CN109200032A

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

Info

Publication number: CN109200032A
Application number: CN201811271188.8A
Authority: CN
Inventors: 侯奇伟; 李晓云; 后旻旸
Original assignee: Hunan Dongting Pharmaceutical Co Ltd
Current assignee: Hunan Dongting Pharmaceutical Co Ltd
Priority date: 2018-10-29
Filing date: 2018-10-29
Publication date: 2019-01-15
Anticipated expiration: 2038-10-29
Also published as: CN109200032B

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, paralepsy Recur the Venlafaxine combination of oral medication of prevention, social anxiety disorder, panic disorder etc., especially venlafaxine sustained-release glue Capsule 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 and Noradrenaline reuptake inhibitor, SNRI) class antidepressant.Zoopery finds that the medical instrument has antidepression Effect, while not having obvious affinity to muscarinic or histamine sample receptor.Therefore, Venlafaxine is in the same of antidepressant effect When, 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 down Strongly fragrant obstacle, depressive disorder, generalized anxiety disorder and the treatment of social anxiety disorder with anxiety symptom.Over 2001, China State food pharmaceuticals administration general bureau also has approved the idicatio of depression, generalized anxiety disorder in succession, until 2012 7 Month, which is unique novel antidepressant that Discussion on Chinese Listed has generalized anxiety disorder idicatio.Venlafaxine becomes plus takes Greatly, 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 and The reuptake of norepinephrine (NE) transporter acts on, and to be higher by nearly 8 times to the affinity ratio NE of 5-HT.Venlafaxine exists When 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/d NE and 5-HT has dual monoamine-reuptake inhibiting effect.In rodent depression original mold type research, Venlafaxine is played Quick beta receptor desensitization out needs repeat administration that could stimulate the hyposensitivity of NE rather than other antidepressants.Text The 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 seam Border 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 with Low or nothing.The NE neuronal synapse terminal and cell space-dendron autoreceptor of 5-HT neuron to dorsal raphe nucleus and blue spot and Heterogeneous 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 excellent It 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 shadow Ring degree of absorption.After liver carries out first-pass metabolism, forming unique active metabolite is ODV.It takes after general formulation in 2h Reach the blood peak concentration of drug of Venlafaxine, 3h reaches the Cmax of ODV.The absorptance general formulation of Effexor ER type is slow Slowly, 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 avoid The peak and low valley defect of general formulation.Two kinds of dosage forms are all comparable in terms of degree of absorption and bioavilability.Treatment It can reach steady state plasma concentration after 3-4d afterwards.Dosage range is in 75mg/d-450mg/d, Venlafaxine and its active metabolism The linear medicine of product is for feature.Venlafaxine and its metabolite are mainly through kidney excretion.Venlafaxine half-life period is 4h, ODV Remove, 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 every The 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 enzyme Based on, since Venlafaxine and its active metabolite ODV pharmacologically have equivalence, at least in treatment concentration, suppression Direct 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 to The 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 spansule Agent is taken twice for conventional tablet one day, and sustained release preparation only needs to take daily once.Have many related venlafaxine sustained-releases The document report of capsule preparation method thereof.For example, CN102772390A (Chinese Patent Application No. 201210291863X, new coach Gram) disclose a kind of venlafaxine hydrochloride slow-release capsule and preparation method thereof.The content of the spansule is sustained release pellet, is delayed It 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 acid Venlafaxine 45-48%, filler 15-18%, disintegrating agent 3-3.5%, PVP K30 4-6%, dehydrated alcohol 24-26%, it is remaining Amount is water；Separation layer is made of the ingredient of following weight percent: PVP K30 11-13%, dehydrated alcohol 83-86%, remaining Amount is talcum powder；Slow release layer is made of the ingredient of following weight percent: ethylcellulose mixed suspension liquid 