WO2011154118A1

WO2011154118A1 - Quetiapine prolonged-release tablets

Info

Publication number: WO2011154118A1
Application number: PCT/EP2011/002758
Authority: WO
Inventors: Dieter Ruchatz; Chaitanya Gujjar Yogananda; Rallabandi Bala Ramesha Chary; Manohar Lal Pasahn
Original assignee: Alfred E. Tiefenbacher (Gmbh & Co. Kg)
Priority date: 2010-06-07
Filing date: 2011-06-06
Publication date: 2011-12-15

Abstract

The present invention relates to a prolonged-release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof, preferably quetiapine hemifumarate, and propylene glycol alginate (PGA). The present invention further relates to the use of PGA for providing prolonged-release of a pharmaceutically active ingredient from a pharmaceutical composition.

Description

Quetiapine prolonged-release tablets

The present invention relates to a prolonged-release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof, preferably quetiapine hemifumarate (hereinafter referred to as "quetiapine fumarate") and propylene glycol alginate (PGA). The present invention further relates to the use of PGA for providing prolonged-release of a pharmaceutically active ingredient from a pharmaceutical composition. Quetiapine is an atypical antipsychotic which is marketed in form of a prolonged- release film-coated tablet under the trade names Seroquel^® XR or Seroquel^® Prolong. Quetiapine is approved for the treatment of schizophrenia and bipolar disorder. If used in the treatment of bipolar disorder, it may be used in a monotherapy or combination therapy together with lithium or divalproex sodium (valproate semisodium). The quetiapine containing prolonged-release tablet should be administered once daily, preferably in the evening.

Quetiapine and its salts are soluble in an aqueous environment. Therefore, if formulated as a prolonged-release pharmaceutical composition, such a product is susceptible to a phenomenon known as dose dumping. Dose dumping means that the release of a pharmaceutically active ingredient is delayed for a time but once release begins to occur the rate of release is very high. In this regard, the state of the art describes various formulations which try to overcome the problem encountered with dose dumping, such as fluctuations occurring in the plasma concentration of quetiapine, and the diurnal variation in plasma concentration of the active ingredient.

WO 97/45124 (AstraZeneca) describes a prolonged-release formulation of quetiapine comprising a hydrophilic matrix made from the active ingredient and a gelling agent. According to this application a gelling agent is a substance which forms a gel when in contact with water. The preferred gelling agent is hydroxypropyl methycellulose (HPMC). Preferably, the quetiapine containing prolonged-release tablet contains the gelling agent in combination with a pH-modifier, such as sodium citrate.

WO 97/45124 covers the commercially available Seroquel^® XR tablet, which contains in the tablet core HPMC and sodium citrate together with lactose monohydrate, microcrystalline cellulose and magnesium stearate.

WO 2008/060228 relates to a further development of the tablet disclosed in

WO 97/45124, wherein quetiapine and HPMC are contained in specific amounts, and sodium citrate is used in the form of its dihydrate as a pH-modifier.

WO 2004/012699 relates to a modified-release dosage form comprising quetiapine. The modified-release profile of the active ingredient is achieved by using a dual retard technique, wherein the active ingredient is contained in a micro matrix particle together with a hydrophobic release controlling agent, which particle is surrounded by a coating containing a hydrophobic release controlling agent.

WO 2005/041935 discloses a quetiapine containing prolonged-release tablet, which is characterized in that quetiapine is contained in a matrix made from a hydrophobic material, preferably a wax material. A wax material according to the application is a substance which is solid at room temperature and has a melting point of from 30° C to 100° C. The hydrophobic material includes neutral or synthetic waxes, fatty alcohols, fatty acids, including fatty acids esters, hydrocarbons, and the like. WO 2007/086079 discloses a sustained-release dosage form containing quetiapine, which comprises a rate controlling agent and a channelizer. The channelizer acts as a pore forming agent and facilitates the release of the drug from the dosage form through the pores. Preferred rate controlling agents are cellulose derivatives, pyrrolidone derivates, vinyl acetate-copolymers, and the like. The channelizer is preferably selected from electrolytes, water-soluble excipients, osmotic agents and diluents.

