafaxine (C17H27NO2) labelled amount of each time point i dissolution is calculated as follows

As a result 1=C1 × V × (1/L) × 100

As a result 2={ [C2 × (V-VS)]+[C1 × VS] } × (1/L) × 100

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

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

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

In above formula, Ci=time point i samples Venlafaxine concentration (mg/mL), V=dissolution medium volume in solutionThe volume (mL) of the sample solution that 900mL, VS=are drawn from dissolution medium, L=concentration determination labelled amount are (that is, dissolution rate triesTest each stripping rotor Venlafaxine theoretical addition amount, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsuleVenlafaxine labelled amount in agent, mg).

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the blank capsule core is by selected from followingBlank capsule core made of substrate: sucrose, starch, microcrystalline cellulose and combinations thereof.These blank capsule cores can make by oneself, can also pass throughCommercially available approach obtains.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the blank capsule core is made of sucroseBlank capsule core.In one embodiment, the average diameter of the blank capsule core be 0.3~0.6mm, preferably 0.35~0.5mm, preferably 0.35~0.45mm.In specific experiment herein below, if not otherwise specified, blank capsule core used is sugarcaneBlank capsule core made of sugar, average diameter are 0.35~0.45mm.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein with the drawing of every 84.86 parts by weight hydrochloric acid textThe pungent meter of method, the amount of the blank capsule core are 35~45 parts by weight, such as 38~44 parts by weight, such as 39~42 parts by weight.

In the present invention, 84.86 parts by weight VENLAFAXINE HCLs are equivalent to 75 parts by weight Venlafaxines.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein in the load medicine clothing layer in addition to activity atIt exceptionally, further include selected from following adhesive: ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl fiberElement and combinations thereof.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein further including being selected from the load medicine clothing layerFollowing adhesive: ethyl cellulose, hydroxypropyl cellulose and combinations thereof.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein further including following in the load medicine clothing layerAdhesive: ethyl cellulose, hydroxypropyl cellulose.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein with the drawing of every 84.86 parts by weight hydrochloric acid textThe pungent meter of method, the amount of described adhesive are 10~15 parts by weight, such as 11~14 parts by weight, such as 12~13 parts by weight.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein further including following in the load medicine clothing layerAdhesive: ethyl cellulose, hydroxypropyl cellulose, in terms of every 84.86 parts by weight VENLAFAXINE HCL, the ethyl celluloseAmount be 5~10 parts by weight, such as 6~9 parts by weight, such as 7~9 parts by weight.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein further including following in the load medicine clothing layerAdhesive: ethyl cellulose, hydroxypropyl cellulose, in terms of every 84.86 parts by weight VENLAFAXINE HCL, the hydroxy propyl celluloseThe amount of element is 3~7 parts by weight, such as 4~6 parts by weight, such as 4~5 parts by weight.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the sustained release coating in the sustained-release coating layerMaterial is selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer such as Utech NE30D, ethyl cellulose, ethylCellulose and the mixture of hypromellose etc.；Preferred Sustained release coating materials are ethyl acrylate and methacrylic acidMethyl esters (2:1) copolymer such as Utech NE30D.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein with the drawing of every 84.86 parts by weight hydrochloric acid textThe pungent meter of method, the amount of the Sustained release coating materials are 5~15 parts by weight, such as 6~12 parts by weight, such as 7~10 parts by weight.Sustained releaseThe amount of coating material is herein if not otherwise specified in terms of its dry product.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein further including being used in the sustained-release coating layerPrevent the antiplastering aid that Sustained release coating materials bond in coating process.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the antiplastering aid in the sustained-release coating layer selectsFrom: talcum powder, colloidal silicon dioxide, magnesium trisilicate etc., preferred antiplastering aid are talcum powder.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein with the drawing of every 84.86 parts by weight hydrochloric acid textThe pungent meter of method, the amount of the antiplastering aid are 1~5 parts by weight, such as 1~3 parts by weight, such as 1~2 parts by weight.One of antiplastering aidMain function is for preventing Sustained release coating materials from bonding in coating process.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the load medicine clothing layer is by such as lower sectionFormula is coated in the blank capsule core outer surface: active constituent and adhesive being dissolved and/or are suspended in the first solvent, then is sprayedIt is applied to the blank pellet surface, then makes coating piller dry to remove first solvent.In one embodiment, describedFirst solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, and preferred first solvent is isopropanol.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the amount of the first solvent is that gained is made to be suspendedSolid content weight accounts for 20~40%, such as 25~35%, such as 28~32% in liquid.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the sustained-release coating layer is by such as lower sectionFormula is coated in the load medicine clothing layer outer surface: Sustained release coating materials and antiplastering aid dispersion being suspended in the second solvent, then are sprayedIt is applied to the load medicine clothing layer outer surface, then makes coating piller dry to remove second solvent.In one embodiment, instituteState the second solvent to be selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred second solvent is water.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, wherein the amount of the second solvent is that gained is made to be suspendedSolid content weight accounts for 20~35%, such as 25~30%, such as 25~28% in liquid.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention carries medicine clothing wherein spraying to blank pellet surfaceLayer and to carry medicine clothing layer trypsin method sustained-release coating layer be to be carried out in fluidized bed coating equipment.It is same during to piller coatingWhen solvent can be removed, the solvent used twice is readily removed to reach the requirement for meeting pharmaceutical purpose.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention is according to the method preparation included the following stepsIt obtains:

(1) blank capsule core is provided, (such as temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidisationState；

(2) it is dissolved in described adhesive in first solvent, preparatory be crushed to is added can be by the hydrochloric acid of 150 meshesVenlafaxine is uniformly mixed to obtain suspension, by being atomized the blank pill for being sprayed on the suspension in fluidized-bed coating machine in fluidized stateContinuing to be fluidised on core, after spraying is removed solvent, obtains drug-loaded pellets；

(3) Sustained release coating materials and antiplastering aid are dispersed in the second solvent, spray the suspension by atomizationIn on the drug-loaded pellets for being in fluidized state in fluidized-bed coating machine, continues to be fluidised to after spraying to be removed solvent, obtainSlow-release pill；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.

Further, second aspect of the present invention provides a kind of venlafaxine hydrochloride slow-release capsule comprising gelatin is hollowCapsule and the venlafaxine hydrochloride sustained-release pellet being hermetically encapsulated in the gelatin hollow capsule.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletSuch as described in first embodiment of the invention；Alternatively, for example comprising blank capsule core, coated in the blank capsule core outer surfaceMedicine clothing layer, the sustained-release coating layer coated in the load medicine clothing layer outer surface are carried, is drawn in the load medicine clothing layer comprising active ingredient hydrochloric acid textMethod is pungent.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletMiddle active ingredient hydrochloric acid Venlafaxine accounts for the 50~65% of the sustained release pellet weight, such as 52~62%, such as 53~61%.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet14 meshes can be passed through but 30 meshes cannot be passed through.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet16 meshes can be passed through but 25 meshes cannot be passed through.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention is measured according to [dissolution method] herein,2h the amount of dissolution be no more than 30%, 4h the amount of dissolution 40% -60%, 8h the amount of dissolution 60% -80%, 12h the amount of dissolution 70% -90%, for 24 hoursThe amount of dissolution is not less than 85%.

Venlafaxine hydrochloride sustained-release pellet according to a first aspect of the present invention, [dissolution method] include following behaviourMake:

It is carried out according to Chinese Pharmacopoeia 2015 version four " 0931 dissolution rate and drug release determination method " specifications, with every part of test specimensProduct include that the amount of active medicine Venlafaxine is that (50~250mg of the Venlafaxine is also referred to as herein for 50~250mg measurementTest volume, such as when sample is piller, takes the piller for being equivalent to 50~250mg amount containing Venlafaxine to be placed in dissolution test and turn indigo plantIn be measured；When test sample is capsule of the piller in hard capsule case, the amount phase of the piller in every capsuleWhen in 50~250mg containing Venlafaxine)；

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

Sample time: with i be 1~5 integer representation 5 point in time sampling, respectively be 2h, 4h, 8h, 12h,24h；

Buffer: 10mL/L triethylamine aqueous solution simultaneously adjusts pH=3.0 with phosphoric acid；

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

Standard solution: take VENLAFAXINE HCL reference substance that standard solution is made with dissolution medium dissolution in right amount, in the standardIn solution, Venlafaxine concentration is suitable with each stripping rotor Venlafaxine theoretical concentration of Dissolution Rate Testing；

Sample solution: testing liquid centrifugation；

Liquid chromatographic system: ultraviolet 226nm detector, 4.6mm × 15cm-5 μm of specification of C18 column, flow velocity 2.5mL/min,20 μ L of sample volume,

Record 1.5 times that the time is Venlafaxine retention time；

System suitability: being tested with standard solution, and tailing factor is no more than 2.0, and relative standard deviation is no more than 2.0%；

Measurement:

Sample be standard solution and sample solution,

The calculating of medium Venlafaxine (C17H27NO2) concentration C i (mg/mL) after time point i:

As a result i=(rU/rS) × CS × (Mr1/Mr2)

In formula, the peak response value of rU=sample solution, the peak response value of rS=standard solution, hydrochloric acid in CS=standard solutionThe concentration (mg/mL) of Venlafaxine reference substance, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight313.86

The percentage of Venlafaxine (C17H27NO2) labelled amount of each time point i dissolution is calculated as follows

As a result 1=C1 × V × (1/L) × 100

As a result 2={ [C2 × (V-VS)]+[C1 × VS] } × (1/L) × 100

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

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

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

In above formula, Ci=time point i samples Venlafaxine concentration (mg/mL), V=dissolution medium volume in solutionThe volume (mL) of the sample solution that 900mL, VS=are drawn from dissolution medium, L=concentration determination labelled amount are (that is, dissolution rate triesTest each stripping rotor Venlafaxine theoretical addition amount, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsuleVenlafaxine labelled amount in agent, mg).