38-42%, poly- second two Alcohol -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 uses Ethyl 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-release Capsule and its preparation process, using ethyl cellulose and enteric acrylate's resin compounded as adhesive, outside blank capsule core Separation 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 HCL Spansule 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 weight Composition, 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 layer Quality be drug-loaded layer quality 14~17%.The invention additionally provides the preparation side of venlafaxine hydrochloride slow-release capsule composition Method 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 invention For 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-release Capsule and preparation method thereof.The pellet core of the spansule includes VENLAFAXINE HCL, microcrystalline cellulose, gas phase titanium dioxide Silicon, Tween-80 and hypromellose, sustained release coating include polyacrylic resin, talcum powder, polyethylene glycol and dodecyl Sodium sulphate.The invention changes the flowing of material, and the selection to sustained release coating by addition fumed silica, makes the capsule Production realize pure aquatic system.The venlafaxine hydrochloride slow-release capsule drug release being prepared by the system is steady, effectively holds Continuous release time is 24 hours, is taken only once a day.It is believed that this method simple process, mild condition have without using any Solvent, 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 HCL Spansule and preparation method thereof belongs to pharmaceutical technology field.The venlafaxine hydrochloride slow-release capsule, by sustained release content with Capsule 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 drawn The 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 HCL Spansule and preparation method thereof, wherein spansule is made of slow-release pill and capsule shells.Slow-release pill is with inertia capsule core Substrate, 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 letter It 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 HCL Spansule, spansule content prepared by the present invention are sustained release pellet, and the pellet is by pellet core and sustained release clothing film group At pellet core contains VENLAFAXINE HCL, hypromellose and microcrystalline cellulose.The hydrochloric acid text daraf(reciprocal of farad) of invention preparation Pungent spansule drug release is steady, and organic solvent-free residue problem, product takes safety, and production environment is friendly.The invention also provides A kind of venlafaxine hydrochloride slow-release capsule preparation method, it is believed that this method high production efficiency, simple process, easy to operate, cost It 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 HCL Spansule and preparation method thereof belongs to pharmaceutical technology field.The venlafaxine hydrochloride slow-release capsule is by sustained release content and glue Softgel 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 invention Venlafaxine hydrochloride slow-release capsule can be sustained release 24 hours, and discharge steadily without burst release.It is also believed that described in the invention The 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 HCL Spansule and preparation method thereof.Existing method is coated using aqueous dispersion, since the height of VENLAFAXINE HCL is water-soluble Property, cause VENLAFAXINE HCL to migrate in coating, in the case where coating membrane thickness low LCL, VENLAFAXINE HCL may As 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 institute The medicated pellet stated includes the controlled release layer of separation layer and packet outside separation layer of pellet core, packet outside pellet core, described Pellet core is made of the component of following weight percentage: VENLAFAXINE HCL 30-60%, filler 30-80%, sustained-release matrix Material 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 molten Agent 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 its The 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 delay The 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 its Spansule.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, coating Load 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 layer Include 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 this The 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 invention Sustained 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 mesh Sieve.

