EA013213B1 - High-dosage extended release formulation of gepirone, method of making thereof and method of treating depression using thereof - Google Patents

Abstract

The present invention relates to high-dosage extended-release formulation of gepirone and methods of treating major depression by administering the same to a subject in need thereof. More specifically, the present invention relates to a high-dosage extended-release tablet form of gepirone. The present invention also relates to a method of treating depression in mammals by administering to a subject in need thereof an effective amount the high-dosage extended-release formulation of gepirone in accordance with the present invention.

Description

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a dosage form of a high dosage, sustained release bioactive metabolite of hepiron and methods for treating depression by administering this dosage form to a subject in need thereof. More specifically, the present invention relates to a tablet dosage form of a high dosage bioactive metabolite of hepiron with a sustained release of the active ingredient. The present invention also relates to a method for treating depression in mammals by administering to a subject in need thereof an effective amount of a high dosage and sustained release dosage form of the bioactive metabolite of hepiron according to the present invention.

State of the art

Hepiron (also known as 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6piperidinedione hydrochloride) can be obtained by the method described in example 7 of US patent No. 4423049 , Tetr1e (which is incorporated into this description in its entirety by reference), and has the following structure:

Gepirone and its salts are known to have antidepressant and anxiolytic properties, presumably being 5-HT _1A receptor agonists. They are usually used to treat depression, dysthymia, impulsive disorders, acute anxiety states with a panic reaction, and the like. However, in drugs with immediate release, gepirone has a short half-life. The time to reach the maximum concentration of the drug in the bloodstream (T _max ) for gepirone is about 1 hour and its T ₅₀ (i.e., the time to 50% of the drug release under controlled conditions ίη νίίτο) is about 2.5-3 hours (see US patent No. 5478572, incorporated herein by reference in its entirety).

Due to the rapid metabolism, gepirone was administered in the past in several small doses, for example, doses of 5 to 10 mg, 2-3 times a day. However, this multiple dose regimen can lead to compliance issues. In addition, skipping the second or third dose leads to unacceptably low plasma gepirone levels. Moreover, studies show that within 15–20 hours after ingestion, immediate release oral gepirone preparations can produce significant variations in human plasma concentrations. (For further discussion, see Ό.δ.ΚοΒίηδοη et al., Sbssa1 Tyegarei Bsk, 1618-1633 (2003)).

However, each patient requires different dosage levels, as for any medical compound, in order to specifically adapt the treatment to the physical condition, age and complexity of the disease of this patient. Thus, even with the low dose, sustained release form of gepirone disclosed in US Pat. No. 5,478,572, multiple doses may be required (i.e., 4 tablets with a dosage of 20 mg as opposed to 1 tablet with a high dosage), which is inconvenient and dear. Essentially, there remains a critical need for a high dosage and sustained release form of gepirone having a dissolution profile similar to the low dosage and sustained release form of gepirone disclosed in US Pat. No. 5,478,572, while maintaining the same relative bioequivalence.

It was previously thought that it was not possible to obtain a high-dosage, sustained-release form of gepirone that does not give an unsatisfactory increase in the amount of 1- (2-pyrimidinyl) piperazine (the main metabolite of gepirone, which is believed to be responsible for harmful side effects, including dizziness, nausea, headache and drowsiness) or decreased relative effectiveness. This skepticism appeared because, in order to sufficiently control the release of gepirone, it would be necessary to increase the binder content to such an extent that the resulting oral tablet would become a horse pill (i.e. unacceptably large). Alternatively, a dosage form would have to be prepared for delivery by less desirable methods (e.g., via intravenous administration).

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SUMMARY OF THE INVENTION

The subject of the present invention is a dosage form containing:

(a) from about 14 to 25% by weight of a bioactive metabolite of hepiron in the form of a free base or a pharmaceutically acceptable salt thereof;

(b) from about 70 to 85% by weight of a pharmaceutically acceptable cellulosic polymer matrix; and (c) suitable amounts of one or more pharmaceutically acceptable excipients, wherein the rate of release of the bioactive metabolite of gepirone from the dosage form is such that to achieve approximately 90-95% absorption of the bioactive Gepirone metabolite requires approximately 18 to 24 hours.

In preferred embodiments of the invention, (c) further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of dye, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate; (B) represents hydroxypropyl methylcellulose having a viscosity of from about 15,000 to about 100,000 cP; and the concentration (a) is from about 15.5 to 18.7 wt.% The specified bioactive metabolite of hepiron can be selected from the group consisting of 3'-OH hepiron, 3 ', 5-dihydroxyhepiron and 5-OH hepiron.

The invention also relates to a dosage form, which is presented in the form of a tablet, where the total weight of said tablet is from 350 to 450 mg and the mass (a) in said tablet is from 60 to 80 mg.

Preferably, said tablet has an oval-rectangular shape with biconvex faces and a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches.

In an alternative embodiment of the invention, said tablet has an oval-rectangular shape with flat faces and a total size of 0.400 ± 0.05 inches by 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches.

Another embodiment of the invention includes a dosage form containing:

(a) from about 14.0 to 24.4% by weight of a bioactive metabolite of hepiron in the form of a free base or a pharmaceutically acceptable salt thereof;

(b) from 70.5 to 82.1 wt.% hydroxypropylmethyl cellulose having a viscosity of from about 15,000 to 100,000 cP;

(c) from 0 to about 1 wt.% a dye;

(ά) from about 8.0 to 16.7 wt.% microcrystalline cellulose;

(e) from about 0.39 to 0.47 wt.% colloidal silicon dioxide; and (D) from about 0.29 to 1.0 wt.% magnesium stearate.

Preferably (a) is from about 15.5 to 18.7 wt.%, And the pharmaceutically acceptable salt of the bioactive metabolite of hepiron is a hydrochloride.

In a specific embodiment, (c) is one or more iron oxides, wherein (c) is from 0 to about 0.3 wt.%, (E) is from about 0.42 to 0.47 wt.%, where the total mass of the indicated tablets is from 350 to 450 mg. The weight (a) in said tablet is from 60 to 80 mg, and the tablet has an oval-rectangular shape with biconvex faces and a total size of 0.400 ± 0.05 inches by 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches.

In another embodiment, said tablet has an oval-rectangular shape with flat faces and a total size of 0.400 ± 0.05 inches by 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches.

Another embodiment of the invention includes a method for producing a tablet, comprising:

(ί) mixing all or part of the components from (a) to (D);

(ίί) mixing the mixture obtained in stage (1);

(ΐίϊ) adding part or remaining components from (a) to (D);

(ίν) mixing the mixture obtained in step (ίίί) if any components are added in step (ίίί);

(ν) obtaining a workpiece from the mixture from step (ίν);

(νί) grinding the workpiece obtained in stage (ν);

(νίί) adding the remaining component (D), if a part is stored in stages (ί) and (ίν);

(νίίί) mixing the mixture from step (νίί);

(ίχ) compressing the mixture from step (νίίί) to obtain a tablet.

Preferably, a method for producing a tablet includes:

ί) mixing of all components (a), all components (c), all components (e) and 20% of the total concentration of component (b);

ίί) mixing the mixture from step (1);

ίίί) adding to the mixture from step (ίί) all components (ά), half of the total concentration of component (G) and the remaining 80% of the total concentration of component (b);

ίν) mixing the mixture from step (ίίί);

ν) obtaining a preform of the mixture from step (ίν);

- 2 013213 νί) grinding the workpiece from stage (ν);

νίί) adding the remaining 50% of component (D) to the shredded workpiece from stage (νί);

νίίί) mixing the mixture from step (νίί);

ίχ) compressing the mixture from step (νίίί) to the final desired form.

