CN101076320A - High-dosage extended-release formulation of gepirone - Google Patents

Abstract

A machine ( 1 ) for making filter bags ( 4 ) of tetrahedral shape for infusion products comprises a revolving conveyor drum ( 15 ) driven by a first drive shaft ( 16 ) to feed a web ( 5 ) of filter paper along a path (P) on which there are positioned: a station ( 25 ) for feeding the filter paper web ( 5 ); a station ( 21 ) for feeding a succession of tags ( 6 ); a station ( 22 ) for feeding tie string ( 7 ) connecting the filter bags ( 4 ) to the respective tags ( 6 ); a station ( 23 ) for arranging the tie string ( 7 ) according to a defined pattern on the path (P); and a plurality of sealers ( 24 ) facing the path (P) to attach the tie string ( 7 ) and the tags ( 6 ) to the filter paper web ( 5 ). The sealers ( 24 ) perform a defined movement between a sealing position and a waiting position, and this movement, which is performed simultaneously and synchronously by all the sealers ( 24 ), is imparted, through a transmission element ( 39 ) shared by all the sealers ( 24 ), by a second cam drive shaft ( 36 ) connected to the same source of motion ( 18 ) to which the first shaft ( 16 ) that drives the conveyor drum ( 15 ) is connected.

Description

The high dose time-delay delivery formulations of gepirone

Technical field

The present invention relates to the high dose time-delay delivery formulations of gepirone and by to there being the curee who needs to give the method for said preparation treatment serious symptom depression.More specifically, the present invention relates to the high dose time-delay release tablet of gepirone.The present invention also relates to treat the method for mammal depression, this method gives the high dose time-delay delivery formulations according to gepirone of the present invention of effective dose to the curee who needs is arranged.

Background technology

Gepirone ((Gepirone, be also referred to as 4,4-dimethyl-1-[4-[4-(2-pyrimidine radicals)-1-piperazinyl]-butyl]-2,6-piperidine dione hydrochlorate) can be by the United States Patent (USP) 4 of Temple, 423,049 embodiment 7 described processes are made (quoting in full at this as a reference), have following array structure:

Gepirone and salt thereof is known to possess antidepressant and anxiolytic property, is inferred and serves as 5-HT _1AThe agonist of receptor.They are generally used for treatment depressed, dysthymia, get excited disease, panic attack etc.But, in IR formulation, the half-life of gepirone is short.In blood flow, reach the time (T of the maximum drug level of gepirone _Max) be about 1 hour, its T ₅₀(just under in check conditions in vitro until the time that discharges 50% medicine) is about 2.5-3 hour (referring to U.S.5,478,572, quote in full at this as a reference).

Because it is by rapidly metabolism, the past all is to give gepirone in some low doses, 5 to 10mg dosage for example, every day 2 to 3 times.But, this multiple dose scheme can cause compliance issues.And, take the failure of the second or the 3rd dosage and cause the blood plasma level of gepirone unacceptablely low.And then, studies show that with regard to after the administration 15 to 20 hours oral instant-free gepirone preparation can produce significant human plasma concentration difference (about further discussion, referring to D.S.Robinson et al, Clinical Therapeutics, 1618-1633 (2003)).

But, about any pharmaceutical compound, every dosage level that needs of patients is different makes therapy specifically be adapted to patient's body condition, age and disease complexity.Therefore, even utilize U.S. Patent No. 5,478,572 disclosed low dosage gepirone time-delay releasing patterns also may need repeatedly to take (just 4 20mg dosage are different from single high dose sheet fully), and this is inconvenient and expensive.And the solubility behavior that still presses for high dose gepirone time-delay releasing pattern is similar to U.S. Patent No. 5,478, and 572 disclosed low dosage gepirone time-delay releasing patterns are kept identical relative bioequivalence simultaneously.

So far, it is believed that and to prepare high dose gepirone time-delay releasing pattern, to can not cause 1-(2-pyrimidine radicals) piperazine (main metabolites of gepirone, its is believed to be responsible for bad side effect, comprise dizziness, feel sick, headache and drowsiness) amount the reduction of not satisfied increase or relative potency is arranged.This suspection is from the following fact: for the fully release of control gepirone, will have to increase adhesive ingredients to a kind of like this degree, so that the gained tablet for oral administration will become " horse is used pill " (just big must being under an embargo).Select as an alternative, dosage will have to be formulated into by not too desirable means and send (for example intravenous administration).

Summary of the invention

The purpose of this invention is to provide pharmaceutical composition, contain:

(1) about gepirone of 14 to about 25wt% or its biologically active metabolite product are free alkali or its pharmaceutically acceptable salt;

(2) about 70 to about 85wt% pharmaceutically acceptable cellulosic polymer substrate; With

(3) an amount of one or more pharmaceutically acceptable excipient,

Wherein the speed that discharges from dosage form of gepirone is such, reaches about 90 to about 95% gepirone and absorbs and need about 18 to 24 hours.

In this purpose of the present invention, (3) further comprise at least a pharmaceutically acceptable excipient, are selected from the group of being made up of coloring agent, microcrystalline Cellulose, colloid silicon and magnesium stearate; (2) be hydroxypropyl emthylcellulose, viscosity is from about 15, and 000cps is to about 100,000cps; (1) accounts for about 15.5 to about 18.7wt%.

Another object of the present invention provides compositions, contains:

(a) about gepirone of 14.0 to about 24.4wt% or its biologically active metabolite product are free alkali or its pharmaceutically acceptable salt,

(b) 70.5 to 82.1wt% hydroxypropyl emthylcellulose, viscosity be from about 15,000 to about 100,000cps,

(c) 0 to about 1wt% coloring agent,

(d) about microcrystalline Cellulose of 8.0 to about 16.7wt%,

(e) about 0.39 to about 0.47wt% colloid silicon and

(f) about magnesium stearate of 0.29 to about 1.0wt%.

Another object of the present invention provides compositions, contains:

(a) the gepirone hydrochlorate of about 15.6wt%,

(b) hydroxypropyl emthylcellulose of about 75.3wt%,

(c) yellow ferric oxide of about 0.31wt%,

(d) microcrystalline Cellulose of about 8.0wt%,

(e) the colloid silicon of about 0.42wt% and

(f) magnesium stearate of about 0.31wt%.

Another object of the present invention provides compositions, contains:

(a) the gepirone hydrochlorate of about 19.5wt%,

(b) hydroxypropyl emthylcellulose of about 70.7wt%,

(c-1) yellow ferric oxide of about 0.24wt%,

(c-2) red ferric oxide of about 0.61wt%,

(d) microcrystalline Cellulose of about 8.2wt%,

(e) the colloid silicon of about 0.39wt% and

(f) magnesium stearate of about 0.29wt%.

In every kind of above-mentioned purpose, further purpose of the present invention provides the tablet form of high dose gepirone time-delay releasing pattern.

In preferred purpose of the present invention, avette-orthogonal shape that tablet has has biconvex or smooth surface.In this purpose, the overall dimension of tablet is 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch (biconvex surface) or 0.195 ± 0.025 inch (flat surfaces).Also in this purpose, the gross weight of described tablet preferably from 350 to 450mg.

Another object of the present invention provides the method for improving depression, anxiety or mental maladjustment (particularly depressed), and this method gives the tablet form according to compositions of the present invention or compositions of effective dose to the patient (particularly people) who needs is arranged.