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

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 hours The 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 behaviour Make:

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 specimens Product include that the amount of active medicine Venlafaxine is that (50~250mg of the Venlafaxine is also referred to as herein for 50~250mg measurement Test 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 plant In be measured；When test sample is capsule of the piller in hard capsule case, the amount phase of the piller in every capsule When 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 standard In 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 solution The concentration (mg/mL) of Venlafaxine reference substance, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight 313.86

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 solution The volume (mL) of the sample solution that 900mL, VS=are drawn from dissolution medium, L=concentration determination labelled amount are (that is, dissolution rate tries Test each stripping rotor Venlafaxine theoretical addition amount, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsule Venlafaxine 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 following Blank capsule core made of substrate: sucrose, starch, microcrystalline cellulose and combinations thereof.These blank capsule cores can make by oneself, can also pass through Commercially 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 sucrose Blank 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 sugarcane Blank 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 text The 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 at It exceptionally, further include selected from following adhesive: ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl fiber Element 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 layer Following 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 layer Adhesive: 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 text The 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 layer Adhesive: ethyl cellulose, hydroxypropyl cellulose, in terms of every 84.86 parts by weight VENLAFAXINE HCL, the ethyl cellulose Amount 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 layer Adhesive: ethyl cellulose, hydroxypropyl cellulose, in terms of every 84.86 parts by weight VENLAFAXINE HCL, the hydroxy propyl cellulose The 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 layer Material is selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer such as Utech NE30D, ethyl cellulose, ethyl Cellulose and the mixture of hypromellose etc.；Preferred Sustained release coating materials are ethyl acrylate and methacrylic acid Methyl 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 text The 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 release The 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 layer Prevent 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 selects From: 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 text The 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 aid Main 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 section Formula 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 sprayed It is applied to the blank pellet surface, then makes coating piller dry to remove first solvent.In one embodiment, described First 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 suspended Solid 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 section Formula 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 sprayed It is applied to the load medicine clothing layer outer surface, then makes coating piller dry to remove second solvent.In one embodiment, institute State 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 suspended Solid 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 surface Layer 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 coating When 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 steps It 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 fluidisation State；

(2) it is dissolved in described adhesive in first solvent, preparatory be crushed to is added can be by the hydrochloric acid of 150 meshes Venlafaxine 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 state Continuing 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 atomization In 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, obtain Slow-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 oven In 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 hollow Capsule 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 pellet Such as described in first embodiment of the invention；Alternatively, for example comprising blank capsule core, coated in the blank capsule core outer surface Medicine 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 text Method is pungent.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet Middle 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 pellet 14 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 pellet 16 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 hours The amount of dissolution is not less than 85%.

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

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

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；

Measurement:

Sample be standard solution and sample solution,

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

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

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet Described 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 pellet Described in blank capsule core be the blank capsule core made of sucrose.In one embodiment, the average diameter of blank capsule core is 0.35~0.45mm.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet In 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 weight Part, such as 39~42 parts by weight.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet Described 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 pellet Described 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 pellet Described 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 pellet In 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 weight Part, 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 pellet Described in load medicine clothing layer in further include following adhesive: ethyl cellulose, hydroxypropyl cellulose, with every 84.86 parts by weight salt Sour 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 pellet Described in load medicine clothing layer in further include following adhesive: ethyl cellulose, hydroxypropyl cellulose, with every 84.86 parts by weight salt Sour 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 pellet Described in Sustained release coating materials in sustained-release coating layer be selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer are for example Utech NE30D, ethyl cellulose, ethyl cellulose and mixture of hypromellose etc.；Preferred sustained release coating Material 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 pellet In 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 weights Measure 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 pellet Described 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 pellet Described in antiplastering aid in sustained-release coating layer be selected from: talcum powder, colloidal silicon dioxide, magnesium trisilicate etc., preferred antiplastering aid are to slide Mountain flour.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet In 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, example Such 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 pellet Described 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 dissolved And/or be suspended in the first solvent, then be sprayed at the blank pellet surface, then make coating piller dry with remove this first Solvent.In one embodiment, first solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred first solvent It is isopropanol.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet In 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 pellet Described 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 aid Dispersion is suspended in the second solvent, then is sprayed at the loads medicine clothing layer outer surface, then dry coating piller with remove this Two solvents.In one embodiment, second solvent is selected from: water, ethyl alcohol, isopropanol and combinations thereof, preferred second is molten Agent is water.

Venlafaxine hydrochloride slow-release capsule according to a second aspect of the present invention, wherein the venlafaxine hydrochloride sustained-release pellet In 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 pellet It 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 equipment It carries out.Solvent can be removed simultaneously during to piller coating, the solvent used twice is readily removed to reach Meet 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 pellet It is to be prepared according to the method included the following steps:

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

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation oven In 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 into Gelatin 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 salt The 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 in The 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 follows It is rapid:

Method according to a third aspect of the present invention, wherein active ingredient hydrochloric acid text in the venlafaxine hydrochloride sustained-release pellet Daraf(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 but 30 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 but 25 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 herein Determine 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 dissolution 70% -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:

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

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

Sample solution: testing liquid centrifugation；

Measurement:

Sample be standard solution and sample solution,

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

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

Method according to a third aspect of the present invention, wherein blank capsule core described in the venlafaxine hydrochloride sustained-release pellet is Being 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 is The 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 pellet Part 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 weights Measure part.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pellet It further include selected from following adhesive: ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl other than active constituent Ylmethyl 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 pellet It 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 pellet It 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 pellet Part 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 weight Part.

