CN101180039A - Modified release composition of at least one form of venlafaxine - Google Patents

Abstract

The present invention relates to a modified release composition of at least one form of venlafaxine, which is a delayed controlled release composition. The composition comprises a core comprising at least one form of venlafaxine selected from the group consisting of venlafaxine, an active metabolite of venlafaxine, a pharmaceutically acceptable salt of venlafaxine, a pharmaceutically acceptable salt of an active metabolite of venlafaxine, and combinations thereof, less than 10% of a gelling agent and a pharmaceutically acceptable excipient. The composition further comprises a modified release coating which substantially surrounds the core which provides a delayed controlled release of the at least one form of venlafaxine.

Description

The slow releasing composition of the venlafaxine of at least a form

Technical field

The present invention relates to the slow releasing composition of the venlafaxine (venlafaxine) of at least a form of oral administration, relate to their preparation method and relate to their medical application.Specifically, this slow releasing composition relates to a kind of release composition that postpones to control of the venlafaxine of at least a form.

Background technology

For many medicines, an ideal dosage regimen is to reach acceptable treatment concentration of medicine immediately by this dosage regimen position in action, keeps constant then during treating.If the dosage of administration size and frequency are correct, the repeat administration of the oral administration form by routine can promptly reach and keep " stable state " plasma concentration of a kind of Drug therapy.Yet conventional oral administration form has many potential shortcomings.These shortcomings make the medicine scientist consider to provide the therapeutic activity molecule in " prolong and discharge " preparation.

Oral medication is the approach that conventionally preferably gives medicine, and a kind of facilitated method that all is effective in local and system effectively is provided.A kind of ideal oral drugs drug-supplying system should all stably be delivered to target site with a measurable and reproducible medication amount in the time period of a prolongation.Prolong to discharge (Extended-release) (ER) drug-supplying system provide the concentration/amount of this medicine unanimity absorbing the site, and therefore allowing plasma concentration to maintain in the therapeutic domain after the absorption in the time period of a prolongation, this can make side effect minimize and also reduce the frequency of administration.The ER dosage form discharges medicine lentamente, so plasma concentration all maintains treatment level in the time period of a prolongation.Typically, these products are compared with the compositions that discharges immediately has many advantages, be included in the treatment of chronic disease that effect is stronger, side effect still less, convenient more and because the drug dosage schedule of simplifying makes patient's compliance higher.Because above-mentioned advantage, such system has formed a major part in administration market.

In order to eliminate conventional drug-supplying system observed plasma drug level circulation change after administration, many drug-supplying systems have been developed.Various terms have been used to describe these systems: postpone to discharge (delayed release), repeat function (repeat action), extension release (prolonged release), continue to discharge (sustained release), prolong release (extended release), sustained release (controlled release) and slow release (modified release).What is interesting is, notice that USP thinks that term " sustained release ", " extend and discharge ", " continuing to discharge " and " prolong and discharge " can exchange.

The sustained release preparation has been described in the prior art, and for the therapeutic serum levels of keeping medicine and make, used many methods that the pharmaceutical dosage form of sustained release is provided owing to the effect that lacks the drug dose disappearance that patient's compliance causes minimizes.Antidepressants are material standed fors of better controlled delivery formulations, because because these medicines drug dosage schedule every day a kind of complexity or repeatedly makes patient lack the most frequent result of compliance is exactly the interruption of these medicines, and the interruption of these medicines can often cause serious disconnected medicine symptom (discontinuation symptoms).

Venlafaxine, chemical expression is (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] Hexalin or (±)-1-{a[α-(dimethylamino) methyl] right-methoxybenzyl Hexalin, be a kind of dicyclic compound chemical messenger, that have antidepressant character in the brain that influences.These chemical messengers are called as neurotransmitter, for example can be 5-hydroxy tryptamine, dopamine and norepinephrine.Neurotransmitter is produced by neurocyte and discharges.These neurotransmitteies arrive adjacent neurocyte and cause that this cytoactive is stronger or more weak.The imbalance that it is believed that these neurotransmitteies is to cause that the depressed reason and the imbalance of these neurotransmitteies also play a major role in anxiety.It is believed that venlafaxine works by release that suppresses these neurotransmitteies or the activity that influences these neurotransmitteies.

Chemically, venlafaxine is uncorrelated with other antidepressants, but is classified as 5-hydroxy tryptamine-NRI (SNRI) sometimes.When low dosage, the reuptake of venlafaxine blocking 5-hydroxytryptamine is similar to selective serotonin reuptake inhibitor (SSRI).When middle dosage, except 5-hydroxy tryptamine, venlafaxine is also blocked the reuptake of norepinephrine.When high dose, venlafaxine is blocked the reuptake of norepinephrine, 5-hydroxy tryptamine and also is the weak blocker of dopamine reuptake.

Venlafaxine is well absorbed behind oral administration and metabolism has had good document record.After the absorption, venlafaxine has experienced presystemic metabolism widely at liver, and main metabolic is O-desmethylvenlafaxine (ODV), also metabolism is N-desmethylvenlafaxine (NDV), N, O-two desmethylvenlafaxines (DDV) and N, N, O-three desmethylvenlafaxines (TDV).In vitro study demonstration ODV is that the catalysis of process CYP2D6 forms; Clinical research has also confirmed this point, the patient of the low CYP2D6 level of clinical studies show (" difference metabolizer " (" poor metabolizers ")) compares with the people (" metabolizer widely " (" extensive metabolizers ")) of common CYP2D6 level, and the higher level of venlafaxine and the level of ODV are lower.Yet, CYP2D6 difference and widely the difference between the metabolizer think inessential clinically because the total amount of venlafaxine and ODV is similar in two colonies, and venlafaxine and ODV pharmaceutically approx isoreactivity or etc. tire.In 48 hours, the venlafaxine dosage near 87% reclaims in urine as unaltered venlafaxine (5%), uncombined ODV (29%), bonded ODV (26%) or other less active metabolites (27%).It is main excretion pathway that the diabetes involving the kidney of venlafaxine and metabolite thereof removes.The metabolic pathway of venlafaxine can be summarized as follows:

The short about 4 hours elimination half-life of venlafaxine, its active metabolite has about 8 hours half-life.This has caused venlafaxine to be administered twice every day, and lacks the problem that patient dependence is easy to produce disconnected medicine in adhering to the drug dosage schedule process of this every day.Suddenly the disconnected medicine of venlafaxine can cause withdrawal symptoms (withdrawal symptoms), and this comprises fatigue, dizzy, nauseating, headache and dysphoria.Therefore, venlafaxine is a kind of good material standed for of sustained release oral formulations.