Another object of the present invention provides the method for the above-mentioned tablet form of the preparation present composition.

Above-mentioned purpose looms large some aspect of invention.Other purposes of the present invention, aspect and embodiment are referring to following detailed invention description.

Description of drawings

By with reference to following accompanying drawing,, will better understand invention and much follow advantage in conjunction with hereinafter describing in detail.

Fig. 1 shows described 20mg of preparation example and the 60mg sheet contrast dissolution mechanism (referring to embodiment 1) in 0.01M HCl.

Fig. 2 shows described 20mg of preparation example and the 60mg sheet contrast dissolution mechanism (referring to embodiment 1) in water.

Fig. 3 shows described 20mg of preparation example and the 60mg sheet contrast dissolution mechanism (referring to embodiment 1) in pH 4.5 media.

Fig. 4 shows described 20mg of preparation example and the 60mg sheet contrast dissolution mechanism (referring to embodiment 1) in pH 6.8 media.

Summary of the invention

Unless specific definition, all technology used herein and scientific terminology all have the implication that the biochemistry of being commonly, chemistry, pharmacology and medical science technical staff understand.

All similar or be equivalent to described herein those method and material can both be used for be implemented or test the present invention, suitable method and material are as described herein. All publications mentioned in this article, patent application, patent and other lists of references all quote in full at this as a reference. Having in the situation of conflict, will with this specification, comprise the definition be as the criterion. And then only for setting forth, it is restrictive not planning for material, method and example, and other has except the appointment.

The present invention on the part degree based on inventor's discovery, namely, can access the high dose time-delay releasing pattern of Gepirone, wherein the solubility behavior of this formulation and bioequivalence (with regard to 1-PP, 3 '-OH Gepirone and Gepirone) are equivalent to U.S. Patent No. 5,478, the low dosage of 572 disclosed Gepirones time-delay releasing pattern is although reduced population proportion between active component and the release control polymer (adhesive).

Time-delay discharges medicament forms (especially Gepirone) provides some instant-free advantage of systems that are better than. Patient's compliance is better, because the time-delay release dosage form only need be taken once in 24 hours. Thereby when giving the ER formulation, the PC level does not have unacceptable variation, namely produces the high initial drug level relevant with undesirable side effect generation, and levels of drugs is dropped rapidly to and is lower than treatment level. In addition, in the situation of Gepirone, because the 1-PP level of keeping slow release is in gratifying level, thereby avoided the remarkable complication that caused by this metabolite.

In general embodiment, the invention provides the pharmaceutical composition that discharges the Gepirone formulation for the preparation of oral time-delay, comprise:

(1) about Gepirone of 14 to about 25wt% or its biologically active metabolite product are free alkali or its pharmaceutically acceptable salt;

(2) about 70 to about 85wt% pharmaceutically acceptable cellulosic polymer matrix; With

(3) the pharmaceutically acceptable excipient of an amount of one or more,

Wherein the speed that discharges from formulation of Gepirone is such, reaches about 90 to about 95% Gepirone and absorbs and need about 18 to 24 hours.

Particularly preferred embodiment of the present invention is the time-delay liberation port oral dosage form of Gepirone, represents to contain with percentage by weight:

(a) about 14.0 Gepirone or its biologically active metabolite products to about 24.4% (preferred about 15.5 to about 18.7%) are free alkali or its pharmaceutically acceptable salt, hydrochloride for example,

(b) about 70.5 to about 82.1% hydroxypropyl methylcellulose, viscosity be from about 15,000 to about 100,000cps,

(c) 0 ferriferous oxide to about 1% (preferred 0 to about 0.3%),

(d) about 8.0 to about 16.7% microcrystalline cellulose,

(e) the about 0.39 colloid silicon to about 0.47% (preferred about 0.42 to about 0.47%), and

(f) about 0.29 to about 1.0% dolomol.

Although with regard to every kind of component, defined above-mentioned embodiment with specific compound, but self-evident be within the scope of the invention, these components can difference as described below or are replaced with various combinations. With regard to following every kind of component, self-evident is the total concentration of every kind of component of percentage by weight reflection of quoting. For example, if there is the compound mixture that falls in the defined component class range, the percentage by weight of quoting so reflects the overall of this compound mixture.

Component (a):

In preferred embodiment, the percentage by weight of component (a) in time-delay liberation port oral dosage form is about 14.0 to about 24.4%, more preferably from about 15.5 to about 18.7%. Particularly preferably being component (a) is Gepirone or its pharmaceutically acceptable salt.

Gepirone is by metabolism in the body, cause two kinds of main pharmacologically active metabolite: 1-(2-pyrimidine radicals) piperazines (1-PP) and 3 '-OH Gepirone (D.S.Robinson et al, Clinical Therapeutics, pp.1618-1633 (2003)). Also generate in the body two kinds other also may possess bioactive metabolite: 5-OH Gepirone and 3 ', 5-dihydroxy Gepirone.

In the mankind, the release of grand (azapirone) metabolite 1-PP of common azepine piperazine is considered to cause bad side effect, comprises dizziness, nauseating, headache and drowsiness. And, 1-PP is a kind of presynaptic α-2-adrenoreceptor antagonist, have been reported it and in clinical precursor test, do not show antidepressant sample feature (D.S.Robinson et al, Clinical Therapeutics, pp.1618-1633 (2003)). On the contrary, biologically active metabolite product (particularly 3 '-OH Gepirone) has significant 5-HT_1AReceptor affinity. The mode that 3 '-OH Gepirone has been proved to be to be similar to Gepirone changes the 5-HT neurotransmission, even 3 '-OH Gepirone has been found to show completely hippocampus postsynaptic receptor agonism, and Gepirone is a kind of partial agonist (D.S.Robinson et al, Clinical Therapeutics, pp. 1618-1633 (2003)).

In view of above-mentioned, in embodiments of the present invention, can use one or more biologically active Gepirone metabolites 3 '-OH Gepirone, 5-OH Gepirone and 3 ', 5-dihydroxy Gepirone or its pharmaceutically acceptable salt to replace Gepirone.

And then although the pharmaceutically acceptable salt form is preferred, but Gepirone or biologically active Gepirone metabolite also can be hydrate forms, enantiomeric form or mixture or crystal form.

The medical compounds that is suitable for administration among the present invention can be hydrochloride, but free alkali and other pharmaceutically acceptable salts also are fit to. Term " pharmaceutically acceptable salt " is well known in the art, and the technical staff can be with reference to further specify (the J Pharmaceutical Sciences, 66:1-19 (1977) is referenced herein by reference) of S.M.Berge. The pharmaceutically acceptable salt that is suitable for administration among the present invention comprises acid-addition salts. Acid-addition salts can followingly generate, the solution of the solution of mixing cpd and pharmaceutically acceptable avirulence acid, described acid is hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, butanedioic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, perchloric acid, sulfuric acid, oxalic acid or malonic acid for example. If compound carries acidic-group, hydroxy-acid group for example, its salt is also contained in the present invention, preferably its avirulence pharmaceutically acceptable salt, for example its sodium, potassium and calcium salt.