In one specific embodiment, the dosage form may comprise:

(a) about 15.6 wt.% hydrochloride of a bioactive metabolite of hepiron;

(b) about 75.3 wt.% hydroxypropyl methylcellulose;

(c) about 0.31 wt.% yellow ferric oxide;

(b) about 8.0 wt.% microcrystalline cellulose;

(e) about 0.42 wt.% colloidal silicon dioxide; and (D) about 0.31 wt.% magnesium stearate.

In one embodiment, the total weight of said tablet is 385 mg; weight (a) in the indicated tablet is 60 mg; wherein said tablet has an oval-rectangular shape with biconvex faces and a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches.

In another embodiment, said tablet has an oval-rectangular shape with flat faces and a total size of 0.400 ± 0.05 inches by 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches.

In one embodiment, the dosage form essentially comprises:

(a) about 15.6 wt.% hydrochloride of a bioactive metabolite of hepiron;

(b) about 75.3 wt.% hydroxypropyl methylcellulose;

(c) about 0.31 wt.% yellow ferric oxide;

(b) about 8.0 wt.% microcrystalline cellulose;

(e) about 0.42 wt.% colloidal silicon dioxide; and (D) about 0.31 wt.% magnesium stearate.

In another embodiment, the dosage form comprises:

(a) about 19.5 wt.% hydrochloride of a bioactive metabolite of hepiron;

(b) about 70.7 wt.% hydroxypropyl methylcellulose;

(c-1) about 0.24% by weight of yellow ferric iron oxide;

(c-2) about 0.61 wt.% red ferric iron oxide;

(b) about 8.2 wt.% microcrystalline cellulose;

(e) about 0.39 wt.% colloidal silicon dioxide; and (D) about 0.29 wt.% magnesium stearate.

In a specific embodiment, the total weight of said tablet is 410 mg; weight (a) in the indicated tablet is 80 mg.

In another specific embodiment, the dosage form essentially comprises:

(a) about 19.5 wt.% hydrochloride of a bioactive metabolite of hepiron;

(b) about 70.7 wt.% hydroxypropyl methylcellulose;

(c-1) about 0.24% by weight of yellow ferric iron oxide;

(c-2) about 0.61 wt.% red ferric iron oxide;

(b) about 8.2 wt.% microcrystalline cellulose;

(e) about 0.39 wt.% colloidal silicon dioxide; and (D) about 0.29 wt.% magnesium stearate.

The present invention also relates to a method for treating depression in a patient in need thereof, comprising administering to said patient an effective amount of a dosage form of the invention.

In a preferred embodiment, said patient is a person suffering and said effective amount is from 0.01 to 40 mg / kg body weight per day.

The above items indicate certain aspects of the invention. Additional objectives, aspects and variations of the invention are in the following detailed description of the invention.

Brief Description of the Drawings

A more complete understanding of the invention and many of the accompanying advantages is easy to obtain, and they will become clearer when referring to the following figures in combination with their detailed description.

In FIG. 1 shows a comparative dissolution profile of tablets weighing 20 production example, in 0.01 M HC1 (see example 1).

In FIG. 2 shows a comparative dissolution profile of tablets weighing 20 production example, in water (see example 1).

In FIG. 3 shows a comparative dissolution profile of tablets weighing 20 production example, in an environment with a pH of 4.5 (see example 1).

In FIG. 4 shows a comparative dissolution profile of tablets weighing 20 production example, in an environment with a pH of 6.8 (see example 1).

mg, described mg, described mg, described mg, described

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DETAILED DESCRIPTION OF THE INVENTION

Unless specifically defined, all technical and scientific terms used here have the same meanings as those commonly understood by those skilled in the biochemical, chemical, pharmacological, and medical sciences.

All methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or verification of the present invention, while suitable methods and materials are described herein. All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entireties. In the event of a conflict, the present description, including definitions, is decisive. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting unless otherwise indicated.

The present invention is based in part on the Applicant’s discovery that it is possible to obtain a high dosage and sustained release bioactive metabolite of hepirone, where the dosage form has a dissolution profile and bioequivalence (for 1-PP, 3'-OH hepiron and hepiron) comparable to the characteristics of the hepiron form with the low dosage and sustained release disclosed in US Pat. No. 5,478,572, despite lowering the final ratio between the active ingredients and the release controlling polymer (binder).

Sustained-release formulations of the active ingredient (especially gepirone) offer many advantages over immediate-release systems. It is easier to obtain patient consent to receive dosage forms with prolonged release, since they must be taken once every 24 hours. Thus, if EB-dosage forms are administered, there is no unacceptable change in plasma concentrations, namely, there are no high initial drug levels that associated with the appearance of unwanted side effects, as well as rapid drops in drug levels below therapeutic levels. In addition, in the case of a bioactive metabolite of gepirone due to the slow release, the concentrations of 1-PP are maintained at a satisfactory level, thereby avoiding significant complications resulting from the action of this metabolite.

In a General embodiment, the present invention relates to a dosage form of a bioactive metabolite of gepirone for oral administration with prolonged release, containing:

(1) from about 14 to 25 wt.% Bioactive metabolite of hepiron in the form of a free base or its pharmaceutically acceptable salt;

(2) from about 70 to 85% by weight of a pharmaceutically acceptable cellulosic polymer matrix; and (3) suitable amounts of one or more pharmaceutically acceptable excipients, wherein the rate of release of the bioactive metabolite of gepirone from the dosage form is such that to achieve from about 90 to 95% absorption a bioactive metabolite of gepirone is required from approximately 18 to 24 hours

In a particularly preferred embodiment of the present invention, a sustained release oral dosage form of gepirone contains (in wt.%):

(a) from about 14.0 to 24.4% (preferably from about 15.5 to 18.7%) of hepiron or its bioactive metabolite in the form of a free base or a pharmaceutically acceptable salt thereof, for example hydrochloride;

(b) from about 70.5 to 82.1% hydroxypropyl methyl cellulose having a viscosity from about 15,000 to 100,000 cP;

(c) from 0 to about 1% (preferably from 0 to about 0.3%) of iron oxide;

(i) from about 8.0 to 16.7% microcrystalline cellulose;

(e) from about 0.39 to 0.47% (preferably from about 0.42 to 0.47%) of colloidal silicon dioxide; and (1) from about 0.29 to 1.0% of magnesium stearate.

Although the above option is determined based on the specific compounds for each component, it should be understood that within the scope of the present invention, these components can be replaced individually or in various combinations, as described below. For each component below, it should be understood that the following percentages by weight reflect the total concentration of each component. For example, if there is a mixture of compounds that falls within the region of a particular group of components, then the indicated percentage by weight reflects the total amount of compounds for this mixture.

Component (a).

In a preferred embodiment, component (a) is present in a dosage form for oral administration with a sustained release in an amount of from about 14.0 to 24.4 wt.%, More preferably from about 15.5 to 18.7 wt.%. Particularly preferred component (a) is the bioactive metabolite of hepiron or a pharmaceutically acceptable salt thereof.

Гепη νίνο gepirone metabolism yields the main pharmacologically active metabolites: 1- (2-pyrimidinyl) piperazine (1-PP) and 3'-OH hepiron ((.8. Wolshbop et al., Syssa1 Tyegareisb, p. 16181633 (2003)). Ιη νίνο two additional metabolites are also formed, which may also have bioactivity: 5-OH hepirone and 3 ', 5-dihydroxyhepiron.

