WO2010089259A2

WO2010089259A2 - Sustained release composition containing quetiapine

Info

Publication number: WO2010089259A2
Application number: PCT/EP2010/051098
Authority: WO
Inventors: Juergen Heim; Sandra Weigel
Original assignee: Woerwag R&D Gmbh
Priority date: 2009-02-04
Filing date: 2010-01-29
Publication date: 2010-08-12
Also published as: WO2010089259A3

Abstract

The present invention is directed to a sustained release pharmaceutical composition containing quetiapine, a pharmaceutically acceptable salt or a derivative thereof, which allows a once-a-day administration of said sustained release pharmaceutical composition to a patient in need thereof. The present invention is further directed to the use of this composition for the treatment of schizophrenia and acute manic episodes associated with bipolar I disorder, and to a process for preparing the pharmaceutical composition.

Description

Sustained release composition containing quetiapine

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

After administration of an immediate or rapid release formulation, the concentrations of the active compound in the blood are subject to high fluctuations when the drug formulation is administered repeatedly, as is customary in therapies. After peroral administration of formulations having immediate or rapid release of an active compound, the maximum concentrations of the active compound in the blood are usually reached within 4 hours. They then decrease considerably until the next administration occurs. Thus, a multiple administration of tablet formulations having rapid release of the active compound results in high fluctuations of the concentration of the active compound in the blood.

However, in some cases high concentrations of the active compound in the blood which occur after administration of a formulation having immediate or rapid release of active compound are undesired, since, for example, side effects may also occur more frequently. Additionally, it is desirable in some cases to maintain the concentrations of the active compound in the blood at a higher level over a prolonged period. Such a drug formulation having sustained or prolonged release moreover offers a number of fundamental advantages, such as less frequent administration, which improves patient compliance. Additionally, advantages may be achieved in the case of certain diseases where even longer- lasting active compound levels than with an immediate or rapid release dosage form are important. Altogether, a drug formulation having sustained or delayed release offers greater possibilities to adjust the level of active compound to match the specific disease.

Quetiapin is an example for an active pharmaceutical ingredient that shows the above mentioned behaviour. Said agent and its salts have been employed as pharmaceutically active agents in the treatment of schizophrenia and bipolar mania. Due to the high degree of bioavailability and rapid metabolism of quetiapine, the agent typically has to be administered twice a day.

Such multiple administrations, however, may result in problems related to patient compliance and increased health care costs. Accordingly, it would be advantageous to provide a formulation which allows for the delivery of quetiapine in a controlled or sustained release profile. More specifically, it would be a tremendous benefit to patients suffering from schizophrenia or acute manic episodes associated with bipolar I disorder if the agent could be formulated to be released over an extended period of time, in particular, a twenty- four hour period, instead of being rapidly metabolized. In this manner, patients suffering from schizophrenia or acute manic episodes associated with bipolar I disorder would benefit from the therapeutic effects of the antipsychotic agent for extended periods of time without the need to consume more than one dosage per day.

Previously described formulations of quetiapine have certain properties that are not ideal under all circumstances. For example, previously disclosed formulations do not provide a constant or substantially constant level of quetiapine for 24 hours at steady-state. These previous formulations provide quetiapine blood or plasma concentrations that vary with time, i. e., at certain time points between administrations there are higher concentrations of quetiapine than at other times.

This means that at certain time points of a 24-hour period, a patient may receive therapeutically effective amounts of quetiapine, while at other time points the concentration of quetiapine in the blood may fall below therapeutic levels (i.e. symptomatic relief may not be maintained). While some sustained release formulations of quetiapine have been disclosed (see for example US Patent No. 5948437, WO 97/45124), these formulations require a gelling agent for sustained release.

While WO 2005/041935 describes quetiapine matrix formulations comprising wax, WO 2007/000778 describes a composition comprising two pH independent swellable polymers which are polyalkylene oxide and a hydrophilic polymer. Improved control of pharmacokinetic properties may be achieved with alternative formulations, such as described in WO 2005/023228 or WO 03/039519. Control of quetiapine plasma levels may be useful during treatment. For example, when a patient is present with an acute psychosis, it may be desirable to introduce an immediate large dosage of quetiapine, followed by a maintained sustained plasma level of quetiapine.

Currently, these plasma levels can be effected only by administering multiple dosages. Single dosage forms that provide particular plasma profiles of quetiapine are thus desirable.

SUMMARY OF THE INVENTION

For the above mentioned reasons, it is an object of the present invention to provide drug formulations containing quetiapine which meet the requirements described above, in particular to provide a once-a-day dosage form of such a formulation. It is a further object of the invention to provide a sustained release pharmaceutical composition resulting in a generally uniform and constant rate of release over an extended period of time which achieves a stable and desired blood (plasma) level of the active ingredient without the need for frequent administration of the medicament.

After having performed intensive investigations, it was surprisingly possible to develop drug formulations containing quetiapine which release a form of quetiapine over a prolonged period in the entire gastrointestinal tract, and finally to develop drug formulations having certain release profiles which are suitable for solving the above-described problems of the prior art. By using particles combined in larger dosage units it was for example possible to flatten the tail of the release curve which usually is achieved by state-of-the art formulations. DETAILED DESCRIPTION OF THE INVENTION

In accordance with the first aspect of the present invention, there is provided a sustained release pharmaceutical composition containing at least one form o f 2-(2- (4dibenzo[b,fJ[l,4]thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol (quetiapine), wherein the form of quetiapine is selected from the group consisting of quetiapine, a pharmaceutically acceptable salt of quetiapine, or a derivative or a pharmaceutically acceptable salt thereof, characterized in that it contains one or more populations of a form of quetiapine containing particles, such that following oral delivery to a subject, an in vivo peak plasma concentration of said form of quetiapine from about two to about eight hours after administration, and an in vivo release pattern is provided such that the blood plasma concentration of said form of quetiapine is as follows based on the overall content of said form of quetiapine: at 1 hour after delivery, 5 % to 25 % is released, at 2 hours 10 % to 35 % is released, at 4 hours 15 % to 45 % is released, at 8 hours 30 % to 75 % is released, and at 16 hours less than 95 % by weight is released, in order to allow a once-a-day administration of said sustained release pharmaceutical composition.

The above release pattern is ideal for the once-a-day-administration of quetiapine to a patient in need thereof. Apart from the specific in vivo release pattern provided by the pharmaceutical formulation of the present invention, it is a crucial element that the present composition contains one or more populations of a form of quetiapine containing particles, or, in other words, is a multiparticulate composition. Such a multiparticulate composition is defined as a composition, wherein the active ingredient is contained in several distinct units which allow an in vivo release not from one single entity only (such as a conventional compressed tablet), but a release from a multitude of entities once the composition enters the gastrointestinal tract of a patient.