Other pharmaceutically acceptable salts comprise adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphorate, camsilate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, the 2-isethionate, Lactobionate, lactate, laruate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, Pivalate, propionate, stearate, succinate, sulfate, tartrate, rhodanate, p-toluene fulfonate, the hendecane hydrochlorate, valerate etc. Representative alkali metal or alkali salt comprise sodium, lithium, potassium, calcium, magnesium etc. Further pharmaceutically acceptable salt according to circumstances comprises the salt of amine groups. The salt of amine groups also can comprise quaternary ammonium salt, wherein amino nitrogen atom is carried alkyl, thiazolinyl, alkynyl or aralkyl, use counter ion counterionsl gegenions to generate avirulence ammonium, quaternary ammonium and amine cation, for example halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, low-grade alkane sulfonate and arylsulphonate.

Component (b):

In preferred embodiment, the percentage by weight of component (b) in time-delay liberation port oral dosage form is about 70.5 to about 82.1%. Preferably, component (b) is hydroxypropyl methylcellulose, and viscosity is from about 15,000 to about 100,000cps, and it is a kind of release control polymer and adhesive (a.k.a. continues agent).

With regard to oral formulations and formulation, the use of polymerism cellulose matrix or lasting agent (sustaining agent) is preferred. The matrix that is fit to comprises the alkylcellulose that hydroxy alkyl replaces, and viscosity is about 15,000 to about 100,000cps. The example of acceptable hydroxymethyl-propyl cellulose (HPMC) sample comprise K15M and K100M level (namely respectively 15,000 and 100,000cps).

Can (all or part of) replace or adding HPMC in the present invention, can replace some or all HPMC matrix with Dicalcium Phosphate or lactose, they generally increase rate of dissolution.

Except the adhesive of component (b), preparation of the present invention also can contain complementary adhesive, for example syrup, Arabic gum, gelatin, D-sorbite, bassora gum or polyvinylpyrrolidone. The filler that is fit to or the example of replenishers also comprise starch (for example cornstarch), lactose, D-sorbite, glycine, sucrose, glucose, mannitol, silicic acid, natrium citricum and Dicalcium Phosphate. The example of the adhesive that other are fit to can comprise shitosan, alginates, gelatin, polyvinylpyrrolidone, sucrose, Arabic gum and composition thereof.

In embodiments of the present invention, the ratio (Gepirone: adhesive) from 1: 3.5 to 1: 14.5 of Gepirone and adhesive. Preferably, adhesive is hydroxymethyl-propyl cellulose (HPMC).

Component (c):

In preferred embodiment, the percentage by weight of component (c) in time-delay liberation port oral dosage form is 0 to about 1%, preferred 0 to about 0.3%. Although component (c) can be any colouring agent, but preferably colouring agent is ferriferous oxide. In particularly preferred embodiments, ferriferous oxide is red ferric oxide, yellow ferric oxide or its mixture.

Can be used to replace other exemplary coloring agent of above-mentioned or other adding to include but not limited to FD﹠amp; C and D﹠amp; C color lake, titanium dioxide, iron oxides, natural pigment or obtain the stain that drug administration of the United States Federal permission is ingested, perhaps its combination.

Component (d):

In preferred embodiment, the percentage by weight of component (d) in time-delay liberation port oral dosage form is about 8.0 to about 16.7%.Although component (d) can be any diluent and/or compression aid, but preferably diluent/compression aid is a microcrystalline Cellulose.

Other diluent can include but not limited to water or other solvents, solubilizing agent and emulsifying agent, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzoic acid benzyl ester, propylene glycol, 1, the fatty acid ester of 3-butanediol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol and sorbitan, and composition thereof.

In another embodiment of the invention, the ratio (gepirone: of gepirone and diluent diluent) from 1: 3 to 2.5: 1.Preferably, diluent is a microcrystalline Cellulose.

Component (e):

In preferred embodiment, the percentage by weight of component (e) in time-delay liberation port oral dosage form is about 0.39 to about 0.47%, preferred about 0.42 to about 0.47%.Although component (e) can be any fluidizer, but preferably fluidizer is colloid silicon (silica sol).

Other fluidizer include but not limited to corn starch, Talcum or stearic acid, perhaps its mixture.

Component (f):

In preferred embodiment, the percentage by weight of component (f) in time-delay liberation port oral dosage form is about 0.29 to about 1.0%.Although component (f) can be any lubricant, but preferably lubricant is a magnesium stearate.

Other lubricants can include but not limited to cellulose, Talcum, Polyethylene Glycol, Silicon stone, sodium lauryl sulfate, calcium stearate and composition thereof.

Or select component:

Among the present invention, except component (a) to (f), time-delay liberation port oral dosage form can also contain various annexing ingredients.Based on above illustrating and Remington ' s PharmaceuticalsSciences the 18th edition (quoting as a reference) at this, especially wherein the 8th part " Pharmaceutical Preparations and Their Manufacture " is added new chemical compound to above-mentioned preferred implementation and is incited somebody to action in the complete scope the technical staff.

In embodiments of the present invention, time-delay liberation port oral dosage form can comprise one or more other pharmaceutically acceptable carrier.Term used herein " pharmaceutically acceptable carrier " expression nontoxic, inert solid, semisolid or liquid filling agent, diluent, encapsulating material or formulation aid.Some can serve as the example of material of pharmaceutically acceptable carrier existing mentioning above, therefore self-evident in inventing in this respect is that pharmaceutically acceptable carrier can be filler, diluent, encapsulating material or the formulation aid of the former any type of not mentioning.

In another embodiment, time-delay liberation port oral dosage form also can comprise one or more releasing agents, coating materials, sweeting agent, correctives and flavouring agent, antiseptic and antioxidant.

The correctives that is mainly used in taste masking and/or abnormal smells from the patient can be vanillin, sodium citrate, citric acid, Herba Menthae, Fructus Citri junoris, Fructus Citri Limoniae oil or other pharmaceutically licensed correctivess or taste masked agent arbitrarily, and combination.

The shape and the physical state of the high dose time-delay releasing pattern of gepirone

The time-delay liberation port oral dosage form that is suitable for oral administration is contained in the present invention.These forms comprise the form that tablet, capsule, folliculus, lozenge, powder, suspension, syrup etc. are fit to.Preferably, tablet can be included as those of convex, sphere (promptly circular) or scrotiform.

In preferred embodiment, the time-delay liberation port oral dosage form of gepirone is a tablet.Preferably, tablet is avette, and this enlarges their surface area, improves gepirone and therefrom discharges.More preferably, tablet is avette-rectangle, and it can have the surface of smooth or biconvex.

When the time-delay liberation port oral dosage form of gepirone be avette-during the rectangle tablet, preferably the overall dimension of these tablets is 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch (biconvex surface) or 0.195 ± 0.025 inch (flat surfaces).

In another embodiment of the invention, total sheet is heavily from 350 to 450mg, and preferred 375 to 425mg, and more preferably 385 to 410mg.And then, in context of the present invention, 350 to 450mg, the heavy scope of preferred 375 to 425mg, more preferably 385 to 410mg sheet is equivalent to the gross weight of unit dosage form.

Therefore, pharmaceutical composition of the present invention (the time-delay liberation port oral dosage form of gepirone just) preferably contain and have an appointment 55 to 100mg (preferred 60 to 80mg, more preferably 60 or 80mg) the every dosage unit of active component.