Venlafaxine, as its hydrochlorate, as the second filial generation prolong release tablet be obtainable and on market with trade name Effexor ^XR sells for using once every day.This preparaton has been eliminated the first generation venlafaxine Effexor of releasing pattern immediately ^The disconnected medicine problem of (be administered twice its frequent every day).The prolongation of venlafaxine discharges preparaton and describes in the prior art.

For example, U.S. Patent number 6,274,171,6,403,120 and 6,419,958 have disclosed the preparaton of the VENLAFAXINE HCL that comprises the last effective dose of treatment in film-coating ball (film-coated spheroids).These bags contain a nuclear, and this nuclear has VENLAFAXINE HCL, microcrystalline Cellulose and hydroxypropyl emthylcellulose randomly.Mixture with ethyl cellulose and hydroxypropyl emthylcellulose wraps up these nuclear, is encapsulated into subsequently in the capsule of glutoid.These patents are also described and claimed method and composition; this method and composition can reach the treatment plasma concentration of the venlafaxine of a time period above 24 hours; the incidence rate of nausea and vomiting descends simultaneously; this comprises to a kind of prolongation of the patient's orally give that it is had needs and discharges preparaton, and the peak of plasma levels of the venlafaxine that is no more than about 150ng/ml was provided after the administration in 4-8 hour.

U.S. Patent number 6,703,044 is intended to teach a kind of preparaton, wherein this preparaton realized that after administration a kind of delay-action blasting of venlafaxine discharges at least in three hours, mainly was to diffuse into blood flow by colon thereby cause venlafaxine to make venlafaxine as the result who absorbs at the colon through time period of at least 24 hours.Said preparation be characterized as the compression core that comprises a kind of Blasting Control agent and a kind of disintegrating agent.This nuclear is with relatively harder water-insoluble hydrophobic polymer parcel, wherein embedding water-insoluble but the granule of water wetted material.These granules have formed many passages when contacting with aqueous medium, and they suck liquid and cause this coating of Blasting Control agent explosion, and venlafaxine delay-action blasting is discharged.Should ' 044 patent have also taught in example 11 with the venlafaxine preparaton that discharges of present available prolongation on the market and compared, this preparaton unexpectedly provides the bioavailability that exceeds 30% venlafaxine in fasting volunteer's body.On the other hand, Effexor ^State on the label of XR: " Effexor XR should be in about identical time every day, in the morning or evening with the food single-dose." example 11 of only pharmacokinetic study does not provide the intravital biological utilisation degrees of data of volunteer of any feed in this patent, the said preparation of therefore not knowing to teach in ' 044 patent is when giving at Effexor ^During patient under the situation of recommending in the XR label, promptly on the feed under the situation, whether also can provide higher bioavailability.Data or side effect feature that any adverse events of claimed compositions should ' 044 patent be provided.

Above-mentioned ' 120, ' 171 and the content of ' 958 Patent publish above teaching has been discussed: " ... the various trials of the prolongation release tablet by hydrogel technology production VENLAFAXINE HCL all are proved to be futile because these compressed tabletses be physically unsettled (compressibility difference or become medicated cap problem (capping problems)) or in dissolution studies dissolving too fast." capable with the 4th hurdle 60-64 of ' 958 patents ' 120, ' 171.Yet Makhija of the chemical technology of Bombay,India university system (independently mechanism) pharmaceutical department and Vavia have described the continuous release tablet (Eur.J.Pharmaceut.Biopharmaceut.2002.54:9-15) of the venlafaxine that is administered once every day of utilizing the hydrogel technology.Makhija and Vavia list of references have been taught the sustainable release tablet that utilizes the VENLAFAXINE HCL that is administered once a kind of not every day of the matrix system of coating based on expandable and nondistensible polymer.What is interesting is, although (Fig. 4) do not show any delay in discharging in medicine external (Fig. 2) or body, the bioavailability of the venlafaxine of this preparation, similar to the bioavailability of ' 044 preparation, also than Effexor ^The bioavailability of XR is significantly improved.Yet similar with ' 044 invention, said preparation is the individuality that is in fasting state.Therefore, do not know whether Makhija and Vavia preparaton can provide higher bioavailability under the state on the feed.Finally, the list of references of Makhija and Vavia is not also taught and Effexor ^XR compare their effect of preparation and the generation and the frequency of any adverse events.

Also described in the prior art and comprised the delayed release preparation of venlafaxine as active component.For example, the U.S. Patent application the 10/244th that May 15, disclosed publication number was US2003/0091634A1 in 2003, No. 059 and March 27, disclosed publication number was US 2003/0059466A1 in 2003 U.S. Patent application the 09/953rd, a kind of delayed-release tablet has all been described in No. 101, this tablet comprises a nuclear, this nuclear comprises 10% to 70% active substance, 10% to 80% a kind of gellant and optional conventional excipients; And a coating, this coating is basically by the weight based on this coating, the permeable film forming polymer of 20% to 85% water-insoluble by weight, and 10% to 75% water-soluble polymer or material and a kind of plasticizer of 3% to 40% are formed.