WO 2008/090569 relates to a modified-release pharmaceutical composition comprising a pharmaceutical active ingredient having a pH-depended solubility, such as quetiapine, a release rate controlling polymer that controls the release of the active agent in an acidic environment, and a release rate modifying system that controls the release of the active agent in both an acidic and basic environment. It is reported that the release rate modifying system consists of a combination of a gelling agent and at least one gelation facilitating agent. Preferably the gelling agent is selected from locust bean gum, xanthan gum, tragacanth, gellan gum, guar gum, alginate, carrageenan, and the like, whereas the gelation facilitating agent is selected from calcium sulphate, calcium chloride, magnesium citrate, and the like. WO 2009/1 13051 discloses a modified-release formulation comprising quetiapine, a non-gelling and/or waxy excipient. Examples of non-gelling and/or waxy excipients include polymethacrylates and their copolymers, polyvinyl acetate, hydrophobic modified cellulose derivatives, non-gelling polysaccharides, pharmaceutically acceptable waxes, and the like.

The European patent application EP 2 153 834 relates to an extended-release multiparticulate system comprising quetiapine and a hydrophobic release controlling agent, preferably selected from oils, fatty acids and salts thereof, vinyl acetate, siloxane, (meth)acrylic acid esters and vinyl alcohol/vinyl acetate-copolymers. WO 2010/001413 discloses a sustained-release dosage form comprising quetiapine and a non-gelling agent release controlling polymer preferably selected from cellulose acetate, an acrylic polymer such as ethyl acrylate/methyl methacrylate- copolymer, and ammonio methacrylate copolymers.

US 2009/0264408 discloses a prolonged-release dosage form comprising quetiapine and a rate controlling polymer, wherein the rate controlling polymer is selected from polyethylene oxide, sodium alginate, natural gums, such as xanthan gum or locust bean gum, and combinations thereof.

WO 2010/012490 describes a pharmaceutical composition comprising a solid matrix system of quetiapine and a non-gelling carrageenan as λ-carrageenan.

Hence, several techniques are reported in the state of the art to overcome the problem of dose dumping of quetiapine in prolonged-release formulations. These techniques are based on the provision of a hydrophilic matrix, which contains the active ingredient together with a gelling agent, such as HPMC, or a non-gelling agent, such as λ-carrageenan, or a hydrophobic matrix, in which the active ingredient is contained within a hydrophobic material, such as waxes. Techniques based on release retarding coatings are reported as well. Accordingly, it was the object of the present invention to provide a further prolonged-release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof, preferably quetiapine fumarate, which provides for a sufficiently high prolonged-release effect without dose dumping.

This object is solved by the subject matter as defined in the claims.