If necessary, tablet can utilize known method and excipient coating, and they can comprise enteric coating, for example uses hydroxypropyl emthylcellulose phthalic acid salt.If necessary, this class tablet can have enteric coating, and known method is for example used cellulose acetate phthalic acid salt.They can contain opacifying agent alternatively, and also can be a kind of like this compositionss, and they only or preferential in certain part of intestinal, alternatively with the delayed mode release of active ingredients.The example of the embedding composition that can use comprises polymeric material and wax class.

Similarly, contain reactive compound and adding or do not add the capsule of excipient, for example hard or Perle can prepare by known method, has enteric coating if necessary in a known way.Capsular content can utilize the known method preparation, to obtain the lasting release of reactive compound.In this class solid dosage forms, reactive compound can be mixed with at least a inert diluent, for example sucrose, lactose or starch.As normal practice, this class dosage form also can comprise other materials except that inert diluent, for example tabletting lubricant and other compression aids, for example magnesium stearate and microcrystalline Cellulose.Under the situation of capsule, tablet and pill, dosage form also can comprise buffer agent.They can contain opacifying agent alternatively, also can be a kind of like this compositionss, and they only or preferential in certain part of intestinal, alternatively with the delayed mode release of active ingredients.The example of the embedding composition that can use comprises polymeric material and wax class.

The solid composite that also can adopt similar type uses excipient as filler soft and hard gelatine capsule of filling, for example lactose or toffee, and high molecular weight polyethylene glycol etc.

Therapeutic Method

Gepirone can wherein contain gepirone hydrochlorate (or its biologically active metabolite product), cellulosic polymer substrate and an amount of drug excipient by oral administration in time-delay release dosage form once a day.Gained gepirone oral formulations product spends about 19 to about 24 hours and discharges 90 to 95% active component.

Therefore, another embodiment of the invention is method that treatment is diagnosed as (constitutional or generalization) the depressed companion's (being with or without generalized-anxiety disorder) that suffers from serious symptom patient, comprises the gepirone time-delay liberation port oral dosage form as described in the present application that described patient is given effective dose.

In this embodiment, need patient's (preferred people still comprises all mammals) of treatment at first to be diagnosed as and to suffer from specific depressed disease.Discussion about anxiety and depressed patient's evaluation, diagnostic criteria etc., the technical staff can reference: DSM-IV-TR (Diagnosticand Statistical Manual of Mental Disorders, AmericanPsychiatric Association, Washington, D.C, 2000; DepressiveDisorders:369-428, and Anxiety Disorders:429-484).

For this reason, gepirone of the present invention time-delay release composition and dosage form are designed to send the gepirone of effective antidepressant and/or anxiety amount or its pharmaceutically acceptable salt to mammal, preferred human patients.

" effectively " used herein dosage is represented the amount of about 0.01 to 40mg/kg body weight/day, preferred 0.05 to 20mg/kg body weight/day, more preferably 0.1 to 2mg/kg body weight/day.With regard to some central nervous system's illness, recommended preferred 30-60mg/ days 15 to 90mg/ days.Referring to U.S. Patent No. 4,771,053 and U.S. Patent No. 5,478,572.Select as an alternative, effective dose or delivery system should cause plasma concentration at about 1ng/ml to the scope of about 20ng/ml, preferably about 1ng/ml is about 5ng/ml extremely.

As mentioned above, in embodiments of the present invention, represent to contain with percentage by weight with gepirone time-delay liberation port oral dosage form in the methods of the invention:

(a) about 14.0 gepirone or its biologically active metabolite products to about 24.4% (preferred about 15.5 to about 18.7%) are free alkali or its pharmaceutically acceptable salt, hydrochlorate for example,

(b) about 70.5 to about 82.1% hydroxypropyl emthylcellulose, viscosity be from about 15,000 to about 100,000cps,

(c) 0 iron oxides to about 1% (preferred 0 to about 0.3%),

(d) about 8.0 to about 16.7% microcrystalline Cellulose,

(e) about 0.39 to the colloid silicon of about 0.47% (preferred about 0.42 to about 0.47%) and

(f) about 0.29 to about 1.0% magnesium stearate.

As defined above, the gepirone in the gepirone time-delay liberation port oral dosage form is also contained biological activity gepirone metabolite, is selected from by 3 '-OH gepirone, 3 ' group that 5-dihydroxy gepirone and 5-OH gepirone are formed.This method can adopt any these chemical compounds.But, also contain the combination of these metabolites or the combination of these metabolites and other activity or inert fraction.

The present invention further provides improvement needs the patient of this class treatment (preferred people, but comprise all mammals) the method for depression, anxiety or mental maladjustment, this method gives the gepirone or the biological activity gepirone metabolite of effective dose or dosage to this patient, for example 3 '-OH gepirone, 3 ', 5-dihydroxy gepirone and 5-OH gepirone.The administration of gepirone used herein or biological activity gepirone metabolite comprises the administration of any active salt form, hydrate forms, enantiomeric form or the mixture or the crystal form of this chemical compound.

Also have such method within the scope of the invention, wherein (successively or simultaneously) gives time-delay liberation port oral dosage form and one or more antidepressants or the antianxiety drug of gepirone in the conjoint therapy of treatment depression and/or anxiety.

Production method

Gepirone of the present invention time-delay liberation port oral dosage form can be by following prepared:

(i) blending ingredients (a) to (f) is all or part of,

(ii) this mixture of fusion,

(iii) add a part or all the other (if any) components (a) to (f),

(iv) this mixture of fusion (if during (iii), adding remainder),

(v) bang,

(vi) mill,

(vii) add all the other lubricants (component (f) is if keep a part at (i) and (iv)),

(viii) this mixture of fusion,

(ix) suppress the tablet admixture that finally obtains.

Certainly, self-evident is that above-mentioned steps can be rearranged or replace, as long as this is rearranged or replaces the pharmacological effect that can not change the said process resulting dosage forms basically.In this, the technical staff is with reference to Remington ' s Pharmaceuticals Sciences the 18 half (quoting at this as a reference), for example the 8th part wherein " PharmaceuticalPreparations and Their Manufacture ".

And then the technical staff is with reference to U.S. Patent No. 4,423, and 049 and 5,478,572 (quoting at this as a reference) described processing technique is to provide the related example of above-mentioned gepirone time-delay liberation port oral dosage form production process.

In preferred embodiment, abide by following prepared gepirone time-delay of the present invention liberation port oral dosage form:

I) 20% of mixing all ingredients (a), whole component (c), whole component (e) and component (b) total concentration;

Ii) fusion is from the mixture of (i);

Iii) to half-sum component (b) total concentration that adds whole components (d), component (f) total concentration from (ii) admixture all the other 80%;

Iv) fusion is from (iii) mixture;

V) thump from (iv) admixture;

Vi) mill from (ball piece v);

Vii) to from (the ball piece of milling of process vi) adds all the other components of 50% (f);

Viii) fusion is from (mixture vii);

Ix) will be from (admixture viii) is pressed into final required form.

Usually, the gained admixture is pressed into tablet or microgranule in step (ix).If make microgranule, they wrap alternatively with conventional coating auxiliary agent, then tabletting or be filled in the capsule.

Needing under the situation of enteric coating, this coating will add in step (ix) usually afterwards.