As used herein, the term "quetiapine" refers to quetiapine base, a pharmaceutically acceptable salt of quetiapine base, a derivative of quetiapine or a pharmaceutically acceptable salt of a derivative of quetiapine and combinations thereof.

In a preferred embodiment the form of quetiapine is quetiapine hemifumarate. Other salts of quetiapine include oxalate, succinate, benzoate and formate salts. As outlined above, the present compositions of quetiapine contain multiple particles. The term "particle" is employed herein to in particular refer to pellets, beads, spheroids, granules, micro tablets, or mini tablets. Pellets, beads, spheroids or granules can be prepared according to any method known to persons skilled in the manufacture of pharmaceutical compositions. The preferable particle size varies between 0.3 mm and 2.0 mm, in case of particles compressed into tablets between 0.1 mm and 0.6 mm.

In addition to the active ingredient pharmaceutically acceptable excipients are also involved in the particle forming process (and thus may be an integral part of the particles), which promote the formation of said particles of appropriate shape and surface.

Such excipients may be fillers, lubricants, glidants, antiadhesives, disintegrants or drug release controlling additives/agents, buffers, surfactants, surface-active substances, surface- active additives, pelletization promoting additives, or spheronization promoting substances.

Micro tablets, or mini tablets can be prepared according to any method known to persons skilled in the manufacture of pharmaceutical compositions. The preferable micro/mini tablet size varies between 0.1 mm and 4.0 mm.

There are several formulations possible to provide said sustained release dosage form. Thus, the one or more populations of a form of quetiapine containing particles preferably are provided in a formulation selected from the group consisting of matrix formulations, diffusion controlled membrane coated, encapsulated formulations and combinations thereof.

In an embodiment, the particles are formulated as matrices, i.e. as a matrix dosage form comprising particles consisting of a pharmaceutical effective amount of a form of quetiapine, a sustained release (matrix forming) agent, optionally other excipients and optionally coatings.

Any suitable sustained release matrix material or suitable combination of sustained release matrix materials may be used. Such materials are known to those skilled in the art.

In an embodiment, the quetiapine comprising particles are forming a noneroding matrix formulation. Such a noneroding matrix formulation preferably is a pharmaceutical composition, wherein the particles are comprising, a) a pharmaceutical effective amount of 20 % to 80 % by weight of a form of quetiapine, b) a sustained release matrix forming agent of 20 % to 70 % by weight, including lipophilic matrix materials like a water-insoluble and non-swellable material that slows the diffusion of the active agent, preferably waxes like beeswax or paraffines, hydrophilic matrix materials like a polymeric material that swells upon contact with water, and inert matrix materials,

(c) optionally other excipients of 0 % to 50 % by weight like pharmaceutically acceptable auxiliaries and carriers; and

(d) optionally coatings.

It should be noted that the present invention comprises matrix formulations wherein the particles themselves are containing the matrix materials (and thus are forming the matrix), or, as an alternative, a formulation wherein particles which do not include a matrix material are embedded in a matrix material.

In a preferred embodiment of the present invention sustained release matrix forming agents include lipophilic matrix materials and inert matrix materials. The typical matrix material, if present, is a lipophilic matrix material.

A process for preparing a sustained release formulation of quetiapine as mentioned above comprises:

(a) blending the form(s) of quetiapine, matrix forming agent(s) and optionally other excipients,

(b) forming particles from the blended mixture and drying it if necessary,

(c) optionally lubricating and optionally coating the dried particles,

(d) optionally compressing the particles into tablets, and optionally coating the tablets with an aqueous or non-aqueous dispersion of water insoluble and water soluble component,

(e) optionally filling the (coated) particles into capsules,

(f) optionally filling the (coated) particles into sachets.

In case of a water-swellable polymer as matrix forming agent, the polymer preferably has a viscosity of at least 15 mPas measured as a 2 % strength aqueous solution at 20 ⁰C.

In another embodiment, the particles are formulated as erodible matrices. In this embodiment, a dosage form comprises particles consisting of a pharmaceutically effective amount of a form of quetiapine, an erodible matrix, optionally other excipients and optionally a coating. In said erodable formulation, the formulation may employ a sustained release coating and/or a sustained release matrix material, either or both of which dissolve in water over time, thus losing their structural integrity. One manner in which this could occur would be that one form of quetiapine and sustained release coating and/or matrix material dissolves after human ingestion over a controlled period of time.

In a preferred embodiment, the particles are comprising

(a) a pharmaceutically effective amount of a form of quetiapine, preferably 10 % to 70 % by weight of the final particle,

(b) an erodible/biodegradable matrix, preferably 10 % to 70 % by weight, which optionally dissolves in water over time, thus losing its structural integrity, or is water insoluble,

(c) optionally binders of 0 % to 20 % by weight,

(d) optionally lubricants or lubricating materials of up to 5 % by weight,

(e) optionally other excipients,

(f) optionally a sustained release coating, which might dissolve in water over time, thus losing its structural integrity, and

(g) optionally further coatings.

A process for preparing the above mentioned formulation comprises the steps of:

(a) blending the active ingredient with a suitable erodible polymer,

(b) forming particles from the blended mixture and drying it if necessary,

(c) lubricating and optionally coating the dried particles,

(e) optionally filling the (coated) particles into capsules,

(f) optionally filling the (coated) particles into sachets.

The lubricant or lubricating material forms a film around the particles (granules) and helps the material flow, compress and eject from the tableting machine. The lubricant or lubricating material may be present in levels up to 5 % by weight of the final composition.

particles contained in the composition of the invention may be particles with a rate rolling coating or membrane, for example a formulation comprising particles having a and an outer coating, the core comprising at least one form of quetiapine, a pharmaceutically acceptable carrier and optionally one or more excipients, and a rate controlling coating.

In an embodiment, the formulation contains particles comprising a core and an outer coating, the core comprising

(a) at least one form of quetiapine in an amount of 10 % to 90 % by weight,

(b) one or more pharmaceutically acceptable carrier(s) in an amount of 10 % to 90 % by weight, and

(c) optionally one or more excipients,

(d) and a rate controlling coating of from 1 % to 19 % by weight of each particle, comprising a water insoluble and water soluble component.

Optionally, particles differing in the thickness and/or material of the rate controlling layer are mixed before being combined in larger units. By combining particles, which differ in the thickness of their coating the release profile can be tailored as desired. The coating is preferably designed so that when the formulation enters the gastrointestinal tract, the particles absorb liquid, thus forming channels that interconnect the core with the outer surface of the coating.