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In humans, the release of 1-PP, a common metabolite of azapiron, is believed to be responsible for harmful side effects, including dizziness, nausea, headache, and drowsiness. In addition, 1-PP is an antagonist of presynaptic α-2-adrenergic receptors, and it has been reported that in preclinical trials it does not exhibit characteristics similar to those of antidepressants (Ό.8. KoYpkoi et al., C11shsa1 Tyegarei Nsk, p. 1618-1633 ( 2003)). In contrast, bioactive metabolites (in particular, 3'-OH hepirone) have a significant affinity for 5-ΗΤι _Α receptors. It has been shown that 3'-OH hepiron modifies the 5-HT neurotransmission in a manner comparable to that of hepiron, although 3'-OH has been found to show complete agonism with respect to postsynaptic receptors in the hippocampus, while hepiron is a partial agonist (Ό.8. Kölškoi et al. ., C11shsa1 Tyegareiysk, p. 1618-1633 (2003)).

In view of the foregoing, in an embodiment of the present invention, one or more of the bioactive metabolites of hepiron can be used: 3'-OH hepiron, 5-OH hepiron, and

3 ', 5-dihydroxyhepiron, or their pharmaceutically acceptable salts.

In addition, although a pharmaceutically acceptable salt form is preferred, it is contemplated that the bioactive metabolites of gepirone may be in the form of a hydrate, enantiomeric form, or a mixture, or crystalline form.

Pharmaceutical compounds suitable for administration by the present invention may be hydrochloride salts, but free bases and other pharmaceutically acceptable salts are also suitable. The expression pharmaceutically acceptable salt is well known in this field, for further description, we send specialists to work 8.M. Vegde et al., 1. P11aaaaaaaaaaa8aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa; Suitable pharmaceutically acceptable salts of the present invention for administration include acid addition salts. An acid addition salt can be prepared by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, perchloric acid, sulfuric acid, oxalic acid or malonic acid. If the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates its salts, preferably non-toxic pharmaceutically acceptable salts, such as sodium, potassium and calcium salts.

Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, heptofluorosulfate, glufonate glufonate, gumfonate glufonate, fumarate gluconate, , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin, t, 3-phenylpropionate, phosphate, piktat, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Typical alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, if appropriate, amino group salts. Salts of amino groups may also contain quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group, non-toxic cations of ammonium, quaternary ammonium and amine formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate , (lower alkyl) sulfonate and aryl sulfonate.

Component (b).

In a preferred embodiment, component (b) is present in a dosage form for oral administration with a sustained release in an amount of about 70.5 to 82.1 wt.%. A preferred component (b) is hydroxypropylmethyl cellulose having a viscosity of about 15000 to 100000 cP, which is a controlled release polymer and a binder (also known as a release inhibitor).

For oral preparations and dosage forms, it is preferable to use a polymer cellulose matrix or a release inhibitor. Suitable matrices include hydroxyalkyl-substituted alkylcelluloses having viscosities of from about 15,000 to about 100,000 cP. Examples of suitable hydroxymethylpropyl cellulose (HPMC) samples include the K15M and K100M grades (i.e. 15,000 and 100,000 cP, respectively).

In the present invention, the HPMC can be replaced (in whole or in part) or added, replaced with some or all of the HPMC matrix can be calcium diphosphate or lactose, each of which, as a rule, increases the dissolution rate.

In addition to the binder component (b), the preparation of the present invention may also contain auxiliary binders, such as syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone. Examples of suitable excipients or diluents also include starches (e.g., corn starch), lactose, sorbitol, glycine, sucrose, glucose, mannitol, silicic acid, sodium citrate and calcium diphosphate. Examples of other suitable binders may include

- 5 013213 chitosan, alginates, gelatin, polyvinylpyrrolidinone, sucrose, gum arabic and mixtures thereof.

In an embodiment of the present invention, the ratio of gepirone to binder (gepirone: binder) is from 1: 3.5 to 1: 14.5. A preferred binder is hydroxymethylpropyl cellulose (HPMC).

Component (s).

In a preferred embodiment, component (c) is present in a dosage form for oral administration with a sustained release in an amount of from 0 to about 1 wt.%, Preferably from 0 to about 0.3 wt.%. Although component (c) may be any dye, it is preferred that the dye is iron oxide. In a particularly preferred embodiment, the iron oxide is red ferric oxide, yellow ferric oxide, or mixtures thereof.

Additional typical colorants that can be used in place of or in addition to those indicated above include, but are not limited to, EL & C and E & C pigments. titanium dioxide, iron oxides, natural pigments or dyes approved by the U.S. Federal Drug Administration, or combinations thereof.

Component (b).

In a preferred embodiment, component (b) is present in a dosage form for oral administration with a sustained release in an amount of about 8.0 to 16.7% by weight. Although component (b) may be any diluent and / or compression aid, it is preferred that the diluent / compression aid is microcrystalline cellulose.

Additional diluents may include, but are not limited to, water or other solvents, dissolution aids, and emulsifiers, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, wheat germ oil, olive, castor and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, esters of fatty acids and sorbitol, and mixtures thereof.

In yet another embodiment of the present invention, the ratio of gepirone to diluent (gepirone: diluent) is from 1: 3 to 2.5: 1. A preferred diluent is microcrystalline cellulose.

Component (e).

In a preferred embodiment, component (e) is present in a dosage form for oral administration with a sustained release in an amount of about 0.39 to 0.47 wt.%, Preferably about 0.42 to 0.47 wt.%. Although component (e) can be any glidant, it is preferred that the glidant is colloidal silica (colloidal silicon dioxide).

Additional glidants include, but are not limited to, corn starch, talc, stearic acid, or combinations thereof.

Component (1).

In a preferred embodiment, component (1) is present in a dosage form for oral administration with a sustained release in an amount of about 0.29 to 1.0 wt.%. Although component (1) may be any lubricant, it is preferred that the lubricant is magnesium stearate.

Additional lubricants may include, but are not limited to, cellulose, talc, polyethylene glycol, silicas, sodium lauryl sulfate, calcium stearate, and mixtures thereof.

Alternative components.

In the present invention, it is contemplated that the sustained release oral dosage form, in addition to components (a) to (1), may also contain various additional components. Based on the above and the work of VeshshTsop'k Ryattaseibsak 8s1eisek, 18 ' ¹ ' Ebyuy (incorporated by reference in this description), mainly part 8 Pharmaceutical preparations and their preparation, an experienced specialist will easily add new compounds to the preferred options described above .

In an embodiment of the present invention, an oral sustained release dosage form of the active ingredient may include one or more additional pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier” as used herein means a non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or adjuvant. Some examples of materials that can serve as pharmaceutically acceptable carriers have already been mentioned above, therefore, it is understood that in this aspect of the invention, the pharmaceutically acceptable carrier may be any type of excipient, diluent, encapsulating material or adjuvant not previously mentioned.

In another embodiment, the oral sustained release dosage form of the active ingredient may also include one or more release agents, coating agents, sweeteners, flavoring agents and flavoring agents, preservatives and antioxidants.

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The flavoring agent (s), which are mainly used to mask the taste and / or smell, may be vanillin, sodium citrate, citric acid, peppermint oil, orange, lemon oil or any other pharmaceutically approved flavoring or flavor masking agent and their combinations.

