CA2705685A1

CA2705685A1 - Pharmaceutical dosage form containing an antipsychotic agent

Info

Publication number: CA2705685A1
Application number: CA2705685A
Authority: CA
Inventors: David Wai Fung Ma; Prashant Manohar Mandaogade; Naresh Talwar
Original assignee: Pharmascience Inc
Current assignee: Pharmascience Inc
Priority date: 2010-05-27
Filing date: 2010-05-27
Publication date: 2011-11-27
Also published as: EP2575820A4; SG187172A1; WO2011147025A1; CA2800910A1; EP2575820A1

Abstract

The present invention is directed to a novel stable controlled release pharmaceutical dosage form comprising: a matrix comprising: quetiapine or a pharmaceutically acceptable salt thereof; at least one hydrophobic controlled release agent; at least one pH
dependent polymer; and at least one pharmaceutically acceptable excipient.

Description

PHARMACEUTICAL DOSAGE FORM
CONTAINING AN ANTIPSYCHOTIC AGENT
FIELD OF THE INVENTION
The present invention relates to a novel dosage form, a process for the manufacturing the same. More specifically, the present invention relates to a controlled release oral dosage form comprising an antipsychotic agent.

BACKGROUND OF THE INVENTION
Quetiapine, chemically designated as 2-[2-(4-dibenzo[bf][1,4]thiazepin-11-yl-1-piperazinyl) ethoxy]ethanol (also known as 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo-[b,f][1,4] thiazepine), is a compound of formula (I):

/ten O OH
ds r i (I) which has been employed as an antipsychotic or neuroleptic agent in the treatment of schizophrenia and bipolar mania, due to its antidopaminergic activity, as well as depressive episodes assicated with bipolar disorder. As a combined serotonin (5HT2) and dopamine (D2) receptor antagonist, quetiapine, including its fumarate salt, is also known for the effective treatment of psychiatric conditions. Quetiapine belongs to a group of drugs known as "atypical" or second generation antipsychotics which have become increasingly popular alternatives to "typical" antipsychotics.

When administered orally, quetiapine is rapidly absorbed and generally reaches a peak plasma level within about 1.5 hours. Quetiapine is highly metabolized, with elimination occurring mainly through hepatic metabolism in the liver. The plasma half-life of quetiapine is typically about 5 to about 7 hours. Quetiapine is currently marketed as a hemifumarate salt in the form of tablets of several doses of 25 mg, 100 mg, 150 mg, 200 mg and 300 mg, 400 mg for the administration two or three times per day.

One of the first preparations of quetiapine is described in United States Patent No.
4,879,288, which corresponds to European Patent No. 0 240 228, which issued in the late 1980's. Since then, many prior art documents have been published, describing various formulations of quetiapine, in which certain drawbacks derived from the poor dissolution properties of this medicament and the uncontrolled release profile provided by said formulations. For example, International Patent Application describes quetiapine formulations which do not provide a constant or substantially constant level of quetiapine, such that the patient can, at certain time intervals, receive therapeutic amounts of quetiapine exceeding the recommended doses, whereas at other times the amount may be below the therapeutically effective limits.

International Patent Applications W01997/45124 and W02005/041935 describe modified-release pharmaceutical compositions containing quetiapine. More specifically, International Patent Application W02005/041935 (corresponding to Canadian Patent No. 2,542,836 to Alpharma Inc.) describes a solid dosage pharmaceutical composition comprising a matrix formed by means of melted waxes, whereas International Patent Application W01997/45124 describes the use of matrices with a gelling agent.
However, in the latter application, the use of water-soluble active ingredients, such as quetiapine or its pharmaceutically acceptable salts, combined with gelling agents such as hydroxypropyl-methylcelluloses, can give rise to a phenomenon known as dumping in which the release of the active ingredient is delayed but once it starts the release occurs at very high rates. Canadian Patent No. 2,251,944 is directed to a quetiapine formulation that comprises a gelling agent. It therefore similar drawbacks as to what is described hereinabove.

