CA2616416A1

CA2616416A1 - Trazodone composition for once a day adminisitiation

Info

Publication number: CA2616416A1
Application number: CA002616416A
Authority: CA
Inventors: Pauline Contamin; Angela Ferrada; Sonia Gervais; My Linh Ma; Rachid Ouzerourou; Milloud Rahmouni; Damon Smith; Fouzia Soulhi
Original assignee: Individual
Current assignee: Labopharm Barbados Ltd; Labopharm Inc; Paladin Labs Europe Ltd
Priority date: 2005-09-09
Filing date: 2006-09-11
Publication date: 2007-05-03
Also published as: JP5269595B2; BRPI0615860B8; EP1931346A4; ZA200801158B; EP1940467A4; AU2006308449A8; KR20080047538A; IL189139A; WO2007048219A3; EP1931346A2; US20110033537A1; US8795723B2; JP2009507047A; CN101242856A; AR109571A2; RU2008113439A; KR20080047539A; AU2006308449B2; ES2389666T3; BRPI0615860A2

Abstract

The invention relates to a once a day formulation of trazodone or a trazodone derivative. The formulation contains trazodone or a trazodone derivative and a controlled release excipient so that, once administered orally, the trazodone or the trazodone derivative is maintained at a therapeutic plasma concentration from at least 1 hour to at least 24 hours after initial administration. After administration, the initial therapeutic action takes effect within the first hour and lasts at least about 24 hours. This therapeutic effect remains relatively and substantially stable for the remaining period of 24 hours. The formulations can be used for treating depression and/or sleeping disorders.

Description

'X'RAZODONE COIVIPUSITXOl~T
FOR ONCF, ADAY ADMINYSTRATIOI~T
TECI3NICAY, FZE.Y.I]

[00111] The present invention relates to the anti-depressant trazodone and in particular to a once a day formulation of trazodone, axid to its use for treating depression and certain sl eep disorders.

BACKGROUND ART

[0002] Trazodone is a serotonin-2 receptor antagonist/reuptake irihibitor that also decreases extracellular gamtua-amino-butyric acid (GA8A) levels in the cerebral cortex, through the blockade of 5-hydroxytryptamine 2A (5-HT2A) receptors. This decrease is accompanied by an increase in (5 -1-TT) release. I-Iigher doses of trazodone inhibit 5-HT
txansport and this uptake inhibition results in a further increase in 5-HT
levels. It is ooantemplated that this double mechanism may be responsible for the anti-depressant pt'operties of t.tazodone. 1Vloreover, the interaction between the GABAergic and serotoninergic systems may explain its sedative, anxiolytic properties.

[0003] Trazodone is tb.erefore a psychoactive compound with sedative and anti-depressant properties. It is rapidly absorbed from the upper gastro-intestinul tract and is extensively metabolized after oral administration. It is normally used to relieve symptoms of depression such as feelings of sadness, worthlessness, or guilt;
loss of interest in daily activities; changes in appetite; tiredness; thoughts of death or suicide; and insomnia, Trazodone may also be used for other purposes, and details thereof are well documented in the art.

[0004] Trazodone is a triazolopyridine derivative of the formula which is shown in its normally used hydrochloride form, Preparation of this compound was fust disclosed in U.S. Patent No. 3,381,009 which issued in 1968 to G.
Palazzo et ad.
SUBSTITUTE S6iEET (RULE 26)

[0005) The solubility of trazodone is pH dependent and has a pKa of 6,74 in water.
As a result, trazodone is higWy soluble in acid media (as found in the stomach and upper intestines) i.e., when below its pKa. In contrast, when above its pKa, its solubil#y is very low, for example, in the neutral atid basic conditions of the lower intestine.
Such izasolubility obviously has an effect on its dissolution and, therefore, on, the ava.ilability of the drug for absorption in the lower intestine. These features would be expected to hinder the development of long acting (for exa.mple, greater than 8 hours) forms of trazodone, whzch require substautially utxiform absorption along the length of the gastrointestinal tract, in parCicular, absorption during passage through both the upper and lower intestinal tracts.

As with many dxugs, trazodone is normally prescribed as an immediate release forzn for use two times (BID) or three' times (TID) a tlay, with all the inconveniences attd clisadvantages that this involves. For 'example, BID or TlD dosing with immediate release forms of trazod4ne resu.lts in concentrations of the drug in the blood that do not remain within the so-called therapeutic window and which, therefore, can be associated with higher risks of dose related adverse effects when reaclwlg high levels, or lower degree of efficacy when reaching low levels. In addition, multiple daily doses may lead to several periods of drowsiness throughout the day associated with peak trazodone concentrations occurring immediately after adminxstratiou, [00061 As a-result, there is a need for a once a day (OAD) formulation of trazodone that from a single tablet rapidly achieves and maintains sts.ble, effective concentrations over 24 hours and more and that is pH-indepeadent in its release profile so that trazodone may be uniformly absorbed along substantially the entirety of the upper and lower gastrointestinal tract, thereby reducing the fxequency and severity of side effects such as drowsiness during the day.