The form and physical condition of the dosage form of the bioactive metabolite of hepiron with a high dosage and prolonged release.

The present invention contemplates oral sustained release dosage forms that are suitable for oral administration. These forms include tablets, capsules, capsule tablets, lozenges, powders, suspensions, syrups and the like, suitable forms. Preferably, a tablet may be mentioned, including a tablet having a convex shape, a spherical (i.e. spherical) shape, or a capsule shape.

In a preferred embodiment, the oral dosage form of the bioactive sustained release hepiron metabolite is a tablet. The tablet is preferably oval in shape, which increases its surface area and improves the release of gepirone from it. More preferably, the tablet has an oval-rectangular shape, which may have flat or biconvex faces.

If the oral dosage form of the sustained release bioactive metabolite of gepirone is a tablet having an oval-rectangular shape, it is preferable that the tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches (biconvex faces ) or 0.195 ± 0.025 inches (flat faces).

In another embodiment of the present invention, the final tablet weight is from 350 to 450 mg, preferably from 375 to 425 mg, more preferably from 385 to 410 mg. In addition, in the context of the present invention, the tablet mass range is from 350 to 450 mg, preferably from 375 to 425 mg, more preferably from 385 to 410 mg, corresponds to the total weight of the unit dosage form.

Therefore, the pharmaceutical compositions (namely, an oral dosage form of a sustained release bioactive metabolite of hepiron) of the present invention preferably contain from about 55 to 100 mg (preferably from 60 to 80 mg, more preferably 60 or 80 mg) of the active ingredient per unit dose.

If desired, tablets can be coated using known methods and excipients, which may include an enteric coating using, for example, hydroxypropyl methylcellulose phthalate. If desired, such enteric coated tablets may be prepared by known methods, for example, using cellulose acetate phthalate. They may optionally contain opacity agents and may also be a composition that releases the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with delay. Examples of coating compositions that can be used include polymeric substances and waxes.

Similarly, capsules can be prepared by known methods, for example, hard or soft gelatin capsules containing the active compound with or without fillers, and if desired, enteric coatings can be provided in a known manner. The contents of the capsule can be prepared using known methods in such a way as to obtain a sustained release of the active compound. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. In normal practice, such dosage forms may also contain additional substances other than inert diluents, for example, tabletting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacity agents and may also be a composition that releases the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with delay. Examples of coating compositions that can be used include polymeric substances and waxes.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Ways of treatment.

The bioactive metabolite of gepirone can be administered orally once a day in the form of sustained release dosage forms that contain a bioactive metabolite of gepiron, a cellulosic polymer matrix, and suitable amounts of pharmaceutical excipients. The resulting gepirone formulation provides oral products that release 90 to 95% of the active agent over a period of about 19 to 24 hours.

- 7 013213

Therefore, another embodiment of the present invention relates to a method for treating a patient diagnosed as suffering from severe (primary or general) depression, with or without generalized anxiety, comprising administering to said patient an effective amount of an oral dosage form of a sustained release bioactive metabolite of hepiron, which is described in the present invention.

In this embodiment, a patient in need of treatment (preferably a human, but including all mammals) is first diagnosed as suffering from a particular depressive state. For a discussion of patient assessment, diagnostic criteria, and others in a state of anxiety and depression, we send specialists to the work of ΌδΜ-ΐν-ΤΚ. (Οίαβηοδίίο aib 81aY8Ysa1 Mapia1 o1 Mep1a1 Όίδοτ6θτδ, Lshepsap R8us1ia1ps L88os1aboy, Ua81ipd1op E.S .. 2000; Eerge881ue U |

To this end, the sustained release bioactive metabolite of gepirone and the dosage forms of the invention are intended to deliver an effective antidepressant and / or anxiolytic amount of the bioactive metabolite of gepirone or a pharmaceutically acceptable salt thereof to a mammal, preferably a human.

The expression effective doses, as used herein, referring to an amount of about 0.01 to 40 mg / kg body weight per day, preferably 0.05 to 20 mg / kg body weight per day, more preferably 0.1 to 2 mg / kg body weight per day. For some specific central nervous system disorders, 15 to 90 mg / day, preferably 30-60 mg / day, is recommended. See US Patent No. 4,771,053 and US Patent No. 5,478,572. Alternatively, an effective dose or delivery system should provide plasma concentrations in the range of about 1 to 20 ng / ml, preferably about 1 to 5 ng / ml.

As described above in an embodiment of the present invention, an oral dosage form of a bioactive sustained release hepiron metabolite for use in the method of the invention comprises (expressed in wt.%):

(a) from about 14.0 to 24.4% (preferably from about 15.5 to 18.7%) of the bioactive metabolite of hepiron in the form of a free base or a pharmaceutically acceptable salt thereof, for example hydrochloride;

(b) from about 70.5 to 82.1% hydroxypropyl methyl cellulose having a viscosity from about 15,000 to 100,000 cP;

(c) from 0 to about 1% (preferably from 0 to about 0.3%) of iron oxide;

(b) from about 8.0 to 16.7% microcrystalline cellulose;

(e) from about 0.39 to 0.47% (preferably from about 0.42 to 0.47%) of colloidal silicon dioxide; and (1) from about 0.29 to 1.0% of magnesium stearate.

As indicated above, the bioactive metabolite of gepirone in the form of a dosage form for oral administration with prolonged release also includes bioactive metabolites of gepirone selected from the group consisting of 3'-OH hepiron, 3 ', 5-dihydroxyhepiron and 5-OH hepiron. The method may use one of these compounds. However, combinations of these metabolites or combinations of metabolites with other active or inert ingredients are also contemplated.

In addition, the present invention relates to methods for alleviating depression, anxiety, or psychological disorders in a patient (preferably a human, but including all mammals) in need of such treatment, by administering to the patient an effective amount or dose of hepiron or a bioactive metabolite of hepiron, for example 3'-OH hepiron, 3 ', 5-dihydroxyhepiron and 5-OH hepiron. Administration of gepirone or a bioactive metabolite of gepirone, as is understood herein, includes the administration of any active salt, hydrate, enantiomeric form, mixture or crystalline form of the compound.

Also within the scope of the present invention are methods in which an oral dosage form of a sustained release bioactive metabolite of hepiron is administered (sequentially or simultaneously) with one or more antidepressant or anxiolytic agents in combination therapy for the treatment of depression and / or anxiety.

Methods of obtaining.

The oral dosage form of the bioactive sustained release hepiron metabolite of the present invention can be prepared by the following procedure:

(ί) mixing all or part of the components from (a) to (1);

(i) mixing the mixture;

(ΐίϊ) adding part or residue (if any) of components (a) to (1);

(ίν) stirring the mixture (if the residue was added in step (w));

(ν) obtaining the workpiece from the mass;

(νί) grinding;

(νίί) adding a lubricant residue (component (1), if a part was left in stages (ί) and (ίν));

(νίίί) mixing the mixture;

- 8 013213 (ίχ) pressing tablets from the final mixture.

Of course, it is understood that the above steps can be interchanged or replaced until rearrangement or substitution substantially alters the pharmacological efficacy of the dosage form obtained by the process described above. In this regard, the specialist is referred to the work of Ketshd1oi'8 Ryagtasei1ya1 8s1epse5, 18 ' ¹ ' Εάίίίοη (included here by reference), for example, to its part 8 Pharmaceutical preparations and their preparation.