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in blank capsule core be the blank capsule core made of the following substrate: sucrose, starch, microcrystalline cellulose and combinations thereof.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in blank capsule core be the blank capsule core made of sucrose.In one embodiment, the average diameter of blank capsule core is0.35~0.45mm.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIn in terms of every 84.86 parts by weight VENLAFAXINE HCL, the amount of the blank capsule core is 35~45 parts by weight, such as 38~44 weightPart, such as 39~42 parts by weight.

In the present invention, 84.86 parts by weight VENLAFAXINE HCLs are equivalent to 75 parts by weight Venlafaxines.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in load medicine clothing layer other than active constituent, further include selected from following adhesive: ethyl cellulose, methylcellulose,Hydroxypropyl cellulose, hydroxypropyl methyl cellulose and combinations thereof.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in further include selected from following adhesive in load medicine clothing layer: ethyl cellulose, hydroxypropyl cellulose and combinations thereof.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in load medicine clothing layer in further include following adhesive: ethyl cellulose, hydroxypropyl cellulose.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIn in terms of every 84.86 parts by weight VENLAFAXINE HCL, the amount of described adhesive is 10~15 parts by weight, such as 11~14 weightPart, such as 12~13 parts by weight.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in load medicine clothing layer in further include following adhesive: ethyl cellulose, hydroxypropyl cellulose, with every 84.86 parts by weight saltSour Venlafaxine meter, the amount of the ethyl cellulose are 5~10 parts by weight, such as 6~9 parts by weight, such as 7~9 parts by weight.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in load medicine clothing layer in further include following adhesive: ethyl cellulose, hydroxypropyl cellulose, with every 84.86 parts by weight saltSour Venlafaxine meter, the amount of the hydroxypropyl cellulose are 3~7 parts by weight, such as 4~6 parts by weight, such as 4~5 parts by weight.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in Sustained release coating materials in sustained-release coating layer be selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer are for exampleUtech NE30D, ethyl cellulose, ethyl cellulose and mixture of hypromellose etc.；Preferred sustained release coatingMaterial is ethyl acrylate and methyl methacrylate (2:1) copolymer such as Utech NE30D.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIn in terms of every 84.86 parts by weight VENLAFAXINE HCL, the amounts of the Sustained release coating materials is 5~15 parts by weight, such as 6~12 weightsMeasure part, such as 7~10 parts by weight.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in further include antiplastering aid for preventing Sustained release coating materials from bonding in coating process in sustained-release coating layer.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in antiplastering aid in sustained-release coating layer be selected from: talcum powder, colloidal silicon dioxide, magnesium trisilicate etc., preferred antiplastering aid are to slideMountain flour.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIn in terms of every 84.86 parts by weight VENLAFAXINE HCL, the amount of the antiplastering aid is 1~5 parts by weight, such as 1~3 parts by weight, exampleSuch as 1~2 parts by weight.One main function of antiplastering aid is for preventing Sustained release coating materials from bonding in coating process.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in load medicine clothing layer be to be coated in the blank capsule core outer surface in the following way: active constituent and adhesive are dissolvedAnd/or be suspended in the first solvent, then be sprayed at the blank pellet surface, then make coating piller dry with remove this firstSolvent.In one embodiment, first solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred first solventIt is isopropanol.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIn the first solvent amount be make gained suspension in solid content weight account for 20~40%, such as 25~35%, such as 28~32%.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletDescribed in sustained-release coating layer be in the following way be coated in the load medicine clothing layer outer surface: by Sustained release coating materials and antiplastering aidDispersion is suspended in the second solvent, then is sprayed at the loads medicine clothing layer outer surface, then dry coating piller with remove thisTwo solvents.In one embodiment, second solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred second is moltenAgent is water.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIn the second solvent amount be make gained suspension in solid content weight account for 20~35%, such as 25~30%, such as 25~28%.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIt is middle to blank pellet surface spray carry medicine clothing layer and to carry medicine clothing layer trypsin method sustained-release coating layer be in fluidized bed coating equipmentIt carries out.Solvent can be removed simultaneously during to piller coating, the solvent used twice is readily removed to reachMeet the requirement of pharmaceutical purpose.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pelletIt is to be prepared according to the method included the following steps:

(1) blank capsule core is provided, (such as temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidisationState；

(2) it is dissolved in described adhesive in first solvent, preparatory be crushed to is added can be by the hydrochloric acid of 150 meshesVenlafaxine is uniformly mixed to obtain suspension, by being atomized the blank pill for being sprayed on the suspension in fluidized-bed coating machine in fluidized stateContinuing to be fluidised on core, after spraying is removed solvent, obtains drug-loaded pellets；

(3) Sustained release coating materials and antiplastering aid are dispersed in the second solvent, spray the suspension by atomizationIn on the drug-loaded pellets for being in fluidized state in fluidized-bed coating machine, continues to be fluidised to after spraying to be removed solvent, obtainSlow-release pill；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention is according to the method preparation included the following stepsIt obtains:

(1) blank capsule core is provided, (such as temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidisationState；

(2) it is dissolved in described adhesive in first solvent, preparatory be crushed to is added can be by the hydrochloric acid of 150 meshesVenlafaxine is uniformly mixed to obtain suspension, by being atomized the blank pill for being sprayed on the suspension in fluidized-bed coating machine in fluidized stateContinuing to be fluidised on core, after spraying is removed solvent, obtains drug-loaded pellets；

(3) Sustained release coating materials and antiplastering aid are dispersed in the second solvent, spray the suspension by atomizationIn on the drug-loaded pellets for being in fluidized state in fluidized-bed coating machine, continues to be fluidised to after spraying to be removed solvent, obtainSlow-release pill；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet；Then the sustained release pellet is filled intoGelatin hollow capsule, it is hermetically sealed, obtain spansule.

Further, third aspect present invention provides a kind of method for preparing venlafaxine hydrochloride sustained-release pellet, the saltThe method of sour venlafaxine sustained-release pellet includes blank capsule core, the load medicine clothing layer coated in the blank capsule core outer surface, is coated inThe sustained-release coating layer of the load medicine clothing layer outer surface includes active ingredient hydrochloric acid Venlafaxine in the load medicine clothing layer, including walks as followsIt is rapid:

(1) blank capsule core is provided, (such as temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidisationState；

(2) it is dissolved in described adhesive in first solvent, preparatory be crushed to is added can be by the hydrochloric acid of 150 meshesVenlafaxine is uniformly mixed to obtain suspension, by being atomized the blank pill for being sprayed on the suspension in fluidized-bed coating machine in fluidized stateContinuing to be fluidised on core, after spraying is removed solvent, obtains drug-loaded pellets；

(3) Sustained release coating materials and antiplastering aid are dispersed in the second solvent, spray the suspension by atomizationIn on the drug-loaded pellets for being in fluidized state in fluidized-bed coating machine, continues to be fluidised to after spraying to be removed solvent, obtainSlow-release pill；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet；Then the sustained release pellet is filled intoGelatin hollow capsule, it is hermetically sealed, obtain spansule.

Method according to a third aspect of the present invention, wherein active ingredient hydrochloric acid text in the venlafaxine hydrochloride sustained-release pelletDaraf(reciprocal of farad) is pungent to account for the 50~65% of the sustained release pellet weight, such as 52~62%, such as 53~61%.

Method according to a third aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet its can by 14 meshes but30 meshes cannot be passed through.

Method according to a third aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet its can by 16 meshes but25 meshes cannot be passed through.

Method according to a third aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet is according to [dissolution rate is surveyed hereinDetermine method] measurement, 2h the amount of dissolution is no more than 30%, 4h the amount of dissolution 40% -60%, 8h the amount of dissolution 60% -80%, 12h the amount of dissolution70% -90%, the amount of dissolution is not less than 85% for 24 hours.

