ES2353235T3 - FORMULATION OF PROLONGED LIBERATION OF 3-AMINO-8- (1-PIPERAZINIL) -2H-1-BENZOPIRAN-2-ONA. - Google Patents

Abstract

An extended release formulation comprising: a) an amount in the range of about 0.1 to maximum about 2.5 mg of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2 °na or a salt pharmaceutically acceptable thereof or a hydrate of said pharmaceutically acceptable salt thereof, b1) a hydroxypropylmethylcellulose or b2) a mixture of two or more hydroxypropylmethylcellulose or b3) a starch excipient comprised between 20 and 80% by weight based on substance Dry chain of long chain amylose, with a polymerization degree of at least 100, a cold water solubility of at most 25% by weight and a specific surface area of at least 1 m2 / g. releasing said prolonged release formulation at most 40% of the active substance in 45 minutes.

Description

The present invention relates to prolonged release formulations of the compound 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one or pharmaceutically acceptable forms thereof. The invention further relates to the preparation of these prolonged release formulations and their use in the prevention or treatment of disorders, such as CNS disorders and pain.

3-Amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one is described in European patent EP 0650964 (Example 8) and is a selective 5-HT1A receptor agonist and 5- receptor antagonist HT1D, which can be used in the treatment of CNS disorders such as anxiety and depression. The compound has the following structure:

image 1

During further development of said compound in the aforementioned indications, it appears that the compound when administered as an immediate release formulation has the serious disadvantage of the high frequency of serious nausea and vomiting in the desired clinical administration range.

It is the object of the present invention to provide a solution to this problem, since the frequency found for nausea and vomiting was prohibitive for further development of an oral formulation of the compound.

This object can be achieved in accordance with the present invention by a prolonged release formulation of 3-amino-8- (1-piperazinyl) -2H-1benzopyran-2-one or a pharmaceutically acceptable salt thereof.

Within the framework of the present invention and in line with the European Pharmacopoeia, an extended-release formulation (alternatively referred to as an extended-release formulation) is defined as a modified-release pharmaceutical form from which the release of the active substance and its subsequent absorption are prolonged compared to a conventional unmodified (immediate release) pharmaceutical form administered by the same route. A modified release formulation is defined as a formulation in which the rate and / or the place of release of the active substance is different from those of an immediate release formulation administered by the same route. In an immediate release formulation more than 75% of the active substance is released in 45 minutes. In an oral prolonged release formulation according to the present invention at most 40% of the active substance is released in 45 minutes.

Various agonists of the 5-HT1A receptor, that is, buspirone and gepirone, have low clinical efficacy and side effects related to rapid metabolism, which leads to the formation of 1-2 (2-pyrimidinyl) piperazine (1-PP). This problem can be solved according to the international patent WO 98/42344 by the use of a rapid dispersion pharmaceutical form that provides astral absorption. Other solutions are the concurrent administration of an autosomal 5-HT1A receptor antagonist such as pindolol (US Patent 6,312,717) or the use of a prolonged release formulation (US Patent 5,478,572).

Due to the fact that 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one originates from a completely different kind of structure, the side effects of this compound are not related to rapid metabolization. and / or the formation of a large amount of a major metabolite.

International patent WO 96/09815 describes the use of a special starch excipient generally indicated as "long chain amylose" for the preparation of drug controlled release formulations and indicates that controlled release formulations can be used to reduce side effects and perform a low dose of drugs in general. There is no indication, however, that a controlled release formulation can be used to reduce nausea and vomiting and increase the dose.

It is known that 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one is useful in the treatment and / or prevention of anxiety, depression, pain and movement disorders and can be administered in different forms of salts. It is effective for a wide range of administration. The term "therapeutically effective amount" in the context of the present invention refers to an amount capable of reducing the adverse symptoms of a particular disease. The preferred dose is in the range of about 0.01 to about 20 mg daily. In the treatment of adult humans, a range of about 0.1 to about 2.5 mg in single or divided doses is preferred. The particular dose of compound administered according to the present invention will, however, be determined by the particular circumstances surrounding the case, including weight, age, the importance of the symptoms and the individual response of the patient and will also depend on the administration path Therefore, it is not desired that the aforementioned administration range limit the scope of the present invention at all.

3-Amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one can be administered in different forms. The present invention relates to an oral extended release formulation. As illustrated in Example 8, the use of an oral extended-release formulation reduces the frequency of nausea and vomiting compared to an immediate-release formulation. Oral prolonged release formulations can be prepared according to any method known in the art for the manufacture of prolonged pharmaceutical compositions.