In addition, the processing techniques described in US Pat. Nos. 4,422,049 and 5,478,572 (incorporated herein by reference), which provide suitable examples of the method described above for the preparation of an oral dosage form of prolonged release hepirone, are provided to a person skilled in the art.

In a preferred embodiment, the following procedure is followed to obtain an oral dosage form of a bioactive sustained release hepiron metabolite according to the invention:

ί) mixing of all components (a), all components (c), all components (e) and 20% of the total concentration of component (b);

ίί) mixing the mixture from step (1);

ίίί) adding to the mixture from step (ίί) all components (ά), half of the total concentration of component (1) and the remaining 80% of the total concentration of component (b);

ίν) mixing the mixture from step (ίίί);

ν) obtaining a workpiece from the mixture from stage (ίν);

νί) grinding the workpiece from stage (ν);

νίί) adding the remaining 50% of component (D) to the shredded workpiece from stage (νί);

νίίί) mixing the mixture from step (νίί);

ίχ) compressing the mixture from step (νίίί) into the final desired form.

Typically, the resulting mixtures are pressed in stage (ίχ) into tablets or microgranules. If microbeads are obtained, they are optionally coated with a topcoat from a conventional coating adjuvant (s) and then tablets are prepared or capsules are filled with them.

In the case where an enteric coating is desired, this coating is usually added after step (ίχ).

It is clear that it is possible to increase the scale of each of the above production methods to an industrially acceptable scale, and the methods are in no way limited to individual methods of preparing dosage forms. It is also contemplated that it is possible to make changes at each stage (individually or collectively) to simplify the production of an oral dosage form of a bioactive metabolite of gepirone with a sustained release according to the invention, as long as the modifications do not alter the composition of the final product beyond the tolerance described above or the bioefficiency of the resulting product.

The above description of the invention relates to a method and method for its preparation and use in such a way that a person skilled in the art would be able to carry out and use it, this possibility is provided, in particular, for the subject of discussion of the attached claims, which forms part of the original description.

The above expressions selected from the group consisting of, selected from and the like include mixtures of the listed materials.

Where a numerical limit or range is indicated, endpoints are included. Also included are all specific values and subranges within numerical limits or ranges, as if they were written in detail. In this regard, if the expression is indicated approximately, it should be understood so that the indicated values are included, as well as values that deviate from the indicated value by 1% (higher or lower, depending on whether it defines approximately the upper or lower boundary), preferably 0.5% of the specified value.

The above description is presented in order to enable one skilled in the art to make and apply the invention, and is given in the context of a specific application and needs. Various modifications of the preferred embodiments are apparent to those skilled in the art, and the general principles defined herein can be applied to other embodiments and applications without departing from the spirit and scope of the invention. Thus, it is not intended that this invention be limited by the options shown, but should provide the broadest possible scope consistent with the principles and features disclosed herein.

Describing the invention in the usual way, one can gain further understanding by referring to some specific examples, which are given here for illustration only and are not intended to be limiting unless otherwise indicated.

- 9 013213

Illustrative examples

Production Example.

Following the above procedure and US Pat. No. 5,478,572, an oral dosage form of a sustained-release tablet form of gepirone is obtained. Typically, this technique includes:

(ί) mixing all gepirone hydrochloride, all dye, all colloidal silicon dioxide and 20% of the total weight of hydroxypropyl methylcellulose;

(ίί) stirring the mixture from step (ί) for 15 minutes and then breaking up the lumps using a plate Εί (ζιηί11 # 0020;

(ίίί) adding to the mixture from step (ίί) all microcrystalline cellulose, 50% of the total weight of magnesium stearate and the remaining 80% of the total weight of hydroxypropyl methylcellulose;

(ίν) stirring the mixture from step (ίίί) for 28 minutes;

(ν) obtaining a workpiece from the mixture from step (ίν) using a rotary tablet press;

(νί) grinding the workpiece from step (ν) using a plate ΕίΙζιηίΙΙ # 0093;

(νίί) adding the remaining 50% magnesium stearate to the ground stock from step (νί);

(νίίί) introducing a lubricant / mixing the mixture from step (νίί) for 7 minutes; and (ίχ) compressing the mixture from step (νίίί) into final tablets of the desired form.

In this way, oval-rectangular tablets are obtained having biconvex faces. The total tablet size is 0.405 inches (102.87 mm) by 0.338 inches (85.85 mm) with a bowl depth of 0.050 inches (12.70 mm). Below in the table. 1 shows the mass of tablets and the number of components per unit.

Table 1

Quantity per unit (units in mg) Ingredients Function Tablets 20 mg 40 mg tablets 60 mg tablets 80 mg tablets Gepiron HC1 Active ingredient 20.0 (18.1) ¹ 40.0 (36.2) ¹ 60.0 (54.3} ¹ 80.0 (72.4) ¹ Colloidal silicon dioxide Agent slip 1,6 1,6 1,6 1,6 Yellow oxide ferric iron Dye 0.4 0.08 1,2 1,0 Ferric Red Oxide Dye 2,5 Hydro Xipropyl methyl cellulose Control Release Polymer and Binder 290.0 290.0 290.0 290.0 Microcrystal cellulose Thinner and auxiliary pressing agent 61.8 52.12 31,0 33.7 Magnesium stearate Lubricant 1,2 1,2 1,2 1,2 Total tablet weight 375.0 385, 0 385.0 410.0

¹ Indicates the content of the free base.

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Example 1. Dissolution profiles for a 60 mg preparation relative to a 20 mg preparation.

Below in the table. 2 shows comparative dissolution profiles for tablets weighing 20 and 60 mg in all dissolving media SHRAS-MK ..

table 2

Time (hour) Wednesday Weight one 2 4 8 10 12 14 sixteen eighteen twenty Ο, ΟΙΜ HC1 20 mg 20,2 30, 4 45, 1 64.7 71, 8 77.8 92.8 86, 9 90, 5 93, 4 0,01M HC1 60 mg 22, 0 32.8 48,2 68.6 76.0 82.0 87.1 91, 2 94.5 97.3 water 20 mg 19.8 29.8 44.0 63.1 70, 1 76.0 80.9 85, 0 88.4 91, 3 water 60 mg 21, 9 32,7 48,2 68.6 75.8 81.7 86.6 90, 5 93.7 96, 2 pH = 4.5 20 mg 17.7 26, 6 39, 5 57, 2 63, 8 69, 4 74.3 78.6 82.3 85, 6 pH = 4.5 60 mg 20,2 30, 0 43.8 62, 2 68.8 74.3 79.1 83, 1 86.5 89, 4 pH = 6, 8 20 mg 15, 9 24, 1 36,4 53.7 60.5 66, 4 71, 5 76, 1 80.2 83.8 pH — 6.8 60 mt 17.5 26, 4 39.6 57, 6 64,4 70,2 75.1 79.5 83.3 86, 6

The results shown above are shown graphically in FIG. 1-4.

The calculation of P1 and P2 (see table. 3) for comparative dissolution profiles demonstrates the equivalence of tablets in all 4 environments.

Table 3

Wednesday ΕΊ ¹ P2 ¹ 0.01 And HC1 5.2 71.2 Water 6.7 66.1 pH = 4.5 one one one one With one ! __._______________one 70.1 pH = 6.8 5, 3 76, 3 Criteria ² 0-15 50-100

¹ K1 and 1'2 provide penetration and / or a measure of the distribution of results in batches.

² Criteria correspond to acceptable ranges of ΙΊ and P2.

Example 2. Bioequivalence of the drug 80 mg relative to the drug 20 mg.