European Patent No. 1 218 009 describes the preparation of granules containing quetiapine and a freely or very water-soluble binder for their use in suspensions or solutions. International Patent Application W02003/039516 describes methods for improving the dissolution of poorly dispersible medicaments, including, for example, quetiapine. The dissolution is improved by means of preparing granules in which a floating agent is added to the medicament. Unfortunately, there is no indication about the release profile of these medicaments in the granulate formulations.

United States Patent Application 2007/0244093 describes a controlled release dosage form comprising quetiapine and at least one excipient, exhibiting a dissolution profile such that at 4 hours after combining the dosage form with a dissolution media 50 to 95%
of the quetiapine, or the pharmaceutically acceptable salt thereof, is released. Examples 10, 12 and 13 are formulations of quetiapine where stearic acid is used as a lubricant and wherein the tablets may further be coated with ethylcellulose.

International Patent Application W02008/152434 relates to a novel process for the synthesis of quetipaine (2-[2-(4-dibenzo[bf][1,4]thiazepin-11-yl-l-piperazinyl) ethoxy]-ethanol).

United States Patent Application 2008/0287418 describes a formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is about 9.6% to about 10.4% by weight and wherein the formulation comprises about 30% hydroxypropyl methylcellulose by weight and about 7.2% sodium citrate dehydrate by weight. The formulation further comprises 25.1% lactose monohydrate by weight, about 25.1 % microcrystalline cellulose and about 1 % magnesium stearate by weight.
United States Patent Application 2009/0035370 describes an orally deliverable pharmaceutical dosage form comprising quetiapine and at least one pharmaceutically acceptable excipient, wherein quetiapine is in a form of free base and/or pharmaceutically acceptable salt thereof and comprising a major component in immediate release form and one or more minor components in delayed extended release or delayed pulsed-release form.

International Patent Application W02007/058593 relates to the a method of treating a patient suffering from or susceptible to a mood disorder or an anxiety disorder comprising administering a sustained release pharmaceutical composition comprising a pharmaceutically effective amount of 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo- [b,f][1,4] thiazepine, or a pharmaceutically acceptable salt thereof to the patient in need thereof. The compositions claimed display a particular mean Gõax characteristics. The proposed method to obtain controlled release of the active ingredient uses the conventional Methocel excipients.

International Patent Application W02008/098969 describes a granule for the preparation of pharmaceutical compositions comprising a core that contains quetiapine or pharmaceutically acceptable salt thereof as active ingredient and a binder, and a coating layer comprising a lubricant. It is said that the presence of a lubricant in an amount ranging from 5 to 10 % would be sufficient to achieve the goal of the invention.
The application suggests the use of lubricants from the glyceryl behenate, glyceryl palmitostearate and macrogol groups.

For the reasons set out above, there is still a need to develop pharmaceutical compositions which incorporate quetiapine or one of its pharmaceutically acceptable salts and which provide desired release rates of the pharmaceutically active agent and a robust manufacturing process. The formulations according to the present invention overcome the drawbacks of the prior art by providing a novel approach by the using at least one hydrophobic controlled release agent in achieving an extended release dosage form.

SUMMARY OF THE INVENTION
Thus, an object of the present invention is to provide a novel controlled release pharmaceutical dosage form comprising:
- a matrix comprising:
- quetiapine or a pharmaceutically acceptable salt thereof;
- at least one hydrophobic controlled release agent, - at least one pH dependent polymer; and - at least one pharmaceutically acceptable excipient.

Another object of the present invention is to provide a novel controlled release pharmaceutical dosage form, wherein the content (in %) of the at least one hydrophobic controlled release agent is about 4.5 - 35 % and the content of the at least one ph dependent polymer ranges from 15 - 35 %.

Yet another object of the present invention is to provide a novel controlled release pharmaceutical dosage form, wherein the ratio of the % content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:3 to 1:7. Preferably, the ratio of the % content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4 to 1:6. More preferably, the ratio of the % content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4.5 to 1:5.5.