Method according to a third aspect of the present invention, wherein [dissolution method] includes following operation:

It is carried out according to Chinese Pharmacopoeia 2015 version four " 0931 dissolution rate and drug release determination method " specifications, with every part of test specimensProduct include that the amount of active medicine Venlafaxine is that (50~250mg of the Venlafaxine is also referred to as herein for 50~250mg measurementTest volume, such as when sample is piller, takes the piller for being equivalent to 50~250mg amount containing Venlafaxine to be placed in dissolution test and turn indigo plantIn be measured；When test sample is capsule of the piller in hard capsule case, the amount phase of the piller in every capsuleWhen in 50~250mg containing Venlafaxine)；

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

Sample time: with i be 1~5 integer representation 5 point in time sampling, respectively be 2h, 4h, 8h, 12h,24h；

Buffer: 10mL/L triethylamine aqueous solution simultaneously adjusts pH=3.0 with phosphoric acid；

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

Standard solution: take VENLAFAXINE HCL reference substance that standard solution is made with dissolution medium dissolution in right amount, in the standardIn solution, Venlafaxine concentration is suitable with each stripping rotor Venlafaxine theoretical concentration of Dissolution Rate Testing；

Sample solution: testing liquid centrifugation；

Liquid chromatographic system: ultraviolet 226nm detector, 4.6mm × 15cm-5 μm of specification of C18 column, flow velocity 2.5mL/min,20 μ L of sample volume, record time are 1.5 times of Venlafaxine retention time；

System suitability: being tested with standard solution, and tailing factor is no more than 2.0, and relative standard deviation is no more than 2.0%；

Measurement:

Sample be standard solution and sample solution,

The calculating of medium Venlafaxine (C17H27NO2) concentration C i (mg/mL) after time point i:

As a result i=(rU/rS) × CS × (Mr1/Mr2)

In formula, the peak response value of rU=sample solution, the peak response value of rS=standard solution, hydrochloric acid in CS=standard solutionThe concentration (mg/mL) of Venlafaxine reference substance, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight313.86

The percentage of Venlafaxine (C17H27NO2) labelled amount of each time point i dissolution is calculated as follows

As a result 1=C1 × V × (1/L) × 100

As a result 2={ [C2 × (V-VS)]+[C1 × VS] } × (1/L) × 100

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

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

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

In above formula, Ci=time point i samples Venlafaxine concentration (mg/mL), V=dissolution medium volume in solutionThe volume (mL) of the sample solution that 900mL, VS=are drawn from dissolution medium, L=concentration determination labelled amount are (that is, dissolution rate triesTest each stripping rotor Venlafaxine theoretical addition amount, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsuleVenlafaxine labelled amount in agent, mg).

Method according to a third aspect of the present invention, wherein blank capsule core described in the venlafaxine hydrochloride sustained-release pellet isBeing selected from blank capsule core made of following substrate: sucrose, starch, microcrystalline cellulose and combinations thereof.

Method according to a third aspect of the present invention, wherein blank capsule core described in the venlafaxine hydrochloride sustained-release pellet isThe blank capsule core made of sucrose.In one embodiment, the average diameter of blank capsule core is 0.35~0.45mm.

Method according to a third aspect of the present invention, wherein with every 84.86 weight in the venlafaxine hydrochloride sustained-release pelletPart VENLAFAXINE HCL meter, the amount of the blank capsule core are 35~45 parts by weight, such as 38~44 parts by weight, such as 39~42 weightsMeasure part.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pelletIt further include selected from following adhesive: ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl other than active constituentYlmethyl cellulose and combinations thereof.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pelletIt further include selected from following adhesive: ethyl cellulose, hydroxypropyl cellulose and combinations thereof.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pelletIt further include following adhesive: ethyl cellulose, hydroxypropyl cellulose.

Method according to a third aspect of the present invention, wherein with every 84.86 weight in the venlafaxine hydrochloride sustained-release pelletPart VENLAFAXINE HCL meter, the amount of described adhesive are 10~15 parts by weight, such as 11~14 parts by weight, such as 12~13 weightPart.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pelletFurther include following adhesive: ethyl cellulose, hydroxypropyl cellulose, it is described in terms of every 84.86 parts by weight VENLAFAXINE HCLThe amount of ethyl cellulose is 5~10 parts by weight, such as 6~9 parts by weight, such as 7~9 parts by weight.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pelletFurther include following adhesive: ethyl cellulose, hydroxypropyl cellulose, it is described in terms of every 84.86 parts by weight VENLAFAXINE HCLThe amount of hydroxypropyl cellulose is 3~7 parts by weight, such as 4~6 parts by weight, such as 4~5 parts by weight.

Method according to a third aspect of the present invention, wherein in sustained-release coating layer described in the venlafaxine hydrochloride sustained-release pelletSustained release coating materials be selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer such as Utech NE30D, ethylCellulose, ethyl cellulose and mixture of hypromellose etc.；Preferred Sustained release coating materials are ethyl acrylateWith methyl methacrylate (2:1) copolymer such as Utech NE30D.

Method according to a third aspect of the present invention, wherein with every 84.86 weight in the venlafaxine hydrochloride sustained-release pelletPart VENLAFAXINE HCL meter, the amount of the Sustained release coating materials are 5~15 parts by weight, such as 6~12 parts by weight, such as 7~10Parts by weight.

Method according to a third aspect of the present invention, wherein in sustained-release coating layer described in the venlafaxine hydrochloride sustained-release pelletIt further include the antiplastering aid for preventing Sustained release coating materials from bonding in coating process.

Method according to a third aspect of the present invention, wherein the antiplastering aid in the sustained-release coating layer is selected from: talcum powder, colloidal state twoSilica, magnesium trisilicate etc., preferred antiplastering aid are talcum powder.

Method according to a third aspect of the present invention, wherein with every 84.86 weight in the venlafaxine hydrochloride sustained-release pelletPart VENLAFAXINE HCL meter, the amount of the antiplastering aid are 1~5 parts by weight, such as 1~3 parts by weight, such as 1~2 parts by weight.It is anti-One main function of stick is for preventing Sustained release coating materials from bonding in coating process.

Method according to a third aspect of the present invention, wherein load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pellet isIn the following way coated in the blank capsule core outer surface: active constituent and adhesive are dissolved and/or are suspended in firstIn solvent, then it is sprayed at the blank pellet surface, then makes coating piller dry to remove first solvent.Implement at oneIn scheme, first solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred first solvent is isopropanol.

Method according to a third aspect of the present invention, wherein the amount of the first solvent is in the venlafaxine hydrochloride sustained-release pelletSolid content weight in gained suspension is set to account for 20~40%, such as 25~35%, such as 28~32%.

Method according to a third aspect of the present invention, wherein sustained-release coating layer described in the venlafaxine hydrochloride sustained-release pellet isBe coated in the load medicine clothing layer outer surface in the following way: it is molten that Sustained release coating materials and antiplastering aid dispersion are suspended in secondIn agent, then it is sprayed at the load medicine clothing layer outer surface, then makes coating piller dry to remove second solvent.Implement at oneIn scheme, second solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred second solvent is water.

Method according to a third aspect of the present invention, wherein the amount of the second solvent is in the venlafaxine hydrochloride sustained-release pelletSolid content weight in gained suspension is set to account for 20~35%, such as 25~30%, such as 25~28%.

Method according to a third aspect of the present invention, wherein to blank pellet surface spray carry medicine clothing layer and to carry medicine clothing layerTrypsin method sustained-release coating layer is carried out in fluidized bed coating equipment.Solvent can be removed simultaneously during to piller coating,The solvent used twice is readily removed to reach the requirement for meeting pharmaceutical purpose.

Method according to a third aspect of the present invention still further comprises and fills the venlafaxine hydrochloride sustained-release pelletIt is hermetically sealed to gelatin hollow capsule, the step of obtaining spansule.

Further, fourth aspect present invention provides hydrochloric acid text daraf(reciprocal of farad) described in first aspect present invention any embodimentVenlafaxine hydrochloride slow-release capsule described in pungent sustained release pellet or second aspect of the present invention any embodiment is in preparation for controllingTreat or prevention of depression, generalized anxiety disorder, paralepsy recurrence prevention, social anxiety disorder, panic disorder drug inPurposes.

Further, fifth aspect present invention provides the venlafaxine hydrochloride sustained-release pellet of measurement first aspect present inventionOr the method for the venlafaxine hydrochloride slow-release capsule dissolution rate of second aspect of the present invention, including operate as follows:

It is carried out according to Chinese Pharmacopoeia 2015 version four " 0931 dissolution rate and drug release determination method " specifications, with every part of test specimensProduct include that the amount of active medicine Venlafaxine is that (50~250mg of the Venlafaxine is also referred to as herein for 50~250mg measurementTest volume, such as when sample is piller, takes the piller for being equivalent to 50~250mg amount containing Venlafaxine to be placed in dissolution test and turn indigo plantIn be measured；When test sample is capsule of the piller in hard capsule case, the amount phase of the piller in every capsuleWhen in 50~250mg containing Venlafaxine)；

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

Sample time: with i be 1~5 integer representation 5 point in time sampling, respectively be 2h, 4h, 8h, 12h,24h；

Buffer: 10mL/L triethylamine aqueous solution simultaneously adjusts pH=3.0 with phosphoric acid；

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

Standard solution: take VENLAFAXINE HCL reference substance that standard solution is made with dissolution medium dissolution in right amount, in the standardIn solution, Venlafaxine concentration is suitable with each stripping rotor Venlafaxine theoretical concentration of Dissolution Rate Testing；

Sample solution: testing liquid centrifugation；

Liquid chromatographic system: ultraviolet 226nm detector, 4.6mm × 15cm-5 μm of specification of C18 column, flow velocity 2.5mL/min,20 μ L of sample volume, record time are 1.5 times of Venlafaxine retention time；

System suitability: being tested with standard solution, and tailing factor is no more than 2.0, and relative standard deviation is no more than 2.0%；

Measurement:

Sample be standard solution and sample solution,

The calculating of medium Venlafaxine (C17H27NO2) concentration C i (mg/mL) after time point i:

As a result i=(rU/rS) × CS × (Mr1/Mr2)

In formula, the peak response value of rU=sample solution, the peak response value of rS=standard solution, hydrochloric acid in CS=standard solutionThe concentration (mg/mL) of Venlafaxine reference substance, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight313.86

The percentage of Venlafaxine (C17H27NO2) labelled amount of each time point i dissolution is calculated as follows

As a result 1=C1 × V × (1/L) × 100

As a result 2={ [C2 × (V-VS)]+[C1 × VS] } × (1/L) × 100

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

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

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

In above formula, Ci=time point i samples Venlafaxine concentration (mg/mL), V=dissolution medium volume in solutionThe volume (mL) of the sample solution that 900mL, VS=are drawn from dissolution medium, L=concentration determination labelled amount are (that is, dissolution rate triesTest each stripping rotor Venlafaxine theoretical addition amount, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsuleVenlafaxine labelled amount in agent, mg).