Previously, efficacy and pharmacokinetics data were obtained for sustained-release hepiron tablets, mainly by administering one or many 20 mg sustained-release hepiron tablets (similar to the tablets described above in the preparation example). Therefore, studies have been conducted to demonstrate the bioequivalence of 40 mg hepirone tablets (data not shown) and 80 mg sustained release (as described above in the preparation example) for a plurality of 20 mg sustained release tablets.

For this purpose, we used a four-way cross-sectional randomized study of drugs with open labels in a single dose with the stage of excretion for one week between different courses of treatment. During each study period, subjects were hospitalized at noon before administration of gepirone until a time point 36 hours after administration. After discharge, blood samples were taken at 48, 60 and 72 hours after administration. Throughout the study, 32 subjects (average age 30.9 ± 6.3 years; average weight 73.8 ± 8.3 kg; average height 178.1 ± 5.6 cm and average BM1 23.3 ± 2.3 kg / m ² ) hepiron was administered as a single oral dose of 40 or 80 mg. For this purpose, the following courses of treatment were carried out in random order (tablet preparation shown above in the preparation example):

1x40 mg sustained release gepirone tablet (data not shown);

2x20 mg sustained release gepirone tablets (data not shown);

1x80 mg sustained release gepirone tablet;

- 11 013213

4x20 mg sustained release gepirone tablets.

After each treatment, blood samples were taken from the subjects at constant intervals for 72 hours to determine the pharmacokinetics of hepiron, 1-PP and 3'-OH hepiron.

To determine the bioequivalence of one 80 mg sustained release tablet of hepiron versus four 20 mg sustained release tablets of hepiron, the following pharmacokinetic parameter is calculated for each subject and treatment:

1 _max (TMAX) - the actual time to reach C _max ;

C _max (CMAX) - measured maximum plasma concentration after a single dose;

ip-C _max (ESMAX) - normalized to the dose of C _max calculated as C _max / dose;

λ _ζ (ΕΖ) and ΐ _1/2 (ТНЬЕ) - the slope (β) of the terminal 1-linear phase curve of the concentration-time curve was determined by linear regression. Data approximated by function

1ode _e С ₁ = 1еёеС ₁ п1егс-в11, starting from the last 3 (С ₁ , ΐ ₁ ) data pairs for which С,>БОО;

FROM; _p4egs represents suppression with the axis of concentration at the zero point in time.

The procedure is continued by adding the previous points one at a time and approximating the regression equation until reaching C _max at time 1 _max . Then determine the terminal 1od-linear part according to the data giving the period with the lowest mean square error (M8E) in the regression analysis. The terminal elimination rate constant (λ _ζ ) is determined as -β, from which the half elimination period (1 _1/2 ) is calculated as 1ode2 // ,. Concentrations below BOR in the elimination phase are ignored;

ABS. .. (AIST) - AIS from zero to 1] _a81 (AIS _0-11a81 ) is calculated using the linear trapezoidal formula, where 1 _1a81 represents the last time point with a measurable concentration in the subject's body;

ip-AiS _{0- | 1} , _s (EIST) - normalized by dose AiS _{0-11a81 is} calculated as AiS _0-11a D / dose;

ABS _{0- /} (AIS) - AIS from zero to infinity is calculated as AiS _{0- /} = AiS _{0- | 1nl |} + AiS _{| 1nl | - /} . For ABS, _: . see above for AIS. ' _{| 1} , _|? , _{| - /} = C. ' _{| 1} , _s //. _? .. where Cp _1a81 is the corresponding concentration at time ΐ _1ΕΒί using the regression line for which λ _ζ is calculated;

ip-ABS _{0- /} (EABS) - normalized to the dose of ABS _{0- /} calculated as AIS _0-m / dose;

Sa _app (sbarro) - true total plasma clearance (Sa) after a single oral dose is the dose-T / AiS _0-m, where T is the fractional absolute bioavailability of the oral preparation. Since G cannot be calculated only from oral data, SB / B = dose / AIS _{0- is} calculated, and is designated as apparent clearance (SB _arr ). The administered dose of gepirone is expressed as the free base. The amount of free base of gepirone is also used to calculate SB _arr for metabolites of hepiron 1-PP and 3'-OH;

tep-SB _arr (U SBARR) - normalized by mass SB _arr calculated as SB _arr divided by body weight (kg);

Y ,, _arr (A ^ APP) - the apparent volume of distribution during the terminal phase after a single oral dose is defined as ^Y ,, arr ^C 'B <1rr ^// - ,;

^ n-Y ,, _arr (YY ^ APP) - normalized by mass Y ,, _{arr is} calculated as Y ,, _arr divided by body weight (kg).

For dn-C _max, dn-ABS _{0- /} dn and _{AiS-0- | 1 s} use allowable range 0,80-1,25. Drugs are declared bioequivalent with respect to the studied parameters if the 90% confidence interval is fully included in the allowable range. This is true for gepirone, 1-PP and 3'-OH gepirone. For all other pharmacokinetic parameters, a classical hypothesis test is performed on 1-od, transformed values, using similar AYOAA models as for bioequivalence studies.

For gepirone, 1-PP and 3'-OH gepirone, the following average (std. Off) pharmacokinetic parameters are calculated (see table 4).

- 12 013213

Table 4

ΙΪΊΙΙψΟΗ GP V) ί ΪΊ * ίηΊ2; ν-ΠΙΙ 7 \ | ("37) 1 [aramsgr („SPOKES ! g 30 h < 4x 2P Μί 1 ι YP μι 4111 μϊ G l yap ma 4 i 26 m ’ 1 ηι ml 1 ί 2 (5 ^ 6) 102 (7 software And 2 (U) P 1 (7 05) 2νΐ (6 99 » ί Ι1Τ Μ.ΤΜ1) 0! 4th (yPL7) <M? I (0.Sh » 0 17810 125) η 1m (shee. 0 / I7K) 991) 0 314 (0 087) (ΊΛΟ 5 5 Ш1- ШП 60 (0 5 17 0) 5 0 PO- 1M1) 6.0 (2.0 120) 6 (44 0-12.0) I 0 (4.0 12.0) CPU hour me) ) 51 (692) 149 (89 L) 259 (219) 2 ") (W) 54 (170) 557 L81) ίΐϊΐ cds, Μ μ Μί) 1 89 (0,865) ("6 (1 12" \ 12ί2 67) 3.25 (2 50) 6.96 (2 27) he hour'ml G7X-P 14 '("K.1) 259 (2V) 26 * 12.92) '53 070) 56 ’(1» 3) (ng hour / mum!) I *> I (0 9T7) ί 04 (1.1 ^ ) .24 (2. ") 13Ή2 52) 6 97 (2 P) 7.1) 3 (2 2 ") one (hour! 7 93 (Y 2Y) 3.22 (9.12) * "43 (606) 7 4 | A.34) Μ 1 P-30) ? .4Y <? thirteen) Π-ίΓ (.1'4 ac! 692 (304) 625 (ZIL! 417 (249) 396 (242) 146 (6Ϊ .7) 144 (53 9) "T <1-4, (lh kg) 9.70 (12 7) Ya6n5 9ch 5 73 (.1 73) 5.41 IM) 2 91 (0 971) 1.93 (0.3) 6) ν (L) 6416 (6.56) 7334 (9TH) 5531 (40I2) 4168 (3289) ("72 (No. 6) 1,437,046) 'Ι'-Άτ St'kg) YAL. | (ΒίΊ.8) 102 (137) 7 1P (62 0 '7.0 (44 7) 22 8 (11.0) 19 3 (5.92)

Medium range.