Method according to a third aspect of the present invention, wherein in load medicine clothing layer described in the venlafaxine hydrochloride sustained-release pellet Further include following adhesive: ethyl cellulose, hydroxypropyl cellulose, it is described in terms of every 84.86 parts by weight VENLAFAXINE HCL The 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 pellet Further include following adhesive: ethyl cellulose, hydroxypropyl cellulose, it is described in terms of every 84.86 parts by weight VENLAFAXINE HCL The 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 pellet Sustained release coating materials be selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer such as Utech NE30D, ethyl Cellulose, ethyl cellulose and mixture of hypromellose etc.；Preferred Sustained release coating materials are ethyl acrylate With 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 pellet Part 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 7~10 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 pellet It 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 two Silica, 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 pellet Part 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 is In the following way coated in the blank capsule core outer surface: active constituent and adhesive are dissolved and/or are suspended in first In solvent, then it is sprayed at the blank pellet surface, then makes coating piller dry to remove first solvent.Implement at one In 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 pellet Solid 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 is Be 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 second In agent, then it is sprayed at the load medicine clothing layer outer surface, then makes coating piller dry to remove second solvent.Implement at one In 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 pellet Solid 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 layer Trypsin 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 pellet It 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 embodiment Venlafaxine hydrochloride slow-release capsule described in pungent sustained release pellet or second aspect of the present invention any embodiment is in preparation for controlling Treat or prevention of depression, generalized anxiety disorder, paralepsy recurrence prevention, social anxiety disorder, panic disorder drug in Purposes.

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

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

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

Sample solution: testing liquid centrifugation；

Measurement:

Sample be standard solution and sample solution,

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

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

Either side according to the present invention, wherein the hydrochloric acid text for including in the venlafaxine hydrochloride slow-release capsule every is drawn The 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 pellet When 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 first In 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 hydroxyl Propyl cellulose is dissolved in first solvent, and solid concentration is identical as upper suspension concentration, obtains solution；Pass through atomization Being sprayed on above-mentioned suspension and solution in fluidized-bed coating machine is in the blank capsule core of fluidized state, after afterflow after spraying Change to solvent is removed, obtains drug-loaded pellets.It has been unexpectedly discovered that fraction hydroxypropyl cellulose is single after medicine-feeding It 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 language In description with the preparation example of following detailed description part described in step different from, however, those skilled in the art The 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 not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The 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 literary When 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 and Phrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms and Phrase 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 invention Subject 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 will Content 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 guarantees It takes completely.