It has been found that a sufficiently high prolonged-release effect is achieved, if quetiapine or a pharmaceutically acceptable salt thereof is contained in a solid matrix with a non-gelling propylene glycol alginate (PGA) as a release retarding polymer, i.e. if the drug is contained in a PGA-matrix. To the best of the inventor's knowledge it has not been reported in the state of the art that PGA can be used as a release retarding polymer to achieve a prolonged-release of a pharmaceutically active ingredient from a pharmaceutical composition. The release retarding technique of the present invention based on PGA is also suitable for other drugs such as omeprazole and esomeprazole and their salts (e.g. omeprazole-Mg and esomeprazole-Mg), montelukast sodium, aprepitant, dipyridamole, bosentan, acetylsalicylic acid and lercanidipine HC1. PGA has been widely used in cosmetics and food products. PGA is usually employed as a thickening agent. It has also been used in the medicinal field as a stabilizing, suspending, and emulsifying agent in oral and topical, liquid pharmaceutical formulations, typically in a concentration of 0.3 to 5% w/v depending on the specific application and the grade of PGA used. Alginate occurs in the seaweed as a mix of calcium, magnesium, sodium and potassium salts. Water soluble alginates are commercially available as sodium, potassium, ammonium, magnesium alginates and PGA. The solubility and thickening properties of PGA in an aqueous medium are pH-independent. Commercially available alginates which swell in water, but are insoluble in water, are alginic acid and calcium alginate. Alginates do not form gels when in contact with water. However, they may form gels in the presence of calcium ions or other multivalent cations. Alginic acid is a copolymer of two uronic acids, namely mannuronic and guluronic. When producing alginates, the uronic acids are converted into the salt form through a neutralization step, or esterified to provide PGA. To form a gel, alginates must contain a sufficient level of guluronate monomers in a block to react with calcium or other multivalent cations. Regions of guluronate monomers in one alginate molecule can be link to a similar region in another alginate molecule by means of calcium ions or other multivalent cations. However, contrary to the alginate salts the esterified alginates as PGA are generally not capable to react with calcium or other multivalent cations, because of the decreased number of free carboxylate groups present in the alginate molecule, and are therefore not able to form gels.

PGA is commercially available with various degrees of esterification ranging from 40 to 90% ester. According to the present invention, the degree of esterification of the PGA is 40% and greater, preferably between 50% and 90%, more preferred between 80% and 85%. A low viscosity, highly esterified (82-85%) PGA is commercially available under the tradename Kelcoloid^® S. This PGA grade is particularly useful for the present invention, but other grades as a low viscosity, 50-59% esterified PGA (Kelcoloid^® LVF), high viscosity, 45-50% esterified PGA (Kelcoloid^® HVF), medium viscosity, 52-56% esterified PGA (Manucol^® Ester M), 40-85% esterified PGA (Protanal^® Ester SD-LB or Kelcoloid^® K3B426), and medium viscosity, highly esterified PGA (Manucol^® Ester E/RK) may be used in the present invention. Kelcoloid^® S, Protanal^® Ester SD-LB and Kelcoloid^® K3B426 are commercially available in pharma grade and therefore preferred for the present invention, but also food grade PGAs, such as Manucol^® Ester E/RK, may be used. A mixture of different PGA types may be contained in the pharmaceutical composition of the present invention. The combination of PGA (single PGA type or mixture of different PGA types) with other hydrophilic, non-gelling polymers like pullulan and other thickeners, or the combination of PGA with hydrophobic water-insoluble non-gelling polymers like cellulose acetate, polyvinyl acetate, (meth)acrylic acid ester-copolymers may be used in the present invention to modify the drug release pattern to achieve in-vitro or in-vivo equivalence. The pharmaceutical composition according to the present invention preferably contains a carboxylic acid. It has been found that the presence of a carboxylic acid promotes the dissolution of quetiapine in an aqueous environment, thereby achieving a complete release of the active ingredient from the composition. In a preferred embodiment of the present invention the carboxylic acid is a dicarboxylic acid or a tricarboxylic acid, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glutaric acid, malic acid and citric acid.

However, it has been found that the carboxylic acid may affect the prolonged-release property of the pharmaceutical composition, so that it should not be contained in the composition in an amount of higher than 25% by weight, based on the total weight of the composition, or it should be abstained from incorporating a carboxylic acid at all. If present, the carboxylic acid is preferably contained in the composition in an amount of 5 to 25% by weight, preferably 10 to 15% by weight, based on the total weight of the composition.