SuBSTiTIITE S':-ÃEET (RULE 26) DYSCLOSURE OF INVENTION

100071 The invention provides a sustained release pharmaceutical composition for once a day oral administration or trazodone or a derivative thereof. The composition comprises ftom about 15% to about 60 % by weight trazodone or a derivative thereof, and from about 15% to about 85% by weight perce-ot of a controlled release exeipient.
The controlled release exeipient, when' orally administered to a mammal, for example, a persoft, permits the trazodone or derivative thereof to aehieve an effective plasma concentration from at least about 1 hour to about 24 hours after initial administration.
[Jnder certain circumstaraces, the controlled release excipient provides a substantially pH
independent controlled release of the trazodone or derivativo thereof so that the trazodone or the trazodone derivative can be absorbed during passage through both the upper and lower gastrointestinal tracts.

C00081 The sustained release foxmulations provide plasma concentrations of trazodone or trazodone derivatives for at_ least 24 hours that are effective at treating, i.e., ameliorating, one ox more of the symptoms of depression. In another embodimertt, the sustained release formulations provide effective amounts of trazodone or a trazodone deriva,~Cive for treating sleeping disoxders, for example, impxoving sleep architecture.

C00091 The sustained release excipient can provide a therapeutically effective plasma trazodone ox trazodone derivative concezatration that remains substantially constarlt between about SO ng/mL and about 3000 ng/mL for a period that extends about one hour -after ingestion to at least about 24 hours. Plasrua concentrations typically are dependent on the dose administered. For example, in one embodiment, a sustained release phannaceuticai composition contemplated herein comprises 150 xug of trazodone hydrochloride. Such a formulation provides an effective plasma trazodone concentration from at least about 1 hour to about 24 hours after initial administration of between about 150 ng/mY. and about 500 ng/mL, In another cm.bodiment,, the sustained release pbarmaceutica7 composition comprises 300 mg of trazodone hydrochloride. Such a formulation provides an effective plasma trazodone concentxation from at least about 1 SUBSTiTtJTE s3-1rET (RULE 24) hour to about 24 hours after initial administration of between about 300 ng/xnl.. and about 1000 ng/mL.

f00101 In certain embodiments, the sustained release pharmaceutical composition comprises from about 15% to about 60% by weight trazodone or a derivative thereof and fi-om about 15% to about 8501o by weight percent of controlled release excipient. In other embodiments, the composition comprises from about 20% to about 50% weight percent ti-azodone and from about 20% to about 50% weight percent of controlled release excipient. For example, the composition may comprise about 35% to about 50%
weight percent trazodone and from about 15% to about 50% weigkA percent of controlled release excipient.

[0011] It is contemplated that a ntumber of dxfferent excipients may be use:ful. in tlae practice of the invention. In one embodyment, the controlled release excipient comprises cross-linked high amylose staxch. In certain embodimea.ts, the cxoss-linked high amylose starch is cross; linked with,phosp4orus oxychioride and/or comprises.
hydroxypropyl side chains. In cextain,embodiments, the cross-linked high amylose starch comprises between , . .,... , _;
about 65% and 75% by weight alnylose and zs cross-lio.ked with phosphorus oxychloride.
One preferred cross-linked high atnylose starch useful in the practice of the invention is ltnown as CC>N'fRAMIUP cross-li.nked, high amylose. staxch, available commercially from Labopharm, Itac.,. Laval, Canada.

(0012] In addition, the sustained reles.se pharmaceutical composition may optiorlally include moxe or more pharmaceutical additives. Exemplary pharmaceutical additives include binding agents (far example, hydxoxypropylmetlzylcellulose), solubilizing agents (for example, povidone or cetylpysidinium chloride), acidifying agents (for example, algiuic acid), pore fornlirig agents (for example, sucrose), lubricants (for example, sodium stearyl fumarate), and glidants (for example, coLloidal silicon dioxide).

[0013] In one embodiment, the invention provides a sustained xelease pharmaceutical composition comprising about 20% to about 50% by wexght, trazodone hydr'ochloride, about 20% to about 50% by weight cross-linked high amylose starch, about 10%
to about 20% by weight hydroxypropylmethylcellulose, about 0% to about 5% by weight SUBSTITUTE S14EET (RULE 26) cetylpyiidir-ium ckYloride, about 0% to about 20% by weight alginic acid, about 1% to about 5 lo by weight percent soditun stearyl fumarate, and up to aboxit 1% by weight percent colloidal silicon dioxide.

[0014] The sustained release pharmaceutical composition can be formulated itito a variety of shapes and forms such as tablets and caplets suitable for ora1, administration. In one embodiment, the invention provides a caplet comprising 300 mg of trazodone. Such a caplet can be adapted for administration before bedtime. Such a formuiation rapidly, induces soznnoletace after oral administration but yet provides substantially no drowsiness in a patient about 8 hours after oral administration as compared to repeat administration of an imnaediate release trazodone composition.

[0015] The invention provides for unit dose sustained release pharmaceutical composition for once a day oral administration of 300 mg trazodone hydrochloride is comprising about 20% to about 40% by weight of a controlled release excipient, wherein _.~=,~.
when ingested orally,,the coxn.position provides area under the'concentration-time curve Substantially equivalent to the commercially available daaly dose of three 100 mg strength ..f:,., ira.zodone hydrochloride tablets, wherein the three tablets are administered over 24 hours.
Also provided herein -is a unit dose sustained release pharmaceutical composition for once a day oral administration of 150 mg trazodone hydrochloride comprising about 30%
to about 50% by weight of a controlled release excipient, wherein when ingested oraily, the composition provides area under the concentration-time curve substantially equivalent to the commercially available daily dose of three, 50 mg strength trazodone hydrochloride tablets, wherein the three tablets are administered over 24 haurs.