In one embodiment, the formulations may be tablets that may contain the active ingredient mixed with pharmaceutically acceptable excipients, such as gelling agents as described above, binding agents (e.g., starch, gum arabic, gelatin), lubricants (e.g., acid stearic acid, magnesium stearate, sodium stearyl fumarate (Pruv®), glycerol behenate (Compritol®, talcum), anti-caking agents (for example, colloidal silicon dioxide (Aerosil®)) and inert diluents (for example, calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, mannitol, lactose and ethyl cellulose), colorants, antioxidants, flavoring agents, sweetening agents and preservatives. In more embodiments, the extended-release formulations may also be soft gelatin or hard gelatin capsules in which the active ingredient is mixed with auxiliary materials producing a prolonged release profile or sprayed into a core followed by coating with a material that causes prolonged release Additional auxiliary materials may be an oily medium such as liquid paraffin, peanut oil or olive oil or solid fats or waxes (for example, hydrogenated castor oil or triglycerides) an inert solid diluent such as kaolin, calcium carbonate or phosphate of calcium

Cellulose ethers are well known in the art and are available as hydrophilic and hydrophobic polymers in pharmaceutical grades and with different average molecular weights leading to different viscosities of a solution of these cellulose ethers. For the purposes of this patent application, hydrophilic polymers can be characterized by their viscosities in a 2% w / w aqueous solution as low viscosity (less than about 1,000 mPas), medium viscosity (about 1,000 mPas to about 10,000 mPas) and high viscosity (greater than approximately 10,000 mPas).

Hydrophilic hydroxypropylmethylcellulose polymers (the HPMCs) are available which can be used in the present invention, at different viscosity grades of Dow Chemical Co., under the trademark Methocel® and Shin Etsu under the trademark Metolose®.

Examples of low viscosity polymers are Methocel E5®, Methocel E15LV®, Methocel E50LV®, Methocel K100LV® and Methocel F50LV®, whose 2% aqueous solutions at 25 ° C have viscosities of 5 mPas, 15 mPas, 50 mPas, 100 mPas and 50 mPas, respectively.

Examples of medium viscosity HPMCs are Methocel E4M® and Methocel K4M, whose 2% aqueous solutions at 25 ° C have viscosities of 4,000 mPas.

Examples of high viscosity HPMCs are Methocel K15M® and Methocel K100M®, whose 2% aqueous solutions at 25 ° C have viscosities of 15,000 mPas and 100,000 mPas.

In a preferred embodiment of the formulation according to the present invention, a combination of a low viscosity HPMC and a medium viscosity HPMC is used to prepare extended release tablets. Most preferred is the combination of an HPMC with a viscosity of 5 mPas and an HPMC with a viscosity of 4,000 mPas is used.

After HPMC, loading binder materials can be added to the tablet formulation to improve tablet properties such as strength and friability. Preferably, the binder fillers are chosen that have no effect or that only have a limited effect on drug release. Examples of such materials are ethyl cellulose (EC) or calcium phosphate.

In a first even more preferred embodiment of the present invention a combination of low viscosity HPMC and medium viscosity HPMC is used. The ratio between medium viscosity HPMC and low viscosity HPMC is between 100: 1 and 10: 1, preferably between 20: 1 and 15: 1 and most preferably around 17: 1.

In a second preferred embodiment of the present invention a special starch excipient generally indicated as "long chain amylose" is used. This type of material is described in the international patent WO 96/09815 and is characterized by a long chain amylose content (with a degree of polymerization (GP) of at least 100) between 20 and 80% by weight based on dry substance , a cold water solubility of at most 25% by weight and a specific surface area of at least 1 m2 / g. A more preferred material has a long chain amylose content (w / w) of between 50 and 70% (w / w) based on dry substance. The most preferred long chain amylose to be used in the present invention

10

fifteen

twenty

25

It is characterized by having a specific surface area of at least 6 m2 / g and long chain amylase content of at least 60% by weight based on dry substance. With cold water within the framework of the present invention means a temperature between about 15 and about 25 ° C.

Also in the second preferred embodiment, other auxiliary materials such as binding agents (for example, starch, gum arabic, gelatin), lubricating agents (for example, stearic acid, magnesium stearate, sodium stearyl fumarate (Pruv®), glycerol behenate (Compritol®), talc), anti-caking agents (for example, colloidal silicon dioxide (Aerosil®)) and inert diluents (for example, mannitol and lactose), colorants, antioxidants, flavoring agents, sweetening and preservative agents.

