Quetiapine granulated composition

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to granulated composition containing 11-[4-[2-(2-hydroxyethyl)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine (quetiapine) or its pharmaceutically acceptable salt, preferably quetiapine fumarate, as an active substance and a water-soluble binding agent. Invention relates to a method for preparing this composition and to a method for treatment of patients with nervous system diseases such as psychotic states including schizophrenia. Invention alleviates dosing of drugs by patients in required dose and solves problem concerning maintenance of regimen and schedule of treatment.

EFFECT: improved and valuable properties of composition.

16 cl, 2 ex

 

The present invention relates to a new pharmaceutical composition comprising 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo[b,f][1,4]thiazepine or its pharmaceutically acceptable salt (hereinafter called "agent"), to methods of its preparation and to its use. In particular, the present invention relates to a composition which is easily suspendered or dissolved in aqueous media.

"Agent" can be used to treat diseases of the Central nervous system, such as psychosis. A concrete example of "agent" is of quetiapine (quetiapine) fumarate (sold under the trade name Seroquel®). Of quetiapine fumarate for several years marketed for the treatment of schizophrenia and related illnesses. A significant amount of literature describes how to use of quetiapine fumarate. Specific references to the manufacture and use of "agent" are European patents EP 240 228 and 282 236, U.S. patent No. 4 879 288 and international patent publication WO 97/45124.

Of quetiapine fumarate sold in pill form. Despite the fact that doctors, nurses and others who care for the sick, try to ensure that the patient took the pill (pill), patients with psychosis often there is the problem of nonadherence and treatment. For example, the patient may hide the tablet Z. the cheek, which leads to the skipping of medication. Problems with failure mode and regimens decreased if the "agent" could be entered in the form of a solution or suspension for oral administration. The solution or suspension for oral administration have the added advantage that they are easy to swallow, and, therefore, this route of administration is better for patients who have difficulty swallowing tablets.

In order to avoid problems with corruption "agent", the composition of the present invention is made in the form of granules with low moisture content, which is easily dissolved or suspendered in aqueous media before use. These granules also have good fluidity, which makes it possible homogeneous filling and emptying of bags, so you can enter the exact dose of therapeutic product.

Were made rich compositions "agent" with low moisture content, but they turned out to be inconvenient, as granules or were too hard and, therefore, could hardly dispersibility, or didn't have a good fluidity and compacted when standing or vibration.

In the end, was found granulated composition "agent", which has good fluidity and, however, also unexpectedly easily dissolved or suspendered in aqueous media. T is thus, the present invention relates to a granular composition "agent", which has good fluidity and is easily dissolved or suspendered in aqueous media. For example, it should be comfortable for insertion within the time intervals during which the patient receives the dose. Usually it should be convenient to introduce in less than 15 minutes, preferably within less than 5 minutes and, more preferably, in less than 2 minutes.

In particular, the present invention relates to a granular composition comprising 11-[4-[2-(2-hydroxyethoxy)-ethyl]-1-piperazinil]dibenzo[b,f][1,4]thiazepine or its pharmaceutically acceptable salt and easy or very soluble in water binding agent, in which the granules have a bulk density in the range of 0.15 g/ml to 0.60 g/ml, and the density after utracki in the range of 0.20 g/ml to 0.70 g/ml, and 80% of the granules have a size in the range from 75 to 850 microns.

Preparation, physical properties and favorable pharmacological properties "agent" described in published European patent 240 228 and 282 236, as well as in U.S. patent No. 4 879 288, which is entirely incorporated herein as references.

Preferably, the agent is a 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo[b,f][1,4]diazepin or it is very soluble in water pharmaceutically acceptable the J. Sol. More preferably, the agent is a 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo-[b,f][1,4]thiazepine or its dihydrochloride salt, maleate, citrate or fumarate. The most preferred "agent" is of quetiapine fumarate (Seroquel).

Easy or very soluble in water binding agent is a binding agent, which is soluble in less than 10 parts water to 1 part binding agent, and includes maltodextrin, mannitol, xylitol, pregelatinized starch, sucrose or poly[1-(2-oxo-1-pyrrolidinyl)ethylene] (povidone). Preferably, the binding agent is dissolved in less than 1 part water to 1 part binding agent.

Preferably, very soluble in water binding agent is a maltodextrin.

Preferably, the present invention relates to a granular composition comprising Seroquel® and maltodextrin, in which the granules have a bulk density in the range of 0.15 g/cm3to 0.60 g/cm3and the density after utracki in the range of 0.20 g/cm3to 0.7 g/cm3and 80% of the granules have a size in the range from 75 to 850 microns.

Bulk density is the density of free current powder. Density after utracki is the density of the powder after shaking and tapping several times on the surface. Volumetric mass is determined by the construction of the powder in a volume of 100 ml in a measuring cylinder and measuring the mass of the powder. Density after utracki determined by placing the same cylinder containing 100 ml of powder, which is used to determine bulk density, on a device that picks up and drops a cylinder 200 times (the amplitude of the rise and fall in this standard test is 0.5 inch). Measure the new volume of powder, and as the bulk of the powder is already known, you can calculate its density after utracki.

Preferably, the granules have a bulk density in the range from 0,261 g/ml to 0.400 g/ml; in particular, from 0,261 g/ml to 0,368 g/ml.

Preferably, the granules have a density after utracki within 0,342 g/ml of 0.500 g/ml; in particular, from 0,342 g/ml to 0,464 g/ml.