Venlafaxine is the antidepressant drug that the quilt that is positioned at TOP V is left prescription at the SSRI/SNRI of antidepressants apoplexy due to endogenous wind at present.Yet only a kind of peroral dosage form that comprises VENLAFAXINE HCL that is administered once every day is at present with trade name Effexor ^XR sells.Suppose the effectiveness of venlafaxine, expectation is obtained the Orally administered composition that be administered once a kind of every day, this Orally administered composition comprises the venlafaxine of at least a form, and with in the market the dealing Effexor ^The capsule of XR 150mg is compared, and can provide higher bioavailability, and the characteristic of side effect or adverse events is less or similar.Such compositions also can allow the amount of a kind of absolute magnitude of active medicine less than this medicine in the reference product, and therefore better security feature is provided.

Summary of the invention

The present invention relates to a kind of slow releasing composition of venlafaxine of at least a form.

In one embodiment of the invention, the slow releasing composition of the venlafaxine of at least a form is to be fit to oral administration every day delay sustained release pharmaceutical composition once, comprising:

A) nuclear, this nuclear comprises the venlafaxine at least a form of the weight from about 10% to about 90% of nuclear dry weight, a kind of gellant less than 10%, with optional conventional excipients, the venlafaxine of this kind form is selected from following group, this group comprises a kind of pharmaceutically acceptable salt of active metabolite of a kind of active metabolite, the venlafaxine of a kind of pharmaceutically acceptable salt, the venlafaxine of venlafaxine, venlafaxine, and their combination, and b) holds a kind of sustained release coating of described nuclear basically; Wherein said compositions provides a kind of release that postpones to control of the venlafaxine of described at least a form, so that when use USP device 1 in the phosphate buffer of the pH 6.8 of 1000ml with 75rpm when detecting down for 37 ℃ ± 0.5 ℃, the venlafaxine of this at least a form discharged no more than 20% after about 2 hours, the venlafaxine of this at least a form discharged about 15% to about 45% after about 4 hours, the venlafaxine of this at least a form discharged about 55% to about 85% after about 8 hours, the venlafaxine of this at least a form discharged after about 12 hours and is no less than approximately 65%, and the venlafaxine of this at least a form discharged after about 16 hours and is no less than about 80%.

In another embodiment of the present invention, the slow releasing composition of the venlafaxine of this at least a form is a kind of suitable oral administration every day delay sustained release pharmaceutical composition once, comprise: a) nuclear, this nuclear comprises the venlafaxine at least a form of the weight from about 10% to about 90% of this nuclear dry weight, a kind of gellant less than 10% and optional conventional excipients, the venlafaxine of this kind form is selected from following group, this group comprises venlafaxine, a kind of pharmaceutically acceptable salt of venlafaxine, a kind of active metabolite of venlafaxine, the pharmaceutically acceptable salt of a kind of active metabolite of venlafaxine, and their combination; And b) holds a kind of sustained release coating of described nuclear basically, described coating comprises the permeable film forming polymer of a kind of water-insoluble in the weight from about 20% to about 85% of this coating dry weight, from about 10% to about 75% a kind of water-soluble polymer or material and a kind of plasticizer of from about 3% to about 40%; Wherein said compositions provides a kind of release that postpones to control of the venlafaxine of described at least a form, thereby when use USP device 1 in the phosphate buffer of the pH6.8 of 1000ml with 75rpm when detecting down for 37 ℃ ± 0.5 ℃, the venlafaxine of this at least a form discharged no more than 20% after about 2 hours, the venlafaxine of this at least a form discharged about 15% to about 45% after about 4 hours, the venlafaxine of this at least a form discharged about 55% to about 85% after about 8 hours, the venlafaxine of this at least a form discharged after about 12 hours and is no less than approximately 65%, and the venlafaxine of this at least a form discharged after about 16 hours and is no less than about 80%.

The specific embodiment

The present invention be directed to the pharmaceutical composition of a kind of slow release of venlafaxine.Specifically, said composition is a kind of compositions that strengthens the delay sustained release of absorption of the venlafaxine of at least a form, said composition comprises a nuclear and a sustained release coating, this coating holds this nuclear basically, and wherein said composition provides a kind of release that postpones to control of the venlafaxine of at least a form.When comparing with reference product, the peroral dosage form that the present invention strengthens the delay sustained release of absorption has higher bioavailability, and side effect or adverse events minimizing or similar.

The nuclear of tablet

This nuclear comprises the venlafaxine of at least a form, a kind of gellant and conventional excipients randomly, the venlafaxine of this kind form is selected from following group, this group comprises a kind of pharmaceutically acceptable salt of active metabolite of a kind of active metabolite, the venlafaxine of a kind of pharmaceutically acceptable salt, the venlafaxine of venlafaxine, venlafaxine, and their combination, hold this nuclear with a kind of release polymer coating.Said composition provides a kind of release that postpones to control of the venlafaxine of this at least a form.

The ratio that the venlafaxine of at least a form exists in this nuclear is the weight from about 10% to about 90%, preferably from about 20% to about 60%, more preferably from about 35% to about 45% and most preferably from about 42% in this nuclear dry weight.Said composition comprises an effective dose pharmaceutically of the venlafaxine of at least a form, the scope that this effective dose can change be from about 0.5 to about 1000mg, more electedly from about 20 to about 200mg and most preferably from about 100 to about 200mg.