The following examples are only to further illustrate the invention, in more detail, and therefore it is not believed that these examples restrict the scope of the invention at all. Example 1. Synthesis of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one and its monohydrate monohydrate Step 1: Nitration

image 1 OR image 1 OR

image2 Br

HBr

H AcOH OH

OH stage 1 NO2

recrist

(1 *) (stage 1a) (2 *)

)

A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1 *) in 3.75 liters of acetic acid (98%) was formed by heating the mixture to approximately 60 ° C. For approximately 1 hour 1.5 moles of concentrated nitric acid (137 g = 97 ml) were added slowly. After completing the addition, stirring was continued at 65 ° C for an additional 10 minutes. Then the solution was cooled to 45 ° C and the product was precipitated by adding 4 liters of water. After stirring for at least 3 hours, the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 ml of acetone under reflux and with stirring. 400 ml of acetone were removed by distillation. After cooling to 20 ° C, the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65 ° C. The solid was dried overnight in a stream of air at 40 ° C. Finally, the crude product (2 *) was recrystallized from acetone to provide a final product with a purity of 98% as indicated by NMR analysis.

5-Bromo-2-hydroxybenzaldehyde (1 *) was identified by its

5 characteristic chemical shift � 9.84 ppm; 5-Bromo-2-hydroxy-3-nitrobenzaldehyde (2 *) had a characteristic chemical shift � of 10.4 ppm. The total yield of this stage was approximately 60% (crude / crude).

Stage 2: Erlenmeyer condensation

image 1 OR image 1 OR

image 1 OH HN Br image 1 NCH3Br HO

H O

OH Ac2O

OO NO2 NaOAc NO2

(2 *) DMF (3 *) 10 stage 2

To a mixture of 1.0 mol of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2 *), 1.0 mol of N-acetylglycine and 1.0 mol of anhydrous sodium acetate, 800 ml of Nmethyl are added -2-pyrrolidone. The mixture was stirred and heated to 50 ° C. Then 2.2 were introduced

15 moles of acetic anhydride in the reaction vessel for approximately 30 minutes. The reaction mixture was heated to 100 ° C. During heating, the reaction mixture became homogeneous for a while; briefly after a solid formed that hindered the agitation. After heating at 100 ° C for 4 hours, the mixture was cooled to 80 ° C and 1,100 ml of acetic acid (98%) was added.

20 Then stirring the mixture was easy. As a next step, the mixture was cooled to room temperature and stirred for 60 minutes. The precipitate was collected on a filter and washed twice with 625 ml of acetic acid (80%), five times with 900 ml of water and once with 300 ml of acetone. The product was dried in an air stream at 40 ° C for 24 hours and had a purity of 98% as indicated by the

25 NMR analysis. 5-Bromo-2-hydroxy-3-nitrobenzaldehyde (2 *) had a characteristic displacement of � 10.4 ppm; the characteristic chemical shift of N- (6-bromo8-nitro-2-oxo-2H-1-benzopyran-3-yl) acetamide (3 *) was � 8.72 ppm. The total yield of this stage was approximately 80% (crude / crude).

30

Stage 3: Reduction

H H

image3 image 1 N

CH3 Br image 1 NCH3

OR

O o

Pd / C

OO OR EtOH NH2

NO2 K2CO3

(4*)

stage 3

(3*)

A mixture of 1.0 mol of N- (6-bromo-8-nitro-2-oxo-2H-1-benzopyran-3-yl) acetamide (3 *), 50 g of palladium on 10% carbon paste (which contains 61% 5 of water), 1.0 mol of potassium carbonate and 15 liters of ethanol was heated to 60 ° C. At this temperature the starting material was reduced with hydrogen at an overpressure of 4x105 Pa (4 bar) at 147 rad / s (1,400 rpm). After completing the reaction (1 hour), the catalyst was separated by filtration, using an auxiliary medium for filtration and washing with 4.5 liters of methyl ethyl ketone (MEK). The filtrate was concentrated to 2 liters and 2.3 liters of MEK were added. To change the ethanol solvent to MEK, 2 liters of the solvent mixture was removed by distillation at normal pressure and 2 liters of MEK were added. This was repeated 4 times. Then 5 liters of MEK and 2.6 liters of water were added and the mixture was stirred. The layers separated. The top layer was concentrated under normal pressure to approximately 3.5

15 liters The residue was cooled to 25 ° C. During this cooling the product crystallized. The mixture was then cooled to -10 ° C and stirred for two hours. The solid was filtered and washed three times with 800 ml of hexane. The product was dried (50 ° C, 20 cm Hg, N2) to constant weight.