Either side according to the present invention, wherein the hydrochloric acid text for including in the venlafaxine hydrochloride slow-release capsule every is drawnThe pungent amount of method can be 50~500mg, such as 50~400mg, such as 50~300mg in terms of Venlafaxine, such as 50mg,100mg、150mg、20mg、250mg、300mg。

Either side according to the present invention, wherein being wrapped during preparing the venlafaxine hydrochloride sustained-release pelletWhen wrapping up in load medicine clothing layer, it is to be carried out according to such as under type: ethyl cellulose and 4/5 amount hydroxypropyl cellulose is made to be dissolved in described firstIn solvent, it is added and is crushed to can be uniformly mixed to obtain suspension by the VENLAFAXINE HCL of 150 meshes in advance；In addition by 1/5 amount hydroxylPropyl cellulose is dissolved in first solvent, and solid concentration is identical as upper suspension concentration, obtains solution；Pass through atomizationBeing sprayed on above-mentioned suspension and solution in fluidized-bed coating machine is in the blank capsule core of fluidized state, after afterflow after sprayingChange to solvent is removed, obtains drug-loaded pellets.It has been unexpectedly discovered that fraction hydroxypropyl cellulose is single after medicine-feedingIt is solely coated on piller, significant more preferably dissolution rate stability is presented in gained pellet.

In the above-mentioned preparation method of the invention the step of, although the specific steps of its description are in certain details or languageIn description with the preparation example of following detailed description part described in step different from, however, those skilled in the artThe detailed disclosure of member's full text according to the present invention can summarize approach described above step completely.

Any embodiment in either present invention face can be combined with other embodiments, as long as they are notIt will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present inventionThe technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.

All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literaryWhen offering expressed meaning and the inconsistent present invention, it is subject to statement of the invention.In addition, the various terms that use of the present invention andPhrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms andPhrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present inventionSubject to the meaning stated.

Venlafaxine hydrochloride slow-release capsule of the present invention is in the morning or night one fixes the time relatively and food is taken simultaneously,Once a day.Capsule, which should integrally take, to be avoided separating, take after crushing, chewing or dissolution, and can also carefully open capsule willContent is put in one spoon of apple sauce, this drug/food mixture should not chew to be swallowed quickly, and water of then having a drink guaranteesIt takes completely.

Venlafaxine hydrochloride slow-release capsule initial treatment of the present invention is used for various types depression.For most of patients, push awayThe initial dose for recommending venlafaxine hydrochloride slow-release capsule is daily 75 milligrams, single medication.In venlafaxine hydrochloride slow-release capsuleIn the clinical research for treating outpatient service moderate depressive patients patient, initial dose is daily 75 milligrams.To certain neopathy patients, adjustingBefore whole dosage increases to daily 75 milligrams, daily 37.5 milligrams may be more suitable for initial treatment 4 to 7 days.Although dosage and antidepressionThe relationship of effect fails sufficiently to inquire into, but when some patients are to daily 75 milligrams of dose inefficiencies may be increased to maximum in dosageAbout daily 225 milligrams are effectively, because reaching Css by the 4th day in most of patient's Venlafaxine and main metabolites,It if necessary can be at 4 days or more intervals, with increment up to the amplitude dosage of 75 milligrams/day.In the research of assessment curative effect,Allow to carry out the titration of drug at 2 weeks or more intervals, mean dose is about daily 140~180 milligrams.

Venlafaxine hydrochloride slow-release capsule of the present invention is used for generalized anxiety disorder.For most of patients, hydrochloric acid text is recommended to drawThe initial dose of the pungent spansule of method is daily 75 milligrams, single medication.It is wide in venlafaxine hydrochloride slow-release capsule treatment outpatient serviceIn the clinical research of general sexual anxiety disease curative effect, initial dose is that daily 75 milligrams of maximum doses are daily 225 milligrams.To certain newFall ill patient, before adjustment dosage increases to daily 75 milligrams, may be more suitable for daily 37.5 milligrams initial treatment 4 to 7 days.AlthoughFail to be unequivocally established in fixative quantifier elimination and treat the dose-effect relationship of GAD, but some patients are to daily 75 milligrams of dosageWhen invalid about daily 225 milligrams may be increased to effectively in dosage, if necessary can be at 4 days or more intervals, it can with incrementUp to the amplitude dosage of 75 milligrams/day

It is often released from VENLAFAXINE HCL in the case that piece uses spansule instead, current application VENLAFAXINE HCL is often released piece and controlledThe patients with depression for the treatment of can use daily therapeutic dose almost equivalent spansule instead, and it is daily such as to take 37.5mg VenlafaxineTwice, the spansule of 75mg can be used instead, once a day.It needs to be adjusted according to the individual instances of patient when necessary.

Venlafaxine hydrochloride slow-release capsule be used for maintenance therapy in the case where, there is no from comparative study certainly according toHow long treatment is needed according to when showing that venlafaxine hydrochloride slow-release capsule treats depression and GAD.It is generally acknowledged that pressing down in treatmentAfter the acute symptom of strongly fragrant disease is effective, drug after treatment several months or longer time are needed.In 1 research, VENLAFAXINE HCLSpansule treats 8 weeks effective patients, is randomly divided into placebo treatment group, hydrochloric acid text daraf(reciprocal of farad) identical with prior treatment dosagePungent spansule (75,150 or 225 milligrams of every morning) treatment group, confirms venlafaxine hydrochloride sustained-release in maintenance therapy 26 weeksThe long-term efficacy of capsule.According to these limited data, the dosage of venlafaxine hydrochloride slow-release capsule maintenance therapy is had no knowledge aboutWhether the effective dose of initial treatment should be equal to.The necessity and suitable agent of maintenance therapy should be periodically reappraised in treatingAmount.Venlafaxine hydrochloride slow-release capsule shows effective for the treatment of GAD patient in clinical research in 6 months by a definite date.ForThe necessity that venlafaxine hydrochloride slow-release capsule treats effective GAD patient's continuation medication should be reappraised periodically.

Deactivate venlafaxine hydrochloride slow-release capsule in the case where, venlafaxine hydrochloride slow-release capsule, other SNRIs andThe relevant symptom of SSRIs drug withdrawal has report.It should be noted that when patient is discontinued and monitor these symptoms, recommend gradually to be reduced as far as possibleRather than unexpected drug withdrawal.If the use of Venlafaxine being more than 6 weeks, it is proposed that being gradually reduced the time at least will be more than two week.IfSubtract medicine or intolerable reaction occur during being discontinued, it may be considered that restores to previous prescribed dose, later doctor can be withMedicine is subtracted with slower speed again.Often to reduce 75 milli of daily dose every 1 weeks in the clinical research of venlafaxine hydrochloride slow-release capsuleGram gradually subtract medicine, clinically can determine the time being gradually reduced according to dosage, the course for the treatment of and patient individual difference.

When using instead with monoamine oxidase inhibitors (MAOI), it can just begin to use salt after at least deactivating MAOI 14 daysSour Venlafaxine sustained-release capsule, in addition, controlling for MAOI could be started after at least deactivating venlafaxine hydrochloride slow-release capsule 7 daysIt treats.

Clinical test

Various types depression:

Completed 2 venlafaxine hydrochloride slow-release capsules and placebo can adjust the short-term clinical research of dosageIts curative effect for treating depression is had rated, object is the major depression's disease outpatient service for meeting DSM-III-R or DSM-IV diagnostic criteriaPatient.1 research in 12 weeks by a definite date uses the dosage range of venlafaxine hydrochloride slow-release capsule (to complete examination for 75~150mg/ daysThe mean dose for the person of testing is 136mg/ days), another 1 research in 8 weeks by a definite date uses the dosage range of venlafaxine hydrochloride slow-release capsuleIt is 75~225mg/ days (mean dose for completing experimenter is 177mg/ days), 2 researchs confirm venlafaxine hydrochloride sustained-releaseCapsule HAM-D total score, the HAM-D depressive emotion factor, MADRS total score, clinical global impression scale (CGI) disease severity andPlacebo is superior in terms of improvement degree；Simultaneously show venlafaxine hydrochloride slow-release capsule in HAM-D scale it is some it is specific becauseSon such as anxiety and somzatization, cognition, the improvement of sluggishness and anxiety Factor minute are substantially better than placebo.

One 4 weeks by a definite date, inpatient (meeting DSM-III-R for depression standard) is slow using VENLAFAXINE HCLRelease the clinical test for the treatment of in capsule (often releasing) (150-375mg/ days, three times per day), it was demonstrated that venlafaxine hydrochloride slow-release capsule is excellentIn placebo.The mean dose for completing the patient of test is 350mg/ days.The curative effect indifference of men and women patient.

The use venlafaxine hydrochloride slow-release capsule (75,150 or 225mg, qAM) of one opening in 8 weeks by a definite date is treatedClinical research after, will wherein treatment is effective and meets DSM-IV for the out-patient of depression standard, random pointGroup carries out follow-up study, (venlafaxine hydrochloride slow-release capsule or placebo of giving same dose).Continue in observation 26 weeksPalindromia situation.Effectively it is defined as serious item score≤3 of CGI disease in evaluation in the 56th day in open phase treatmentWith total score≤10 HAM-D-21.Be defined as in the recurrence of doubleblind phase: (1) recurrence of depression, which is defined as meeting DSMIV, examinesDisconnected standard and serious item score >=4 of CGI disease (moderate disease), the serious project of CGI disease point of (2) 2 continuous follow-upsNumber >=4, or (3) any patient is because of the final serious item score of CGI disease that a variety of causes is exited from test≥4.Compared with placebo, the recurrence rate that venlafaxine hydrochloride slow-release capsule patient is used continuously in 26 weeks is obviously low.