The prolonged-release pharmaceutical composition according to the present invention contains quetiapine or a pharmaceutically acceptable salt thereof preferably in an amount of 30 to 70% by weight, more preferred 40 to 60% by weight, based on the total weight of the composition. In a particular preferred embodiment of the present invention, the pharmaceutical composition consists of quetiapine or a pharmaceutical acceptable salt thereof, PGA, a binder, a lubricant, and optionally a carboxylic acid. The pharmaceutical composition of the present invention can be produced by manufacturing methods known in the state of the art such as direct compression of a powder mixture containing quetiapine or a pharmaceutically acceptable salt thereof and PGA, or compression of a pre-granulated powder mixture containing quetiapine or a pharmaceutically active ingredient and PGA, wherein both wet granulation techniques and dry granulation techniques, i.e. techniques which are based on direct compression and dry granulation, are suitable. Preferred is a wet granulation technique, in which a non-aqueous granulation liquid is used, such as an alcohol, preferably isopropyl alcohol and/or anhydrous ethanol. Accordingly, binders suitable for the present invention include polyvinyl pyrrolidone (povidone), methyl cellulose, microcrystalline cellulose and vinyl pyrrolidone/vinyl acetate-copolymer (copovidone; Plasdone^® S-630).

Lubricants useful for the present invention include magnesium stearate, stearic acid, sodium stearyl fumarate and the like.

Glidants, as colloidal silicon dioxide, may be contained in the composition of the present invention.

Since, it has been found that PGA provides for a sufficiently high prolonged-release effect of a pharmaceutical active ingredient from a pharmaceutical composition, the presence of a gelling agent, such as HPMC is not required.

Preferably, the pharmaceutical composition according to the present invention is a prolonged-release tablet or prolonged-release granules. The prolonged-release granules may be contained in a capsule.

The prolonged-release tablet and prolonged-release granules according to the present invention are optionally covered by a conventional film coating (Opadry^®).

The invention is further illustrated by reference to the following examples.

Examples

The dissolution rate of quetiapine from the pharmaceutical composition of the present invention and the Seroquel^® XR tablet (comparative tablet) have been determined in an aqueous 0.1 N hydrochloric acid solution, in an aqueous acetate buffer (pH 4.5) and in an aqueous phosphate buffer (pH 6.8), using a basket apparatus (100 rpm) at 37° C ± 0.5° C according to the dissolution test for solid dosage forms described in the European Pharmacopeia 6.6, 2.9.3. The release rate reported as the active ingredient released [%] per time [h].

Examples 1 and 2

Ingredients Example 1 Example 2

[mg] [mg]

Stage-A (Dry Mix and Compaction)

Quetiapine Fumarate 230.26 230.26

Tartaric Acid 99.74 99.74

Propylene Glycol Alginate (Kelcoloid S) 100.00 150.00

Magnesium Stearate 10.00 10.00

Stage-B (Blending and Lubrication)

Magnesium Stearate 5.00 5.00

Total tablet weight 445.00 495.00 Procedure:

Quetiapine fumarate, tartaric acid, PGA and magnesium stearate were sifted, blended and subsequently subjected to compaction. The resulting dry granules were lubricated with magnesium stearate, and the mixture was compressed into tablets. Table 1. Comparative differential dissolution profile (quetiapine prolonged release tablets 200 mg with Seroquel^® Prolong 200 mg)

Media Time Seroquel^® Prolong Example 1 Example 2

[hour]

200 mg

0.1 N HC1 1 21 28 27

2 35 42 38 pH 4.5 53 51

3 43

buffer

pH 6.8 4 45 65 62 buffer 6 54 86 78

8 67 94 90

12 88 95 94

16 99 96 94

Examples 3 to 6

Ingredients Ex. 3 Ex. 4 Ex. 5 Ex. 6

[mg] [mg] [mg] [mg]

Stage-A (Dry Mix and

Compaction)

Quetiapine Fumarate 230.26 230.26 230.26 230.26

Tartaric Acid 75.00 50.00

Propylene Glycol Alginate 150.00 150.00 200.00

150.00

(Kelcoloid S)

Copovidone (Plasdone S630) 52.84 49.74 43.52 49.74

Magnesium Stearate 10.60 10.00 8.80 10.00 Stage-B (Blending and

Lubrication)

Magnesium Stearate 5.30 5.00 4.42 5.00

Total tablet weight 524.00 495.00 437.00 495.00 Procedure:

Quetiapine fumarate, optionally tartaric acid, PGA, copovidone and magnesium stearate were sifted, blended and subsequently subjected to compaction. The resulting dry granules were lubricated with magnesium stearate, and the mixture compressed into tablets. Table 2. Comparative differential dissolution profile (quetiapine prolonged release tablets 200 mg with Seroquel^® Prolong 200 mg)

Media Time Seroquel® Example 3 Example 4 Example 5 Example 6

[hour] Prolong

200 mg

0.1 N 1 21 24 24 22 21

HCI 2 35 34 36 34 32 pH 4.5

3 43 46 48 46 43 buffer

pH 6.8 4 45 55 57 51 49 buffer 6 54 75 76 66 63

8 67 88 88 79 76

12 88 93 96 95 96

16 99 96 96 95 97

Examples 7 to 12

Ingredients Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 1 1 Ex. 12

[mg] [mg] [mg] [mg] [mg] [mg]

Stage-A

(Dry Mix and Compaction)

Quetiapine Fumarate 230.26 230.26 230.26 230.26 230.26 230.26

Propylene Glycol Alginate

30.00 60.00 90.00 100.00 150.00 200.00 (Kelcoloid 3B426)

Propylene Glycol Alginate

120.00 90.00 60.00 - - - (Kelcoloid S)

Pullulan - - - 50.00 - -

Copovidon (Plasdone S630) 43.52 43.52 43.52 43.52 43.34 49.56

Magnesium Stearate 8.80 8.80 8.80 8.80 8.80 10.00

Stage-B

(Blending and Lubrication)

Magnesium Stearate 4.42 4.42 4.42 4.42 4.42 5.00

Core tablet weight 437.00 437.00 437.00 437.00 437.00 495.00

Stage-C (Coating)

Opadry^® AMB

- - - - 12.00 - White 81W48080

Water purified - - - - q.s. -

Total tablet weight 437.00 437.00 437.00 437.00 449.00 495.00

Opadry^® AMB White 81 W48080 contains:

polyvinyl alcohol (partially hydrolyzed), titanium dioxide, talc, lecithin

Procedure:

Quetiapine fumarate, optionally pullulan, PGA, copovidone and magnesium stearate were sifted, blended and subsequently subjected to compaction. The resulting dry granules were lubricated with magnesium stearate, and the mixture was compressed into tablets, and optionally coated with Opadry . Table 3. Comparative differential dissolution profile (quetiapine release tablets 200 mg with Seroquel^® Prolong 200 mg)

Media Time Seroquel^® Ex. 8 Ex. 9 Ex. 10 Ex. 1 1 Ex. 12

[hour] Prolong

200 mg

0.1 N HCI 1 21 23 22 25 23 21

2 35 35 34 39 35 32 pH 4.5

3 43 44 43 49 43 39 buffer

pH 6.8 4 45 51 49 54 49 45 buffer 6 54 66 65 71 62 57

8 67 83 81 84 78 67

12 88 99 96 95 96 97

16 99 99 97 97 98 98

Examples 13 to 16

Ingredients Ex. 13 Ex. 14 Ex. 15 Ex. 16

[mg] [mg] [mg] [mg]

Stage-A (Dry Mix and Compaction)

Quetiapine Fumarate 230.44 230.44 230.44 230.44

Propylene Glycol Alginate

200.00 225.00 250.00 298.00 (Kelcoloid K3B426)

Cellulose, Microcrystalline

17.56 19.56 14.56 14.56 (Avicel^® PH 101)

Copovidone (Plasdone S630) 70.00 75.00 80.00 90.00

Magnesium Stearate 10.00 10.00 10.00 10.00

Stage-B (Blending and Lubrication)

Magnesium Stearate 8.00 10.00 10.00 12.00

Colloidal Silicon Dioxide

4.00 5.00 5.00 5.00 (Aerosil^® 200 Pharma)

Core tablet weight 540.00 575.00 600.00 660.00

Stage-C (Coating)

Opadry^® II Yellow 85F32004 16.00 17.00 18.00 20.00

Water purified q.s. q.s. q.s. q.s.