Statistical analysis in relation to the study of the average bioequivalence for gepirone, 1-PP and 3'-OH hepiron is given in table. 5.

Table 5

Gepirone comparison: 1 * 80 mg (test) versus 4 * 20 mg (comparison) Parameter Wed 9 geom. researched a drug Wed geome. will compare. a drug Spot assessment of studies / comp. 90% will trust. interval Output C1P — Stpah 0.123 0, 105 1.17 1.02-1.33 Not defin. s1p-Ais ₀ - _0O 1.71 1, 68 1,02 0.89-1.16 Bioequiv. bp-AOSo-Ya.s 1, 63 1,59 1,03 0.90-1.18 Bioequiv. Comparison of 1-PP: 1 * 80 mg (test) versus 4 * 20 mg (comparison) Parameter Wed geom. researched a drug Wed geom. will compare. a drug Spot assessment of studies / comp. 90% will trust. interval Output dn-C _max 0.151 0.146 1,03 0.94-1.13 Not identification bp-aiso-oo 2.60 2.74 0.95 0.87-1.04 Bioequiv. bp-dis ₀ - _g 1 _a5C 2, 47 2, 62 0, 94 0.86-1.03 Bioequiv.

- 13 013213

Comparison of Z'-OH Gepirone: 1 * 80 mg (test) versus 4x20 mg (comparison) Parameter Wed geom. researched a drug Wed geom. compare drug Spot assessment of studies / comp. 90% will trust. interval Output 0, 325 0,303 1,07 0.98-1.18 Bioequiv. άη-AiSo-oo 6.62 6, 67 0.99 0.90-1.09 Bioequiv. άη-AiSo-Yaz !; 6.54 6, 61 0, 99 0.90-1.09 Bioequiv.

As can be seen from the table. 5, for all compounds it was found that one 80 mg tablet is on average bioequivalent to four 20 mg tablets with respect to bp-AIS. This is also true for bp-C _max for 1-PP and 3'-OH hepiron. An inconclusive result was found for gepirone for bp-C _max .

Since the study of average bioequivalence in some cases leads to uncertain conclusions for gepirone, despite the fact that a point estimate of the ratio of the geometric means of the studied and comparative methods of treatment lies within the acceptable range of 0.80-1.25, therefore, an additional statistical analysis is carried out, using a quantitative approach that reinforces experimental data. The results are shown in table. 6, where:

S _t ² : the total dispersion of the sample (i.e., the sum of the variance for one subject and the variance between the subjects) of the studied method of treatment based on 1od-transformed parameters;

Sv ² : the total variance of the sample (i.e., the sum of the variance for one subject and the variance between the subjects) of the comparative course of treatment based on 1od-transformed parameters;

Z _b ² : the variance of the sample intrasubject differences;

θ ₁ , (0.50): 50% quantile of the bioequivalence criterion θ ₁ (= average value for θ ₁ );

θ ₁ , (0.95): 95% quantile of the bioequivalence criterion θ ₁ (= upper limit of the 95% confidence interval for θ1).

Since for all analyzes 3 _Β ² > σ _{Τ 0} ² (= 0.2 ² = 0.04), a method with a reference scale is used.

Table 6

Gepirone comparison: 1 * 80 mg (test) versus 4 * 20 mg (comparison) Parameter 3 / 5 _k ² Per θι (0.50) Θ1 (0.95) Conclusion ' ¹ 0.3318 0.3755 0.2699 -0.033 0.401 Bioequiv. Tsp-Ais ₀ _ _oa 0.4063 0.3114 0.2747 0.268 0.876 Bioequiv. DP-AiSo-sKhazt; 0.4154 0.3449 0.3233 0.193 0.768 Bioequiv.

Comparison of 1-PP: 1 * 80 mg (test) versus 4 * 20 mg (comparison) Parameter s _t Memory Per Θ1 (0.50) Θ, (0.50) Output*' C1 ^- 0.2467 0.2435 0,0763 0.018 0.269 Bioequiv. άη-Αϋϋο-οο 0.4128 0.4108 0,0883 0.007 0.253 Bioequiv. Ap-ACSo_ _11aes 0.4338 0.4383 0.0935 -0.007 0.251 Bioequiv.

Comparison of Z'-OH Gepirone: 1 * 80 mg (test) versus 4 * 20 mg (comparison) Parameter 5/ 5/ Per θχ (0.50) θι (0.50) Conclusion ¹ ύπ — S _taak 0,0684 0,0648 0.1069 0.108 0.632 Bioequiv. άη-ACSo-oo 0.1132 0.1054 0.1333 0,078 0.710 Bioequiv. C P "OVER C o - ΐ £ _al 0.1137 0.1058 0.1360 0,077 0.714 Bioequiv.

* ⁾ Bioequivalent if θ ₁ (0.50), 0.95) <0 _P (= 1.745).

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The results obtained by the quantitative approach show bioequivalence for C _max , Ais, -, and Ais0-aaz1 hepiron, 1-PP and 3'-OH hepiron in relation to one 80 mg sustained release tablet and four 20 mg prolonged release hepiron tablets release (the same is observed for one sustained release 40 mg hepiron tablet and two sustained release 20 mg hepiron tablets). In addition, it was determined that a comparison of a 40 mg tablet and an 80 mg tablet shows no statistically significant differences for gepirone or its metabolites. This discovery shows proportionality to the dose of gepirone in the dose range of 40-80 mg.

In light of the above description, numerous modifications and variations of the present invention are possible. Thus, it is understood that, within the framework of the appended claims, the invention can be practiced in other ways than the particular embodiments described herein.

Claims (60)