The outer coating might include at least one plasticizer. The amount of plasticizer or a mixture of plasticizers is optionally and more preferably in a range of from about 0 % to about 50 % weight per weight of the water insoluble polymer in the film coat. In addition or alternatively, a stiffening agent such as cetyl alcohol could optionally be used.

The outer coating may also optionally contain at least one of a wetting agent, suspending agent, surfactant, and dispersing agent, or a combination thereof, in addition to the plasticizer. The content of the wetting agent, surfactant, dispersing agent and suspending agent may optionally be in an amount of from about 0 % to about 30 % of the weight of the film coat of the formulation.

The coating for this embodiment preferably comprises ethyl cellulose, cetyl alcohol, microcrystalline cellulose or calcium pectinate (CaP). Optionally an enteric coating may be applied to these coated cores. Each particle of the sustained release formulation comprising of 10 % (w/w) to 90 % (w/w) of one form of quetiapine, 10 % (w/w) to 90 % (w/w) of one more carriers, and optionally one or more pharmaceutically acceptable excipients; the said particles being coated with a coat comprising 1 % to 18 % by weight of each particle.

(a) blending the form(s) of quetiapine, carrier and optionally other excipients,

(b) forming particles from the blended mixture and drying it if necessary,

(c) optionally lubricating and optionally coating the dried particles,

(e) optionally filling the (coated) particles into capsules,

(f) optionally filling the (coated) particles into sachets.

In a further embodiment, the particles are in form of an osmotic-controlled formulation. Said dosage forms, based on osmotic pressure, can be achieved by preparing a core, containing a form of quetiapine dispersed in a combination of ingredients able to generate an osmotic pressure, when contained by an osmotic membrane. The release from such systems is obtained with a calibrated hole in the membrane surrounding the particle which regulates, together with the level of osmotic pressure generated by the intrinsic characteristics of the particle core, the rate of release.

The particles containing a form of quetiapine might also be formulated with osmotic ingredients and coated with semipermeable film forming polymers to achieve zero-order release. The osmotic device of the invention comprises at least one passageway (pore, hole, or aperture) which communicates the exterior of the semipermeable wall with the core of the device. The passageway can be formed according to any of the known methods of forming passageways in a semipermeable membrane. Such methods include, for example,

(a) drilling a hole through the semipermeable membrane with a bit or laser, (b) including a water soluble material within the composition that forms the semipermeable membrane such that a pore forms when the osmotic device is in an aqueous environment of use,

(c) punching a hole through the semipermeable membrane,

(d) employing a tablet punch having a pin to punch a hole through the semipermeable lamina.

The passageway can pass through the semipermeable wall and one or more of any other lamina coated onto the semipermeable membrane or between the semipermeable membrane and the core. The passageway(s) can be shaped as desired. In some embodiments, the passageway is laser drilled and is shaped as an oval, ellipse, slot, slit, cross or circle. The advantages of said osmotic formulation include the combination of the mechanism of the control of the release based on the osmotic pressure (finely tuned and independent from the motility, pH, composition of the digestive fluids and food) with the concept of multiple units (improved inter and intrasubjects variability of absorption).

Preferably, the osmotic-controlled formulation comprises

(a) a core, containing a form of quetiapine 0.5 % to 99.5 % by weight dispersed in

(b) a combination of ingredients of 99.5 % to 0.5 % by weight able to generate an osmotic pressure, when contained by an osmotic membrane,

(c) said osmotic membrane consisting of semipermeable film forming polymers, preferably polymers that are high molecular weight derivatives of cellulose which are insoluble in water and might be selected from the group consisting of ethylcellulose with a degree of ethylation between 43 % and 50 %, cellulose acetate with 30 % to 45 % of acetyl value, polyvinylacetate, ammonium methacrylate copolymers, and mixtures thereof) to achieve zero-order release, and having a film thickness of the coating varying from 20 μm to 100 μm to achieve the desired extended release profile,

(d) a calibrated passageway in the membrane surrounding the particle which regulates, together with the level of osmotic pressure generated by the intrinsic characteristics of the particle core, the rate of release, preferably formed by

(1) drilling a hole through the semipermeable membrane with a bit or laser; the passageway(s) being shaped a. as an oval, b. as an ellipse, c. as a slot, d. as a slit, e. as a cross, or f. as a circle

(2) including a water soluble material within the composition that forms the semipermeable membrane such that a pore forms when the osmotic device is in an aqueous environment of use optionally plasticizers in the range of 3 % to 40 %,

(3) punching a hole through the semipermeable membrane,

(4) employing a tablet punch having a pin to punch a hole through the semipermeable lamina,

(5) any other suitable process generate a passageway, where the passageway passes through the semipermeable wall and one or more of any other lamina coated onto the semipermeable membrane or between the semipermeable membrane and the core,

(e) optionally 0 % to 50 % by weight of pharmaceutically acceptable auxiliaries and carriers, and

(f) optionally further coatings like an enteric coat, a polymeric coating to form a delayed release formulation, or coatings containing forms of quetiapine for an immediate release.

Osmotic ingredients can be any active principle ingredient with a solubility in aqueous media, in the range of pH from 1 to 7.5 and in an amount of not less than 0.1 %. Any inorganic salt may be used which is highly dissociated in aqueous media in the range of pH from 1 to 7.5 and suitable to be included in pharmaceutical preparations for oral administration.

Semipermeable membranes are generally permeable to small solvent molecules, such as water, but comparatively impermeable to dissolved solutes. Even small ions are not readily exchanged across such membranes. Accordingly, semipermeable membranes, although able to prevent neutralizing ions from entering the core of an osmotically active dosage form, do not have the flexibility desired for modulating the rate of release of the beneficial agent from the device.

Semipermeable film forming polymers can be high molecular weight derivatives of cellulose which are insoluble in water as ethylcellulose with a degree of ethylation between 43 % and 50 %, cellulose acetate with 30 % to 45 % of acetyl value, polyvinylacetate, ammonium methacrylate copolymers. Suitable plasticizers can be added in the range of 3 % to 40 %.

The film thickness may vary from 20 μm to 100 μm to achieve the desired extended release profile. The size of the particles may vary between 0.1 mm to 7 mm of diameter and height. Depending on the composition of the core and on the type and thickness of the film different zero order kinetics can be achieved.

Optionally the particles are coated with a polymeric coating to form a delayed release formulation. In this aspect, the delayed release oral dosage form is based on osmotic pressure and then a crown coating in the coating polymer formed in situ when the dose is ingested.