Total tablet weight 556.00 592.00 618.00 680.00

Opadry* II Yellow 85F32004 contains:

polyvinyl alcohol (partially hydrolyzed), titanium dioxide, talc, macrogol, iron oxide yellow

Procedure:

Quetiapine fumarate, microcrystalline cellulose, PGA, copovidone and magnesium stearate were sifted, blended and subsequently subjected to compaction. The resulting dry granules were lubricated with magnesium stearate and colloidal silicon dioxide, and the mixture was compressed into tablets, and coated with Opadry^®. Table 4. Comparative differential dissolution profile (quetiapine prolonged release tablets 200 mg with Seroquel^® Prolong 200 mg)

Media Time Seroquel® Ex. 13 Ex. 14 Ex. 15 Ex. 16

[hour] Prolong

200 mg

0.1 N HC1 1 21 23 22 21 21

2 35 37 34 33 32 pH 4.5

3 43 46 43 43 41 buffer

pH 6.8 4 45 51 50 49 47 buffer 6 54 69 66 65 63

8 67 86 82 81 80

12 88 97 98 96 95

16 99 98 98 97 96

Examples 17 to 20

Ingredients Ex. 17 Ex. 18 Ex. 19 Ex. 20

[mg] [mg] [mg] [mg]

Stage-A (Dry Mix and Compaction)

Quetiapine Fumarate 57.61 230.44 345.66 460.88

Cellulose, Microcrystalline

4.14 16.56 24.84 33.12 (Avicel^® PH 102)

Propylene Glycol Alginate

43.75 175.00 262.50 350.00 (Kelcoloid K3B426)

Copovidone (Plasdone S630) 15.00 60.00 90.00 120.00

Magnesium Stearate 2.50 10.00 15.00 20.00 Stage-B (Blending and Lubrication)

Magnesium Stearate 2.00 8.00 12.00 16.00

Colloidal Silicon Dioxide

_Λ 1.00 4.00 6.00 8.00 (Aerosil^® 200)

Core tablet weight 126.00 504.00 756.00 1008.00 Stage-C (Coating)

Opadry® II Yellow 85F32004 - 16.00

Water purified - q.s.

Total tablet weight 126.00 520.00 756.00 1008.00

Opadry^® II Yellow 85F32004 contains:

polyvinyl alcohol (partially hydrolyzed), titanium dioxide, talc, macrogol, iron oxide yellow Procedure:

Quetiapine fumarate, microcrystalline cellulose, PGA, copovidone and magnesium stearate were sifted, blended and subsequently subjected to compaction. The resulting dry granules were lubricated with magnesium stearate and colloidal silicon dioxide, and the mixture was compressed into tablets, and optionally coated with Opadry^®. Table 5. Comparative dissolution profile (quetiapine prolonged release tablets 50 mg, 200 mg, 300 mg and 400 mg with Seroquel^® Prolong 200 mg)

Media Time Seroquel® Ex. 17 Ex. 18 Ex. 19 Ex. 20

[hour] Prolong

200 mg

1 6 12 6 6 4

2 14 28 14 12 10

4 32 63 33 27 22 pH 4.5

6 49 91 52 40 33 buffer

8 68 101 65 50 42

12 91 99 91 71 59

16 101 99 100 89 74

Examples 21 to 24

Ingredients Ex. 21 Ex. 22 Ex. 23 Ex. 24

[mg] [mg] [mg] [mg]

Stage-A (Dry Mix)

Quetiapine Fumarate 230.44 230.44 230.44 230.44

Cellulose, Microcrystalline 1 1.56 - 10.56 1 1.56 (Comprecel^® M 101 D+)

Cellulose, Microcrystalline - 10.56

(Avicel^® PH 101)

Propylene Glycol Alginate 150.00 147.00 157.00 140.00 (Kelcoloid^® K3B426)

Stage-B (Granulation)

Copovidone (Plasdone S630) 10.00 20.00 10.00 10.00

Isopropyl Alcohol q.s. q.s. q.s. q.s.