CLAIM 1. A dosage form containing: (a) from about 14 to 25% by weight of a bioactive metabolite of hepiron in the form of a free base or a pharmaceutically acceptable salt thereof; (b) from about 70 to 85% by weight of a pharmaceutically acceptable cellulosic polymer matrix; and (c) a suitable amount of one or more pharmaceutically acceptable excipients, wherein the rate of release of the bioactive metabolite of gepirone from the dosage form is such that to achieve approximately 90-95% absorption of the bioactive Gepirone metabolite requires approximately 18 to 24 hours. 2. The dosage form of claim 1, wherein (c) further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of a colorant, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. 3. The dosage form according to claim 1, where (b) is hydroxypropylmethyl cellulose having a viscosity of from about 15,000 to about 100,000 cP. 4. The dosage form according to claim 1, where the concentration (a) is from about 15.5 to 18.7 wt.%. 5. The dosage form of claim 1, wherein said bioactive hepiron metabolite is selected from the group consisting of 3'-OH hepiron, 3 ', 5-dihydroxyhepiron and 5-OH hepiron. 6. The dosage form according to claim 1, where the specified dosage form is presented in tablet form. 7. The dosage form according to claim 6, where the total weight of said tablet is from 350 to 450 mg. 8. The dosage form according to claim 7, where the mass (a) in the specified tablet is from 60 to 80 mg. 9. The dosage form according to claim 6, wherein said tablet has an oval-rectangular shape with biconvex faces. 10. The dosage form according to claim 9, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches. 11. The dosage form according to claim 6, where the specified tablet has an oval-rectangular shape with flat faces. 12. The dosage form according to claim 11, where the specified tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches. 13. A dosage form containing: (a) from about 14.0 to 24.4% by weight of a bioactive metabolite of hepiron in the form of a free base or a pharmaceutically acceptable salt thereof; (b) from 70.5 to 82.1 wt.% hydroxypropylmethyl cellulose having a viscosity of from about 15,000 to 100,000 cP; (c) from 0 to about 1 wt.% a dye; (b) from about 8.0 to 16.7 wt.% microcrystalline cellulose; (e) from about 0.39 to 0.47 wt.% colloidal silicon dioxide; and (ί) from about 0.29 to 1.0 wt.% magnesium stearate. 14. The dosage form according to item 13, where (a) is from about 15.5 to 18.7 wt.%. 15. The dosage form of claim 13, wherein the pharmaceutically acceptable salt of the bioactive metabolite of gepirone is hydrochloride. 16. The dosage form of claim 13, wherein said bioactive hepiron metabolite is selected from the group consisting of 3'-OH hepiron, 3 ', 5-dihydroxyhepiron and 5-OH hepiron. 17. The dosage form according to item 13, where (C) is from 0 to about 0.3 wt.%. 18. The dosage form of claim 13, wherein (c) is one or more iron oxide. 19. The dosage form according to item 13, where (e) is from about 0.42 to 0.47 wt.%. 20. The dosage form according to item 13, where the specified dosage form is presented in tablet form. 21. The dosage form of claim 20, wherein the total weight of said tablet is from 350 to 450 mg. 22. The dosage form according to item 21, where the mass (a) in the specified tablet is from 60 to 80 mg. 23. The dosage form of claim 20, wherein said tablet has an oval-rectangular shape with biconvex faces. - 15 013213 24. The dosage form according to claim 23, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches. 25. The dosage form according to claim 20, where the specified tablet has an oval-rectangular shape with flat faces. 26. The dosage form of claim 25, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches. 27. The method of obtaining tablets according to claim 20, including: (ί) mixing all or part of the components from (a) to (£); (ίί) mixing the mixture obtained in stage (1); (ίίί) adding part or remaining components from (a) to (£); (ίν) mixing the mixture obtained in step (ίίί) if any components are added in step (ίίί); (ν) obtaining a workpiece from the mixture from step (ίν); (νί) grinding the workpiece obtained in stage (ν); (νίί) adding the remaining component (ί), if the part is stored in stages (ί) and (ίν); (νίίί) mixing the mixture from step (νίί); (ίχ) compressing the mixture from step (νίίί) to obtain a tablet. 28. The method of obtaining tablets according to claim 20, including: ί) mixing of all components (a), all components (c), all components (e) and 20% of the total concentration of component (b); ίί) mixing the mixture from step (1); ίίί) adding to the mixture from step (ίί) all components (b), half of the total concentration of component (ί) and the remaining 80% of the total concentration of component (b); ίν) mixing the mixture from step (ίίί); ν) obtaining a preform of the mixture from step (ίν); νί) grinding the workpiece from stage (ν); νίί) adding the remaining 50% of component (ί) to the shredded workpiece from stage (νί); νίίί) mixing the mixture from step (νίί); ίχ) compressing the mixture from step (νίίί) to the final desired form. 29. The dosage form according to claim 20, containing: (a) about 15.6 wt.% hydrochloride of a bioactive metabolite of hepiron; (b) about 75.3 wt.% hydroxypropyl methylcellulose; (c) about 0.31 wt.% yellow ferric oxide; (b) about 8.0 wt.% microcrystalline cellulose; (e) about 0.42 wt.% colloidal silicon dioxide; and (ί) about 0.31 wt.% magnesium stearate. 30. The dosage form of claim 29, wherein the total weight of said tablet is 385 mg. 31. The dosage form of claim 30, wherein the weight (a) in said tablet is 60 mg. 32. The dosage form according to clause 29, where the specified tablet has an oval-rectangular shape with biconvex faces. 33. The dosage form of claim 32, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches. 34. The dosage form according to clause 29, where the specified tablet has an oval-rectangular shape with flat faces. 35. The dosage form according to claim 34, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches. 36. The dosage form according to claim 20, containing essentially: (a) about 15.6 wt.% hydrochloride of a bioactive metabolite of hepiron; (b) about 75.3 wt.% hydroxypropyl methylcellulose; (c) about 0.31 wt.% yellow ferric oxide; (b) about 8.0 wt.% microcrystalline cellulose; (e) about 0.42 wt.% colloidal silicon dioxide; and (ί) about 0.31 wt.% magnesium stearate. 37. The dosage form of claim 36, wherein the total weight of said tablet is 385 mg. 38. The dosage form according to clause 37, where the mass (a) in the specified tablet is 60 mg. 39. The dosage form according to clause 36, where the specified tablet has an oval-rectangular shape with biconvex faces. 40. The dosage form of claim 39, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches. 41. The dosage form according to clause 36, where the specified tablet has an oval-rectangular shape with flat faces. - 16 013213 42. The dosage form according to paragraph 41, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches. 43. The dosage form according to claim 20, containing: (a) about 19.5 wt.% hydrochloride of a bioactive metabolite of hepiron; (b) about 70.7 wt.% hydroxypropyl methylcellulose; (c-1) about 0.24% by weight of yellow ferric iron oxide; (c-2) about 0.61 wt.% red ferric iron oxide; (ά) about 8.2 wt.% microcrystalline cellulose; (e) about 0.39 wt.% colloidal silicon dioxide; and (ί) about 0.29 wt.% magnesium stearate. 44. The dosage form of claim 43, wherein the total weight of said tablet is 410 mg. 45. The dosage form according to claim 44, wherein the weight (a) in said tablet is 80 mg. 46. The dosage form according to item 43, where the specified tablet has an oval-rectangular shape with biconvex faces. 47. The dosage form of claim 46, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches. 48. The dosage form according to item 43, where the specified tablet has an oval-rectangular shape with flat faces. 49. The dosage form of claim 48, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches. 50. The dosage form according to claim 20, consisting essentially of: (a) about 19.5 wt.% hydrochloride of a bioactive metabolite of hepiron; (b) about 70.7 wt.% hydroxypropyl methylcellulose; (c-1) about 0.24% by weight of yellow ferric iron oxide; (c-2) about 0.61 wt.% red ferric iron oxide; (ά) about 8.2 wt.% microcrystalline cellulose; (e) about 0.39 wt.% colloidal silicon dioxide; and (ί) about 0.29 wt.% magnesium stearate. 51. The dosage form of claim 50, wherein the total weight of said tablet is 410 mg. 52. The dosage form of claim 51, wherein the weight (a) of said tablet is 80 mg. 53. The dosage form according to claim 50, wherein said tablet has an oval-rectangular shape with biconvex faces. 54. The dosage form of claim 53, wherein said tablet has a total size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.240 ± 0.025 inches. 55. The dosage form according to claim 50, wherein said tablet has an oval-rectangular shape with flat faces. 56. The dosage form according to claim 55, wherein said tablet has a final size of 0.400 ± 0.05 inches per 0.325 ± 0.05 inches with a thickness of 0.195 ± 0.025 inches. 57. A method of treating depression in a patient in need thereof, comprising administering to said patient an effective amount of a dosage form according to any one of claims 1, 6, 13, 20, 29, 36 and 43. 58. The method of claim 57, wherein said patient is a human. 59. The method according to clause 57, where the specified patient, in addition, suffers from generalized anxiety. 60. The method according to clause 57, where the specified effective amount is from 0.01 to 40 mg / kg of body weight per day.