Self-evident is that every kind of above-mentioned manufacture process can scale up to industrial available scale, and never is limited to discrete dosimetric system Preparation Method.Also can change (indivedual or common) to every kind of step, to help the production of gepirone time-delay liberation port oral dosage form of the present invention, as long as these modify the biological effect that the composition that can not change final products exceeds above-mentioned tolerance limit or products obtained therefrom.

Above-mentioned written explanation of the present invention provides preparation and uses its mode and process, so that any technical staff in this area can both prepare and use it, particularly the purpose of accessory claim provides this possibility, and they constitute the part of original explanation.

Above used wording " is selected from by ... the group of composition ", " being selected from " etc. comprises specified mixtures of material.

If this paper has stipulated digital limit or scope, then terminal point is included.And all numerical value in digital limit or scope and all specifically being included among a small circle are as clearly writing out.In this, if quote term " about ", then this term is understood to include the numerical value of being quoted, and the numerical value of being quoted 1% with interior (above or once, as to depend on " pact " and whether defined boundary up and down), the preferred numerical value of quoting 0.5% with interior numerical value.

Above-mentioned explanation makes those skilled in the art can prepare and use invention, is to provide in the background of application-specific and requirement thereof.Various modifications for preferred implementation will be apparent for those skilled in the art institute, and General Principle defined herein can be applied to other embodiments and application, and does not deviate from the spirit and scope of invention.Thereby the present invention does not plan to be limited to shown embodiment, but meets and principle disclosed herein and characteristic the most wide in range corresponding to scope.

Describe on the basis of the present invention in generality, can obtain further understanding with reference to some instantiation, these examples only supply purposes of illustration, and it is restrictive not planning, and other has except the appointment.

Embodiment

Preparation example

Abide by above and U.S. Patent No. 5,478,572 described technologies, the tablet form of preparation gepirone time-delay liberation port oral dosage form.Generally speaking, this arts demand (i) mixes whole gepirone hydrochlorates, whole coloring agent, whole silica sol and 20% hydroxypropyl emthylcellulose; (ii) fusion reaches 15 minutes from the mixture of (i), utilizes the Fitzmill#0020 flat board to smash subsequently; (iii) to adding whole microcrystalline Cellulose, 50% magnesium stearate and all the other hydroxypropyl emthylcelluloses of 80% from (ii) admixture; (iv) fusion reaches 28 minutes from (iii) mixture; (v) utilize rotary tablet machine bang from (iv) admixture; (vi) utilize the Fitzmill#0093 flat board to mill from (ball piece v); (vii) to from (the ball piece of milling of process vi) adds all the other magnesium stearate of 50%; (viii) lubricated/fusion is from (mixture vii) reaches 7 minutes; (ix) compacting is from (admixture viii) is final required tablet form.

In this mode, obtain having the avette-rectangular sheet on biconvex surface.The overall dimension of tablet is 0.405 inch (102.87mm) * 0.338 inch (85.85mm), and the cup degree of depth is 0.050 inch (12.70mm).Following table 1 provides tablet weight and constituent content/unit:

Table 1:

		Every unitary content (unit is in mg)
						Composition	Function	The 20mg sheet	The 40mg sheet	The 60mg sheet	The 80mg sheet
Gepirone HCl	Active component	20.0 (18.1) 1	40.0 (36.2) 1	60.0 (54.3) 1	80.0 (72.4) 1
						Silica sol	Fluidizer	1.6	1.6	1.6	1.6
Yellow ferric oxide	Coloring agent	0.4	0.08	1.2	1.0
						Red ferric oxide	Coloring agent				2.5
Hydroxypropyl emthylcellulose	Discharge controlled polymer ﹠ binding agent	290.0	290.0	290.0	290.0
						Microcrystalline Cellulose	Diluent ﹠ compression aid	61.8	52.12	31.0	33.7
Magnesium stearate	Lubricant	1.2	1.2	1.2	1.2
						Total sheet is heavy		375.0	385.0	385.0	410.0

¹Show free alkali content

The dissolution mechanism of embodiment 1:60mg preparation and 20mg preparation

Following table 2 is listed 20mg and the contrast dissolution mechanism of 60mg sheet in all SUPAC-MR dissolve mediums.

Table 2:

		Time (hour)
												Medium	Intensity	1	2	4	8	10	12	14	16	18	20
0.01M HCl	20mg	20.2	30.4	45.1	64.7	71.8	77.8	82.8	86.9	90.5	93.4
												0.01M HCl	60mg	22.0	32.8	48.2	68.6	76.0	82.0	87.1	91.2	94.5	97.3
Water	20mg	19.8	29.8	44.0	63.1	70.1	76.0	80.9	85.0	88.4	91.3
												Water	60mg	21.9	32.7	48.2	68.6	75.8	81.7	86.6	90.5	93.7	96.2
pH＝4.5	20mg	17.7	26.6	39.5	57.2	63.8	69.4	74.3	78.6	82.3	85.6
												pH＝4.5	60mg	20.2	30.0	43.8	62.2	68.8	74.3	79.1	83.1	86.5	89.4
pH＝6.8	20mg	15.9	24.1	36.4	53.7	60.5	66.4	71.5	76.1	80.2	83.8
												pH＝6.8	60mg	17.5	26.4	39.6	57.6	64.4	70.2	75.1	79.5	83.3	86.6

The above results plots Fig. 1-4 with graphics mode.

The f1 of contrast dissolution mechanism and f2 calculate (referring to table 3) and have proved the identity property of tablet between all 4 kinds of media.

Table 3:

Medium	F1 1	F2 1
			0.01M HCl	5.2	71.2
Water	6.7	66.1
			pH＝4.5	6.8	70.1
pH＝6.8	5.3	76.3
			Standard 2	0-15	50-100

¹Distribution of results seeing clearly and/or measuring between F1 and F2 provided batch.

²Standard is equivalent to acceptable F1 and F2 numerical range.

Embodiment 2:80mg preparation is with respect to the bioequivalence of 20mg preparation

So far, the effect of time-delay release gepirone sheet mainly obtains (to above preparation example is described similar) by giving one or more pieces 20mg time-delay release gepirone sheets with pharmacokinetic data available.Therefore, take research to discharge the bioequivalence of gepirone sheet with proof 40mg (data not shown) and 80mg time-delay release gepirone sheet (as above preparation example is described) and multi-disc 20mg time-delay.

For this reason, adopt open-label, randomized, four paths intersect, single dose research design, the removing phase in a week is arranged between different disposal.During each conceptual phase, the experimenter was since after the gepirone administration 36 hours in hospital afternoon.After draining, after administration, carried out blood sample collection in 48,60 and 72 hours.During conceptual phase, give gepirone (30.9 ± 6.3 years old mean age to 32 (32) experimenters; Average weight 73.8 ± 8.3kg; Average height 178.1 ± 5.6; Average BMI 23.3 ± 2.3kg/m ²), be the single oral dose of 40mg or 80mg.For this reason, give following processing (as above tablet shown in the preparation example) with random order:

A) 1 * 40mg time-delay discharges gepirone sheet (data not shown);

B) 2 * 20mg time-delay discharges gepirone sheet (data not shown);

C) 1 * 80mg time-delay discharges the gepirone sheet;

D) 4 * 20mg time-delay discharges the gepirone sheet.

After each the processing, in 72 hours, obtain blood sample from the experimenter at interval, be used to measure the pharmacokinetics of gepirone, 1-PP and 3 '-OH gepirone by rule.