N- (6-Bromo-8-nitro-2-oxo-2H-1-benzopyran-3-yl) acetamide (3 *) had a characteristic chemical shift of � 8.72 ppm; the displacement of N- (8 amino-2-oxo-2H-1-benzo-piran-3-il) acetamide (4) was � 8.55 ppm. The total yield of this stage was approximately 70% (crude / crude).

Stage 4: Piperazine Ring Formation

H

Cl image 1

image 1 Cl

image 1 N

CH3

H image 1 N CH3 N

OR

H

O o

OR

image 1 N image 1

O o

MCB

NH2

stage 4

N

recrist

(4 *) .H (5 *)

(stage 4a)

to)

A mixture of 2.5 liters of monochlorobenzene, 1.0 mol of N- (8-amino-2-oxo2H-1-benzo-pyran-3-yl) acetamide (4 *) and 1.2 moles of bischloroethylamine hydrochloride It was heated to reflux under nitrogen. Part of the monochlorobenzene (0.5 liters) was distilled off. This mixture was heated at reflux for 10 days. The reaction was followed by HPLC. After the reaction, the mixture was cooled to 20 ° C and stirred overnight. The solid product was collected on a filter and washed once with 360 ml of monochlorobenzene and 3 times with 360 ml of ethanol. The product was dried under vacuum at

10 50 ° C. Half of the crude product was dissolved in 3 liters of water. After the addition of 18 g of Celite and 50 g of charcoal, the mixture was stirred for 1 hour at room temperature. After filtration the solution was concentrated by distillation of water. Meanwhile, the second half of the crude product was treated

15 as previously described. When the total volume of the combined aqueous solutions was approximately 1.5 liters, the distillation was stopped and the mixture was cooled to room temperature. Then 125 g of sodium bicarbonate were added portionwise. After stirring for 1.5 hours at 15 ° C, the precipitate formed was collected on a filter. After washing with 360 ml of water and 2 times

With 270 ml of ethanol, the product was dried under vacuum at 50 ° C. N- (8-amino-2-oxo-2H-1-benzo-pyran-3-yl) acetamide (4 *) had a characteristic chemical shift of � 8.55 ppm; the displacement of N- (8- (1piperazinyl) -2-oxo-2H-1-benzopyran-3-yl) acetamide (5 *) was � 8.57 ppm. The total yield of this stage was approximately 50% (crude / crude).

25

image4

image 1

image 1

image5

image5

image 1

image 1

image6

of hexane. The isolated crude product was dried in vacuo (40 ° C, 200 mm Hg, N2, 24 hours).

The dried product (1 mol) was dissolved in 9 liters of methanol by heating at reflux temperature. The solution did not become completely transparent. After cooling to 20 ° C the mixture was filtered. 300 ml of water and 150 ml of methanol were added to the filtrate, after which approximately 3 liters of the solvent mixture was distilled at normal pressure. The entire procedure was repeated with another mole of the dried product. The combined fractions were then concentrated to a volume of approximately 12 liters by distillation. After the addition of 6 liters of ethanol, 6 liters of the solvent mixture was removed by distillation at normal pressure. The mixture was then cooled to 0 ° C and stirred for 2 hours. The precipitate was collected on a filter and washed twice with 750 ml of acetone. The product was dried under vacuum (40 ° C, 200 mm Hg, N2, 24 hours) and then homogenized by crushing and, if necessary, by micronization.

The trichlorohydrate salt of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one (6 *) had a characteristic chemical shift of � 6.77 ppm; The displacement of the final product, 3-amino-8- (1-piperazinyl) -2H-1benzopyran-2-one monohydrate monohydrate, was 6.7 ppm. The total yield of this stage was approximately 85% (crude / crude).

The 3-amino-8- (1-piperazinyl) -2H-1benzopyran-2-one monohydrate monohydrate had a molecular formula C13H18ClN3O3 and a molecular mass of 299.5. The pure product (99.8%, NMR) was a white to yellowish powder. Its chloride content was 11.7% (m / m), as determined by titulometry. Its water content, determined by the water titration test according to Karl Fisher, was 6.5% (m / m). Example 2. Preparation of a prolonged release formulation of 3-amino8- (1-piperazinyl) -2H-1-benzopyran-2-one (based on HPMC).