In another subsequent research, the venlafaxine hydrochloride sustained-release that effective patient is given same dose at random is treatedCapsule or placebo, (outpatient service depression meets DSM-III-R diagnostic criteria, and recurrence, treatment is effectively (in evaluation in the 56th dayTotal score≤12 HAM-D-21) and continue to make progress [it is defined as standard, it is total without HAM-D-21 at 56 days to 180 days (1)Divide >=20；(2) total score >=10 HAM-D-21 use hydrochloric acid text daraf(reciprocal of farad) in the random of 26 weeks originally no more than 2 follow-ups and (3)Pungent spansule (often releasing) [100-200mg/ days, two times a day] without single serious item score >=4 of CGI disease (moderate diseaseDisease)]).52 weeks observation patient's recurrences later, recurrence are defined as serious score >=4 of CGI disease.Subsequent 52 weeks after continued accessBy venlafaxine hydrochloride slow-release capsule treat patient disease recurrence rate compared with placebo, hence it is evident that it is lower.

Generalized anxiety disorder:

The clinical research packet of completed related venlafaxine hydrochloride slow-release capsule treatment generalized anxiety disorder (GAD) curative effectInclude: 28 weeks by a definite date, placebo, fixative quantifier elimination, 16 months by a definite date placebo, fixed dosage are groundStudy carefully with 16 months by a definite date, for meet DSM-IV GAD diagnostic criteria adult out-patient placebo variable doseResearch.

1 assessment venlafaxine hydrochloride slow-release capsule 75,150 of research in 8 weeks by a definite date and 225mg/ days dosage and comfortsAgent to the curative effect of GAD, find 225mg/ days venlafaxine hydrochloride slow-release capsule HAM-A scale total score, HAM-A anxiety andThe improvement of stress factor score value and CGI score value is substantially better than placebo, at the same 75 and 150mg/ days VENLAFAXINE HCLs it is slowThe curative effect of capsule is released also superior to placebo, only the curative effect of smaller dose drug continuous and effective not as good as high dose medicament.2ndResearch in 8 weeks by a definite date assess venlafaxine hydrochloride slow-release capsule 75,150mg/ days dosage and placebo to the curative effect of GAD,The curative effect of the venlafaxine hydrochloride slow-release capsule of 2 kinds of dosage is superior to placebo as the result is shown, however, using 75mg/ days drugsThe patient for the treatment of, curative effect are better than 150mg/ days patients.When treating GAD patient, in 75~225mg/ days dosage ranges,Correlation between its curative effect and dosage cannot still establish.

In 2 researchs in 6 months by a definite date, wherein 1 37.5,75 and 150mg/ of assessment venlafaxine hydrochloride slow-release capsuleIt, the another 1 assessment venlafaxine hydrochloride slow-release capsule 75~225mg/ days curative effects for GAD, discovery was with 75mg/ days or was higher thanAfter treatment in 75mg/ days 6 months, the improvement of HAM-A scale total score, HAM-A anxiety and stress factor score value and CGI score value is obviousBetter than placebo.The curative effect of 37.5mg/ days drugs is also prompted to be better than placebo on evidence simultaneously, but the curative effect of this dosage is not as good as heightThe such continuous and effective of dose drug.The curative effect of different sexes patient is analyzed, the difference in any curative effect is found no.

Pharmacological toxicology

Pharmacological action: non-clinical study shows, Venlafaxine and its active metabolite O-DMV be 5-HT,The potent inhibitor of NE reuptake is the weak inhibitor of dopamine.In vitro test does not find Venlafaxine and O- demethyl text daraf(reciprocal of farad)It is pungent to have apparent affinity to M choline receptor, H1 histamine receptor, alpha 1 adrenergic receptor.Venlafaxine and O- demethyl textThe pungent no MAO inhibitory activity of daraf(reciprocal of farad).

In terms of toxicological study, genetoxic: Venlafaxine and O-DMV Salmonella reversion test, CHO/HGPRT are fedNewborn zooblast forward direction gene mutation test result is feminine gender.The conversion test of Venlafaxine BALB/c-3T3 mouse cell, CHOCell sister chromosome exchange test, rat micronucleus test result are feminine gender.O-DMV CHO chromosome aberrationTest result is feminine gender, and rat micronucleus test result is the positive.Genotoxicity: calculating (the same below) by mg/m2, male rat warpWhen mouth dosage reaches 2 times of maximum recommended people dosage (MRHD), the influence to fertility is had no.Rat and family's rabbit pregnancy andOral administration during lactation when dosage is respectively 2.5 and 4 times of maximum recommended day for human beings dosage, has no deformity, but visible ratYoung baby's weight loss, the death rate increase, 5 days dead young baby's numbers increase before lactation.Animal dead reason is unknown, dead to young babyNo-effect level is 0.25 times of maximum recommended day for human beings dosage.In addition, at one in male and female sd inbred rats orally administrationO-desmethylvenlafaxine succinate 30,100,300mg/kg, it is seen that when oestrous cycle disorder and mating occurs in each dosage groupBetween extend；The visible fertility of middle and high dosage group reduces, and the death rate increases before high dose group implantation, fetus weight loss.100mg/The exposed amount of O-DMV is about Venlafaxine people's agent when kg dosage (4.5 times that are equivalent to Venlafaxine MRHD)2-3 times at amount 225mg/ days.Carcinogenicity: mouse oral gives venlafaxine dosages and is up to 120mg/kg/ days (most adult pushes away1.7 times for recommending dosage) it is 18 months continuous, rat oral gives venlafaxine dosages and is up to 120mg/kg/ days 24 months continuous (heros1 times and 6 times of people's blood concentration when property rat and female rats Venlafaxine blood concentration are respectively maximum recommended people's dosage,But O-DMV level is lower than human body) it is 24 months continuous, have no that Tumor incidence increases.

Pharmacokinetics

By multiple oral medication, Venlafaxine and ODV reached steady state plasma concentration in 3 days.At 75~450mg/ daysDosage range in Venlafaxine and ODV belong to linear pharmacokinetic model, mean steady state plasma clearance rate is respectively 1.3 ± 0.6 Hes0.4 ± 0.2L/h/kg, apparent to remove half-life period be respectively 5 ± 2 and 11 ± 2h, and apparent (stable state) distribution volume is respectively 7.5 ±3.7 and 5.7 ± 1.8L/kg.Venlafaxine and ODV are smaller with the Percentage bound of plasma protein under therapeutic plasma concentrations, respectively27% and 30%.Absorb: Venlafaxine is easy to absorb, and mainly in liver intracellular metabolite, ODV is its main active metabolite.After single oral Venlafaxine, at least 92% is absorbed.The absolute bioavailability of Venlafaxine is about 45%.Take hydrochloric acidVenlafaxine sustained-release capsule (150mg, q24h) usually has lower Cmax, and (Venlafaxine and ODV are respectively 150ng/mLAnd 260ng/mL), slower peak time (Venlafaxine be respectively 5.5h and 9h with ODV).When the Venlafaxine taken dailyWhen dosage is identical, the fluctuation for taking the blood concentration of the patient of venlafaxine hydrochloride slow-release capsule is significant lower.Therefore hydrochloric acid textThe absorption compared with often releasing piece of the pungent spansule of daraf(reciprocal of farad) is slower, but the drug total amount absorbed is identical.It is drawn using the hydrochloric acid text of 75mgDiscovery food does not influence the bioavilability of Venlafaxine and its active metabolite ODV when method pungent spansule, takes medicineThe difference of time (morning or afternoon) nor affects on Venlafaxine and the drug metabolism of ODV.Metabolism and excretion: Venlafaxine absorbsFirst-pass metabolism is carried out in liver afterwards, main metabolites ODV, while including N- Demethyl Venlafaxine, N, O- removes dimethylVenlafaxine and other a small amount of metabolites.In vitro study shows that ODV is generated by the metabolism of CYP2D6 enzyme, and clinic is groundStudy carefully the patient for also confirming that CYP2D6 activity low (slow metabolism) text daraf(reciprocal of farad) with higher compared with normal CYP2D6 activity personPungent and lower ODV drug concentration.Because the total amount of Venlafaxine and ODV connect in 2 groups of different patients of CYP2D6 activityClosely, and ODV and Venlafaxine have similar pharmacological action and an action intensity, thus the difference of this metabolic capability have no it is importantClinical meaning.

After taking Venlafaxine 48 hours there are about 87% drug through urine excretes, including 5% prototype medicine,The ODV and 27% that 29% uncombined ODV, 26% combine inactive metabolite.Thus, Venlafaxine and its metaboliteMainly pass through kidney excretion.

The venlafaxine hydrochloride sustained-release pellet composition and spansule that the method for the present invention is prepared have excellent systemAgent performance

Specific embodiment

The present invention can be further described by the following examples, however, the scope of the present invention and unlimitedIn following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present inventionVarious change and modification are carried out to the present invention.The present invention carries out the material and test method arrived used in test generalAnd/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art thatBut the present invention is still described in this detail as much as possible.