Term " effective dose " is meant that what considered is one " effective dose pharmaceutically " as used herein.One " effective dose pharmaceutically " is meant the quantity or the value of the venlafaxine of this at least a form in a kind of dosage shape type of the present invention, when giving that with single or multiple dosage it is had patient who needs, be enough to cause appreciable reaction clinical or treatment.Be to be understood that precise therapeutic dosage amount according to the state of age of patient and situation and this disease to be treated and decide, and depend on diagnosis and treatment doctor's final judgement.Those skilled in the art know on a kind of specific treatment for diseases or effective dose clinically can by use comprise one of venlafaxine of at least a form pharmaceutically the dosage form of effective dose carry out clinical research and determine.

Term " pharmaceutically acceptable salt " is meant the salt that is equipped with pharmaceutically acceptable non-toxicity processed with acid as used in this article, comprises mineral acid and organic acid.Suitable non-toxicity acid comprises inorganic and organic acid, for example acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylene-sulfonic acid (ethenesulfonic), fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, pounce on acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid or the like.Hydrochlorate most preferably.Other salt, for example, venlafaxine maleate and venlafaxine benzene sulfonate have been described in respectively among international patent application no PCT/EP03/03319 (WO 03/082805) and the PCT/EP03/03318 (WO 03/082804), and their content is incorporated into this in the mode of quoting as proof.

Venlafaxine in the pharmaceutically acceptable salt of venlafaxine or venlafaxine can be any type of venlafaxine.For example, venlafaxine has the carbon of an optically-active, so permission two optical antimers of existence and a raceme.Two optical antimers all are pharmaceutically activated.Therefore, the effective dose of preferred active ingredient hydrochloric acid venlafaxine can be based on the mixture of the raceme of venlafaxine or optical antimer or based on (+) or (-) optical antimer of pure or pure basically venlafaxine in the nuclear of peroral dosage form of the present invention.(+) and (-) optical antimer of this article traction therapy suffering has been described in U.S. Patent number 6,197 respectively, and in 828 and 6,342,533, their content is incorporated into this in the mode of quoting as proof.These all forms of venlafaxine all are included in the implication of term " venlafaxine ", " venlafaxine pharmaceutically acceptable salt ", " active metabolite of venlafaxine " and " pharmaceutically acceptable salt of the active metabolite of venlafaxine ".

This at least a gellant comprises a kind of material, this kind material be hydrophilic in essence and can show as same hydrophilic substrate.The US publication of announcing on May 15th, 2003 is to have described the example of gellant among the Handbook of PharmaceuticalExcipients of 2003/0091634 U.S. Patent number 10/244,059 and the Pharmaceutical Press and the American PharmaceuticalAssociation that edit by people such as Rowe the 4th edition (2003) of issuing.The amount of this at least a gellant in weight of this nuclear dry weight less than 10%, preferably approximately less than 8%, more preferably from about less than 6% even more preferably approximately less than 4% and most preferably approximately less than 2%.Ideal gellant is a polyvinyl alcohol, its amount in the weight of this nuclear dry weight about 1.5% (for one 180,120 or the venlafaxine tablet of 60mg) or about 1% (for venlafaxine tablet of a 30mg).This at least a gellant can comprise a kind of mixture of two or more gellant, as long as the total amount of this gellant is less than 10% of this nuclear dry weight.An example of gellant combination can comprise the mixture in the methylcellulose of the polyvinyl alcohol of the mixture of the methylcellulose of the polyvinyl alcohol of the weight of this nuclear dry weight about 1.5% and about 5% or about 3% and about 5%.

Do not wish to be fettered by any concrete theory, it is believed that a kind of low gelling preparaton, be a kind of preparaton that has less than 10% gellant, except compositions described herein has the feature that enhanced absorption postpones sustained release, can also help or further improve its security feature.Venlafaxine is that first and most important 5-hydroxy tryptamine absorb or reuptake inhibitor (SRI).Under higher dosage/concentration, venlafaxine also suppresses the picked-up of norepinephrine.Because it is approaching relatively producing these two active dosage, venlafaxine also is considered to 5-hydroxy tryptamine/NRI (SNRI).Yet the SRI part is more important for nausea and vomiting is discussed.The 5-hydroxy tryptamine amount that the activity of venlafaxine blocking 5-hydroxytryptamine picked-up can cause touching in all synapses of venlafaxine increases.Synapse does not exist only between the neuron among the central nervous system, is present between neuron and the muscle fiber promptly neuromuscular junction yet.Known stomach has 5-hydroxytryptamine receptor.Cohen and Fludzinski, JPET 1987; 243:264-269.Therefore, and do not wish to be fettered by any concrete theory, the release of venlafaxine can cause the 5-hydroxy tryptamine of stomach synapse place on every side to increase under one's belt, thereby causes nausea and vomiting.In theory, gellant is reduced to less than 10% can produces a kind of compositions, said composition do not expand fully or do not resemble at least have greater than the compositions of 10% gellant expansible many.Can expect that a kind of so low cementitious compositions is compared with the compositions that has greater than 10% gellant, the holdup time under one's belt is shorter, thereby causes few many of venlafaxine release under one's belt.Venlafaxine still less amount under one's belt can cause the level of the 5-hydroxy tryptamine of stomach peripheral process synapsis to reduce and and then cause for example minimizing of nausea and vomiting of side effect relevant with gastrointestinal tract or adverse events.

Except mentioned component, can also comprise in this tablet that a series of excipient can carry out satisfactorily with the operation of guaranteeing tabletting and guarantees to prepare the tablet with specified characteristic.According to the main effect that expectation obtains, the excipient that uses in the tablet can be subdivided into different groups.Yet a kind of excipient can influence the character of tablet in every way, so the many excipient that use in the tablet composition can be described as multi-functional.