Another object of the present invention is to provide a novel controlled release pharmaceutical dosage form comprising:
- a matrix comprising:
- granules comprising:
- quetiapine or a pharmaceutically acceptable salt thereof;
- at least one hydrophobic controlled release agent; and - at least one pH dependent polymer; and - at least one pharmaceutically acceptable excipient.

The novel controlled release pharmaceutical dosage form can be optionally coated with a water insoluble/non gelling polymer.

Another object of the present invention is to provide a controlled release pharmaceutical dosage form that allows a single daily administration with a prolonged effect, simplified production and is cost effective.

Another object of the present invention is to provide a novel stable controlled release pharmaceutical dosage form comprising:
- a matrix comprising:
- quetiapine or a pharmaceutically acceptable salt thereof;
- at least one hydrophobic controlled release agent, - at least one pH dependent polymer; and - at least one pharmaceutically acceptable excipient, wherein said dosage form provides a dissolution of quetiapine or pharmaceutically acceptable salt thereof between 30% and 40% within 1 hour, between 50 and 70 %
within 6 hours and between 75 and 95 % within 16 hours as measured by Apparatus I USP
(baskets) at 100 rpm, in 1000mL of 0.1N HCl (1.2 pH) for the first hour, in 1000mL of 4.5 pH acetate buffer for the 2 hour and subsequently in 1000mL of 6.8 pH
phosphate buffer.

One can also measure the in vitro dissolution rate of the dosage form, according to the present invention, by the following USP Basket (Apparatus 1) Method: at 200 rpm at 1000 ml aqueous buffer (pH 1.2 from 0 to 2 hours and 6.8 from 4 to 20 hours) at 37 C.
Preferably, the dissolution rates for dosage forms of the present invention, obtained by using the above method is between 50% and 60% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 2 hours; between 60%
and 70%
(by wt) after 4 hours; between 65% and 80% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 8 hours; between 70% and 80% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 12 hours; and over 75% (by wt) of quetiapine or pharmaceutically acceptable salt thereof released after 16 hours.

Yet another object of the present invention is to provide a process for manufacturing the novel dosage form.

Other embodiments and further scope of applicability of the present invention will become apparent from the detailed description and examples given hereinafter.
It should be understood, however, that this detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations and methods of use are disclosed and described, it is to be understood by a person skilled in the art that unless otherwise indicated this invention is not limited to specific pharmacologically active agents, specific pharmaceutical carriers, or to particular administration regimens, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes mixtures of active agents, reference to "a pharmaceutical carrier" includes combinations of two or more carriers, and the like.

"Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

The terms or expressions "active agent," "active pharmaceutical ingredient", "drug", "pharmacologically active agent", "pharmaceutically acceptable active agent"
and/or "pharmaceutically acceptable active substance" are used interchangeably herein to refer to a chemical material or compound which, when administered to an organism (human or animal, generally human) induces a desired pharmacologic effect. In the context of the present invention, the terms or expressions refer to a compound that is capable of being delivered orally.

According to the present invention, the pharmaceutically active substance can be an antipsychotic agent, including for example and not limited to quetiapine (marketed as Seroquel ), olanzapine (marketed as Zyprexa ), aripiprazole (marketed as Abilify ), risperidone (marketed as Risperdal ), clozapine (marketed as Clozaril ), ziprasidone (marketed as Geodon ) and olanzapine/fluoxetine (marketed as Symbyax ), palipevidone, asenapine, sertindole, zotepine, amisulride, melperone, biteprunox. More preferably, the pharmaceutically acceptable active substance is quetiapine or a pharmaceutically acceptable salt thereof or solvate thereof. The term "quetiapine" as used herein includes all optical isomers, racemic mixtures and the like of the compound and all pharmaceutically acceptable salts, amides, prodrugs and analogs thereof.

Similarly, a "pharmaceutically acceptable salt" or a "pharmaceutically acceptable ester"
of the compound as provided herein is a salt or ester which is not biologically or otherwise undesirable.

By the terms "effective amount" or "pharmaceutically effective amount" of an agent as provided herein are meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like. Thus, it is not possible to specify an exact "effective amount." However, an appropriate "effective"
amount in any individual case may be determined by a person of ordinary skill in the art using routine experimentation.