[0016] In addition, the invention provides a method of treating depression by administering once a day to a person in need of an anti-depressant, one of the sustained release pkiarmaceutical compositions described above. The composition can be administered before bedtime.

[0017] In addition, the invention provides a method of improving the sleep architecture in a person in need of treatment thereof, the method comprises administering ,SUFSTR.TU'Tr-- vl~~~~ (~ULE 26) once a day to such a person, ote of the sustained release pltarma.ceutical compositions described above., The composition preferably is administered before bedtime.
SRIEF T)ESCEIPTI+ON OF+ THE DRAWINGS
[0018] The ixtvention is illustratecl but is not limited by the annexed drawings, in which.

100191 FIGURE 1 is a graph illustrating the in vitro dissolution profile of a first 300 mg trazodone OAD formuutation;

[0020] FIGUXtE 2 is graph that illustrates the plasma trazodone concentra,tion derived from a single tablet of the first 300 mg trazodone OAD for.mula.tion as a function of time when administered to a human;

[0021] FiGC?'RE 3 is a graph illustrating the in vitro dissolution profile of a second 300 mg trazodoae OAD formulation;

[0022] FIGURE 4 is graph tfxat illustrates the plasma trazodone concentration derived from a siztgle tablet of a second 300 mg trazodone OAD formulation as a fun.ction of time.
when administered to a human; [0023) FIGURE 5 is a graph illustrating the in vitro dissolution profile of a 150 mg trazodone OAD formulation; and [0024] FIGURE 6 is graph that illustrates the plasma trazodone concentration derived from a single tablet of a 150 mg trazodone OAD formulation as a fun.etion of time when administered to a huma,n.

DETAILED IIESCIiIP"CTON OF TF1E INVENTION

[0025) The invention is based, in part, upon the discovery that it is possible to formulate a once a day formulation of trazodone or a trazodone derivative that provides a plasma concentration of the active ingredient that is essentially stable between one hour aiid twenty four hours that is effective in the treatment of, i.e., ameliorating one or more of the systems of depression. This discovery was surprising because, even th.ougfi the solubiiity of trazodonc is pH dependent, and decreases rapidly at the higher pH found in

6 SUBSTITUTE SHEET (RULE 26) he lower gastrointestinal tract, it has been found that it is possible to provide therapeutic, 1'able and/or effective conoentrations of trazodone in,the blood stream for at least 24 iours irrespectave of changes in pH through the upper and lower intestinal tracts.

0026) Accordingly, the invention provides a sustained release plaarmaceutical oinposition for once a day oral administration or,txazodone- or a derivative thereof. The onaposition comprises from about 15% to about 60 % by vveight trazodone or a lerivative thereof, and from about 15% to about 85% by weight percent of a controlled clease excipient. The controlled release exoipient, when oxaIly administered to a na.rnmal, for exatnple, a person, permits the trazodone or derivative thereof to achieve nd/ot maintain an effective plasina concentration, for example, a therapeutically ,fi'ective plasma concentration from at least about 1 hour to about 24 hours after initial .dministration for treating depression, 0027) In addition, it is possible to use the satue or similar formulations for treating leep disarders, for example, improving sleep architecture. I The controlled release :xcipient, when orally administered to a mammal, for example, a person, permits the razodone or derivative thereof to achieve an effective plasma concentration for treating a leep disorder. Such a formulation rapidly (for example, withiii 1 hour) induces omnolence after oral administration but yet provides substantially no drowsiness in a atieh.t about 8 hours after oral administration, as compared to repeat admi.z1istration of an mmediate release trazodone composition.

0028) The foMuulations described herein provide a rapid rise izx plasma oncentrations of the active ingredient, which thereafter remain relatively and ubstantially stable for at least 24 hours or more. The plasma concentration between 1 our and 24 hours remains within about 45% of the mean plasma aoncentra'Gion, more referably between about 30% of the mean plasxna concentration., and most preferably etween about 15% of the mean plasma concezatration. In certain formulations, after an litial rapid release of trazodone or the trazodone derivative within an hour of ingestion ie trazodone or the trazodone derivative is released fn vivo witli approximately zero rder kinetics for at least about 24 hours, leading to plateau plasma concentrations. In

7 ~,SUBST1TU s 1~ SHEET CRlb.i.E 26) these form.ulations, the effective plasma concentration of the trazodone formulation remains generally constant about 1 hour after ingestion, and can be between about 60 ng/mL and about 3000 ng/mL, between about 150 ng/mb, and 1500 ng/mL, between about 600 ng/niL and 1300 ng/mL, between about 500 ng/rnL s,nd 1200 ng/mL, or between about 300 ng/mL and 650 ng/mL at least up to about 24 hours after oral adminYstration.

[-0029] Formulations contemplated herein may reach steady-state, for example, on-average, vvitliin a normal population, after about the fourth administration.
The peak-to-trough xatio produced by such farmulations at steady-state may be about 60% to about Ii 00%.