Venlafaxine hydrochloride slow-release capsule initial treatment of the present invention is used for various types depression.For most of patients, push away The initial dose for recommending venlafaxine hydrochloride slow-release capsule is daily 75 milligrams, single medication.In venlafaxine hydrochloride slow-release capsule In the clinical research for treating outpatient service moderate depressive patients patient, initial dose is daily 75 milligrams.To certain neopathy patients, adjusting Before 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 antidepression The 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 dosage About 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 draw The 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 service In 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 new Fall 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.Although Fail 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 dosage When 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 increment Up 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 controlled The 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 Venlafaxine Twice, 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 to How 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 treatment After the acute symptom of strongly fragrant disease is effective, drug after treatment several months or longer time are needed.In 1 research, VENLAFAXINE HCL Spansule treats 8 weeks effective patients, is randomly divided into placebo treatment group, hydrochloric acid text daraf(reciprocal of farad) identical with prior treatment dosage Pungent spansule (75,150 or 225 milligrams of every morning) treatment group, confirms venlafaxine hydrochloride sustained-release in maintenance therapy 26 weeks The long-term efficacy of capsule.According to these limited data, the dosage of venlafaxine hydrochloride slow-release capsule maintenance therapy is had no knowledge about Whether the effective dose of initial treatment should be equal to.The necessity and suitable agent of maintenance therapy should be periodically reappraised in treating Amount.Venlafaxine hydrochloride slow-release capsule shows effective for the treatment of GAD patient in clinical research in 6 months by a definite date.For The 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 and The 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 possible Rather 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.If Subtract medicine or intolerable reaction occur during being discontinued, it may be considered that restores to previous prescribed dose, later doctor can be with Medicine 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 capsule Gram 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 days Sour Venlafaxine sustained-release capsule, in addition, controlling for MAOI could be started after at least deactivating venlafaxine hydrochloride slow-release capsule 7 days It treats.

Clinical test

Various types depression:

Completed 2 venlafaxine hydrochloride slow-release capsules and placebo can adjust the short-term clinical research of dosage Its 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 criteria Patient.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/ days The 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 capsule It is 75~225mg/ days (mean dose for completing experimenter is 177mg/ days), 2 researchs confirm venlafaxine hydrochloride sustained-release Capsule HAM-D total score, the HAM-D depressive emotion factor, MADRS total score, clinical global impression scale (CGI) disease severity and Placebo is superior in terms of improvement degree；Simultaneously show venlafaxine hydrochloride slow-release capsule in HAM-D scale it is some it is specific because Son 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 HCL Release 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 excellent In 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 treated Clinical research after, will wherein treatment is effective and meets DSM-IV for the out-patient of depression standard, random point Group carries out follow-up study, (venlafaxine hydrochloride slow-release capsule or placebo of giving same dose).Continue in observation 26 weeks Palindromia situation.Effectively it is defined as serious item score≤3 of CGI disease in evaluation in the 56th day in open phase treatment With 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, examines Disconnected standard and serious item score >=4 of CGI disease (moderate disease), the serious project of CGI disease point of (2) 2 continuous follow-ups Number >=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 treated Capsule or placebo, (outpatient service depression meets DSM-III-R diagnostic criteria, and recurrence, treatment is effectively (in evaluation in the 56th day Total 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 disease Disease)]).52 weeks observation patient's recurrences later, recurrence are defined as serious score >=4 of CGI disease.Subsequent 52 weeks after continued access By 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 effect Include: 28 weeks by a definite date, placebo, fixative quantifier elimination, 16 months by a definite date placebo, fixed dosage are ground Study carefully with 16 months by a definite date, for meet DSM-IV GAD diagnostic criteria adult out-patient placebo variable dose Research.