The term "excipient" refers to a generally pharmaceutically inactive or inert substance used as a diluent or vehicle for a drug. Different forms of drug administration may require a different excipient and a "pharmaceutically acceptable excipient"
includes a "pharmaceutically acceptable carrier." For example, tablets, troches, pills, capsules, and the like, may contain excipients including binders, such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate. Capsules may contain additional excipients such as a liquid carrier.

By "pharmaceutically acceptable carrier" is meant a carrier comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The term "carrier" is used generically herein to refer to any components present in the pharmaceutical formulations other than the active agent or agents, and thus includes diluents, binders, lubricants, disintegrants, fillers, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.

According to the present invention, the expression "dosage form" may consist of granules, spheroids, beads, pellets, capsules, tablets or any other suitable unit. In the present invention, the dosage form is preferably a tablet.

The novel delayed release dosage form comprising a pharmaceutically acceptable active substance is characterized in the following way. Individual units, for example granules, containing a pharmaceutically acceptable active substance are mixed with other pharmaceutically acceptable excipients and compressed into a final dosage form, preferably a tablet. By the expression "individual units" is meant small beads, particles, granules or pellets, in the following referred to as granules.

The compaction process (or compression process) must not significantly affect the chemical, i.e. degradation and/or mechanical properties of the individual unit or the final dosage form, even if it were to be further layered with a coating layer.

Of course, other components, such as fillers, binders, disintegrants, and other pharmaceutically acceptable additives can be envisaged, and compressed into tablets.
The compressed tablet is optionally covered with a coating layer(s) to obtain a smooth surface of the tablet and further enhances the stability of the tablet during packaging and transport. Such a tablet coating layer may further comprise additives like anti-tacking agents, colorants and pigments or other additives to obtain a tablet of good appearance.

Furthermore, the granules or tablets may be covered with one or more coating layer(s).
The coating layer(s) can be applied onto the tablets by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating or layering process. The materials for coating layers are chosen among pharmaceutically acceptable compounds such as, for instance methacrylic acid copolymer, ethylcellulose, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the coating layer(s). The coating layer may further protect the tablet from environmental conditions.

According to the present invention, the coating layer is preferably made up of an aqueous dispersion of, for example, Eudragit (i.e. methacrylic acid copolymer), a plasticizer (i.e. triethyl citrate) and a diluent (i.e. colloidal silicon dioxide), which can be applied onto the final dosage form.

The novel drug dosage forms are to be administered orally to a mammal and can be used to administer the pharmaceutically acceptable active substance (i.e.
quetiapine or a pharmaceutically acceptable salt or solvate thereof) to treat or prevent a variety of disorders, conditions and diseases. In accordance with the present invention, administration of quetiapine or a pharmaceutically acceptable salt or solvate thereof may be carried out in order to treat any disorder, condition or disease for which quetiapine is generally indicated. Such disorders, conditions and diseases include, for example:

= treat the symptoms of schizophrenia, such as hallucinations (hearing or seeing things which are not there), fixed false beliefs, unusual suspiciousness, or emotional withdrawal. Patients may also feel depressed, anxious or tense.
= treat the symptoms of mania associated with bipolar disorder, such as racing thoughts, irritability, aggressiveness, agitation, impulsive behaviour or excessively elevated mood; and = treat the symptoms of depression associated with bipolar disorder, such as sadness, feeling guilty, lack of energy, loss of appetite and/or sleep disturbance.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention.
Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

EXAMPLES
The following examples are illustrative of the wide range of applicability of the present invention and are not intended to limit its scope. Modifications and variations can be made therein without depending from the spirit and scope of the invention.
Although any method and material whether similar or equivalent to those described herein can be used in the practice for testing the present invention, the preferred methods and materials as described.

All of the percentages given hereinabove and below are percentages by weight.
Examples of various formulations and/or dosage forms, i.e. tablets, containing quetiapine as choice of pharmaceutically active ingredient, are provided herein below.