Hereafter preparation step in order to citing purpose, and the comparability based on each citing and make some specific description,Those skilled in the art can therefrom summarize to obtain the method that the present invention prepares composition according to existing knowledge completely.System belowIn the standby various compositions of the present invention, if not otherwise indicated, the preparation amount of every batch of is 5kg inventory.But list formula and preparationWhen process, for pellet, formula and system are illustrated with every forming for Venlafaxine 75mg (being equivalent to VENLAFAXINE HCL 84.86mg)Method fills the amount of Venlafaxine 75m or 150mg when practical encapsulated in every capsule.If not otherwise specified, when preparation, respectivelyMaterial crushes in advance before preparation and crosses 120 meshes.If not otherwise specified, the VENLAFAXINE HCL bulk pharmaceutical chemicals used when preparation areWith a batch.

Cane sugar type medicinal fine pellet core used in the present invention is commercial preparation intermediate commodity, meets the Shanghai City drug standardsShanghai Q/WS-1-2274-2001；Utech NE30D used in the present invention is commercially available auxiliary material commodity, meets import drugs registered standardJX20020019。

One, the embodiment part of pellet and capsule is prepared

Embodiment 1: venlafaxine hydrochloride sustained-release pellet and spansule are prepared

Formula:

Preparation method:

(1) blank capsule core is provided, (temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) package carries medicine clothing layer: being dissolved in described adhesive in first solvent, addition is crushed to and can pass through in advanceThe VENLAFAXINE HCL of 150 meshes is uniformly mixed to obtain suspension, is sprayed on the suspension in fluidized-bed coating machine in fluidisation by atomizationContinuing to be fluidised in the blank capsule core of state, after spraying is removed solvent, obtains drug-loaded pellets；[through detecting, first is moltenAgent residual volume is less than 500ppm, general far below this field to require limit]

(3) bundled slow-releasing clothing layer: the Sustained release coating materials and antiplastering aid are dispersed in the second solvent, pass through mistChanging is sprayed on the suspension in fluidized-bed coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to make solventIt is removed, obtains slow-release pill；[through detecting, the water content of gained slow-release pill is lower than the general requirement in this field less than 1%Limit]

(4) it aging: mixes slow-release pill obtained by previous step with 0.35% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.[wherein to the measurement of gained sustained release pelletThe content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

(5) sustained release pellet obtained by previous step is loaded into gelatin hollow capsule, the pellet amount phase of every capsule fillingWhen obtaining venlafaxine hydrochloride slow-release capsule in Venlafaxine containing 75mg or 150mg Venlafaxine.

Embodiment 2: venlafaxine hydrochloride sustained-release pellet and spansule are prepared

Formula:

Preparation method:

(1) blank capsule core is provided, (temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) package carries medicine clothing layer: being dissolved in described adhesive in first solvent, addition is crushed to and can pass through in advanceThe VENLAFAXINE HCL of 150 meshes is uniformly mixed to obtain suspension, is sprayed on the suspension in fluidized-bed coating machine in fluidisation by atomizationContinuing to be fluidised in the blank capsule core of state, after spraying is removed solvent, obtains drug-loaded pellets；[through detecting, first is moltenAgent residual volume is less than 500ppm, general far below this field to require limit]

(3) bundled slow-releasing clothing layer: the Sustained release coating materials and antiplastering aid are dispersed in the second solvent, pass through mistChanging is sprayed on the suspension in fluidized-bed coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to make solventIt is removed, obtains slow-release pill；[through detecting, the water content of gained slow-release pill is lower than the general requirement in this field less than 1%Limit]

(4) it aging: mixes slow-release pill obtained by previous step with 0.2% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.[wherein to the measurement of gained sustained release pelletThe content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

(5) sustained release pellet obtained by previous step is loaded into gelatin hollow capsule, the pellet amount phase of every capsule fillingWhen obtaining venlafaxine hydrochloride slow-release capsule in Venlafaxine containing 75mg or 150mg Venlafaxine.

Embodiment 3: venlafaxine hydrochloride sustained-release pellet and spansule are prepared

Formula:

Preparation method:

(1) blank capsule core is provided, (temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) package carries medicine clothing layer: being dissolved in described adhesive in first solvent, addition is crushed to and can pass through in advanceThe VENLAFAXINE HCL of 150 meshes is uniformly mixed to obtain suspension, is sprayed on the suspension in fluidized-bed coating machine in fluidisation by atomizationContinuing to be fluidised in the blank capsule core of state, after spraying is removed solvent, obtains drug-loaded pellets；[through detecting, first is moltenAgent residual volume is less than 500ppm, general far below this field to require limit]

(3) bundled slow-releasing clothing layer: the Sustained release coating materials and antiplastering aid are dispersed in the second solvent, pass through mistChanging is sprayed on the suspension in fluidized-bed coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to make solventIt is removed, obtains slow-release pill；[through detecting, the water content of gained slow-release pill is lower than the general requirement in this field less than 1%Limit]

(4) it aging: mixes slow-release pill obtained by previous step with 0.5% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.[wherein to the measurement of gained sustained release pelletThe content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

(5) sustained release pellet obtained by previous step is loaded into gelatin hollow capsule, the pellet amount phase of every capsule fillingWhen obtaining venlafaxine hydrochloride slow-release capsule in Venlafaxine containing 75mg or 150mg Venlafaxine.

Embodiment 4: venlafaxine hydrochloride sustained-release pellet and spansule are prepared

Formula:

Preparation method:

(1) blank capsule core is provided, (temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) package carries medicine clothing layer: being dissolved in described adhesive in first solvent, addition is crushed to and can pass through in advanceThe VENLAFAXINE HCL of 150 meshes is uniformly mixed to obtain suspension, is sprayed on the suspension in fluidized-bed coating machine in fluidisation by atomizationContinuing to be fluidised in the blank capsule core of state, after spraying is removed solvent, obtains drug-loaded pellets；[through detecting, first is moltenAgent residual volume is less than 500ppm, general far below this field to require limit]

(3) bundled slow-releasing clothing layer: the Sustained release coating materials and antiplastering aid are dispersed in the second solvent, pass through mistChanging is sprayed on the suspension in fluidized-bed coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to make solventIt is removed, obtains slow-release pill；[through detecting, the water content of gained slow-release pill is lower than the general requirement in this field less than 1%Limit]

(4) it aging: mixes slow-release pill obtained by previous step with 0.4% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.[wherein to the measurement of gained sustained release pelletThe content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

(5) sustained release pellet obtained by previous step is loaded into gelatin hollow capsule, the pellet amount phase of every capsule fillingWhen obtaining venlafaxine hydrochloride slow-release capsule in Venlafaxine containing 75mg or 150mg Venlafaxine.

Embodiment 5: venlafaxine hydrochloride sustained-release pellet and spansule are prepared

Formula:

Blank capsule core:	Composition	Dosage (in mg ratio)
				Medicinal fine pellet core	39
Carry medicine clothing layer:
				VENLAFAXINE HCL	84.86
	Ethyl cellulose	9
				Hydroxypropyl cellulose	5
	First solvent (isopropanol)	In right amount, until solid concentration is 28% (being finally removed)
			Sustained-release coating layer:
	Utech NE30D	7
				Talcum powder	1.5
	Second solvent (purified water)	In right amount, until solid concentration is 28% (being finally removed)

Preparation method:

(1) blank capsule core is provided, (temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) package carries medicine clothing layer: being dissolved in described adhesive in first solvent, addition is crushed to and can pass through in advanceThe VENLAFAXINE HCL of 150 meshes is uniformly mixed to obtain suspension, is sprayed on the suspension in fluidized-bed coating machine in fluidisation by atomizationContinuing to be fluidised in the blank capsule core of state, after spraying is removed solvent, obtains drug-loaded pellets；[through detecting, first is moltenAgent residual volume is less than 500ppm, general far below this field to require limit]

(3) bundled slow-releasing clothing layer: the Sustained release coating materials and antiplastering aid are dispersed in the second solvent, pass through mistChanging is sprayed on the suspension in fluidized-bed coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to make solventIt is removed, obtains slow-release pill；[through detecting, the water content of gained slow-release pill is lower than the general requirement in this field less than 1%Limit]

(4) it aging: mixes slow-release pill obtained by previous step with 0.25% talcum powder, is subsequently placed into heated-air circulation ovenIn aging 24 hours under the conditions of 52 DEG C ± 4 DEG C, screen out talcum powder, obtain sustained release pellet.[wherein to the measurement of gained sustained release pelletThe content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

(5) sustained release pellet obtained by previous step is loaded into gelatin hollow capsule, the pellet amount phase of every capsule fillingWhen obtaining venlafaxine hydrochloride slow-release capsule in Venlafaxine containing 75mg or 150mg Venlafaxine.

Embodiment 6: venlafaxine hydrochloride sustained-release pellet and spansule are prepared

The method for respectively referring to Examples 1 to 5, different is only that step (2) is changed to operate as follows:

(2) package carries medicine clothing layer: it is dissolved in ethyl cellulose and 4/5 amount hydroxypropyl cellulose in first solvent,It is added and is crushed to can be uniformly mixed to obtain suspension by the VENLAFAXINE HCL of 150 meshes in advance；In addition 1/5 amount hydroxypropyl is fineDimension element is dissolved in first solvent, and solid concentration is identical as upper suspension concentration, obtains solution；Successively made by atomizationAbove-mentioned suspension and solution are sprayed in fluidized-bed coating machine in the blank capsule core of fluidized state, continue to be fluidised to after spraying to makeSolvent is removed, and obtains 5 batches of drug-loaded pellets.