10030] 'Me sustained release trazodone fQrmulati.ons contemplated herein may have effective plasma concentrations that are for example bioequivalent with respect to the AUC (area under the curve) of a immediate release formulation that is administexed, for example, two or three times day. The AUC is a mathematical calculation to evaluate the body's total exposure over time to a given drug and xefers to the area uinder the curve in a plot of concentration of drug against time. AUC's are used as a guide for dosing schedules and to compaxe the bioavailability of different drug formulations in the body.
[0031] The formulations described herein are particularly useful in the del.ivery of trazodone and trazodone derivatives. Derivatives include pharmaceutically acceptable prodrugs, metabolites, salts and estexs, or the like of trazodone. For example, the term ' pharmaceutically-acceptable salts" is art--recognized and refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention. In a preferred embodiment, the active ingredient in the formulation is trazodozie hydrochloride.

f4032] A composition according to the invention may include trazodone or its derivatives and a controlled release excipient. In some embodiments, compositions disclosed herein include more than about 15% trazodorie or its derivatives by weight, for example between about 15% and about 60%, or between about 20% and about 60%, or between about 20% and about 55% by weight, In other embodiments, compositions

8 S1~~ST-lTUTE SliEETjRLtl..~ -20, contemplated herein may include more,than about 15% weight controlled release excipient, for example, between about, 15% and about 85%, or about 20% and about 85%, or about 20% and about 60%, or about 20% and about 50%, or about 30% to about 50% by wveight. The composition according to the invention preferably comprises from about 20% to about 50% by weight, more preferably from about 25% to about 50 !o trRzodone or trazodone derivative, and from about 20% to 50% by weight, more preferably from about 25% to about 50% by weight of controlled release excipient. In a particular embodiment, this invention is directed to a composition comprising about 25%
to about 50% trazodone hydrochloride by weight and about 30% to about 50%
cross-linked high amylose starch, such as disclosed lnerein.

[0033] A practical example of a sustained release pharlnaceutical composition according to the invention, is one containing 150 mg of trazodone hydrochtoride, This formulation can provide an effective plasma Goncent,ration preferably in the range of about 150 ng/mL to 500 ngJmL between about 1 and 24 hours after the first administration. Another pxactical exatnple is one wherein the composition comprises 300 ing of trazodone hydrochloride, This formulation can provide a plasma trazodone conaen.tra.tion preferably in the range of about 300 ng/mL to 1000 ng/mL. Of course, other compositions according to the invention may be prepared with different amounts of trazodone or its derivatives with correspondingly varying plasma concentrations that can be for example, between about 50 ng/mL and about 3000 ng/mL.

[0034] Controlled release excipa.ents contemplated herein may vary to a large extent as is well known to, one skilled in the art, provided that a formulation including an excipient has the disclosed therapeutic action and/oz provides a pH independent delivery of trazodone or a trazodone derivative. Controlled release excipients may include cross-linked starches, hydrogels, celluloses, and/or polymers, and other controlled release excipients known to those skilled in the art.

(0035] In on.e embodiment, the controlled release excipient preferably comprises a cross-linlzed high arnylose starch, for example, where the cross-linked high amylose starch is cross-linked with phosphonts oxychloride and/or comprises hydroxypropyl side

9 SU"S"tl'UTE'S4~~ET (RUIE 26) cliains. In certain embodiments, the cross-linked hi,gh amylose starch comprises bettween about 65% and 75% by weight amylose and is cross-linked with phosphorus Qxychloride.
A suitable excipient has been developed by and is available comMercially from I.abopharm, Inc., f.ava,l, Canada, under the trademark +C+DNTRAMIf1O. The synthesis of the CON'IRAMIL7o excipient is described, for example, in U.S. Patent No, 6,607,748, hereby incorporated by reference in its entirety for all purposes.
Compositions contemplated herein may include cross-linked high amylose starch together with one or more additional controlled release excipients.

[0036] Cross-linking of starch represents a powerful method for modifyi;ng starch.
Usually, starch granules are cross-linked to increase resistance of the paste to shear or heat. Such chemically cross-linked starches provide a desirable smooth texture and possess viscosity stability throughout processing operations and normal shelf life. In 4ome embodiments, cross-linked high amylose starch as contemplated herein may be gelatinized after cross-linking. In a preferred embodiment, cross-linlcing high amylose starch may include additional chemical modification (e:g., hydroxypropylation) prior to gelatinization.

[0037] The cross-linking of high amylose starch may be realized according to procedures descxibed in the art! For example, cross-linking of amylose can be catried out in the manner described in ivlateescu [Rz4CFIEivi1(P, 60: 535-537 (1978)] by reacting amylose with epichlorohydrin in an alkaline medium. In the same manner, starch can also be cross-linked with a reagent selected from the group consisting of epichlorohydrin, adipic acid anhydride, sodium trimetaphosphate and phosphorous oxyohloride or other cross-linking agents including, but not limited to, 2,3-dibroznopropanol, linear mixed anhydrides of acetic and di- or tribasic carboxylic acids, vinyl sulfone, diepoxides, cyanuric chloride, hexahydro-1,3,5-trisacryloyl-s-triazine, hexam.ethylene diisocyanate, toluene 2,4-diisocyaxiate, N,N-methylenebisacxyIamide, N,N'-bis (hydroxymethyl) ethyleneurea, mixed carbonic-carbo,tylic acid anhydrides, imidazolides of carbonic and polybasic carboxylic acids, imidazolium salts of polybasic carboxylic acids, and guanidine derivatives of polyoarboicylic acids, The reaction conditions employed will : CIBSTFTU7"lr SHEe1' (R11.i.E 26) vary with the type a-nd amount of the cross-1h*ing agent that is used, as well as the base conceritration, arnount and type of starch. . , [003$] It is contemplated that starches containing more than about 40% w/w amylose can be used to form cross-linked high arnylose star~h, e.g., pea and wrinkled pea starch, bean starch, hybrids or genetically modified tapioca or potato starch, or any other root, tuber or cereal starch. Preferably, high amylose starch containing about 70%
w/w amylose is used as the base material. For example, high arnylose starch, Cerestar F-myloGe103003 (Cerestar U.S.A. Inc.), may be used.