For example, this nuclear may further include at least a lubricant.Lubricant is added in the pharmaceutical preparation to guarantee formation and the At time of eject at tablet, the low-frictional force between solid and the mold wall.In the tabletting process, high frictional force can cause a series of problem, comprise tablet quality defective (become medicated cap or even broken in the process that ejects, and the vertical cut at tablet edge) and even can block production.The non-limiting instance of the lubricant of the peroral dosage form that can be used for describing herein comprises magnesium stearate, Talcum, sodium stearyl fumarate, calcium stearate, silica gel, colloidal silica, Compritol 888 ATO, glyceryl behenate, stearic acid, hydrogenated vegetable oil (cotmar (Sterotex for example ^), hydrogenated soybean oil (Sterotex ^HM) and hydrogenated soybean oil and castor wax (Sterotex ^K), stearyl alcohol, leucine, Polyethylene Glycol (MW 4000 and higher), and their various mixture.The amount of this at least a lubricant can be the weight from about 0.02% to about 5% in this nuclear dry weight.Preferred lubricant is that Tridocosanoin and preferred amount are in the weight of this nuclear dry weight about 3%.

Some peroral dosage forms require that one or more are planted excipient and are incorporated in this dosage form to increase the heap volume of powder, therefore increase the size of this dosage form.Therefore, this is endorsed further to comprise at least a filler (or diluent).The limiting examples that can be used at least a filler of peroral dosage form described here comprises lactose monohydrate, Lactis Anhydrous, mannitol, Sorbitol, microcrystalline Cellulose, dibasic calcium and calcium sulfate.Also can use the mixture of filler.This at least a filler preferably amount is up to about 75% in this weight of examining dry weight.Preferred filler is a lactose monohydrate.Most preferably, this lactose monohydrate is called as spray-dired lactose #315 (Lactose#315 Spray Dried) type, and this is a kind of pure alpha-lactose monohydrate of special preparation and the mixture of amorphous state lactose in a small amount.Preferably, spray-dired lactose #315 amount is about 53% (for the venlafaxine tablet of 180g, 120g or 60g) of weight or 72% (for the venlafaxine tablet of 30mg) in this nuclear dry weight.

The venlafaxine of this at least a form and filler, the aqueous solution of preferred lactose #315 (spray drying) and gellant, preferably polyethylene alcohol at first forms granule in a suitable thermopnore granulator.This granule is dried and sieves with the sieve of 1.4mm then.Then, the granule that sieved and more filler and a kind of lubricant, preferably glycerine docosane acid esters, in a V-agitator or any other suitable mixing arrangement, mix together, and if necessary, mix with any other other inert excipient, this inert excipient can help the processing of peroral dosage form of the present invention.Scheme as an alternative, these compositions also can dry mixed and are directly suppressed by methods known in the art.

Dry ground granule is compressed into tablet then and is called as " tablet core " hereinafter or abbreviates " nuclear " as.Can make tablet core by using standard technique well known to those skilled in the art and device.Preferably, this tablet core is to make by the rotary press (being also referred to as the multistation press) that suitable puncher is housed.In this stage, this caryogamy preparation is a kind of preparaton that discharges immediately, causes discharging in about 30 minutes the venlafaxine more than this at least a form of about 90%.

Coating

These stone graftings with a kind of polymer coating and are wrapped up, and this polymer coating is designed to the release of the delay control of the venlafaxine of realizing this at least a form.This coating is designed to realize the venlafaxine of this at least a form, the hydrochlorate of preferred venlafaxine, a kind of extracorporeal releasing characteristic, so that this chemical compound is when using USPI type method to carry out vitro detection under 37 ℃ with 75rpm in the phosphate buffer of the pH6.8 of 1000ml, the venlafaxine of this at least a form discharged no more than 20% after about 2 hours, the venlafaxine of this at least a form discharged about 15% to about 45% after about 4 hours, the venlafaxine of this at least a form discharged about 55% to about 85% after about 8 hours, the venlafaxine of this at least a form discharged after about 12 hours and is no less than approximately 65%, and the venlafaxine of this at least a form discharged after about 16 hours and is no less than about 80%.

For the preferred polymers coating of the delay sustained release of the venlafaxine of realizing at least a form be a kind of be permeable to the semi-permeable coating of venlafaxine and do not have for example resemble U.S. Patent number 5, the preformed hole of describing in 654,005 (preformed pore).This semi-permeable coating comprises at least a water-insoluble permeable film forming polymer, at least a water-soluble polymer or material, and at least a plasticizer.This polymer coating is designed in the water of purification, continue the time period at least about 24 hours in the phosphate/ester buffer of the simulated gastric fluid of 0.1N HCl, pH1.2 (SGF) or pH6.8, and the integrity of this coating keeps harmless and do not dissolve and/or not disintegrate.Because these conditions are for simulated in vivo environment, the integrity that it is believed that this polymer coating also can be kept perfectly and not dissolve and/or disintegrate in gastrointestinal tract.Therefore, this polymer coating of describing herein is different from U.S. Patent number 6,117 basically, 453 (being a rapidly-soluble film) and U.S. Patent numbers 6, the polymer coating of describing in 703,044 (being designed to the dura mater of energy explosion, therefrom release of active ingredients from nuclear).

The limiting examples of the permeable film forming polymer of this at least a water-insoluble can be a for example ethyl cellulose of a kind of cellulose ether, a kind of cellulose esters is cellulose acetate, methyl-prop diluted acid derivant for example, and the water solublity ethylcellulose dispersion is Surelease for example ^, water solublity enteric coating system is Sureteric for example ^With water-soluble acrylic enteric coating Acryl-EZE for example ^Also allow to use multiple combination.The amount of the permeable film forming polymer of this at least a water-insoluble in the weight of this coating dry weight from about 20% to about 85% scope, preferably from about 55% to about 62% scope, and most preferably from about 60%.Most preferably, ethyl cellulose be the permeable film forming polymer of this at least a water-insoluble and preferred amount for this coating dry weight from about 55% to about 62% and be most preferably about 60%.