Embodiment 7: the method for respectively referring to Examples 1 to 5, different is only to replace hydroxypropyl cellulose thereinFor equivalent hydroxypropyl methyl cellulose, 5 batches of sustained release pellets and spansule are obtained.

Embodiment 8: the method for respectively referring to Examples 1 to 5, different is only to replace with ethyl cellulose thereinEquivalent methylcellulose obtains 5 batches of sustained release pellets and spansule.

Embodiment 9: the method for respectively referring to Examples 1 to 5, different is only to use the first solvent therein instead equivalentEthyl alcohol obtains 5 batches of sustained release pellets and spansule.

Two, the test example of preparation Performance

Test example 1: pellet granularity

It is average diameter is 0.35~0.45mm that the present invention, which respectively tests blank capsule core granularity used,.Most by each embodiment gained14 mesh standard sieves of sustained release pellet at end, 16 mesh standard sieves, 25 standard screens, the sieving of 30 target quasi-s.As a result: the sustained release of whole batchesPellet can pass through 16 mesh standard sieves by 14 mesh standard sieves, the sustained release pellet of whole batches, and the sustained release of whole batches is micro-Ball cannot be by 30 mesh standard sieves, and 98% or more sustained release pellet of whole batches cannot be by 25 mesh standard sieves, such as implementThe whole of the whole batches of example 1~6, which delays sustained release pellet, can pass through 16 mesh standard sieves but cannot pass through 30 mesh standard sieves.Supplement10 sample of embodiment: sustained release pellet is prepared referring to the method for CN103054835B its [0056]~[0067] i.e. embodiment 1With spansule (75mg/), used in blank capsule core use blank capsule core of the invention.

Test example 2: dissolution determination

(75mg in terms of Venlafaxine) and import are thought to each batch venlafaxine hydrochloride slow-release capsule obtained by the present inventionComparison medicine venlafaxine hydrochloride slow-release capsule Efexor XR (75mg, national drug standard J20160078 in terms of Venlafaxine) is tested.

[dissolution method]:

It is carried out according to Chinese Pharmacopoeia 2015 version four " 0931 dissolution rate and drug release determination method " specifications, with every part of test specimensProduct include that the amount of active medicine Venlafaxine is that (50~250mg of the Venlafaxine is also referred to as herein for 50~250mg measurementTest volume, such as when sample is piller, takes the piller for being equivalent to 50~250mg amount containing Venlafaxine to be placed in dissolution test and turn indigo plantIn be measured；When test sample is capsule of the piller in hard capsule case, the amount phase of the piller in every capsuleWhen in 50~250mg containing Venlafaxine)；

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

Sample time: with i be 1~5 integer representation 5 point in time sampling, respectively be 2h, 4h, 8h, 12h,24h；

Buffer: 10mL/L triethylamine aqueous solution simultaneously adjusts pH=3.0 with phosphoric acid；

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

Standard solution: take VENLAFAXINE HCL reference substance that standard solution is made with dissolution medium dissolution in right amount, in the standardIn solution, Venlafaxine concentration is suitable with each stripping rotor Venlafaxine theoretical concentration of Dissolution Rate Testing；

Sample solution: testing liquid centrifugation；

Liquid chromatographic system: ultraviolet 226nm detector, 4.6mm × 15cm-5 μm of specification of C18 column, flow velocity 2.5mL/min,20 μ L of sample volume, record time are 1.5 times of Venlafaxine retention time；

System suitability: being tested with standard solution, and tailing factor is no more than 2.0, and relative standard deviation is no more than 2.0%；

Measurement:

Sample be standard solution and sample solution,

The calculating of medium Venlafaxine (C17H27NO2) concentration C i (mg/mL) after time point i:

As a result i=(rU/rS) × CS × (Mr1/Mr2)

In formula, the peak response value of rU=sample solution, the peak response value of rS=standard solution, hydrochloric acid in CS=standard solutionThe concentration (mg/mL) of Venlafaxine reference substance, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight313.86

The percentage of Venlafaxine (C17H27NO2) labelled amount of each time point i dissolution is calculated as follows

As a result 1=C1 × V × (1/L) × 100

As a result 2={ [C2 × (V-VS)]+[C1 × VS] } × (1/L) × 100

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

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

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

In above formula, Ci=time point i samples Venlafaxine concentration (mg/mL), V=dissolution medium volume in solutionThe volume (mL) of the sample solution that 900mL, VS=are drawn from dissolution medium, L=concentration determination labelled amount are (that is, dissolution rate triesTest each stripping rotor Venlafaxine theoretical addition amount, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsuleVenlafaxine labelled amount in agent, mg).

Measurement result:

(1) glutoid Capsules are packed into for the whole samples of Examples 1 to 9 with above-mentioned [dissolution method]Or be directly measured with sustained release pellet, the two there are no the difference of dissolution rate, show that glutoid Capsules are micro- to being sustainedThe dissolving out capability of ball is without influence, when dissolution rate carries out, capsule shells i.e. all dissolutions in 3 minutes.

(2) whole samples of Examples 1 to 9 are loaded with glutoid Capsules with above-mentioned [dissolution method]75mg, 150mg, 300mg Venlafaxine are tested, and how much discovery capsule loadings do not influence dissolving out capability, same sample threeDissolution curve is consistent under kind loadings.

(3) with above-mentioned [dissolution method], the general requirement of dissolution determination result is: 2h the amount of dissolution is no more than30%, 4h the amount of dissolution 40%~60%, 8h the amount of dissolution 60%~80%, 12h the amount of dissolution 70%~90%, the amount of dissolution is not low for 24 hoursIn 85%, after measured:

Efexor XR: 2h the amount of dissolution 11~14%, 4h the amount of dissolution 48~51%, 8h the amount of dissolution 67~69%, 12h the amount of dissolution79%~82%, the amount of dissolution 94~96% for 24 hours；

Examples 1 to 6 whole samples: 2h the amount of dissolution 9~16%, 4h the amount of dissolution 47-53%, 8h the amount of dissolution 65~71%,12h the amount of dissolution 77% -84%, for 24 hours the amount of dissolution 91~97%；It calculates and dissolves out release profiles between each embodiment sample and Efexor XRBetween similarity f2 (typically f2 is greater than and 70% is acceptable, and is preferred greater than 80%), acetonideexample 1~5For the f2 of whole samples between 89~93%, the f2 of 6 whole samples of embodiment shows embodiment 1 between 92~94%~6 whole samples and former grind have excellent dissolution release profiles consistency between commercial product.

7~9 whole samples of embodiment: 2h the amount of dissolution 26~37%, 4h the amount of dissolution 56-74%, 8h the amount of dissolution 84~90%,12h the amount of dissolution is all larger than 95%, and the amount of dissolution is all larger than 95% for 24 hours；It calculates and dissolves out release between each embodiment sample and Efexor XRSimilarity f2 between curve, the f2 of 7~9 whole samples of acetonideexample between 31~38%, show these samples withOriginal grind the dissolution release profiles between commercial product significantly will not property, it is unacceptable.10 sample of embodiment: 2h the amount of dissolution 24%,4h the amount of dissolution 55%, 8h the amount of dissolution 78%, 12h the amount of dissolution are all larger than 89%, for 24 hours the amount of dissolution 97%, f2 76%, grind production with originalThe dissolution release profiles similitude of product can substantially receive.

Dissolution rate stability test: Examples 1 to 6 and the whole capsules of 10 gained of embodiment and Efexor XR is made to be placed in 40At a temperature of DEG C sealing place 6 months, measure June when each batch of tablet dissolution release profiles, for every batch of sample, make its result withData at same sample 0 month are compared its similarity f2, as a result: the f2 of Efexor XR is 99.6%, and the f2 of embodiment 10 is79.6%, the f2 of embodiment 1 is 88.3%, and the f2 of embodiment 2~5 is 86~90%, and embodiment 6 is referring to 1 gained glue of embodimentThe f2 of capsule is 99.1%, and embodiment 6 is 98.4~99.8% referring to the f2 of 2~5 gained capsule of embodiment.This shows the present inventionExcellent dissolution stability is presented in some Duracaps of preparation.

Spirit of the invention is elaborated above by present pre-ferred embodiments.Those skilled in the art's reasonSolution, all any modification, equivalent variations and modification to the above embodiments according to the technical essence of the invention, all falls within this hairIn bright protection scope.