In order to measure the bioequivalence that a slice 80mg time-delay discharges gepirone sheet and four 20mg time-delay release gepirone sheets, calculate every experimenter and each following pharmacokinetic parameters of handling:

-t _max(TMAX)

C _MaxThe actual time that occurs.

-C _max(CMAX)

Take the measured maximal plasma concentration in back at single.

-dn-C _max(DCMAX)

According to C _Max/ Rapid Dose Calculation dosage-normalized C _Max

-λ _Z(LZ) and t _1/2(THALF)

Measure the slope (β) of the terminal logarithm of concentration-time curve-linearity phase by linear regression.Data must be brought function: log into _θC _i=log _θC _Interc-β t _i, start from least 3 C _i(the C of 〉=LOQ _i, t _i) data are right; C _IntercIt is the intercept of zero-time place's concentration axle.Continue this process, once add a data point formerly, bring regression equation into, until reaching at t _MaxC appears _MaxThen by the terminal logarithm-linear segment of the data definition that in regression analysis, produces minimum average B configuration variance (MSE).Define terminal elimination rate constant (λ according to-β _Z), calculate thus and eliminate half-life (t _1/2), be log _θ2/ λ _ZIgnore in the concentration of eliminating the interim LOQ of being lower than.

-AUC _0-tlast(AUCT)

Calculate from zero to t by linear trapezoidal rule _LastAUC (AUC _0-tlast), t wherein _LastRepresent that last can measure the time point of concentration in the experimenter.

-dn-AUC _0-tlast(DUCT)

According to AUC _0-tlast/ Rapid Dose Calculation dosage-normalized AUC _0-tlast

-AUC _0-∞(AUC)

According to AUC _0-∞=AUC _0-tlast+ AUC _Tlast-∞Calculating is from zero extremely infinite AUC.About AUC _0-tlast, see and go up AUC _Tlast-∞=C _Tlast/ λ _Z, C wherein _TlastBe to utilize to calculate λ _ZRegression line gained time t _LastThe concentration at place.

-dn-AUC _0-∞(DAUC)

According to AUC _0-∞/ Rapid Dose Calculation dosage-normalized AUC _0-∞

-CL _app(CLAPP)

True total blood plasma Cl (CL) after the single oral dose equals f dosage/AUC _0-∞, wherein f is the part absolute bioavailability of oral prepared product.Because therefore f can not calculate CL/F=dosage/AUC from independent oral data computation _0-∞, be expressed as " apparent Cl " (CL _App).The gepirone dosage that is given is represented with free alkali.The free alkali number of gepirone also is used for the CL of 1-PP and 3 '-OH gepirone metabolite _AppCalculate.

-wn-CL _app(WCLAPP)

According to CL _AppDivided by body weight (kg) calculated weight-normalized CL _App

-V _z，app(VZAPP)

According to V _{Z, app}=CL _App/ λ _ZApparent volume of distribution during the definition single oral dose kataphase.

-wn-V _z，app(WVZAPP)

According to V _{Z, app}Calculate body weight-normalized V divided by body weight (kg) _{Z, app}

With regard to dn-C _Max, dn-AUC _0-∞And dn-AUC _0-tlast, utilize 0.80-1.25 as accepting scope.If 90% confidence interval is completely contained in this and accepts in the scope, declare that so these preparations are bioequivalent about the parameter of being tested.Gepirone, 1-PP and 3 '-OH gepirone are not always the case.With regard to every other pharmacokinetic parameters, utilize the ANOVA model identical, to log with the bioequivalence test _θ-conversion values is carried out classical hypothesis test.

Calculate following column average (std.dev.) pharmacokinetic parameters (referring to table 4) of gepirone, 1-PP and 3 '-OH gepirone:

Table 4:

		Gepirone (n=32)		1-PP(n＝32)		3 '-OH gepirone (n=32)
								Parameter	Unit	1×80mg	4×20mg	1×80mg	4×20mg	1×80mg	4×20mg
C max	(ng/mL)	11.2(5.36)	10.2(7.05)	14.2(10.0)	13.1(7.05)	26.9(7.24)	25.1(6.99)
								dn-C max	(ng/mL/mg)	0.140(0.067)	0.128(0.088)	0.178(0.125)	0.164(0.088)	0.337(0.091)	0.314(0.087)
t max 1	(h)	5.5(2.0-12.0)	6.0(0.5-12.0)	5.0(3.0-18.0)	6.0(2.0-12.0)	6.0(4.0-12.0)	8.0(4.0-12.0)
								AUC 0-tlast	(ng.h/mL)	151(69.2)	149(89.8)	250(214)	260(200)	551(170)	557(181)
dn-AUC 0-tlast	(ng.h/mL/mg)	1.89(0.865)	1.86(1.12)	3.12(2.67)	3.25(2.50)	6.89(2.13)	6.96(2.27)
								AUC 0-∞	(ng.h/mL)	158(73.4)	155(88.1)	259(213)	268(202)	558(170)	562(183)
dn-AUC 0-∞	(ng.h/mL/mg)	1.98(0.917)	1.94(1.10)	3.24(2.66)	3.35(2.52)	6.97(2.13)	7.03(2.29)
								t 1/2	(h)	7.93(8.26)	8.22(9.12)	9.43(6.06)	7.41(3.34)	8.14(3.30)	7.40(2.13)
CL app	(L/h)	692(804)	625(386)	417(249)	396(242)	146(61.7)	144(53.9)
								wn-CL app	(L/h/kg)	9.70(12.7)	8.61(5.95)	5.73(3.78)	5.41(3.54)	2.01(0.971)	1.98(0.836)
V z，app	(L)	6416(6156)	7334(9108)	5531(4982)	4168(3289)	1672(806)	1437(346)
								wn-V z，app	(L/kg)	86.1(80.8)	102(137)	74.0(62.1)	57.0(44.7)	22.8(11.0)	19.8(5.92)

¹Average range

Following table 5 provides the statistical analysis of the average bioequivalence test that relates to gepirone, 1-PP and 3 '-OH gepirone.

Table 5:

Gepirone contrast: 1 * 80mg (test) and 4 * 20mg (reference)
						Parameter	Geometric average is for test preparation	Geometric average is with reference to preparation	Point estimation test/reference	90% confidence interval	Conclusion
dn-C max	0.123	0.105	1.17	1.02-1.33	Uncertain
						dn＝AUC 0-∞	1.71	1.68	1.02	0.89-1.16	Bioequivalence
dn＝AUC 0-tlast	1.63	1.59	1.03	0.90-1.18	Bioequivalence

1-PP contrast: 1 * 80mg (test) and 4 * 20mg (reference)
						Parameter	Geometric average is for test preparation	Geometric average is with reference to preparation	Point estimation test/reference	90% confidence interval	Conclusion
dn-C max	0.151	0.146	1.03	0.94-1.13	Uncertain
						dn＝AUC 0-∞	2.60	2.74	0.95	0.87-1.04	Bioequivalence
dn＝AUC 0-tlast	2.47	2.62	0.94	0.86-1.03	Bioequivalence

3 '-OH gepirone contrast: 1 * 80mg (test) and 4 * 20mg (reference)
						Parameter	Geometric average is for test preparation	Geometric average is with reference to preparation	Point estimation test/reference	90% confidence interval	Conclusion
dn-C max	0.325	0.303	1.07	0.98-1.18	Bioequivalence
						dn＝AUC 0-∞	6.62	6.67	0.99	0.90-1.09	Bioequivalence
dn＝AUC 0-tlast	6.54	6.61	0.99	0.90-1.09	Bioequivalence

As can be seen from Table 5, with regard to whole chemical compounds, find 1 * 80mg sheet about the average bioequivalence of dn-AUC in four 20mg sheets.The dn-C of 1-PP and 3 '-OH gepirone _MaxAlso be like this.With regard to gepirone, find dn-C _MaxUncertain result is arranged.