Stage-C (Lubrication and

Blending)

Colloidal Silicon Dioxide 2.00 4.00 4.00 2.00 (Aerosil^® 200 Pharma)

Magnesium Stearate 6.00 8.00 8.00 6.00

Core tablet weight 410.00 420.00 420.00 400.00

Stage-D (Coating)

Opadry^® II Yellow 85F32004 12.00 12.00 12.00 12.00

Water purified q.s. q.s. q.s. q.s.

Total tablet weight 422.00 432.00 432.00 412.00 Opadry^® II Yellow 85F32004 contains:

Quetiapine fumarate, microcrystalline cellulose and PGA were sifted and blended in a rapid mixer granulator. The resulting mixture was granulated with a granulation liquid made from copovidone and isopropyl alcohol. The obtained granules were dried and sifted through appropriate screen. The dried granules were subsequently blended and lubricated with magnesium stearate and colloidal silicon dioxide. The mixture was compressed into tablets, and the tablets were coated with Opadry^®. Table 6. Comparative differential dissolution profile (quetiapine prolonged release tablet 200 mg with Seroquel^® Prolong 200 mg)

Media Time Seroquel^® Ex. 21 Ex. 22 Ex. 23 Ex. 24

[hour] Prolong 200 mg

1 21 26 25 26 28

0.1 N HC1

2 35 41 38 38 43 pH 4.5 3 43 50 48 46 51 buffer

4 45 55 54 51 57

6 54 62 67 58 65 pH 6.8

8 67 76 83 71 79 buffer

12 88 98 101 92 101

16 99 102 102 100 103

Claims

1. Prolonged-release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof and propylene glycol alginate (PGA).

2. Pharmaceutical composition according to claim 1 , wherein the degree of esterification of the PGA is 40% and greater, preferably between 50% and 90%, more preferred between 80% and 85%.

3. Pharmaceutical composition according to claim 1 or 2, comprising a carboxylic acid.

4. Pharmaceutical composition according to claim 3, wherein the carboxylic acid is a dicarboxylic acid or tricarboxylic acid.

5. Pharmaceutical composition according to claim 4, wherein the carboxylic acid is selected from oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glutaric acid, malic acid and citric acid.

6. Pharmaceutical composition according to claim 4 or 5, wherein the carboxylic acid is contained in the composition in an amount of 5 to 25% by weight, preferably 10 to 15% by weight, based on the total weight of the composition.

7. Pharmaceutical composition according to any of the preceding claims, wherein the quetiapine or a pharmaceutically acceptable salt thereof is contained in the composition in an amount of 30 to 70% by weight, preferably 40 to 60% by weight, based on the total weight of the composition.

8. Pharmaceutical composition according to any of the preceding claims, comprising a hydrophilic non-gelling polymer other than PGA, such as pullulan, and/or a hydrophobic water-insoluble non-gelling polymer, such as cellulose acetate, polyvinyl acetate, and (meth)acrylic acid ester-copolymers.

9. Pharmaceutical composition according to any of the preceding claims consisting of quetiapine or a pharmaceutically acceptable salt thereof, PGA, a binder, a lubricant, and optionally a carboxylic acid, a hydrophilic non-gelling polymer other than PGA or a hydrophobic water-insoluble non-gelling polymer.

10. Pharmaceutical composition according to any of the preceding claims, wherein the PGA is a mixture of different PGA types.

1 1. Pharmaceutical composition according to any of the preceding claims in the form of a prolonged-release tablet or prolonged-release granules.

12. Use of PGA for providing prolonged-release of a pharmaceutically active ingredient from a pharmaceutical composition.