Claims (10)

1. measuring venlafaxine hydrochloride sustained-release pellet or venlafaxine hydrochloride slow-release capsule dissolution rate described in claim 2-9Method, including operate as follows:

It is carried out according to Chinese Pharmacopoeia 2015 version four " 0931 dissolution rate and drug release determination method " specifications, with every part of test sample packetThe amount of the Venlafaxine containing active medicine is that (50~250mg of the Venlafaxine is also referred to as tested herein for 50~250mg measurementAmount, such as when sample is piller, takes the piller for being equivalent to 50~250mg amount containing Venlafaxine to be placed in dissolution test and turn Lan ZhongjinRow measurement；When test sample is capsule of the piller in hard capsule case, the amount of the piller in every capsule is equivalent toContaining 50~250mg of Venlafaxine)；

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

Sample time: taking i as 5 point in time sampling of 1~5 integer representation, respectively be 2h, 4h, 8h, 12h, for 24 hours；

Buffer: 10mL/L triethylamine aqueous solution simultaneously adjusts pH=3.0 with phosphoric acid；

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

Standard solution: take VENLAFAXINE HCL reference substance that standard solution is made with dissolution medium dissolution in right amount, in the standard solutionIn, Venlafaxine concentration is suitable with each stripping rotor Venlafaxine theoretical concentration of Dissolution Rate Testing；

Sample solution: testing liquid centrifugation；

Liquid chromatographic system: ultraviolet 226nm detector, 4.6mm × 15cm-5 μm of specification of C18 column, flow velocity 2.5mL/min, sample introduction20 μ L are measured, the record time is 1.5 times of Venlafaxine retention time；

System suitability: being tested with standard solution, and tailing factor is no more than 2.0, and relative standard deviation is no more than 2.0%；

Measurement:

Sample be standard solution and sample solution,

The calculating of medium Venlafaxine (C17H27NO2) concentration C i (mg/mL) after time point i:

As a result i=(rU/rS) × CS × (Mr1/Mr2)

In formula, the peak response value of rU=sample solution, the peak response value of rS=standard solution, hydrochloric acid text is drawn in CS=standard solutionThe concentration (mg/mL) of the pungent reference substance of method, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight313.86

The percentage of Venlafaxine (C17H27NO2) labelled amount of each time point i dissolution is calculated as follows

As a result 1=C1 × V × (1/L) × 100

As a result 2={ [C2 × (V-VS)]+[C1 × VS] } × (1/L) × 100

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

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

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

In above formula, Ci=time point i samples Venlafaxine concentration (mg/mL), V=dissolution medium volume 900mL, VS in solutionThe volume (mL) of=sample solution drawn from dissolution medium, L=concentration determination labelled amount are (that is, Dissolution Rate Testing is each moltenCup Venlafaxine theoretical addition amount out, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsule Nei WenlaThe pungent labelled amount of method, mg).

2. a kind of venlafaxine hydrochloride sustained-release pellet comprising blank capsule core, the load medicine clothing coated in the blank capsule core outer surfaceLayer, the sustained-release coating layer coated in the load medicine clothing layer outer surface include active ingredient hydrochloric acid Venlafaxine in the loads medicine clothing layer.

3. venlafaxine hydrochloride sustained-release pellet according to claim 2, wherein it is micro- to account for the sustained release for active ingredient hydrochloric acid VenlafaxineThe 50~65% of ball weight, such as 52~62%, such as 53~61%.

4. venlafaxine hydrochloride sustained-release pellet according to claim 2,

It can pass through 14 meshes but cannot pass through 30 meshes；

It can pass through 16 meshes but cannot pass through 25 meshes；

It is no more than 30%, 4h the amount of dissolution 40% -60%, 8h the amount of dissolution according to [dissolution method] measurement herein, 2h the amount of dissolution60% -80%, 12h the amount of dissolution 70% -90%, the amount of dissolution is not less than 85% for 24 hours.

5. venlafaxine hydrochloride sustained-release pellet according to claim 2, wherein

The blank capsule core is being selected from blank capsule core made of following substrate: sucrose, starch, microcrystalline cellulose and combinations thereof；

The blank capsule core is the blank capsule core made of sucrose；

The average diameter of the blank capsule core is 0.3~0.6mm, preferably 0.35~0.5mm, preferably 0.35~0.45mm；

In terms of every 84.86 parts by weight VENLAFAXINE HCL, the amount of the blank capsule core is 35~45 parts by weight, such as 38~44 weightsMeasure part, such as 39~42 parts by weight；

It further include selected from following adhesive: ethyl cellulose, Methyl cellulose in the load medicine clothing layer other than active constituentElement, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and its group；

It further include selected from following adhesive in the load medicine clothing layer: ethyl cellulose, hydroxypropyl cellulose and combinations thereof；

It further include following adhesive in the load medicine clothing layer: ethyl cellulose, hydroxypropyl cellulose；

In terms of every 84.86 parts by weight VENLAFAXINE HCL, the amount of described adhesive is 10~15 parts by weight, such as 11~14 weightPart, such as 12~13 parts by weight；

Further include following adhesive in the load medicine clothing layer: ethyl cellulose, hydroxypropyl cellulose, with every 84.86 parts by weightVENLAFAXINE HCL meter, the amount of the ethyl cellulose are 5~10 parts by weight, such as 6~9 parts by weight, such as 7~9 parts by weight；

Further include following adhesive in the load medicine clothing layer: ethyl cellulose, hydroxypropyl cellulose, with every 84.86 parts by weightVENLAFAXINE HCL meter, the amount of the hydroxypropyl cellulose are 3~7 parts by weight, such as 4~6 parts by weight, such as 4~5 weightPart；

Sustained release coating materials in the sustained-release coating layer are selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer exampleSuch as mixture of Utech NE30D, ethyl cellulose, ethyl cellulose and hypromellose；Preferred sustained release packetClothing material is ethyl acrylate and methyl methacrylate (2:1) copolymer such as Utech NE30D；

In terms of every 84.86 parts by weight VENLAFAXINE HCL, the amounts of the Sustained release coating materials is 5~15 parts by weight, such as 6~12Parts by weight, such as 7~10 parts by weight；

It further include the antiplastering aid for preventing Sustained release coating materials from bonding in coating process in the sustained-release coating layer；

Antiplastering aid in the sustained-release coating layer is selected from: talcum powder, colloidal silicon dioxide, magnesium trisilicate etc., and preferred antiplastering aid isTalcum powder；

In terms of every 84.86 parts by weight VENLAFAXINE HCL, the amount of the antiplastering aid is 1~5 parts by weight, such as 1~3 parts by weight,Such as 1~2 parts by weight.

6. venlafaxine hydrochloride sustained-release pellet according to claim 2, wherein

The load medicine clothing layer is to be coated in the blank capsule core outer surface in the following way: active constituent and adhesive is moltenSolve and/or be suspended in the first solvent, then be sprayed at the blank pellet surface, then make coating piller dry with remove thisOne solvent；

First solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred first solvent is isopropanol；

The amount of first solvent is that solid content weight in gained suspension is made to account for 20~40%, such as 25~35%, such as 28~32%；

The sustained-release coating layer is to be coated in the load medicine clothing layer outer surface in the following way: by Sustained release coating materials and anti-stickAgent dispersion is suspended in the second solvent, then is sprayed at the load medicine clothing layer outer surface, then makes coating piller dry to remove thisSecond solvent；

Second solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred second solvent is water；

The amount of second solvent is that solid content weight in gained suspension is made to account for 20~35%, such as 25~30%, such as 25~28%.

7. venlafaxine hydrochloride sustained-release pellet according to claim 2, wherein

It is in fluidized bed coating equipment to blank pellet surface spraying load medicine clothing layer and to medicine clothing layer trypsin method sustained-release coating layer is carriedMiddle progress；

It is prepared according to the method included the following steps:

(1) blank capsule core is provided, (such as temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) it is dissolved in described adhesive in first solvent, addition is crushed to and can draw by the hydrochloric acid text of 150 meshes in advanceMethod is pungent, be uniformly mixed to obtain suspension, by be atomized make the suspension be sprayed in fluidized-bed coating machine in fluidized state blank capsule core on,Continue to be fluidised to after spraying to be removed solvent, obtains drug-loaded pellets；

(3) Sustained release coating materials and antiplastering aid are dispersed in the second solvent, so that the suspension is sprayed on stream by atomizationChange in bed seed-coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to be removed solvent, be sustainedPiller；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation ovenAging 24 hours under the conditions of 52 DEG C ± 4 DEG C, talcum powder is screened out, sustained release pellet is obtained.

8. a kind of venlafaxine hydrochloride slow-release capsule comprising gelatin hollow capsule and be hermetically encapsulated in the gelatin hollow capsuleInterior venlafaxine hydrochloride sustained-release pellet, the venlafaxine hydrochloride sustained-release pellet is as described in claim any one of 2-7.

9. the method for preparing any one of the claim 2-7 venlafaxine hydrochloride sustained-release pellet, includes the following steps:

(1) blank capsule core is provided, (such as temperature is 42~45 degrees Celsius) is set in fluidized-bed coating machine and is at fluidized state；

(2) it is dissolved in described adhesive in first solvent, addition is crushed to and can draw by the hydrochloric acid text of 150 meshes in advanceMethod is pungent, be uniformly mixed to obtain suspension, by be atomized make the suspension be sprayed in fluidized-bed coating machine in fluidized state blank capsule core on,Continue to be fluidised to after spraying to be removed solvent, obtains drug-loaded pellets；

(3) Sustained release coating materials and antiplastering aid are dispersed in the second solvent, so that the suspension is sprayed on stream by atomizationChange in bed seed-coating machine on the drug-loaded pellets of fluidized state, continues to be fluidised to after spraying to be removed solvent, be sustainedPiller；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation ovenAging 24 hours under the conditions of 52 DEG C ± 4 DEG C, talcum powder is screened out, sustained release pellet is obtained；Then the sustained release pellet is filled into gelatinCapsules, it is hermetically sealed, obtain spansule；Optional, it still further comprises the venlafaxine hydrochloride sustained-release is micro-The step of ball is filled into gelatin hollow capsule, hermetically sealed, obtains spansule.

10. VENLAFAXINE HCL described in any one of the claim 2-7 venlafaxine hydrochloride sustained-release pellet or claim 8Spansule is in preparation for treating or preventing depression, generalized anxiety disorder, the recurrence prevention of paralepsy, Social Anxiety barrierHinder, the purposes in the drug of panic disorder.