Tablets with concentrations of 0.50 and 0.75 mg were prepared according to the following procedures (the quantities required are given in Table 1).

Hydroxypropyl methylcellulose (I) was screened and, if necessary, moistened with water and granulated. This granular material dried and broke. The required amounts of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one (as hydrochloride salt monohydrate), hydroxypropylmethylcellulose (II) and ethylcellulose, were screened if necessary and mixed with the screened granules. Colloidal anhydrous silica and glyceryl behenate were screened, if necessary, and mixed with the granular mixture. This final granular material was compressed into tablets of approximately 120 mg. The products, with the composition indicated in Table 2, were packaged and tested. To obtain the material for the double-blind study described in Example 3, the tablets were loaded into capsules: a 0.50 mg tablet in a capsule or a combination of a 0.50 mg tablet and a 0.75 tablet mg in a capsule Table 1. Required amount of active ingredient and auxiliary materials for a batch size of 100,000 extended-release tablets of 0.50 mg or 0.75 mg tablets of 3-amino-8- (1-piperazinyl) -2H-1 -benzopiran-2-one

Tablet concentration in mg1)

0.50 0.75

Components

Per batch of 100,000 tablets (in g)

active ingredient such as HCl salt monohydrate hydroxypropylmethylcellulose (I) 2) hydroxypropylmethylcellulose (II) 3) ethylcellulose 4) colloidal anhydrous silica glyceryl behenate purified water approx.

61.1 524 8,867 2,339 60 150 340 91.7 522 8,838 2,339 60 150 340

10 Table 2. Theoretical formula per tablet

tablet concentration in mg 1)

0.50 0.75

Components

amounts in mg

active ingredient as HCl salt monohydrate hydroxypropylmethylcellulose (I) 2) hydroxypropylmethylcellulose (II) 3) Ethylcellulose 4) colloidal anhydrous silica glyceryl behenate purified water

0.611 5.24 88.67 23.39 0.6 1.5 - 0.917 5.22 88.38 23.39 0.6 1.5 -

1) as a base 2) marked viscosity: 5 mPa s (2% m / v solution in water) 3) marked viscosity: 4,000 mPa s (2% m / v solution in water) 4) marked viscosity: 5.5 mPa s (5% m / v solution in toluene / ethanol)

Example 3. Preparation of a prolonged-release formulation of 3-amino8- (1-piperazinyl) -2H-1-benzopyran-2-one (based on long chain amylose)

3-Amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one (as a hydrochloride salt monohydrate) was mixed with a special long chain amylose, as described in WO 96 / 09815, material characterized by a long chain amylase content of at least 60% by weight based on the dry substance, a cold water solubility of at most 10% by weight and a specific surface area of at least 6 m2 / g and glyceryl tribehenate according to the composition given in table 3. The mixing was performed in a tubular mixer containing all the components for 30 minutes. This mixture was granulated dry and compressed in a press for diaf TM20 tablets in 120 mg tablets, with a diameter of 6.5 mm and a compressive strength above 150 N. The tablets contained 800 micrograms of 3-amino -8- (1-piperazinyl) -2H-1benzopyran-2-one (calculated as base). In another experiment the

The quantitative composition of the tablets according to Table 3. This composition was compressed into 70 mg tablets, with a diameter of 5.0 mm and a compressive strength above 150 N. Again the tablets contained 800 micrograms of 3 -amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one (calculated as base).

20 Table 3: Composition of slow-release tablets based on long chain amylose

Tablet weight in mg

120 70

Tablet diameter in mm

6.5 5.0

Components:

Relative Amount: Relative Amount:

3-amino-8- (1-piperazinyl) -2H-1benzopyran-2-one HCl.H2O

0.81% 1.39%

Amylose (long chain) (as described above)

96.69% 96.11%

Glyceryl Tribehenate

2.5% 2.5%

Example 4. Preparation of an immediate release formulation of 3-amino8- (1-piperazinyl) -2H-1-benzopyran-2-one.