1 assessment venlafaxine hydrochloride slow-release capsule 75,150 of research in 8 weeks by a definite date and 225mg/ days dosage and comforts Agent to the curative effect of GAD, find 225mg/ days venlafaxine hydrochloride slow-release capsule HAM-A scale total score, HAM-A anxiety and The 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 slow The 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.2nd Research 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 drugs The 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 capsule It, the another 1 assessment venlafaxine hydrochloride slow-release capsule 75~225mg/ days curative effects for GAD, discovery was with 75mg/ days or was higher than After 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 obvious Better 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 height The 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 text The 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 fed Newborn zooblast forward direction gene mutation test result is feminine gender.The conversion test of Venlafaxine BALB/c-3T3 mouse cell, CHO Cell sister chromosome exchange test, rat micronucleus test result are feminine gender.O-DMV CHO chromosome aberration Test result is feminine gender, and rat micronucleus test result is the positive.Genotoxicity: calculating (the same below) by mg/m2, male rat warp When mouth dosage reaches 2 times of maximum recommended people dosage (MRHD), the influence to fertility is had no.Rat and family's rabbit pregnancy and Oral 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 rat Young 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 baby No-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 administration O-desmethylvenlafaxine succinate 30,100,300mg/kg, it is seen that when oestrous cycle disorder and mating occurs in each dosage group Between 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 away 1.7 times for recommending dosage) it is 18 months continuous, rat oral gives venlafaxine dosages and is up to 120mg/kg/ days 24 months continuous (heros 1 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/ days Dosage range in Venlafaxine and ODV belong to linear pharmacokinetic model, mean steady state plasma clearance rate is respectively 1.3 ± 0.6 Hes 0.4 ± 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, respectively 27% 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 acid Venlafaxine sustained-release capsule (150mg, q24h) usually has lower Cmax, and (Venlafaxine and ODV are respectively 150ng/mL And 260ng/mL), slower peak time (Venlafaxine be respectively 5.5h and 9h with ODV).When the Venlafaxine taken daily When 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 text The 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 75mg Discovery food does not influence the bioavilability of Venlafaxine and its active metabolite ODV when method pungent spansule, takes medicine The difference of time (morning or afternoon) nor affects on Venlafaxine and the drug metabolism of ODV.Metabolism and excretion: Venlafaxine absorbs First-pass metabolism is carried out in liver afterwards, main metabolites ODV, while including N- Demethyl Venlafaxine, N, O- removes dimethyl Venlafaxine and other a small amount of metabolites.In vitro study shows that ODV is generated by the metabolism of CYP2D6 enzyme, and clinic is ground Study carefully the patient for also confirming that CYP2D6 activity low (slow metabolism) text daraf(reciprocal of farad) with higher compared with normal CYP2D6 activity person Pungent and lower ODV drug concentration.Because the total amount of Venlafaxine and ODV connect in 2 groups of different patients of CYP2D6 activity Closely, and ODV and Venlafaxine have similar pharmacological action and an action intensity, thus the difference of this metabolic capability have no it is important Clinical 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 metabolite Mainly pass through kidney excretion.

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

Specific embodiment

The present invention can be further described by the following examples, however, the scope of the present invention and unlimited In 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 invention Various change and modification are carried out to the present invention.The present invention carries out the material and test method arrived used in test general And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that But 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 below In 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 preparation When 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, respectively Material crushes in advance before preparation and crosses 120 meshes.If not otherwise specified, the VENLAFAXINE HCL bulk pharmaceutical chemicals used when preparation are With a batch.

Cane sugar type medicinal fine pellet core used in the present invention is commercial preparation intermediate commodity, meets the Shanghai City drug standards Shanghai Q/WS-1-2274-2001；Utech NE30D used in the present invention is commercially available auxiliary material commodity, meets import drugs registered standard JX20020019。

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 advance The VENLAFAXINE HCL of 150 meshes is uniformly mixed to obtain suspension, is sprayed on the suspension in fluidized-bed coating machine in fluidisation by atomization Continuing to be fluidised in the blank capsule core of state, after spraying is removed solvent, obtains drug-loaded pellets；[through detecting, first is molten Agent 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 mist Changing 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 solvent It 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 oven In 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 pellet The 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 filling When 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:

(4) it aging: mixes slow-release pill obtained by previous step with 0.2% talcum powder, is subsequently placed into heated-air circulation oven In 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 pellet The content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

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

Formula:

Preparation method:

(4) it aging: mixes slow-release pill obtained by previous step with 0.5% talcum powder, is subsequently placed into heated-air circulation oven In 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 pellet The content of active constituent calculates the corresponding sustained release pellet weight of 75mg Venlafaxine]

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

Formula:

Preparation method:

(4) it aging: mixes slow-release pill obtained by previous step with 0.4% talcum powder, is subsequently placed into heated-air circulation oven In 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 pellet The content of active constituent calculates the corresponding sustained release pellet weight of 75mg 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:

(4) it aging: mixes slow-release pill obtained by previous step with 0.25% talcum powder, is subsequently placed into heated-air circulation oven In 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 pellet The content of active constituent calculates the corresponding sustained release pellet weight of 75mg 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 fine Dimension element is dissolved in first solvent, and solid concentration is identical as upper suspension concentration, obtains solution；Successively made by atomization Above-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 make Solvent 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 therein For 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 therein Equivalent 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 equivalent Ethyl 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 gained 14 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 batches Pellet 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 implement The 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.Supplement 10 sample of embodiment: sustained release pellet is prepared referring to the method for CN103054835B its [0056]~[0067] i.e. embodiment 1 With 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 invention Comparison medicine venlafaxine hydrochloride slow-release capsule Efexor XR (75mg, national drug standard J20160078 in terms of Venlafaxine) is tested.

[dissolution method]:

Dissolution medium: water 900mL, degassing；

Device: blue laws, revolving speed 100rpm；

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

Sample solution: testing liquid centrifugation；

Measurement:

Sample be standard solution and sample solution,

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

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

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 sustained The 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 three Dissolution 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 than 30%, 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 hours In 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 dissolution 79%~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 XR Between similarity f2 (typically f2 is greater than and 70% is acceptable, and is preferred greater than 80%), acetonideexample 1~5 For 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 XR Similarity f2 between curve, the f2 of 7~9 whole samples of acetonideexample between 31~38%, show these samples with Original 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 original The 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 40 At 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 with Data 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 is 79.6%, 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 embodiment The 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 invention Excellent 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 reason Solution, all any modification, equivalent variations and modification to the above embodiments according to the technical essence of the invention, all falls within this hair In bright protection scope.

Claims

1. measuring venlafaxine hydrochloride sustained-release pellet or venlafaxine hydrochloride slow-release capsule dissolution rate described in claim 2-9 Method, 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 packet The amount of the Venlafaxine containing active medicine is that (50~250mg of the Venlafaxine is also referred to as tested herein for 50~250mg measurement Amount, 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 Zhongjin Row measurement；When test sample is capsule of the piller in hard capsule case, the amount of the piller in every capsule is equivalent to Containing 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；

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 solution In, 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 introduction 20 μ L are measured, the record time is 1.5 times of Venlafaxine retention time；

Measurement:

Sample be standard solution and sample solution,

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 solution The concentration (mg/mL) of the pungent reference substance of method, Mr1=Venlafaxine molecular weight 277.40, Mr2=VENLAFAXINE HCL molecular weight 313.86

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 solution The volume (mL) of=sample solution drawn from dissolution medium, L=concentration determination labelled amount are (that is, Dissolution Rate Testing is each molten Cup Venlafaxine theoretical addition amount out, mg；Such as when with Capsule form progress Dissolution Rate Testing, every capsule Nei Wenla The 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 surface Layer, 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 Venlafaxine The 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 dissolution 60% -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 weights Measure 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 constituent Element, 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 weight Part, 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 weight VENLAFAXINE 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 weight VENLAFAXINE 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 weight Part；

Sustained release coating materials in the sustained-release coating layer are selected from: ethyl acrylate and methyl methacrylate (2:1) copolymer example Such as mixture of Utech NE30D, ethyl cellulose, ethyl cellulose and hypromellose；Preferred sustained release packet Clothing 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 6~12 Parts 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 is Talcum 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 molten Solve and/or be suspended in the first solvent, then be sprayed at the blank pellet surface, then make coating piller dry with remove this One 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-stick Agent 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 this Second 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 carried Middle 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 advance Method 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 atomization Change 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 sustained Piller；

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation oven Aging 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 capsule Interior 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:

(4) it mixes slow-release pill obtained by previous step with 0.2~0.5% talcum powder, is subsequently placed into heated-air circulation oven Aging 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 gelatin Capsules, 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 8 Spansule is in preparation for treating or preventing depression, generalized anxiety disorder, the recurrence prevention of paralepsy, Social Anxiety barrier Hinder, the purposes in the drug of panic disorder.