[0039] It has been discovered that by combining trazodone or a trazodone derivative with a controlled release excipient, fbr example, ctoss-linked high amylase starch (for example, CON'TRAIVIID cross-linked high atnylose starch), trazodone, which is pl;I
sensitive with a pKa of about 6.74 can be released and absorbed not only in the upper gastrointestinal tract where the pH is below the pKa of trazodone (where trazodone is soluble) but also in the lower gastrointestiinal tract where the pH is above the pKa of trazodone (where trazodone is poorly soltible) thereby maintaining stable plasma concentrations in the blood throughout gastroinfestxnal transit. To this day, to our knowledge, no once a day formulation including a pH dependent active agent has been suggested or designed for a composition that has the pharmacokinetic profile described herein.

[0040) The pbarmaceutxGal composition according to the invention may also coznprise pharmaceutically acceptable additives. Such additives can include, for example, sugars, such as lactose, glucose and sucrose; other starches, such as corn starch and potato starch;
cellulose, and its derivatives, such as sodium carboxyniethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol", esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminutn hydroxide; alginic acid; and other non-toxic compatible substances employed in pharmaceutical formulations. Such additives may also inchide colorants.

ll SUBSTITUTE SliEEi' (RULE 2M

[0041] For example, the compositions disclQsed herein may include any one of a mixtute of a binding agent, a solubilizing agent, an a.cidifyi.ng agent, a pore forming agent, a lubricant, a gl.idant, and the like, as is well ktaouTn to those skilled in the art, Preferred pharmaceutical additives that are used in providing a composition according to the invention may include, for example, binding agents that include, for example, hydroxypropylmethylcollulose, hydroxypropyloellulose, hydroxyethylcellulose, methylcellulose, dicalciuwn phosphate, calcium phosphate, microcrystalline cellulose, or the like, solubilizing agents that, include, for example, povidone, cetylpyridinium chloride, or the like, acidifying agents that include, for exainple, alginic acid, citric acid, succiiiic acid, bile acid or the like, pore farttxing agents, that include, for example, sucrose, iactose, mannitol or the like, lubricants that include, for exanple, sodium stearyl furnarate, magnesiuna stearate, calcium stearate, steatxc acid, hydrogentated vegetable oils or the like and/or glidsnts that irxcltide, for example, colloidal silicozi dioxide, tale or the like. Other additives that are well known to those skilled in the art may of course be included in the composition according to the invention without departing feom the scope and spirit of the present invention.

[00421 For example, the composition according to the iuvention may comlrrise about 20 to 50 weight percent trazodone hydrochloride, about 20 to 50 weight percent cross-linked high amylase starch (for example, CONTR.AMIDO cross-linked high amylose starch), about 10 to 25 weight percent hydroxypropylmethyicellulose, about 0 to 10 weight percent cetylpyridinium chloride, about 0 to 20 weight percent alginic a.cid, about I to 5 weight percent sodium stearyl fumarate, and up to about 1=trveight percent colloidal silicon dioxide.

[0043] The composition according to the invention is nonnally prepared in the form of a tablet. Although the tablet can adopt a wide variety of sbapes as is well knowt to those skilled in the art, the preferred shape is a caplet. Such caplets may be foxxned using, for example, upper and lower punches as is known in the art. In some embodiments, tablets may include a coat, such as, for example, a coating with a colorant. Suitable coatings include, 'for example, aqueous film coating polymers such as polyvinyl alcohol, talc, SEIEJSTITÃdTF- SHEET (Rtj1.E.2jV

macrogol and the like, az1d mixtures thereof Suitable colorants include, for example, iron oxides, lakes, nattvxal colorants and other colorants known to those skilled in the art.
[00441 In an exemplary formulation protocol for producing a 5 kg batcl-i of an exemplary sustained release formulation, CONTR,4IvHD" excipient, hydroxypropylmetliyl cellulose, trazodone HCl and sodium stearyl fumarate are individually weighed and sifted through a 30 mesh filter, Colloidal silicon dioxide is weighed and pre-blended with CONTkZAIvIIDO, sifted through a 30 mesh filter, and blended for 10-30 seconds, for example, 15 seconds to produce a pre-blend.
lfydroxypropylmethylcellulose, trazodone and the Contramid@-collodial silicon dioxide pre-blend, are coanbined aud blended for 5-10 minutes, for example, 7 minutes, to produce a bulk blend. A small portion of the resulting bulk blend is combined with the sodium stearyl fumarate and blended for 20-60 seconds, for example, 30 seconds. The resulting sodium stearyl fumarate blend is combined with the residual bulk blend, and the resulting mixture blended for about 2-6 minutes, for example, 4 minutes, The tnal blend is compressed into tablets using a compression pressure of 27 kN. Caplets are formed using a caplet standard concave punch.