A process for preparing the above mentioned formulation comprises the steps

(a) blending the active ingredient with a suitable osmotic agent or osmopolymer,

(b) forming particles from the blended mixture and drying it if necessary,

(c) optionally lubricating and optionally coating the dried particles,

(d) optionally compressing the particles into tablets,

(e) coating the particles/tablets with an semipermeable membrane,

(f) optionally further coatings,

(g) optionally filling the particles into capsules,

(h) optionally filling the (coated) particles into sachets.

The invention also comprises a tablet or capsule containing an effective amount of particles with different release traits: thus, another embodiment of the present invention is a dosage form comprising a capsule or tablet containing immediate release particles as well as sustained release particles. The formulation may comprise additional sustained release components as desired.

Said dosage form can in an embodiment be prepared as a pulsating/repeat release product, comprising a capsule having a plurality of particles, said particles comprising at least one form of quetiapine, at least one erodible polymer, optionally at least one lubricating. To provide the pulsating/repeat release at least one of said plurality of particles is prepared from an erodible polymer having a first dissolution rate, and at least another of said plurality of particles is prepared from another or the same erodible polymer having a second dissolution rate, and said first dissolution rate is not equal to said second dissolution rate.

The different dissolution rates can be obtained either by using different materials or by using different thicknesses of the coating.

The pulsating/repeat release formulation, comprising

(a) cores containing at least one form of quetiapine,

(b) particles with at least two different dissolution rates, achieved either by use of different coating materials or by different thicknesses of the coating,

(c) optionally further pharmaceutically acceptable excipients.

A process for preparing the above mentioned formulation comprises the steps

(b) forming particles from the blended mixture and drying it if necessary,

(c) optionally repeating of step (b) either with a different coating material or with a different thickness of the coating,

(d) optionally lubricating and optionally coating the dried granules,

(e) optionally compressing the granules into tablets, and optionally coating the tablets with an aqueous or non-aqueous dispersion of water insoluble and water soluble component,

(f) repeating of steps (c) and (d) either with a different coating material or with a different thickness of the coating,

(g) optionally filling unequally coated particles into capsules.

Non limiting examples for excipients are the following:

Sustained release matrix forming agents include lipophilic matrix materials, hydrophilic matrix materials, inert matrix materials, and biodegradable matrix materials.

An inert matrix material provides a tortuous pathway and includes for example ethylcellulose. The erodible matrix dosage form contemplates that the erodible polymer may be either water soluble or water insoluble. A biodegradable matrix material includes polyesters of lactic acid and glycolic acid, polyorthoesters, polyanhydrides, and caprolactones.

Carriers might be selected from the group consisting of gum acacia, alginic acid, amino methacrylate copolymer, amonio methacrylate copolymer, calcium carbonate, calcium phosphate, calcium sulphate, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, carboxymethylcellulose sodium, microcrystalline cellulose, copovidone, dextrates, dextrin, dextrose excipient, ethyl acrylate, ethylcellulose, fructose, gelatin, glucose, guar gum , 1 o w- substituted hydro xypropyl cellulose, hydro xypropylmethylcellulose (hypromellose), hypromellose acetate succinate, kaolin, keratin, lactitol, lactose, anhydrous lactose, lactose monohydrate, magnesium trisilicate, maltitol, maltodextrin, maltose, mannitol, methyl methacrylate copolymer, methylcellulose, polyethylene oxide, povidone, colloidal silica, sorbitol, starch, corn starch, potato starch, pregelatinized starch, sustained pregelatinzed starch, tapioca starch, wheat starch, starch paste, sucrose, sugar, urea and a lower alcohol or a mixture thereof.

Water insoluble polymers that are for example useful as inert matrix materials and for the described erodible matrix dosage form include, without limitation, amino methacrylate copolymer, cellulose acetate, cellulose acetate butyrate (cellaburate), cellulose acetate phthalate (cellacefate), cellulose acetate methyl carbamate, cellulose acetate valerate, cellulose trivalerate, cellulose trioctanoate, cellulose diacetate, cellulose triacetate, cellulose alkanylate, cellulose tripionate, cellulose diesters, cellulose disuccinate, cellulose acetaldehyde, dimethylcellulose acetate, cellulose dimethylaminoacetate, ethylcellulose (EC), methylcarbamate, polydiethylaminomethylstyrene, monoalkenytes, dialkenytes, trialkenytes, mono-, di-and tri-arolyates, polyvinylchloride, polyurethane, semipermeable sulfonated polystyrenes, semipermeable styrenes, a water insoluble polysaccharide, a dimethylaminoethylacrylate/ethylmethacrylate, an ethylmethacrylate/chlorotrimethyl- ammoniumethylmetha cry late copolymer, a dimethylaminoethylmethacrylate/ methylmethacrylate and butylmethacrylate copolymer, a copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters, an ethylacrylate and methylacrylate/ethylmethacrylate and methyl methylacrylate copolymer, acrylic acid esters, shellac, zein, waxes, a polymer sold under the trade mark Eudragit RS, and mixtures thereof. A water insoluble but swellable polymer might be selected from the group consisting of a water insoluble polysaccharide, a water insoluble cross-linked polysaccharide, a water insoluble polysaccharide metal salt including calcium pectinate (CaP), a water insoluble cross-linked protein, a water insoluble cross-linked peptide, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen, water insoluble cross-linked polyacrylic acid, water insoluble cross-linked cellulose derivatives , water insoluble cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline cellulose, insoluble starch, microcrystalline starch and a combination thereof.

Water soluble polymers/hydrophilic matrix materials are selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxyl- propylmethylcellulose (hydromellose, HPMC), hydroxypropylmethylcellulose- phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, carboxymethyl cellulose, carboxymethylcellulose sodium, methacrylic acid copolymer, ethylacrylate, polyacrylates, polyvinylpyrrolidon (PVP, Kollidone, povidone), a mixture of povidone and polyvinyl acetate, copovidone, polyvinyl alcohols (PVA), polyvinyl acetate, neutral methyl and/or ethyl ester compounds of polymethacrylic acid, propyleneglycol alginate, sodium alginate, gelatine, polysaccharides, maltodextrin, polyethylene glycol, starch, corn starch, potato starch, pregelatinized starch, sustained pregelatinzed starch, tapioca starch, wheat starch, starch paste, sucrose, a polymer sold under the trade mark macrogol, and mixtures thereof.