Example A

Quetiapine tablets according to the present invention Table 1 List of ingredients for the formulation of quetiapine tablets according to the present invention Sr No. Name of Ingredients % w/w m tablet 1 Quetiapine Fumarate 31.98 57.57 E q. to Quetiapine....50 mg 2 Lactose Monohydrate 200M 5.56 10.00 3 Microcrystalline cellulose PH101 10.18 18.33 4 Stearic Acid 31.98 57.57 Povidone K-90 2.78 5.00 6 Purified Water - -7 Microcrystalline cellulose PH102 16.99 30.58 8 Magnesium Stearate 0.53 0.95 Total 100.00 180.00 Manufacturing Process:
In the first step, a pharmaceutically active substance, for example, quetiapine fumarate (equivalent to 57.57 mg/tablet), is mixed with the following pharmaceutical excipients:
lactose monohydrate 200M (equivalent to 10 mg/tablet); microcrystalline cellulose PH101 (equivalent to 18.33 mg/tablet); and stearic acid (equivalent to 57.57 mg/tablet).
The blend was mixed for approximately 5 minutes in a high shear granulator at approximately 800 rpm. The resulting blend is named mixture #1.

In a second step, povidone K-90 (equivalent to 5.0 mg/tablet) was mixed with purified water so as to form a mixture #2. Mixture #2 was then added into mixture #1 obtained from the first step, and mixed until wet granules were obtained.

In a third step, the wet granules obtained in step #2 were dried using a fluid bed dryer until the desired moisture content was achieved.

In a fourth step, the dried granules obtained in step #3 were passed through a suitable screen using a co-mil.

In a fifth step, microcrystalline cellulose PH 102 (equivalent to 30.58 mg/tablet) was passed through a suitable screen and mixed with the dried granules obtained in step 4 using a suitable blender.

In sixth step, magnesium stearate (equivalent to 0.95 mg/tablet) was passed through a screen and mixed with the blend obtained in step 5 so as to obtain a final blend.

The final blend obtained in step #6 was compressed into the novel delayed release pharmaceutical dosage form according to the present invention. This constitutes the seventh step.

It is worth mentioning that direct compression is a preferred manufacturing technique.
However, it is worth mentioning that other dosage forms can be envisaged;
though for the purposes of the present invention, the tablet form is preferred.

According to the present invention, the resulting blend was then compressed, using rotary tablet press to achieve desired strength which can vary based on the desired dosage strengths, for example: 50/150/200/300/400 mg, into the final dosage form, i.e.
tablets.

Generally, the process for manufacturing the novel dosage form according to the present invention generally comprises the following steps:
(a) providing quetiapine or a pharmaceutically acceptable salt thereof, (b) adding to the quetiapine or to the mixture obtained in step (a) a hydrophobic controlled release agent or sodium starch glycolate, and at least one diluent and binder; and (c) adding a solvent mixture, comprising a binder to the mixture obtained step (b);
(d) wet granulating the mixture obtained in step (c);
(e) drying the granules in step (d); and (f) sieving the dried granules with a lubricant ; and (g) compressing the mixture of step (e) into a tableted dosage form; and (h) optionally coating the granules/ tablets with an aqueous dispersion.
Preferably, the at least one hydrophobic controlled release agent is stearic acid. Also preferably, the binder is povidone.

It is also worth mentioning that the dosage form, for example a tablet, of the present invention was subjected to dissolution studies, using either Method 1 where the conditions are as follows:
Apparatus 1 (USP baskets) Speed: 100 rpm 1st hour in 1000mL of 0.1N HCl (1.2 pH) 2nd hour in 1000mL of 4.5 pH acetate buffer Then in 1000mL of 6.8 pH phosphate buffer or by using Method 2 where the conditions are as follows:

Apparatus 1 (USP baskets) Speed: 200 rpm Initial 2 hours in 1000mL of 0.1N HCl (1.2 pH) Then in 1000mL of 6.8 pH phosphate buffer Dissolution Profiles of Example A