[0045] A dosage for once a day administration may be 25 mg to 600 mg of' trazodone or a trazodone derivative. Typical doses for once a day administration include 150 mg or 300 mg of trazodone or a trazodone derivative, although this mount may vary to a large extent depending on required needs, and the specxfic requirements of the treating physician. For example, the dosage of any compositions of the present invetition will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disarder to be treated or prevented, the route of administration, and the form of the subject composition. Dosages for the compositions of the pxesent invention may be readily detemiined by techniques known to those of skill in the art or as taught herein. The precise time of administration and amount of any particular subject composition that will yield the,most effective treatment in a given patient will depend upon the activ'ity, pharmacoldn.etics, and bioavailability of a subject composition, plrysiological condition of the patient (including age, sex, disease type and stage, general 13, INSTlTUTE Si-~ET (RULE 26) physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like. The guidelines presented herein may be used to optimize the treatment, e.g., determining the optiinum time and/or amount of administration, which will require no more thaia routine experimenta.tion consisting of monitoring the subject and adjusting the dosage and/or timing.

[0046] The resulting formulations have in vitro profiles, preferably, as described in Examples I and 3, hereinbelow. The in vitro release profiles were measured as follows.
Briefly, the release rates were determined using a U,S,P. paddle method (apparatus type SI as described in U,S.p. XXVI) at 150 revolutions per minute, at 37~:0.5 C, in 900 mL of k-ydrochlozide/soditun chloride pH 1.2 solution (acid stage) followed after one hour by 900 mL of sodiu.tn phosphate monobasxo buffer pH 6.0 (buffer stage). In some embodxmenCs, formulations may have release kinetics, whereby, when tested by the foregoing method, not more than about 30% of the active ingredient is released by 1 hour after initiation of the experiment, about 35% to 60% of the active ingredient is released by 6 hottxs, not more than about 80% of the active ingredient is released by 12 hours,.
and/or ixot less than about 80% of the active ingredient is 3'eleased by 24 hours.

100471 The compositions described herein are particularly useful in treating depression, disorders associated witl.t depression, and sleep disorders.
According, a mammal suffering from depression can be administered once a day (for exai.nple, at bedtime) with a trazodone formulation as defined above. A ma.rnrnal to be treated by the subject method may mean either a human or non-human animal.

(0048] The compositions described herein may also be useful in treating patients that have difficulty sleeping and/oz have disrupted sleep architectore, x.e., disrupted non-REMM1V1 stage and cycle infrastructure of sleep. In some embodim.ents, formulations discl4sed herein release a therapeutically effective portion of trazodone within one hour after oral administration and thus rapidly induce somnolence'brxt yet provide substantially no drovvsiness in a patient about 8 hours after oral administration as compared to repeat administration of an immediate release trazodone composition, Accordingly, such formWations reduce undesirable drowsiness in waking hours or in the day time.

, SU13STITUTE S&~~ET (RULE 26).

[0049] The invention will now be illustrated by means of the following examples Nvhich are given for the purpose of illttstraUon only and without any intenti.on to limit the scope of the present invention.

EXAMPLES
1~: ~rample 1 j0p50] Aiirst sustained release 300 mg trazodone containing formulation (denoted liormu.lation 1) was prepared having the composition set forth in TABLE 1.

TABLE i - Formulation 1 Ingredients Tablet Tablet (m %
CQN"I'ItAM~ excipient 200 32.7 Trazodone HCI 300 49.0, I-Iydroxylpropylmethyl cellulose K100M 100 16.3 Colloidal silicon dioxide 3 0.5 Sodium stearyl ftunarate 9 1.5 Total 612 100 [0051] The in vitro release kinetics of this formulatioxt were measured using the U.S,p, paddle method (apparatus type II as described in U.S.P. XXVI) at 150 revolutions per minute, at 3%0.5 C, in 900 mL of hydrochloride/sodium chloride pH 1.2 solution (acid stage) f'ollowed after one hour by 900 mL of sodium phosphate monobasio buffer pH 6.0 (buffer stage). This formulation, when tested using the foregoing method, had an irt vitro release profile where not more than about 30% of the active ingredient was released by 1 hour after initiation of the experiment, about 359/t to 55% of the active ingredient was released by 6 hours, not more than $0%a of the active ingredient was released by 12 hours, and not less than 80% of the active ingredient was released by 24 hours.

'SUBSI'1TUTE ShtEET (RULE 26) [0052] Yn addition, the formulation was tested in vivo. The pharmacokinetics of this formulation were compaared with those of the commercial products Tritticoo AC
150 mg CR tablets given BID, and Desyrel~ 100 mg I12. tablets given TID in a human randomized pharnacokinetic crossover stutly. It was found that following administration of Form.ulation 1, trazodone plasma concentrations increased more graclually and pealc trazodone plasma concentrations were lower than those of either of the reference products. The mean plasma trazodone concentration measured in 18 patients is shown in Figure 2. The results indicate that this formulation provides a therapeutic plasma concentration within about 1 hour and provides a subskatitially Gonstant trazodone concentration frQ:m 1 hour to 24 hours, The trazodone plasma concentrations at 24 hours were similar to those following TID administration of Iaesyrel'2and BID
administration of Trittico AC, [0053j The in vauo experiments demonstrate that following oral administration of p'orsnulation 1, after a short period to reach acceptable plasma concentrations, trazodone plasma concentrations were maintained at a relatively constant level froua approximately 1 hour post-administration to at least 24 iZQurs post-administration, [00541 , Example 2 [0055] A second sustained release 300 mg teaz4done containing formulation (denoted Formulation. 2) was prepared haviixg the composition set forth in TABLE 2.