The average bioequivalence test of gepirone is drawing uncertain conclusion in some cases, accepts scope 0.80-1.25 although test is positioned at point estimate with reference to the ratio of the geometric average of handling.Therefore, utilizing colony's method to carry out the additional statistical credit analyses as supportive evidence.The result is as shown in table 6, wherein

S _T ²: transform this variance of gross sample that the test of parameter handles (just within the experimenter and between the summation of variance) based on loge.

S _R ²: based on loge transform parameter with reference to this variance of gross sample of handling (just within the experimenter and between the summation of variance).

S _d ²: the sample variance of difference in the experimenter.

θ ₁, (0.50): θ ₁50% quantile (=θ of bioequivalence standard ₁Intermediate value).

θ ₁, (0.95): θ ₁95% quantile (=θ of bioequivalence standard ₁The upper limit of 95% confidence interval).

Because S with regard to whole analyses _R ²＞σ _T0 ²(=0.2 ²=0.04), adopts reference-scale method.

Table 6:

Gepirone contrast: 1 * 80mg (test) and 4 * 20mg (reference)
							Parameter	S T 2	S R 2	S d 2	θ 1(0.50)	θ 1(0.95)	Conclusion *)
dn-C max	0.3318	0.3755	0.2699	-0.033	0.401	Bioequivalence
							dn＝AUC 0-∞	0.4063	0.3114	0.2747	0.268	0.876	Bioequivalence
dn＝AUC 0-tlast	0.4154	0.3449	0.3233	0.193	0.768	Bioequivalence

1-PP contrast: 1 * 80mg (test) and 4 * 20mg (reference)
							Parameter	S T 2	S R 2	S d 2	θ 1(0.50)	θ 1(0.50)	Conclusion *)
dn-C max	0.2467	0.2435	0.0763	0.018	0.269	Bioequivalence
							dn＝AUC 0-∞	0.4128	0.4108	0.0883	0.007	0.253	Bioequivalence
dn＝AUC 0-tlast	0.4338	0.4383	0.0935	-0.007	0.251	Bioequivalence

3 '-OH contrast: 1 * 80mg (test) and 4 * 20mg (reference)
							Parameter	S T 2	S R 2	S d 2	θ 1(0.50)	θ 1(0.50)	Conclusion *)
dn-C max	0.0684	0.0648	0.1069	0.108	0.632	Bioequivalence
							Dn＝AUC 0-∞	0.1132	0.1054	0.1333	0.078	0.710	Bioequivalence
Dn＝AUC 0-tlast	0.1137	0.1058	0.1360	0.077	0.714	Bioequivalence

^*)If θ ₁, (0.95)≤θ _P(=1.745) then are bioequivalent

Utilize the method gained result of colony to show, with regard to the C of gepirone, 1-PP and 3 '-OH gepirone _Max, AUC _0-∞And AUC _0-tlast, are bioequivalent (a slice 40mg gepirone time-delay releasing piece and two 20mg gepirone time-delay releasing pieces are also observed identical result) about a slice 80mg gepirone time-delay releasing piece and four 20mg gepirone time-delay releasing pieces.Contrast 40mg sheet and 80mg sheet determine that further gepirone or its metabolite do not have significant difference on the statistics.This discovery shows the dosage harmony of gepirone in the 40-80mg dosage range.

In view of above-mentioned instruction, a large amount of modifications of the present invention and variation all are possible.Therefore, in following the scope of claim, can carry out an invention to be different from the specifically described mode of this paper.

Claims (93)

1, pharmaceutical composition comprises:

(a) about gepirone of 14 to about 25wt% or its biologically active metabolite product are free alkali or its pharmaceutically acceptable salt;

(b) about 70 to about 85wt% pharmaceutically acceptable cellulosic polymer substrate; With

(c) an amount of one or more pharmaceutically acceptable excipient,

Wherein the speed that discharges from dosage form of gepirone is such, reaches about 90 to about 95% gepirone and absorbs and need about 18 to 24 hours.

2, the compositions of claim 1, wherein (c) further comprises at least a pharmaceutically acceptable excipient, is selected from the group of being made up of coloring agent, microcrystalline Cellulose, colloid silicon and magnesium stearate.

3, the compositions of claim 1, wherein (b) is hydroxypropyl emthylcellulose, and viscosity is from about 15, and 000cps is to about 100,000cps.

4, the compositions of claim 1, wherein the concentration range of (a) is about 15.5 to about 18.7wt%.

5, the compositions of claim 1, wherein (a) is gepirone or its pharmaceutically acceptable salt.

6, the compositions of claim 1, wherein (a) is biologically active metabolite product or its pharmaceutically acceptable salt of gepirone.

7, the compositions of claim 6, the biologically active metabolite product of wherein said gepirone is selected from by 3 '-OH gepirone, 3 ', the group that 5-dihydroxy gepirone and 5-OH gepirone are formed.

8, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 1 of effective dose.

9, the method for claim 8, wherein said patient is the people.

10, the method for claim 8, wherein said patient further suffers from the generalization anxiety.

11, the method for claim 8, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

12, the compositions of claim 1, wherein said compositions are the forms of tablet.

13, the compositions of claim 12, the gross weight of wherein said tablet from 350 to 450mg.

14, the compositions of claim 13, wherein (a) weight in described tablet from 60 to 80mg.

15, the compositions of claim 12, wherein said tablet are the avette-rectangle with biconvex surface.

16, the compositions of claim 15, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch.

17, the compositions of claim 12, wherein said tablet are the avette-rectangle with flat surfaces.

18, the compositions of claim 17, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.195 ± 0.025 inch.

19, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 12 of effective dose.

20, the method for claim 19, wherein said patient is the people.

21, the method for claim 19, wherein said patient further suffers from the generalization anxiety.

22, the method for claim 19, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

23, compositions comprises:

(a) about gepirone of 14.0 to about 24.4wt% or its biologically active metabolite product are free alkali or its pharmaceutically acceptable salt,

(b) 70.5 to 82.1wt% hydroxypropyl emthylcellulose, viscosity be from about 15,000 to about 100,000cps,

(c) 0 to about 1wt% coloring agent,

(d) about microcrystalline Cellulose of 8.0 to about 16.7wt%,

(e) about 0.39 to about 0.47wt% colloid silicon and

(f) about magnesium stearate of 0.29 to about 1.0wt%.

24, the compositions of claim 23, wherein (a) from about 15.5 to about 18.7wt%.

25, the compositions of claim 23, wherein (a) is the free alkali of gepirone.

26, the compositions of claim 23, wherein (a) is the pharmaceutically acceptable salt form of gepirone.

27, the compositions of claim 26, wherein the pharmaceutically acceptable salt form of gepirone is the gepirone hydrochlorate.