This at least a water-soluble polymer or material can be a kind of part or all of water solublity hydrophilic substances, are intended to adjust the permeability of film to outside aqueous medium.The limiting examples of this at least a water-soluble polymer or material can be polyvinylpyrrolidone, Polyethylene Glycol, hydroxypropyl emthylcellulose, hydration colloid silicon, sucrose, mannitol and combination thereof.This at least a water-soluble polymer comprises in the weight of this coating dry weight from about 10% to about 75%, preferably from about 20% to about 30%, and most preferably about 23% to about 26%.Most preferably, this at least a water-soluble polymer is polyvinylpyrrolidone and comprises preferably weight from about 23% to about 26% in this coating dry weight.

Plasticizer is added to usually in the film coated preparation and makes it more available with the physical characteristic that changes this polymer.The amount of this plasticizer and selection not only help to increase its physics and chemical stability, and can increase the hardness of a tablet, and even can influence its dissolving or broken characteristic.Important characteristic of plasticizer is that they can make a flexible and flexible ability of coating, has therefore reduced the fragility of coating.The limiting examples that can be used at least a plasticizer of preferred polymers coating comprises for example various molecular weight polyethylene glycol of polyhydric alcohol, organic ester for example diethyl phthalate or triethyl citrate, dibutyl sebacate, dibutyl phthalate, and oil/glyceride for example fractionated coconut oil or Oleum Ricini.Allow to use compositions.The amount of this at least a plasticizer, is preferably from about 13% to about 18%, and most preferably is from about 15% to about 17% from about 3% to about 40% in the weight of this coating dry weight.Preferred at least a plasticizer is a dibutyl sebacate, and preferred amount is in the weight from about 15% to about 17% of this coating dry weight.

The relative scale of these preferred polymer coating compositions, should be noted that, the permeable film forming polymer of at least a water-insoluble: at least a water-soluble polymer or material: the ratio of at least a plasticizer can change according to the rate of release that expectation obtains.Those skilled in the art should understand that control is coated to the permeability of the coating on this tablet core and/or the speed that amount can be controlled active component release.For example, the permeability of preferred polymer coating can be coated to the permeable film forming polymer of at least a water-insoluble on this tablet core by change: at least a water-soluble polymer: the ratio of at least a plasticizer and/or its amount are changed.Sustained release that more postpones is to realize by the amount that improves the permeable film forming polymer of water-insoluble, the amount that reduces at least a water-soluble polymer and/or by the amount that increase is coated to the coating solution on this tablet core generally.Scheme as an alternative, rate of release can be realized by the amount that increases this water-soluble polymer, the amount that reduces the permeable film forming polymer of this at least a water-insoluble and/or by the amount that reduces this coating solution that applies faster.The excipient that adds other in this tablet core also can change the permeability of this coating.For example, also comprise a kind of extender, can increase the amount of plasticizer in this coating,, this coating is broken because pressure is applied on the coating (because extender) of pliability difference so that this coating is more pliable and tougher if expect this tablet core.The excipient that also can add other in this coated formula is pigment and mask agent for example.In order to keep this coating at least about 24 hours integrity and realize above-mentioned extracorporeal releasing characteristic, the permeable film forming polymer of this at least a water-insoluble: this at least a water-soluble polymer: the preferred ratio of this at least a plasticizer is about 30-85: 10-40: 5-20.Preferably, this ratio is about 58-60: 23-26: 15-17.

The preparation of this polymer coating and apply as follows.The permeable film forming polymer preferred, ethyl of water-insoluble, water-soluble polymer preferably polyethylene ketopyrrolidine and the preferred dibutyl sebacate of plasticizer all are dissolved in a kind of alcoholic solvent for example in ethanol, isopropyl alcohol or their a kind of mixture.Use a kind of coating pan device, the coating solution that obtains is sprayed onto on this tablet core.By the percetage by weight that applies this coating solution increase on this nuclear can be in the weight from about 2% to about 50% of coating nuclear not, preferably from about 8% to about 30%, more preferably from about 10% to about 18% and most preferably from about 12% to about 15% scope.Even unexpectedly found not have in this coating the monomer pore creating material to exist and this nuclear has gellant less than 10%, above-mentioned coated formula still provides a kind of delay sustained release compositions.

Following example has illustrated the present invention and has been not to be intended to limit the scope of the invention.

Example 1

The venlafaxine of 30mg postpones the sustained release tablet

The material that the is shown in Table 1 tablet core that postpones the sustained release tablet with the venlafaxine of producing 30mg combined together:

Table 1
			Composition	Mg	％w/w
VENLAFAXINE HCL, USP	33.95	24
			Gellant 1	1.21	0.9
Filler 2	100.64	72
			Lubricant 3	4.2	3
Purified water 4，USP	N/A	N/A
			Tablet core weight	140	100

1 polyvinyl alcohol, USP

2 spray-dired lactose #315, USP

3 Tridocosanoins, NF

4 dry evaporations afterwards

VENLAFAXINE HCL and filler, lactose 315 (spray drying) are at first made granule with the aqueous solution of gellant polyvinyl alcohol on suitable thermopnore granulation device.This granule is dried then and the sieve of process 1.4mm sieves.The granule that sieved then with more filler in a V-agitator with a kind of lubricant, the preferably glycerine behenate mixes mutually, the rotary tablet machine with a kind of routine is pressed into tablet then.

Measure the dissolving of resulting tablet core under the following conditions:

Medium: the phosphate buffer of 1000ml pH6.8

Method: USPI type device, 75rpm, 37 ℃ ± 0.5 ℃

Data show discharges in about 30 minutes greater than 90% VENLAFAXINE HCL.