Conditions: Apparatus 1 (USP baskets) Speed: 200 rpm Time 0-2 hours in 1000mL of 0.1N HCl (1.2 pH) Time 4-20 hours in 1000mL of 6.8 pH phosphate buffer Average Percentage Release (%) Time Seroquel XR Example A
(Hours) (50 mg strength) Example 1 (Lot: QERT/135) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26* 38.38 2 Lactose Monohydrate 200M 60.00 10.00 3 Sodium Citrate 60.00 10.00 4 Cutina HR PH 90.00 15.00 Povidone K90 9.00 1.50 6 Purified Water ----- -----EXTRAGRANULAR
7 Cutina HR PH 138.00 23.00 8 Lactose Monoh drate Flowlac 100 6.74 1.12 9 Magnesium Stearate 6.00 1.00 Total 600.00 100.00 * 230.26 mg Quetiapine Fumarate is equivalent to 200 mg Quetiapine Brief Manufacturing Process:
1. Sift Quetiapine fumarate, lactose monohydrate 200M, sodium citrate and cutina HR PH and mix in a high shear granulator.
2. Dissolve Povidone K 90 to get the binder solution.
3. Granulate the mixture of step 1 using binder solution of step 2 4. Dry the granules and size.

5. Blend the granules of step 4 and extragranular ingredients in suitable non shear blender.

6. Compress the blend to Tablets using suitable tooling.
Example 2 (Lot: QERT/137) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetta ine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 30.00 5.00 3 Sodium Citrate dth drate 60.00 10.00 4 Cutina HR PH 135.00 22.50 5 Eudragit L 30-D55 30.00 5.00 EXTRAGRANULAR

7 Lactose Monohydrate Flowlac 100 108.74 18.12 8 Magnesium Stearate 6.00 1.00 Total 600.00 100.00 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate 200M, sodium citrate and cutina HR PH and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.

3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
Compress the blend to Tablets using suitable tooling.
Example 3 (Lot: QERT/142C) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 60.00 10.00 3 Citric Acid Monohydrate 30.00 5.00 4 Cutina HR PH 45.00 7.50 5 Eudragit L100-55 72.00 12.00 6 Eudragit L 30-D55 24.00 4.00 EXTRAGRANULAR
7 Lactose Monohydrate Flowlac 100 132.74 22.12 8 Ma esium Stearate 6.000 1.00 Core Tablet Total 600.00 100.00 9 Opadry Yellow 18.00 3.00 Water g.s.
Total 618.00 103.00 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate 200M, citric acid, cutina HR
PH, Eudragit L100-55 and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5 Compress the blend to Tablets using suitable tooling.
6 Prepare aqueous dispersion of Opadry 7 Coat the tablets of step 5 using the dispersion of step 6 Example 4 (Lot: QERT/152) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Mircocyrstalline Cellulose PH101 114.00 19.00 3 Citric Acid Monohydrate 30.00 5.00 4 Cutina HR PH 45.00 7.50 Eudragit L100-55 36.00 6.00 6 Eudragit L 30-D55 24.00 4.00 EXTRAGRANULAR
7 Mircocyrstalline Cellulose PH102 114.74 19.12 8 Magnesium Stearate 6.000 1.00 Core Tablet Total 600.00 100.00 Manufacturing Process:
1. Sift Quetiapine fumarate, microcrystalline cellulose PH 101, citric acid, cutina HR
PH, Eudragit L100-55 and mix in a high shear granulator.
2. Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3. Dry the granules and size.
4. Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5. Compress the blend to Tablets using suitable tooling.
Example 5 (Lot: QERT./155) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 105.00 17.50 3 Citric Acid Monohydrate 30.00 5.00 4 Eudragit L100-55 90.00 15.00 5 Eudragit L 30-D55 24.00 4.00 EXTRAGRANULAR
6 Lactose Monohydrate Flowlac 100 114.74 19.12 7 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.00 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate 200 M, citric acid, Eudragit 55 and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.