Suitable binders and thickeners are, without limitation, selected from the group consisting of acacia, alginic acid, amino methacrylate copolymer, amonio methacrylate copolymer, calcium carbonate, calcium phosphate, calcium sulphate, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, microcrystalline cellulose, methylcellulose, carboxymethylce llulo s e so dium, low-substituted hydroxypropyl cellulose, hydroxylpropylmethylcellulose (hypromellose), hypromellose acetate succinate, ethylcellulose, ethylacrylate, polyethylene oxide, dextrates, dextrin, dextrose excipient, fructose, gelatin, glucose, guar gum, kaolin, keratin, lactitol, lactose, anhydrous lactose, lactose monohydrate, magnesium trisilicate, maltitol, maltodextrin, maltose, mannitol, methyl methacrylate copolymer, polyvinylpyrrolidone, plasdone, povidone, copovidone, colloidal silica, saccharose, sorbitol, starch, corn starch, potato starch, pregelatinized starch, sustained pregelatinzed starch, tapioca starch, wheat starch, starch paste, sucrose, sugar, urea and a lower alcohol, and mixtures thereof.

As fillers which can be used in the particle forming process e. g. calcium sulfate, calcium hydrophosphate, lactose, mannitol, saccharose, starch and microcrystalline cellulose are mentioned. The mentioned diffusion coating includes at least one water insoluble hydrophobic polymer and at least one type of water insoluble but hydrophilic material or water soluble material embedded in the water insoluble polymer. Suitable materials are, without limitation, selected from the group consisting of ethylcellulose, cellulose acetate or cellulose acetate butyrate, microcrystalline cellulose, cetyl alcohol, acrylates, calcium pectinate (CaP), and mixtures thereof.

Enteric coatings may contain, without any limitation, materials like or cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate succinate phthalate, hydroxylpropylmethylcellulose acetate succinate, a polymer sold under the trade mark Eudragit L, and mixtures thereof.

Suitable plasticizers are, for example, castor oil, acetylated fatty acid glycerides, citric acid derivatives (e. g. alkyl citrate and citrate esters such as tributyl citrate, triethyl citrate, and acetyl triethylcitrate, acetyltributyl citrate, acetyltriethyl citrate, tributyl citrate), acetylated monoglyceride , diacetylated mono glycerides, phthalic acid derivatives (e. g. diaryl phthalates and mixed alkylaryl as represented by dimethyl phthalate, dipropyl phthalate, di-(2- ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dialkyl phthalates, dicycloalkyl phthalates), alkyl and aryl phosphates such as tributyl phosphate, trioctyl phosphate, ricresyl phosphate and triphenyl phosphate, esters like diethyl sebacate, dibutyl sebacate, or triacetin, fatty acids and derivatives (e. g. glycerol monostearate, miglyol), alkyl adipates such as dioctyl adipate, diethyl adipate and di-(2-methyoxy-ethyl)adipate; dialkyl tartrates such as diethyl tartrate and dibutyl succinate; alkyl glycoates, alkyl glycerolates, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol, polyols (glycerol, 1 ,2-propanediol, polyethylene glycol of varying chain length, polyethylene glycol monomethyl ether, propylene glycol), butyl and/or glycerol esters such as glycerol diacetate, glycerol tyriacetate, glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionat, benzyl benzoate, sorbitol, and mixtures thereof. Other plasticizers include camphor, N-ethyl- (o-and p-toluene)sulfonamide, chlorinated biphenyl, benzophenone, N-cyclohexyl-p-toluene sulfonamide, and substituted epoxides.

Exemplary plasticizers suitable for osmotic devices include plasticizers that lower the temperature of the second-order phase transition of the wall of the elastic modulus thereof; and also increase the workability of the wall, its flexibility and its permeability to fluid.

Plasticizers operable for this purpose include both cyclic plasticizers and acyclic plasticizers. Typical plasticizers are those selected from the group consisting of phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristates, sulfonamides, and halogenated phenyls.

A non limiting example of a stiffening agent is cetyl alcohol.

Examples of suitable wetting agents include, but are not limited to, poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium, and mixtures thereof.

Examples of suitable suspending agents include, but are not limited to, alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxylethylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, medium chain triglycerides, methylcellulose, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyvinylpyrrolidone (PVP), propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, tragacanth, and mixtures thereof.

Examples of suitable surfactants include, but are not limited to, anionic surfactants such as docusate sodium and sodium lauryl sulfate; cationic, such as cetrimide; nonionic, such as polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters. Examples of suitable dispersing agents include, but are not limited to, poloxamer, polyoxy ethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.

Examples of usable lubricating materials include, without limitation, fats, emulsifiers, waxes, mineral oil, magnesium stearate, calcium stearate, talc, starches, silicon dioxide, polyethylene glycol, glycerine and propylene glycol, and mixtures thereof.

Among the fats, or fatty materials, useful herein include, without limitation, water insoluble, inert hydrocarbon fats or oils, or their derivatives and mixtures thereof. Such fats or fatty materials include, for example and without limitation, cocoa butter, hydrogenated vegetable tallow, hydrogenated vegetable oils, and derivative mixtures thereof.

Glidants that may be applied during the processes described herein include e. g. colloidal silicon dioxide, magnesium stearate, talc, starch, and mixtures thereof.

The aforementioned emulsifiers include, without limitation, alkyl aryl sulfonates, alkyl sulfates, sulfonated amides and amines, sulfated and sulfonated esters and ethers, alkyl sulfonates, polyethoxylated esters, mono-and diglycerides, diactyl tartaric esters of monoglyderides, polyglycerol esters, sorbitan esters and ethoxylates, lactylated esters, propylene glycol esters, sucrose esters, and mixtures thereof.

Waxes include, for example, amorphous waxes, anionic emulsifying waxes, cationic emulsifying waxes, bleached waxes, caranda waxes, cetyl esters, microcrystalline waxes, paraffins, refined waxes, (white) beeswax, microcrystalline wax, carnauba wax, glyceride esters, hydrogenated vegetable (e. g. hydrogenated castor oil) as well as animal oils, stearyl alcohols and their derivatives, polyethylene glycols and their derivatives, glyceryl behenate, glyceryl palmito stearate, saturated polyglycolyzed glycerate, esters of fatty acids such as palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and mixtures thereof.

Suitable anti-adhesives are, without any limitation, kaolin, talk or silicon dioxide.

Disintegrants or drug release promoting agents are for example alginates, sodium carboxymethyl cellulose, crospovidon, starch, pre-gelatinized starch, sodium carboxymethyl starch, or e. g. ethylcellulose, carnauba wax, shellac. Buffers may be citrate, phosphate, carbonate and hydro-carbonate salts.

Surface-active additives like polysorbate, sodium laurylsulfate and spheronization promoting substances as microcrystalline cellulose or a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose may also be used for the dosage forms.