The material that is shown in Table 2 is combined together to be used to produce this sustained release coating:

Table 2
			Composition	Mg	％w/w
The permeable film forming polymer of water-insoluble 1	12.6	60
			Water-soluble polymer 2	4.9	23.3
Plasticizer 3	3.5	16.6
			Solvent 4	N/A	N/A
Drying solid total amount (weight of % increases)	21(15)	100
			Tablet core	140	-
The gross weight of coated tablet	161	-

1 ethyl cellulose 100, NF

2 polyvidones, USP

3 dibutyl sebacates, NF

4 ethanol (200 close mark), USP and isopropyl alcohol (99%), USP all evaporates after drying

At first plasticizer, dibutyl sebacate are dissolved in (mixture of ethanol/isopropyl alcohol) in the solvent., the permeable film forming polymer of water-insoluble (ethyl cellulose) slowly added to adds water-soluble polymer (polyvidone) in plasticizer/solvent mixture subsequently up to the solution that forms a kind of homogenizing.The tablet core of parcel example 1 increases until the weight that reaches 15% in an O ' Hara Labcoat III system then.

Tablet coated up to the weight that reaches expection to be increased, and is arranged in 50 ± 3 ℃ the intake air dry 5 minutes in temperature subsequently, and the speed of dish is 2rpm.With continuing again dry 40 minutes lentamente of identical dish speed and identical parameter.Inlet is heated and is closed and by keeping ventilation to make the tablet cooling then.Under the experimental condition identical, measure the dissolving of the tablet that is coated with the tablet core of measuring not coating.The result of the release % of VENLAFAXINE HCL total in the tablet core that coats has been shown in the table 3:

Table 3
		Time (hour)	% discharges
1	4
		2	15
3	26
		4	37
5	48
		6	57
7	64
		8	71
9	76
		10	80
11	84
		12	86
13	89
		14	91
15	93
		16	95
17	97
		18	98
19	99
		20	100
21	100
		22	101
23	101
		24	102

Compare with the release characteristics of the nuclear that does not coat, the release characteristics of the tablet core that is coated shows: the not serious release of using in the pelletization that forms this nuclear that influences medicine from this tablet of polymer.This polymer coating provides delay sustained release characteristic.These all dosage form intensity for venlafaxine also are correct.

Example 2

The venlafaxine of 60mg postpones the tablet of sustained release

The material that the is shown in Table 4 tablet core that postpones the sustained release tablet with the venlafaxine of producing 60mg combined together:

Table 4
			Composition	Mg	％w/w
VENLAFAXINE HCL, USP	67.90	42
			Gellant 1	2.4	1.5
Filler 2	84.90	53
			Lubricant 3	4.8	3
Purified water 4，USP	N/A	N/A
			Tablet core weight	160	100

1 polyvinyl alcohol, USP

2 spray-dired lactose #315, USP

3 glyceryl behenates, NF

4 dry evaporations afterwards

With the method for describing in the example 1 produce tablet core and subsequently also as in the example 1 solution of a kind of material that is shown in Table 5 of usefulness of description coat this tablet core:

Table 5
			Composition	Mg	％w/w
The permeable film forming polymer of water-insoluble 1	11.4	60
			Water-soluble polymer 2	4.43	23.3
Plasticizer 3	3.17	16.6
			Solvent 4	N/A	N/A
Drying solid total amount (% that gains in weight)	19(12)	100
			Tablet core	160	-
The gross weight of coated tablet	179	-

1 ethyl cellulose 100, NF

2 polyvidones, USP

3 dibutyl sebacates, NF

4 ethanol (200 close mark), USP and isopropyl alcohol (99%), USP all volatilizees after drying

As the mensuration in example 1, the described tablet core of coating not, measure the dissolving of coated tablet.The result of the release % of VENLAFAXINE HCL total in the tablet core of coating has been shown in the table 6:

Table 6
		Time (hour)	Discharge %
1	3
		2	11
3	21
		4	30
5	40
		6	49
7	57
		8	63
9	68
		10	72
11	75
		12	78
13	81
		14	83
15	85
		16	87
17	89
		18	90
19	91
		20	92
21	93
		22	94
23	94
		24	95

Example 3

The venlafaxine of 120mg postpones the sustained release tablet

The material that the is shown in Table 7 tablet core that postpones the sustained release tablet with the venlafaxine of producing 120mg combined together:

Table 7
			Composition	Mg	％w/w
VENLAFAXINE HCL, USP	135.80	42.4
			Gellant 1	4.8	1.5
Filler 2	169.8	53
			Lubricant 3	9.6	3
Purified water 4，USP	N/A	N/A
			Tablet core weight	320	100

1 polyvinyl alcohol, USP

2 spray-dired lactose #315, USP

3 Tridocosanoins, NF

4 dry evaporations afterwards

According to the method for describing in the example 1 produce tablet core and as in the example 1 solution of a kind of material that is shown in Table 8 of usefulness of description coat these tablet cores:

Table 8
			Composition	Mg	％w/w
The permeable film forming polymer of water-insoluble 1	27.53	58.58
			Water-soluble polymer 2	12.49	26.57
Plasticizer 3	6.98	14.8
			Solvent 4	N/A	N/A
Drying solid total amount (% that gains in weight)	47(15)	100
			Tablet core	320	-
The gross weight of coated tablet	367	-

1 ethyl cellulose 100, NF

2 polyvidones, USP

3 dibutyl sebacates, NF

4 ethanol (200 close mark), USP and isopropyl alcohol (99%), USP all volatilizees after drying

Measure the tablet core of coating according to the description in the example 1, measure by the dissolution of the tablet of coating.The result of the release % of VENLAFAXINE HCL total in the tablet core of coating has been shown in the table 9:

Table 9
		Time (hour)	Discharge %
1	4
		2	11
3	21
		4	31
5	43
		6	53
7	63
		8	70
9	77
		10	82
11	86
		12	90
13	92
		14	94
15	96
		16	97
17	98
		18	98
19	99
		20	99
21	100
		22	100
23	100
		24	100