TABLE 2 - Formulation 2 Ingredients Tablet Tablet m %
CO1W'TFtAMID excipient 169 Trazodone HCl 300 24.1 Hydroxylsropylmethyl cellulose K110M 105 1510 Alginic acid 105 15.0 Cetylpyri.dinium chloride 7 1.0 Colloidal silicon dioxide 3.5 0.5 ~..
SUBSTITUTE SHEET (RULE 26) Soditum stearyl fumarate 10.5 1.5 Total 700 10 100561 The in vftrQ release kinetics of Formulation 2 were measured using the U.S.P.
paddle method as described in Exarn.ple I. The in vih'o dissolution profile (Vigure 3) shows that in this farnlulation, not xnore than about 30% of the active ingredient was released by 1 hour after initiation of the experiment, about 35% to 550/o of the active ingredient was released by 6 hours, not more than 80% of the active ingxedient was released by 12 hours, and not less than 80% of the active ingredient was released by 24 hours j00571 Formulation 2 was also evaluated in viva. The results obtained were substantially the same when )Formulation 2 was compared with TrAttico" AC and DesyrElo. The mean plasma trazodone concentration measured in 19 patients is shown in Figure 4. It was found that following administration of Fonnulation 2, trazodone plasma concentrations increased to provide a therapeutic concentration in about 1 hour, The plasma concentrations increased till about 6 hours after oral administration but tlien gradually deelined. The plasma concentration of trazodone provided by Formulation 1 was more stable between 1hours and 24 hours than that provided by Formulation.
2.

Examnle 3 [00583 A first sustained release 150 mg trazodone containing formulation (denoted Formulation 3) was prepared having the composition set forth in TABLE 3.

TA13LE 3 - FormuYation 3 Ingredients Tablet Tablet (mg) %
CONTRAIV.CIl7 excipient 252 46.8 Trazodone HCl 150 27,$
Hydroxypropylmethylcellulose K10q1Vi 126 23.4 Colloiclal siliean dioxide 3 015 S1r9135T1TUTE SHEET (RU1.G 26) Sodium stearyl f=arate 8 1.5 100591 The in vitro release kinetics of Formulation 3 were measured using the U.S.P.
paddle method as desoxi.bed in. Example 1, The in vitro dissolution profile (Figure 5) shows that in this formulation, not more than about 30% of the active ingredient was released by 1 hour after initiation of the experiment, about 40% to 60% of the active ingedient was released by 6 hours, not more than 80 !o of the active ingredient was released by 12 hours, and not less than 80% of the active ingredient was released by 24 hours.

(00601 Fonnulation 2 was also evaluated in vivo, The mean plasma trazodono concentration measured in 18 patients is shown in Figure 6, It was found that following administration of Formulatiori 3, Ceazodone plasma concentrations increa.sed rapidly to provide a th.exxapeutic concentration in about 1 hour. The results indicate a substantially constant trazodone concentration from 1 hour to 24 hours. As with formulation 1, this appears to show zero order welease kinetics between. 1 hour and 24 hours following oral admiiiistration.
[0061] Although the present invention has been illustrated by means of preferred embodiments the:reof, it is understood that the invention intends to cover broad aspects thereof without departin.g from the spirit and scope of the invetxtion as defined in the appended claims.
SUBSTtTUTE SKSEET (RULE 26)

Claims

WHAT IS CLAIMED IS:

1. A sustained release pharmaceutical composition for once a day oral administration, the composition comprising: about 15% to about 60% by weight trazodone or a derivative thereof, and about 15% to about 85% by weight of a controlled release excipient, wherein the controlled release excipient, when administered to a mammal, permits the trazodone or derivative thereof to maintain an effective plasma concentration from at least about one hour to at least about 24 hours after initial administration.

2. The sustained release pharmaceutical composition according to claim 1, wherein the plasma concentration is effective at treating depression in the mammal.

3. The sustained release pharmaceutical composition according to claim 1 or 2, wherein the plasma concentration is effective at treating a sleep disorder in the mammal.

4. The sustained release pharmaceutical composition according to any one of claims 1-3, wherein the composition comprises trazodone hydrochloride.

5. The sustained release pharmaceutical composition according of any one of claims 1-4, wherein the controlled release excipient provides a plasma trazodone concentration between about 50 ng/mL and about 3000 ng/mL that remains substantially constant for a period that extends from about one hour after administration to about 24 hours.

6. The sustained release pharmaceutical composition according to claim 1, wherein the composition comprises 150 mg of trazodone hydrochloride.

7. The sustained release pharmaceutical composition according to claim 6, wherein the plasma trazodone concentration achieved one hour after ingestion is between about 150 ng/mL and about 500 ng/mL.

8. The sustained release pharmaceutical composition according to claim 1, wherein the composition comprises 300 mg of trazodone hydrochloride.