4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
Compress the blend to Tablets using suitable tooling.
Example 6 (Lot: QERT/179) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate (Flowlac 100) 165.74 27.62 3 Cutina HR PH 30.00 5.00 4 Eudragit L100-55 54.00 9.00 5 Eudragit L 30-D55 60.00 10.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 42.00 7.00 7 Talc 12.00 2.00 8 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 8 Opadry Yellow 03B92736 18.00 3.00 Coated Tablet Total 618.00 103.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5 Compress the blend to Tablets using suitable tooling.
6 Prepare aqueous dispersion of Opadry 7 Coat the tablets of step 5 using the dispersion of step 6 Dissolution Profiles Conditions:
Apparatus 1 (USP baskets) Speed: 100 rpm Time 1 hour in 1000mL of 0.1N HCl (1.2 pH) Time 2 hour in 1000mL of 4.5 pH acetate buffer Time 4-20 hours in 1000mL of 6.8 pH phosphate buffer Average Percentage Release (%) Apparatus I
Time Example Example Example Example Example Example Baskets at 100 (Hour) 1 2 3 4 5 6 rpm 1 22 31 27 33 37 28 0.1 N HCl 2 24 33 31 39 42 32 4.5 pH acetate buffer 25 35 39 44 54 42 6.8 pH
phosphate 6 25 36 42 46 58 45 buffer Example 7 (Lot: QERT/179) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate (Flowlac 100) 165.74 27.62 3 Cutina HR PH 30.00 5.00 4 Eudragit L100-55 54.00 9.00 5 Eudragit L 30-D55 60.00 10.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 42.00 7.00 7 Talc 12.00 2.00 8 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 9 Opadry Yellow 03B92736 18.00 3.00 Coated Tablet Total 618.00 103.000 Manufacturing Process:
1. Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, eudragit L100-and mix in a high shear granulator.
2. Granulate the mix of step 1 using the eudragit L 30 D-55 dispersion in high shear granulator.
3. Dry the granules and size.
4. Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5. Compress the blend to tablets using suitable tooling.
6. Prepare aqueous dispersion of Opadry 7. Coat the tablets of step 5 using the dispersion of step 6 Example 8 (Lot: QERT/141) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 90.00 15.00 3 Cutina HR PH 45.00 7.50 4 Eudragit L100-55 60.00 10.00 Eudragit L 30-D55 36.00 6.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 132.74 22.12 7 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5 Compress the blend to tablets using suitable tooling.
Example 9 (Lot: QERT/149) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Furnarate 230.26 38.38 2 Lactose Monohydrate 200M 72.00 12.00 3 Cutina HR PH 45.00 7.50 4 Eudragit L100-55 96.00 16.00 5 Eudragit L 30-D55 36.00 6.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 114.74 19.12 7 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.

4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
Compress the blend to tablets using suitable tooling.
Example 10 (Lot: QERT/164) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 105.00 17.50 3 Cutina HR PH 30.00 5.00 4 Eudragit L100-55 90.00 15.00 5 Eudragit L 30-D55 24.00 4.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 114.74 19.12 7 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5 Compress the blend to tablets using suitable tooling.
Example 11 (Lot: QERT/165) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 84.00 14.00 3 Cutina HR PH 30.00 5.00 4 Eudragit L100-55 120.00 20.00 5 Eudragit L 30-D55 24.00 4.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 105.74 17.62 7 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.