28, the compositions of claim 23, wherein (a) is biologically active metabolite product or its pharmaceutically acceptable salt of gepirone.

29, the compositions of claim 28, the biologically active metabolite product of wherein said gepirone is selected from by 3 '-OH gepirone, 3 ', the group that 5-dihydroxy gepirone and 5-OH gepirone are formed.

30, the compositions of claim 23, wherein (c) from 0 to about 0.3wt%.

31, the compositions of claim 23, wherein (c) is one or more iron oxides.

32, the compositions of claim 23, wherein (e) from about 0.42 to about 0.47wt%.

33, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 23 of effective dose.

34, the method for claim 33, wherein said patient is the people.

35, the method for claim 33, wherein said patient further suffers from the generalization anxiety.

36, the method for claim 33, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

37, the compositions of claim 23, wherein said compositions are the forms of tablet.

38, the compositions of claim 37, the gross weight of wherein said tablet from 350 to 450mg.

39, the compositions of claim 38, wherein (a) weight in described tablet from 60 to 80mg.

40, the compositions of claim 37, wherein said tablet are the avette-rectangle with biconvex surface.

41, the compositions of claim 40, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch.

42, the compositions of claim 37, wherein said tablet are the avette-rectangle with flat surfaces.

43, the compositions of claim 42, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.195 ± 0.025 inch.

44, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 37 of effective dose.

45, the method for claim 44, wherein said patient is the people.

46, the method for claim 44, wherein said patient further suffers from the generalization anxiety.

47, the method for claim 44, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

48, the method for the tablet of preparation claim 37 comprises;

(i) blending ingredients (a) to (f) is all or part of,

(ii) be blended in the mixture that obtains in (i),

(iii) add a part or all the other components (a) to (f),

The mixture that obtains in (iv) being blended in (iii), if during (iii), add any component,

(v) thump from (iv) admixture,

(vi) mill (the ball piece that obtains v),

(vii) add all the other components (f), if keep a part at (i) and (iv),

(viii) fusion from (mixture vii),

(ix) will be from (admixture compacting viii) in flakes.

49, the method for the tablet of preparation claim 37 comprises:

I) 20% of mixing all ingredients (a), whole component (c), whole component (e) and component (b) total concentration;

Ii) fusion is from the mixture of (i);

Iii) to half-sum component (b) total concentration that adds whole components (d), component (f) total concentration from (ii) admixture all the other 80%;

Iv) fusion is from (iii) mixture;

V) thump from (iv) admixture;

Vi) mill from (ball piece v);

Vii) to from (the ball piece of milling of process vi) adds all the other components of 50% (f);

Viii) fusion is from (mixture vii);

Ix) will be from (admixture viii) is pressed into final required form.

50, the compositions of claim 37 comprises:

(a) the gepirone hydrochlorate of about 15.6wt%,

(b) hydroxypropyl emthylcellulose of about 75.3wt%,

(c) yellow ferric oxide of about 0.31wt%,

(d) microcrystalline Cellulose of about 8.0wt%,

(e) the colloid silicon of about 0.42wt% and

(f) magnesium stearate of about 0.31wt%.

51, the compositions of claim 50, the gross weight of wherein said tablet are 385mg.

52, the compositions of claim 51, wherein (a) weight in described tablet is 60mg.

53, the compositions of claim 50, wherein said tablet are the avette-rectangle with biconvex surface.

54, the compositions of claim 53, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch.

55, the compositions of claim 50, wherein said tablet are the avette-rectangle with flat surfaces.

56, the compositions of claim 55, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.195 ± 0.025 inch.

57, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 50 of effective dose.

58, the method for claim 57, wherein said patient is the people.

59, the method for claim 57, wherein said patient further suffers from the generalization anxiety.

60, the method for claim 57, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

61, the compositions of claim 37, form by following ingredients basically:

(a) the gepirone hydrochlorate of about 15.6wt%,

(b) hydroxypropyl emthylcellulose of about 75.3wt%,

(c) yellow ferric oxide of about 0.31wt%,

(d) microcrystalline Cellulose of about 8.0wt%,

(e) the colloid silicon of about 0.42wt% and

(f) magnesium stearate of about 0.31wt%.

62, the compositions of claim 61, the gross weight of wherein said tablet are 385mg.

63, the compositions of claim 62, wherein (a) weight in described tablet is 60mg.

64, the compositions of claim 61, wherein said tablet are the avette-rectangle with biconvex surface.

65, the compositions of claim 64, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch.

66, the compositions of claim 61, wherein said tablet are the avette-rectangle with flat surfaces.

67, the compositions of claim 66, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.195 ± 0.025 inch.

68, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 61 of effective dose.

69, the method for claim 68, wherein said patient is the people.

70, the method for claim 68, wherein said patient further suffers from the generalization anxiety.

71, the method for claim 68, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

72, the compositions of claim 37 comprises:

(a) the gepirone hydrochlorate of about 19.5wt%,

(b) hydroxypropyl emthylcellulose of about 70.7wt%,

(c-1) yellow ferric oxide of about 0.24wt%,

(c-2) red ferric oxide of about 0.61wt%,

(d) microcrystalline Cellulose of about 8.2wt%,

(e) the colloid silicon of about 0.39wt% and

(f) magnesium stearate of about 0.29wt%.

73, the compositions of claim 72, the gross weight of wherein said tablet are 410mg.

74, the compositions of claim 73, wherein (a) weight in described tablet is 80mg.

75, the compositions of claim 72, wherein said tablet are the avette-rectangle with biconvex surface.

76, the compositions of claim 75, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch.

77, the compositions of claim 72, wherein said tablet are the avette-rectangle with flat surfaces.

78, the compositions of claim 77, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.195 ± 0.025 inch.

79, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 72 of effective dose.

80, the method for claim 79, wherein said patient is the people.

81, the method for claim 79, wherein said patient further suffers from the generalization anxiety.

82, the method for claim 79, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

83, the compositions of claim 37, form by following ingredients basically:

(a) the gepirone hydrochlorate of about 19.5wt%,

(b) hydroxypropyl emthylcellulose of about 70.7wt%,

(c-1) yellow ferric oxide of about 0.24wt%,

(c-2) red ferric oxide of about 0.61wt%,

(d) microcrystalline Cellulose of about 8.2wt%,

(e) the colloid silicon of about 0.39wt% and

(f) magnesium stearate of about 0.29wt%.

84, the compositions of claim 83, the gross weight of wherein said tablet are 410mg.

85, the compositions of claim 84, wherein (a) weight in described tablet is 80mg.

86, the compositions of claim 83, wherein said tablet are the avette-rectangle with biconvex surface.

87, the compositions of claim 86, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.240 ± 0.025 inch.

88, the compositions of claim 83, wherein said tablet are the avette-rectangle with flat surfaces.

89, the compositions of claim 88, the overall dimension of wherein said tablet are 0.400 ± 0.05 inch * 0.325 ± 0.05 inch, and thickness is 0.195 ± 0.025 inch.

90, treatment has the method for the patient's who needs depression, comprises the compositions that described patient is given the claim 83 of effective dose.

91, the method for claim 90, wherein said patient is the people.

92, the method for claim 90, wherein said patient further suffers from the generalization anxiety.

93, the method for claim 90, wherein said effective dose is from 0.01 to 40mg/kg body weight every day.

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