Capsules with concentrations of 0.10 were prepared; 0.20 and 0.50 mg of 25 according to the following procedures (the required amounts are given in Table 4). Approximately 95% of the mannitol was stirred in a mixer. The amount

required of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one (as hydrochloride salt monohydrate) was mixed with the rest of the mannitol and then mixed with the mannitol in the mixer. Glyceryl behenate and sodium starch glycolate were added to the mixture and mixed. This final powder mixture was loaded into capsules, of

5 size no. 2, in an encapsulation machine. The weight of the filling of a capsule is approximately 240 mg, but it can be adjusted depending on the content of 3 amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one in the powder mixture. The product, with the composition indicated in Table 5, was packaged and tested. Table 4. Required amount of active ingredient and auxiliary materials for a

10 lot size of 4,000 capsules of immediate-release capsules of 0.10 mg, 0.20 or 0.50 mg of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one.

Capsule concentration in mg (as base)

0.1 0.2 0.5

Components

Per lot of 4,000 capsules (in g)

active ingredient as HCl salt monohydrate Sodium starch glycolate Glyceryl behenate Mannitol Hard gelatin capsule, opaque blue, size # 2

0.488 38.4 19.2 902 4,000 0.976 38.4 19.2 901.6 4,000 2,444 38.4 19.2 900 4,000

Table 5. Theoretical formula per capsule

Capsule concentration in mg (as base)

0.1 0.2 0.5

Components

amounts in mg

active ingredient such as HCl salt monohydrate Sodium starch glycolate Glyceryl behenate Mannitol

0.122 9.6 4.8 225.5 0.244 9.6 4.8 225.4 0.611 9.6 4.8 225.0

Example 5. In vitro dissolution of extended-release tablets of 3 amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one as prepared in Example 2.

An in vitro dissolution study of 6 tablets with the apparatus was performed

USP II, using an aqueous buffer solution of pH 4.7 as the release medium and

a blade rotation speed of 7.8 rad / s (75 rpm). Table 6 provides the results of this test (also represented in Figure 1). Table 6. Results of in vitro dissolution of prolonged release tablets prepared according to Example 2

tablet concentration in mg1)

0.50 0.75

Time in hours

Release of active substance in% of total

0 1 6 16

0 20 63 102 0 22 67 101

1) as a base

5 Example 6. In vitro dissolution of extended-release tablets of 3 amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one as prepared in Example 3.

An in vitro dissolution study of 6 tablets was performed with the USP II apparatus, using an aqueous buffer solution of pH 4.7 as the release medium and a blade rotation speed of 7.8 rad / s (75 rpm) . Table 7 provides the

10 results of this test (also represented in Figure 2): Table 7. Results of in vitro dissolution of extended-release tablets prepared according to Example 3

tablet concentration in mg1)

0.8 0.8

tablet weight in mg

120 70

tablet diameter in mm

6.5 5.0

Time in hours

Release of active substance in% of total

0 1 6 16

0 10 50 86 0 13 62 90

1) as a base

Example 7. In vitro dissolution of immediate-release tablets of 315 amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one as prepared in Example 4.

An in vitro dissolution study of 6 tablets was performed with the USP II apparatus, using an aqueous buffer solution of pH 4.7 as the release medium and a blade rotation speed of 7.8 rad / s (75 rpm) . Table 8 provides the results of this test.

Table 8. Results of in vitro dissolution of immediate release capsules prepared according to Example 4

Capsule concentration in mg1

0.1 0.2 0.5

Time in minutes

Release of active substance in% of total

15 30 45

99 100 100 96 97 97 97 97 98

1) as a base

Example 8. Frequency of nausea and vomiting after application of an extended-release formulation compared to the application of an immediate-release formulation.

3-Amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one was provided as immediate release (LI) formulations prepared according to Example 4 or as extended release (LP) tablets according to Example 2 in 10 single-dose or multi-dose studies for healthy male volunteers in the age range of 18 to 43 years. From a total of 156 individuals 104 received a

or more single doses and 52 individuals received multiple doses of 3-amino-8- (1piperazinyl) -2H-1-benzopyran-2-one. In multiple dose studies, 3 amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one was administered over a period of 7 days. Be

15 evaluated information on adverse events at regular intervals after single dose and multiple doses using unimportant questions. The frequency of nausea after single-dose, which was one of the most frequently indicated adverse events with an immediate-release formulation, was indicated from single-dose 0.4 mg of 3-amino-8- (1

20 piperazinyl) -2H-1-benzopiran-2-one forward. Vomiting occurred in approximately half of the individuals who indicated nausea. The expected clinical administration interval is between 0.5 and 2.5 mg daily. As a consequence, tolerance problems could prohibit patients being sufficiently dosed with an immediate release formulation to

25 perform any effectiveness. Table 9 and 10 clearly show that the use of the extended-release formulation leads to much less reports of nausea and vomiting. Also, higher dose levels may be provided before these symptoms occur.