9. The sustained release pharmaceutical composition according to claim 8, wherein the plasma trazodone concentration one hour after ingestion is between about ng/mL and about 1000 ng/mL.

10. The sustained release pharmaceutical composition according to any one of claims 1-9, wherein the composition comprises from about 20% to about 50% by weight trazodone or trazodone derivative and from about 20% to about 50% by weight percent of controlled release excipient.

11. The sustained release pharmaceutical composition according to claim 10, wherein the composition comprises from about 35% to 50% by weight percent trazodone or trazodone derivative and from about 15% to 50% by weight of controlled release excipient.

12. The sustained release pharmaceutical composition according to any one of claims 1-11, wherein the controlled release excipient comprises a cross-linked high amylose starch.

13. The sustained release pharmaceutical composition according to claim 12, wherein the cross-linked high amylose starch comprises between about 65% and 75% by weight amylose and is cross-linked with phosphorus oxychloride.

14. The sustained release pharmaceutical composition according to claim 13, wherein the cross-linked high amylose starch comprises hydroxypropyl side chains.

15. The sustained release pharmaceutical composition according to claim 14, wherein the cross-linked high amylose starch is gelatinized.

16. The sustained release pharmaceutical composition according to any one of claims 1-14, wherein the composition further comprises a pharmaceutical additive.

17. The sustained release pharmaceutical composition according to claim 16, wherein the pharmaceutical additive is selected from a binding agent, a solubilizing agent, an acidifying agent, a pore forming agent, a lubricant, and a glidant.

18. The sustained release pharmaceutical composition according to claim 17, wherein the binding agent comprises hydroxypropylmethylcellulose.

19. The sustained release pharmaceutical composition according to claim 17, wherein the solubilizing agent is selected from povidone or cetylpyridinium chloride.

20. The sustained release pharmaceutical composition according to claim 17, wherein the acidifying agent comprises alginic acid.

21. The sustained release pharmaceutical composition according to claim 17, wherein the pore forming agent comprises sucrose.

22. The sustained release pharmaceutical composition according to claim 17, wherein the lubricant comprises sodium stearyl fumarate.

23. The sustained release pharmaceutical composition according to claim 17, wherein the glidant comprises colloidal silicon dioxide.

24. The sustained release pharmaceutical composition according to claim 1, 2 or 3, wherein the mammal is a person.

25. A sustained release pharmaceutical composition comprising about 20% to about 50% by weight trazodone hydrochloride, about 20% to about 50% by weight cross-linked high amylose starch, about 10% to about 25% by weight hydroxypropylmethylcellulose, about 0% to about 5% by weight cetylpyridinium chloride, about 0% to about 20% by weight alginic acid, about 1% to about 5%
by weight percent sodium stearyl fumarate, and up to about 1% by weight percent colloidal silicon dioxide.

76. The sustained release pharmaceutical composition according to any one of claims 1-25, wherein the composition is in the form of a tablet.

27. The sustained release pharmaceutical composition according to claim 26, wherein the tablet is shaped in the form of a caplet.

28. The sustained release pharmaceutical composition according to claim 27, wherein the caplet comprises about 300 mg trazodone.

29. The sustained release pharmaceutical composition according to any of claims 1-28, which is adapted for administration before bedtime.

30. The sustained release pharmaceutical composition according to claim 29, wherein the composition provides substantially no drowsiness in a person about 8 hours after oral administration relative to repeated administrations of an immediate release trazodone composition.

31. A unit dose sustained release pharmaceutical composition for once a day oral administration of 300 mg trazodone hydrochloride comprising about 20% to about 40% by weight of a controlled release excipient, wherein when ingested orally, the composition provides area under the concentration-time curve substantially equivalent to the commercially available daily dose of three 100 mg strength trazadone hydrochloride tablets wherein the three tablets are administered over 24 hours.

32. A unit dose sustained release pharmaceutical composition for once a day oral administration of 150 mg trazodone hydrochloride comprising about 30% to about 50% by weight of a controlled release excipient, wherein when ingested orally, the composition provides area under the concentration-time curve substantially equivalent to the commercially available daily dose of three, 50 mg strength trazodone hydrochloride tablets wherein the three tablets are administered over 24 hours.

33. A method of treating a sleep disorder comprising administering to a person with a sleeping disorder a sustained release pharmaceutical composition comprising trazodone or a trazodone derivative in a controlled release excipient.

34. A method of treating a sleeping disorder comprising administering to a person with the sleeping disorder a sustained release pharmaceutical composition of any one of claims 1-32.

35. The method according to claim 33 or 34, wherein the disorder is treated to improve sleep architecture.

36. The method according to claim 35, wherein the composition is administered before bedtime.

37. A method of treating depression comprising administering once a day to a person with depression a sustained release pharmaceutical composition according to any one of claims 1-32.

38. The method according to claim 37, wherein the composition is administered before bedtime.

39. Use of a sustained release pharmaceutical composition according to any one of claims 1-32 for the treatment of depression.

40. Use of a sustained release pharmaceutical composition according to any one of claims 1-32 for the manufacture of a composition useful for the treatment of depression.

41. Use of a sustained release pharmaceutical composition according to any one of claims 1-32 for the treatment of a sleeping disorder.

42. Use of a sustained release pharmaceutical composition according to any one of claims 1-32 for the manufacture of a composition useful for the treatment of a sleeping disorder,