Semipermeable materials can be any polymer permeable to water but impermeable to solutes. Examples include cellulose acetate; cellulose diacetate; cellulose triacetate; cellulose propionate; cellulose acetate butyrate; cellulose acetate; cellulose triacetylates such as cellulose trivalerate, cellulose trilaurate, cellulosetripalmitate, cellulose trisuccinate, cellulose triheptylate, cellulose tricaprylate, cellulose trioctanoate, and cellulosetripropionate; cellulose diesters such as cellulose dicapyrlate and cellulosedipentanate; and esters prepared from acyl anhydrides or acyl acids in an esterification reaction to yield esters containing different acyl groups attached to the same cellulose polymer such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate palmitate and cellulose acetate heptanoate and the like, and mixtures thereof.

Osmotic agents, i. e. materials that are capable of expanding in size upon imbibing water, include both, salt-containing and salt-free agents. As used herein, the osmotic agent may be an osmagent, an osmopolymer, or a mixture of the two.

Species that fall within the category of osmagent, i.e., the non-volatile species that are soluble in water and create the osmotic gradient driving the osmotic inflow of water, vary widely. Examples are known in the art and include, without any limitation, magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose, and various monosaccharides, oligosaccharides and polysaccharides such as sucrose, glucose, lactose, fructose, and dextran, as well as mixtures of any of these various species.

Species that fall within the category of osmopolymer are hydrophilic polymers that swell upon contact with water. Osmopolymers may be of plant or animal origin, or synthetic, and examples of osmopolymers are known in the art. Examples include: poly(hydroxy-alkyl methacrylates) with molecular weight of 30,000 to 5,000,000; poly(vinylpyrrolidone) with molecular weight of 3,000 to 20,000; anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) having low acetate residual, optionally cross linked with glyoxal, formaldehyde or glutaraldhyde and having a degree of polymerization of 200 to 30,000; a mixture of methyl cellulose, cross linked agar and carboxymethylcellulose, a mixture of hydro xypropylmethylcellulose and sodium carboxymethylcellulose; polymers of N-vinyllactams, polyoxyethylene-polyoxypropylene gels; polyoxybutylene-polyethylene block copolymer gels; carob gum; polyacrylic gels; polyester gels; polyurea gels; polyether gels; polyamide gels; polypeptide gels; polyamino acid gels; polycellulosic gels; carbopol acidic carboxy polymers having molecular weights of 250,000 to 4,000,000; Cyanamer polyacrylamides, cross linked indene-maleic anhydride polymers.

Pore-formers , used to contro l the pore size, are so luble polymers , such as carboxymethylcellulose, hydroxypropylmethylcelluloses, methylcelluloses, dextrins, maltodextrins, cyclo dextrins, dextrans, polyethylene glycols, polyvinylpyrrolidones, or other soluble compounds, such as, for example, salts (common salt, potassium chloride, ammonium chloride, etc.), sugars (glucose, sucrose, fructose, lactose, etc.), sugar alcohols (manitol, sorbitol, lactitol, etc.), urea, and mixtures thereof.

Pore-formers for osmotic driven release formulations can be inorganic or organic.

Inorganic solid additives include alkali metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, potassium nitrate and the like. The alkaline earth metal salts such as calcium chloride, calcium nitrate, and the like. The transition metal salts such as ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride, and the like.

Water may also be used as the pore-former.

Organic pore-formers might be compounds such as saccharides. The saccharides include the sugars sucrose, glucose, fructose, mannose, galactose, aldohexose, altrose, talose, lactose, monosaccharides, disaccharides, and water soluble polysaccharides. Also, sorbitol, manitol, organic aliphatic and aromatic ols, including diols and polyols, as exemplified by polyhydric alcohols, poly (alkylene glycols), polyglycols, alkylene glycols, poly(a-co) alkylenediols, esters or alkylene glycols poly vinylalcohol, polyvinyl pyrrolidone, and water soluble polymeric materials.

Pores may also be formed in the wall by the volatilization of components in a polymer solution or by chemical reactions in a polymer solution which evolves gases prior to application or during application of the solution to the cores mass resulting in the creation of polymer foams serving as the porous wall of the invention.

The pore-formers are nontoxic, and on their removals, channels form that fill with fluid. The channels become a transport path for fluid.

In a preferred embodiment, the non-toxic pore-forming agents are selected from the group consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly(a-co) alkylenediols, esters of alkylene glycols and glycols, that are used in a biological environment.

Additional polymers that can be used for the purpose of the invention include cellulose acetate acetoacetate, cellulose acetate chloroacetate, cellulose acetatefuroate, dimethoxyethyl cellulose acetate, cellulose acetate carboxymethoxy propionate, cellulose acetate benzoate, cellulose butyrate napthylate, methylcellulose acetate methy Icy ano ethyl cellulose, cellulose acetate methoxyacetate, cellulose acetate ethoxyacetate, cellulose acetate dimethylsulfamate, ethylcellulose, ethylcellulose dimethylsulfamate, cellulose acetate ptoluene sulfonate, cellulose acetate methylsulfonate, cellulose acetate dipropylsulfamate, cellulose acetate butylsulfonate, cellulose acetate laurate, cellulose stearate, cellulose acetate methylcarbamate, agar acetate, amylose triacetate beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate dimethyl aminoacetate, cellulose acetate ethyl carbonate, poly(vinyl methyl) ether cop o lymers , c e llulo s e ac etate with acetylated hydro xy-ethylcellulose hydroxylatedethylenevinylacetate, poly(ortho ester)s, polyacetals, semipermeable polyglycolic or polyactic acid and derivatives thereof, selectively permeable associated polyelectrolytes, polymers of acrylic and methacrylic acid and esters thereof, film forming materials with a water sorption of one to fifty percent by weight at ambient temperatures with a presently preferred water sorption of less than thirty percent, acylated polysaccharides, acylated starches, aromatic nitrogen containing polymeric materials that exhibit permeability to aqueous fluids, membranes made from polymeric epoxides, copolymers of alkylene oxides andalkyl glycidyl ethers, polyurethanes, and the like.

Admixtures of various polymers may also be used, for example glyceryl behenate and g lyc ero l o r suit ab ly c o mb in atio n s o f hi g h and low viscosity grades hydroxylpropylmethylcellulose, ethyl cellulose, glyceryl behenate and methyl cellulose.

In embodiments of the present invention the quetiapine or its salt or derivative is present in each component of the formulation in an amount of from about 0.1 mg to about 1 g, preferably in an amount of from about 0.1 mg to 500 mg, more preferably in an amount of from 0.5 to 50 mg, and more preferably in an amount of from 2.5 to 25 mg.