30 The percentage of individuals who indicate nausea after single dose of 0.4;

0.6 and 0.8 mg of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one provided as an IF formulation was 8%, 16% and 50%, respectively, while vomiting These figures were 6%, 4% and 17%, respectively. However, after single dose of 0.5 and 1.25 mg as an LP formulation, these figures were 0% and 11%, respectively.

5 for nausea and 0% for vomiting after both dose levels.

A similar situation is seen after multiple doses. The percentage of individuals indicating nausea after multiple doses of 0.4; 0.8 and 1.2 mg of 3 amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one once daily as IF formulation was 17%, 75% and 50% respectively, while not nausea was indicated after

10 of administration of LP formulation of 1.25 mg and 33% after LP tablets of 2.5 mg. No vomiting was observed at these dosage regimens except at the highest level of dose given (LP of 1.25 mg). Table 9. Number of individuals (% in brackets) indicating nausea and vomiting after different levels of 3-amino-8- (1-piperazinyl) -2H-1

15 benzopyran-2-one given as immediate release (FI) formulations and as extended release (LP) formulations.

Dose (mg)

Pla FI 0.4 FI 0.6 FI 0.8 LP 0.5 LP 1.25

Number of individuals

61 36 67 12 4 18

Sickness

3 3 eleven 6 0 2

(5%)

(8%) (16%) (fifty%) (0%) (eleven%)

Vomiting

0 2 3 2 0 0

(0%)

(6%) (4%) (17%)

(0%)

(0%)

Table 10. Number of individuals (% in brackets) indicating nausea and vomiting after different levels of multiple doses of 3-amino-8- (1-piperazinyl) -2H-1benzopyran-2-one given once a day as formulations immediate release (FI) and as extended release formulations (LP).

Dose (mg)

Placebo FI 0.4 FI 0.8 FI 1.2 LP 1.25 LP 2.5

Number of individuals

eleven 6 4 4 8 10

Sickness

0 one 3 2 0 3

(0%) -

(17%) (75%) (fifty%) (0%) (33%)

Vomiting

0 0 0 0 0 one

(0%)

(0%)

(0%)

(0%)

(0%)

(10%)

5 In conclusion, it can be noted that the 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2-one prolonged-release formulation is associated with much less nausea and vomiting than the immediate-release formulation. As a consequence, higher dose levels of 3-amino-8- (1-piperazinyl) -2H-1benzopyran-2-one can be provided with the extended release formulation.

10.

5

10

fifteen

twenty

25

30

-18

Claims (7)

1. An extended release formulation comprising: a) an amount in the range of about 0.1 to maximum about 2.5 mg of 3-amino-8- (1-piperazinyl) -2H-1-benzopyran-2one or a pharmaceutically acceptable salt thereof or a hydrate of said pharmaceutically acceptable salt thereof, b1) a hydroxypropylmethylcellulose or b2) a mixture of two or more hydroxypropylmethylcellulose or b3) a starch excipient comprised between 20 and 80% by weight based in dry substance of long chain amylose, with a polymerization degree of at least 100, a cold water solubility of at most 25% by weight and a specific surface area of at least 1 m2 / g. releasing said prolonged release formulation at most 40% of the active substance in 45 minutes.

2.

An extended release formulation according to claim 1, wherein said mixture of two or more hydroxypropyl methylcelluloses comprises a low viscosity hydroxypropyl methylcellulose and a medium viscosity hydroxypropyl methylcellulose.

3.

An extended release formulation according to claim 1, wherein said starch excipient comprises at least 60% - by weight based on dry substance - of long chain amylose, with a specific surface area of at least 6 m2 / g.

Four.

An extended release formulation according to any one of claims 1-3, wherein said pharmaceutically acceptable salt is a monohydrochloride salt.

5.

An extended release formulation according to claim 4, wherein said hydrate is a monohydrate.

6.

Use of the formulation according to any one of claims 1-5 for the preparation of a medicament for the treatment of CNS disorders or pain.

7.

Use according to claim 6, wherein the CNS disorder is chosen from depression, anxiety and movement disorders.