Example 4

The venlafaxine of 180mg postpones the tablet of sustained release

The material that the is shown in Table 10 tablet core that postpones the sustained release tablet with the venlafaxine of producing 180mg combined together:

Table 10
			Composition	Mg	％w/w
VENLAFAXINE HCL, USP	203.67	42.4
			Gellant 1	7.2	1.5
Filler 2	254.73	53
			Lubricant 3	14.4	3
Purified water 4，USP	N/A	N/A
			Tablet core weight	480	100

1 polyvinyl alcohol, USP

2 spray-dired lactose #315, USP

3 Tridocosanoins, NF

4 dry evaporations afterwards

According to the method for describing in the example 1 produce tablet core and as in the example 1 solution of a kind of material that is shown in Table 11 of usefulness of description coat these tablet cores:

Table 11
			Composition	Mg	％w/w
The permeable film forming polymer of water-insoluble 1	33.966	58.56
			Water-soluble polymer 2	15.39	26.53
Plasticizer 3	8.64	14.8
			Solvent 4	N/A	N/A
Drying solid total amount (% that gains in weight)	58(12)	100
			Tablet core	480	-
The gross weight of coated tablet	538	-

1 ethyl cellulose 100, NF

2 polyvidon, USP

3 dibutyl sebacates, NF

4 ethanol (200 proof), USP and isopropyl alcohol (99%), USP all dewaters after drying.

Measure the dissolving of coated tablet according to the description in the example 1.The result of the release % of VENLAFAXINE HCL total in the tablet core of coating has been shown in the table 12:

Table 12
		Time (hour)	Discharge %
1	3
		2	11
3	20
		4	30
5	40
		6	50
7	60
		8	68
9	74
		10	80
11	84
		12	87
13	90
		14	92
15	94
		16	95
17	96
		18	97
19	97
		20	98
21	98
		22	98
23	98
		24	98

Claims (10)

1. be suitable for a kind of pharmaceutical composition that postpones sustained release of oral dose administration once a day, comprise:

A) nuclear, this nuclear comprises the venlafaxine at least a form of the weight from about 10% to about 90% of nuclear dry weight, a kind of gellant less than 10% and optional conventional excipients, the venlafaxine of this at least a form is selected from following group, this group comprises a kind of pharmaceutically acceptable salt of active metabolite of a kind of active metabolite, the venlafaxine of a kind of pharmaceutically acceptable salt, the venlafaxine of venlafaxine, venlafaxine, and their combination;

B) hold a sustained release coating of described nuclear basically, described coating comprises the ethyl cellulose in the weight of this coating dry weight about 60%, about 25% polyvinylpyrrolidone and a kind of plasticizer of about 15%;

Wherein said compositions provides a kind of release that postpones to control of the venlafaxine of described at least a form, thereby use USP device 1 in the phosphate buffer of the pH6.8 of 1000ml with 75rpm when detecting down for 37 ℃ ± 0.5 ℃, the venlafaxine of this at least a form discharged no more than 20% after about 2 hours, the venlafaxine of this at least a form discharged about 15% to about 45% after about 4 hours, the venlafaxine of this at least a form discharged about 55% to about 85% after about 8 hours, the venlafaxine of this at least a form discharged after about 12 hours and is no less than approximately 65%, and the venlafaxine of this at least a form discharged after about 16 hours and is no less than about 80%.

2. the compositions that discharges of the delay of claim 1, it randomly comprises at least a other coating.

3. the compositions that discharges of the delay of claim 1, wherein this plasticizer comprises a kind of polyhydric alcohol, organic ester, oil or glyceride.

4. the compositions that discharges of the delay of claim 1, wherein the hot pharmaceutically acceptable salt of this article traction therapy comprises: acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylene-sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, pounce on acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid etc.

5. the compositions that discharges of the delay of claim 4, wherein this salt is hydrochlorate.

6. the compositions of the delay of claim 1 release comprises the venlafaxine from 20mg to 200mg.

7. the compositions that discharges of the delay of claim 6 comprises the venlafaxine of 30mg.

8. treat one to its method that depression of patient who needs is arranged for one kind, comprise a kind of compositions that postpones to discharge that gives once a day according to claim 1.

9. the slow releasing composition of the venlafaxine of at least a form is a kind of pharmaceutical composition that postpones sustained release that is suitable for oral dose administration once a day, comprise: a) nuclear, comprise venlafaxine at least a form of the weight from about 10% to about 90% of this nuclear dry weight, a kind of gellant less than 10% and optional conventional excipients, the venlafaxine of this at least a form is selected from following group, this group comprises the pharmaceutically acceptable salt of a kind of active metabolite of venlafaxine, venlafaxine, and their combination; And b) holds a kind of sustained release coating of described nuclear basically, described coating comprises the permeable film forming polymer of a kind of water-insoluble in the weight from about 20% to about 85% of this coating dry weight, from about 10% to about 75% a kind of water-soluble polymer or material and a kind of plasticizer of from about 3% to about 40%; Wherein said compositions provides a kind of release that postpones to control of the venlafaxine of described at least a form, thereby when use USP device 1 in the phosphate buffer of the pH6.8 of 1000ml with 75rpm when detecting down for 37 ℃ ± 0.5 ℃, the venlafaxine of this at least a form discharged no more than 20% after about 2 hours, the venlafaxine of this at least a form discharged about 15% to about 45% after about 4 hours, the venlafaxine of this at least a form discharged about 55% to about 85% after about 12 hours, the venlafaxine of this at least a form discharged after about 16 hours and is no less than about 80%.

10. treat one to its method that depression of patient who needs is arranged for one kind, comprise a kind of compositions that postpones to discharge that gives once a day according to claim 9.