A formulation according to the present invention may be formulated into any suitable dosage form which facilitates the release of the antipsychotic agent. The dosage form may, for example, be a capsule (e.g., a hard or soft gelatin capsule) which contains, therein, the above described particles. The particles may exist therein in various forms, for example, in the form of mini-tablets, granules or pellets.

In one embodiment, a capsule comprises a particle comprising an immediate release component and/or a particle comprising a delayed immediate release component and a particle comprising a sustained release component. The particle comprising the sustained release component and the particle comprising the delayed immediate release component may, for example, be particles comprising quetiapine and one or more sustained release means. For example, the particle may be made out of a sustained release matrix material and/or coated with a sustained release coating. In the case of a delayed immediate release particle, the sustained release means may, for example, be a coating whose integrity is pH-dependent. The particle comprising the immediate release component may, for example, be in the form of a particle which comprises quetiapine but not a sustained release means.

In embodiments in which the capsule comprises mini-tablets, the capsule may, for example, comprise a mini-tablet comprising an immediate release component and/or a minitablet comprising a delayed immediate release component and a mini-tablet comprising a sustained release component. The mini-tablets may be formed, for example, by compressing the above- described particles (e.g., a sustained release mini-tablet may be formed by compressing sustained release particles).

In addition to the above, the particles may be, for example, in the form of multilayer tablets with one layer comprising an immediate release component or a delayed immediate release component and another layer comprising a sustained release component.

In an embodiment of the present invention the sustained release formulations containing a form of quetiapine comprise amounts equivalent to 25 mg, 50 mg, 100 mg, 200 mg, 300 mg or 400 mg of quetiapine.

In accordance with another aspect of the present invention, there is provided a method of effectively treating schizophrenia in humans, comprising orally administering to a human patient on a once a day basis an oral sustained release dosage form containing at least one form of quetiapine.

In an embodiment of the present invention, there is provided a method for the treatment of acute manic episodes associated with bipolar I disorder in humans, comprising orally administering to a human patient on a once a day basis an oral sustained release dosage form containing at least one form of quetiapine.

In an embodiment of the present invention the dosage form described herein comprises quetiapine hemifumarate.

In accordance with another aspect of the present invention the compositions comprising at least one form of quetiapine contain one or more additional active pharmaceutically ingredients.

In a second aspect, the invention is directed to the use of the pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of

(a) schizophrenia,

(b) acute manic episodes associated with bipolar I disorder. In a third aspect, the invention provides a general process for preparing the pharmaceutical compositions as disclosed above comprising the steps of

(a) blending the form(s) of quetiapine, matrix forming agent(s) or a suitable osmotic agent or osmopolymer and/or optionally other excipients,

(b) forming particles from the blended mixture and drying if necessary,

(c) optionally lubricating and optionally coating the dried particles,

(e) optionally filling the (coated) particles into capsules,

(f) optionally filling the (coated) particles into sachets.

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention.

EXAMPLES

Quetiapine and its pharmaceutically acceptable salts may be prepared as described in published European Patents EP 0 240 228 or EP 0 282 236.

Example 1 : Matrix tablet with coating:

Core: (98.03 % by weight of the final tablet)

(a) 39.27 % by weight of the core quetiapine hemifumarate

(b) 30.02 % by weight of the core HPMC 15 cP

(c) 30.02 % by weight of the core lactose monohydrate

(d) 0.68 % by weight of the core magnesium stearate

Coating: (1.97 % by weight of the final tablet)

(a) 2.04 % by weight of the coating iron oxide

(b) 17.01 % by weight of the coating titan dioxide

(c) 20.41 % by weight of the coating polyethylene glycol

(d) 60.54 % by weight of the coating HPMC 15 cP

Example 2: Matrix tablet with coating: Core: (95.17 % by weight of the final tablet)

(a) 60.87 % by weight of the core quetiapine hemifumarate

(b) 25.38 % by weight of the core ethylcellulose

(c) 12.69 % by weight of the core stearic acid

(d) 1.06 % by weight of the core magnesium stearate

Coating: (4.83 % by weight of the final tablet)

(a) 46.88 % by weight of the coating methylene chloride

(b) 46.88 % by weight of the coating ethyl alcohol

(c) 3.13 % by weight of the coating ethylcellulose

(d) 2.08 % by weight of the coating hypromellose

(e) 1.04 % by weight of the coating of a medium chain triglyceride

The release is pH independent!

Example 3: Eroding matrix tablet without coating:

(a) 6.15 % by weight of the final tablet quetiapine hemifumarate

(b) 29.9 % by weight of the final tablet Polyethylenoxid (Polyox 1105)

(c) 35.03 % by weight of the final tablet Polyethylenoxid (Polyox N-80)

(d) 22.85 % by weight of the final tablet microcrystalline cellulose

(e) 5 % by weight of the final tablet povidone

(f) 1.07 % by weight of the final tablet magnesium stearate

Example 4: Eroding matrix tablet with coating:

Core: (95.17 % by weight of the final tablet)

(a) 60.87 % by weight of the core quetiapine hemifumarate

(b) 25.38 % by weight of the core sodium alginate or Eudragit RS

(c) 12.69 % by weight of the core stearic acid

(d) 1.06 % by weight of the core magnesium stearate

Coating: (4.83 % by weight of the final tablet) (a) 46.88 % by weight of the coating methylene chloride

(b) 46.88 % by weight of the coating ethyl alcohol

(c) 3.13 % by weight of the coating ethylcellulose

(d) 2.08 % by weight of the coating hypromellose

(e) 1.04 % by weight of the coating of a medium chain triglyceride

Example 5: Release controlling coating:

Core: (95.17 % by weight of the final tablet)

(a) 82.56 % by weight of the core quetiapine hemifumarate

(b) 8.78 % by weight of the core microcrystalline cellulose

(c) 5.24 % by weight of the core mannitol

(d) 1.97 % by weight of the core sodium carboxymethylcellulose

(e) 1.61 % by weight of the core magnesium stearate

Coating: (4.83 % by weight of the final tablet)

(a) 49.91 % by weight of the coating ethylcellulose

(b) 0.54 % by weight of the coating triethyl citrate

(c) 2.71 % by weight of the coating crosslinked acrylic acid-based polymer

(d) 46.85 % by weight of the coating purified water

Example 6: Release controlling coating:

Core: (89.32 % by weight of the final tablet)

(a) 82.56 % by weight of the core quetiapine hemifumarate

(b) 8.78 % by weight of the core microcrystalline cellulose

(c) 5.24 % by weight of the core mannitol

(d) 1.97 % by weight of the core sodium carboxymethylcellulose

(e) 1.61 % by weight of the core magnesium stearate

Coating: (10.68 % by weight of the final tablet)