2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
Compress the blend to tablets using suitable tooling.
Example 12 (Lot: QERT/169) S.N. Formulation mg/tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 105.00 17.50 3 Cutina HR PH 30.00 5.00 4 Eudragit L100-55 96.00 16.00 5 Eudragit L 30-D55 48.00 8.00 EXTRAGRANULAR
6 Lactose Monohydrate (Flowlac 100) 72.74 12.12 7 Talc 12.00 2.00 8 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
5 Compress the blend to tablets using suitable tooling.
Example 13 (Lot: OERT/171) S.N. Formulation m tablet % w/w INTRAGRANULAR
1 Quetiapine Fumarate 230.26 38.38 2 Lactose Monohydrate 200M 225.74 37.62 3 Cutina HR PH 30.00 5.00 4 Eudragit L100-55 36.00 6.00 5 Eudragit L 30-D55 60.00 10.00 EXTRAGRANULAR
6 Talc 12.00 2.00 7 Magnesium Stearate 6.00 1.00 Core Tablet Total 600.00 100.000 Manufacturing Process:
1 Sift Quetiapine fumarate, lactose monohydrate, cutina HR PH, Eudragit L100-and mix in a high shear granulator.
2 Granulate the mix of step 1 using the Eudragit L 30 D-55 dispersion in high shear granulator.
3 Dry the granules and size.
4 Blend the granules of step 3 and extragranular ingredients in suitable non shear blender.
Compress the blend to tablets using suitable tooling.
Dissolution Profiles Conditions: Apparatus 1 (USP baskets) Speed: 200 rpm Time 2 hours in 1000mL of 0.1N HCl (1.2 pH) Time 4-16 hours in 1000mL of 6.8 pH phosphate buffer Innovator Lot#: TM0047 Apparatus I
Time Average Percentage Release % Baskets (Hour) Seroquel XR Example 1 200 rpm 1 23 28 0.1 N HCl 12 95 83 6.8 pH phosphate 16 100 94 buffer Dissolution Profiles Conditions:
Apparatus 1 (USP baskets) Speed: 100 rpm Time 1 hours in 1000mL of 0.1N HCl (1.2 pH) Time 2 hours in 1000mL of 4.5 pH acetate buffer Time 4-20 hours in 1000mL of 6.8 pH phosphate buffer Average Percentage Release (%) Time Seroquel Ex. Ex. Ex. Ex. Ex. Ex. Ex. Apparatus I
(Hr) XR 7 8 9 10 11 12 13 Baskets at TM0047 100 rpm 1 21 28 41 34 47 35 31 33 0.1 N HCl 2 27 32 47 40 55 42 36 37 4.5 pH
acetate buffer 30 42 56 49 65 51 45 47 6.8 pH
phosphate 6 47 45 59 52 68 55 49 50 buffer

Claims

1. A novel stable controlled release pharmaceutical dosage form comprising:
- a matrix comprising:
- quetiapine or a pharmaceutically acceptable salt thereof;
- at least one hydrophobic controlled release agent, - at least one pH dependent polymer; and - at least one pharmaceutically acceptable excipient.

2. The novel controlled release pharmaceutical dosage form as claimed in claim 1, wherein the content (in %) of the at least one hydrophobic controlled release agent is about 4.5 - 35 % and the content of the at least one ph dependent polymer ranges from 15-35%.

3. The novel controlled release pharmaceutical dosage form as claimed in claim 1 or 2, wherein the ratio of the % content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:3 to 1:7.

4. The novel controlled release pharmaceutical dosage form as claimed in claim 1 or 2, wherein the ratio of the % content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4 to 1:6.

5. The novel controlled release pharmaceutical dosage form as claimed in claim 1 or 2, wherein the ratio of the % content between the at least one hydrophobic controlled release agent and the at least one pH dependent polymer ranges from about 1:4.5 to 1:5.5.

6. A novel controlled release pharmaceutical dosage form comprising:
- a matrix comprising:
- granules comprising:
- quetiapine or a pharmaceutically acceptable salt thereof;
- at least one hydrophobic controlled release agent; and - at least one pH dependent polymer; and - at least one pharmaceutically acceptable excipient.

7. A novel stable controlled release pharmaceutical dosage form comprising:
- a matrix comprising:
- quetiapine or a pharmaceutically acceptable salt thereof;
- at least one hydrophobic controlled release agent, - at least one pH dependent polymer; and - at least one pharmaceutically acceptable excipient, wherein said dosage form provides a dissolution of quetiapine or pharmaceutically acceptable salt thereof between 30 and 40 % within 1 hour, between 50 and 70 %
within 6 hours and between 75 and 95 % within 16 hours as measured by Apparatus I USP
(baskets) at 100 rpm, in 1000mL of 0.1N HC1 (1.2 pH) for the first hour, in 1000mL of 4.5 pH acetate buffer for the 2 hour and subsequently in 1000mL of 6.8 pH
phosphate buffer.