(a) 33 % by weight of the coating Eudragit RS

(b) 1.5 % by weight of the coating triethyl citrate

(c) 5.2 % by weight of the coating talcum (d) 0.4 % by weight of the coating Carbopol

(e) 59.9 % by weight of the coating purified water

Example 7: Osmotic-controlled formulation:

Core: (84.64 % by weight of the final tablet)

(a) 22.63 % by weight of the core quetiapine hemifumarate

(b) 62.6 % by weight of the core mannitol

(c) 6.55 % by weight of the core polyvinylpyrrolidone

(d) 0.39 % by weight of the core polyethylene glycol 400

(e) 0.79 % by weight of the core colloidal silica

(f) 5.85 % by weight of the core polyethylene glycol 6000

(g) 1.18 % by weight of the core magnesium stearate

Coating 1 : (5.55 % by weight of the final tablet)

(a) 30.12 % by weight of coating 1 copolyvidone

(b) 42.0 % by weight of coating 1 hydroxypropylmethylcellulose 2910

(c) 12.0 % by weight of coating 1 polyethylene glycol 6000

(d) 15.88 % by weight of coating 1 titan dioxide

Coating 2: (6.52 % by weight of the final tablet)

(a) 95.0 % by weight of coating 2 cellulose acetate

(b) 5.0 % by weight of coating 2 polyethylene glycol 400

Coating 3: (3.29 % by weight of the final tablet)

(a) 42.51 % by weight of coating 3 hydroxypropylmethylcellulose 2910

(b) 30.50 % by weight of coating 3 copolyvidone

(c) 12.15 % by weight of coating 3 polyethylene glycol 6000

(d) 14.41 % by weight of coating 3 titan dioxide

(e) 0.40 % by weight of coating 3 aluminum lake quinoline yellow

(f) 0.02 % by weight of coating 3 aluminum lake sunset yellow

Claims

29 January 2010Patent Claims:

1. A sustained release pharmaceutical composition containing at least one form of 2-(2- (4dibenzo[b,fJ[l,4]thiazepine-l l-yl-l-piperazinyl)ethoxy)ethanol (quetiapine), wherein the form of quetiapine is selected from the group consisting of quetiapine, a pharmaceutically acceptable salt of quetiapine, or a derivative or a pharmaceutically acceptable salt thereof, characterized in that it contains one or more populations of a form of quetiapine containing particles, such that following oral delivery to a subject, an in vivo peak plasma concentration of said form of quetiapine from about two to about eight hours after administration, and an in vivo release pattern is provided such that the blood plasma concentration of said form of quetiapine is as follows based on the overall content of said form of quetiapine: at 1 hour after delivery, 5 % to 25 % is released, at 2 hours 10 % to 35 % is released, at 4 hours 15 % to 45 % is released, at 8 hours 30 % to 75 % is released, and at 16 hours less than 95 % by weight is released, in order to allow a once-a-day administration of said sustained release pharmaceutical composition.

2. The pharmaceutical composition of claim 1 , wherein the one or more populations of a form of quetiapine containing particles are provided in a formulation selected from the group consisting of matrix formulations, diffusion controlled membrane coated, encapsulated formulations and combinations thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein said form of quetiapine comprising particles are forming a noneroding matrix formulation.

4. The pharmaceutical composition of claim 3, wherein the particles are comprising, a) a pharmaceutical effective amount of 20 % to 80 % by weight of a form of quetiapine, b) a sustained release matrix forming agent of 20 % to 70 % by weight, including lipophilic matrix materials like a water-insoluble and non-swellable material that slows the diffusion of the active agent, preferably waxes like beeswax or paraffines, hydrophilic matrix materials like a polymeric material that swells upon contact with water, and inert matrix materials, (c) optionally other excipients of 0 % to 50 % by weight like pharmaceutically acceptable auxiliaries and carriers; and

(d) optionally coatings.

5. The pharmaceutical composition of claim 4, wherein in case of a water-swellable polymer as matrix forming agent, the polymer has a viscosity of at least 15 mPas measured as a 2 % strength aqueous solution at 20 ⁰C.

6. The pharmaceutical composition of claim 2, wherein said form of quetiapine comprising particles are forming an eroding matrix formulation.

7. The pharmaceutical composition of claim 6, wherein the particles are comprising

(a) a pharmaceutical effective amount of a form of quetiapine, preferably 10 % to 70 % by weight of the final particle,

(c) optionally binders of 0 % to 20 % by weight,

(d) optionally lubricants or lubricating materials of up to 5 % by weight,

(e) optionally other excipients,

(g) optionally further coatings.

8. The pharmaceutical composition of claim 2, wherein said form of quetiapine comprising particles are taking the form of a diffusion controlled membrane coated formulation.

9. The pharmaceutical composition of claim 8, wherein the formulation contains particles comprising a core and an outer coating, the core comprising

(a) at least one form of quetiapine in an amount of 10 % to 90 % by weight,

(c) optionally one or more excipients, (d) and a rate controlling coating of from 1 % to 19 % by weight of each particle, comprising a water insoluble and water soluble component.

10. The pharmaceutical composition of claim 2, wherein said form of quetiapine comprising particles are contained in an osmotic-controlled formulation.

11. The pharmaceutical composition of claim 10, wherein said dosage form comprises

(3) punching a hole through the semipermeable membrane,

(4) employing a tablet punch having a pin to punch a hole through the semipermeable lamina, (5) any other suitable process generate a passageway, where the passageway passes through the semipermeable wall and one or more of any other lamina coated onto the semipermeable membrane or between the semipermeable membrane and the core,

12. The pharmaceutical composition of one or more of the preceding claims, wherein the particles are in the form of mini tablets, pellets, beads, spheroids, or granules and have a size from 0.3 mm to 6 mm.

13. The pharmaceutical composition of one or more of the preceding claims, wherein the formulations are compressed into tablets, filled into hard gelatine capsules or are filled into single sachets, and/or wherein a single, once-a-day dosage of said composition contains 25 mg, 50 mg, 100 mg, 200 mg, 300 mg or 400 mg of said form of quetiapine.

14. Use of the pharmaceutical composition of one or more of the preceding claims for the manufacture of a medicament for the treatment of

(a) schizophrenia,

(b) acute manic episodes associated with bipolar I disorder.

15. A process for preparing the pharmaceutical composition of one or more of claims 1-13 comprising the steps of

(b) forming particles from the blended mixture and drying if necessary,

(c) optionally lubricating and optionally coating the dried particles,

(e) optionally filling the (coated) particles into capsules,

(f) optionally filling the (coated) particles into sachets.