Granules with the desired bulk density density after utracki and outside dimensions can be produced by a method using a fluidized bed. The way fluidized bed consists of giving fluidity to the components of the composition on the layer of air, adding water, and then drying. The components of the composition, alternatively, can be added in the form of a solution or suspension in water.

Accordingly, in another aspect, the present invention relates to a method for preparing a composition as defined above, which includes:

i) giving a yield of one or more components on a layer of air in the fluidized bed;

ii) adding to pseudois nomu layer of water, optionally containing one or more components;

iii) drying.

Preferably, the "agent" and easy or very soluble in water binding agent and any other components impart fluidity to the layer of air.

The way fluidized bed is well known in the art, see, for example, Schaefer T., Worts O., Control of Fluidized Bed Granulation I. Effect of spray angle, nozzle height and starting materials on granule size and size distribution. Arch. Pharm. Chemi Sci. Ed. 5, 1977.51-60; Schaefer T., Worts O., Control of Fluidized Bed Granulation II. Estimation of Droplet Size of the Atomized Binder Solutions, Arch. Pharm. Chemi Sci. Ed. 5,1977, 178-193; Schaefer T., Worts O., Control of Fluidized Bed Granulation III. Effects of Inlet Air Temperature and Liquid Row Rate on Granule Size and Size Distribution. Control of Moisture Content on Granules in the Drying Phase, Arch. Pharm. Chemi Sci. Ed. 6, 1978.1-13; T. Schaefer, Worts O., Control of Fluidized Bed Granulation IV. Effects of Binder Solution and Atomization on Granule size and size distribution. Arch. Pharm. Chemi Sci. Ed. 6, 1978,14-25: Schaefer T., Worts O., Control of Fluidized Bed Granulation V. Factors Affecting Granule Growth, Arch. Pharm. Chemi Sci. Ed. 6, 1978,69-82; Kawai, S., Granulation and Drying of Powdery or Liquid Materials by Fluidized Bed Technology, Drying technology, 11(4). 1993,719-731; and Kokubo h, Sunada H., Effect of Process Variable on the Properties and Distribution of Binder Granules Prepared in a Fluidized Bed, Chem. Pharm. Bull. 45(6), 1997, 1069-1072.

The size and density of the granules can be influenced by changing conditions, such as temperature, air pressure in the atomization air volume during the process and the spray rate of added water used during the process fluidized bed. A key parameter affecting the properties of g is zero, is the level of moisture in the granules; this level of moisture depends on the moisture level in the fluidized bed. Granules with desired properties can be obtained by changing the moisture level in the fluidized bed using standard methods known in the art, until you get granules of the desired size and density. For example, for a party of 15 kg the level of moisture in the granules is usually from 4 to 10%. The usual conditions for party 15 kg are: temperature of the incoming air 55-70°C, the air pressure in the atomization of from 0.5 to 3.5 bar, the volume of air during the process from 150 to 225 ft3/min and the spray rate of added water from 100 to 150 ml/min Granules with desired physical properties can be obtained also when using other conditions. For example, in the case of larger party (225 kg) of pellets of the present invention was obtained using the temperature of the incoming air 55-80°C, pressure of air atomization from 1.0 to 3.0 bar, air volume during the process from 1600 to 2200 ft3rpm and speed spraying of added water from 600 to 900 ml/min

In a preferred aspect, the present invention relates to a method fluidized bed, in which the moisture content is controlled to obtain granules with a moisture level in the range from 1.5 to 15%.

In another aspect, the present invention con is seeking to granules with a moisture level in the range from 1.5 to 15%, preferably, from 3 to 10%, more preferably from 4 to 8%.

Preferably, the moisture level in the fluidized bed gives granules having a moisture level ranging from 3 to 10%. More preferably, the moisture level in the fluidized bed gives granules having a moisture level ranging from 4%to 8%.

In a preferred aspect, the present invention relates to a method fluidized bed in which the air pressure when atomization is in the range from 0.5 to 3.5 bar, for example, from 1.0 to 3.0 bar.

In another aspect, the present invention relates to granular compositions, including "agent" and easy or very soluble in water binding agent, which is obtained by the method fluidized bed, in which the level of moisture in the pellets before drying is in the range from 1.5 to 15%.

In a preferred aspect, the present invention relates to granular compositions, including "agent" and easy or very soluble in water binding agent, which is obtained by the method fluidized bed in which the air pressure when atomization is in the range from 0.5 to 3.5 bar, for example, from 1.0 to 3.0 bar.

In another aspect, the present invention relates to granular compositions, including "agent" and easy or very soluble in water binding agent, in which g is annuli have a bulk density in the range of 0.15 g/ml to 0.60 g/ml, and the density after utracki in the range of 0.20 g/ml to 0.70 g/ml, and 80% of the granules have a size in the range from 75 to 850 microns; you get way fluidized bed.

Preferably, the present invention relates to a granular composition comprising Seroquel® and maltodextrin, in which the granules have a bulk density in the range of 0.15 g/ml to 0.60 g/ml, and the density after utracki in the range of 0.20 g/ml to 0.70 g/ml, and 80% of the granules have a size in the range from 75 to 850 microns; you get way fluidized bed.

Preferably, the composition comprises a sweetener or sweeteners to improve the taste. Suitable sweeteners include aspartame, MagnaSweet®, sucrose, saccharin, cyclamate sodium and Acesulfame potassium. Preferred sweeteners are aspartame and MagnaSweet®.

Other fillers such as suspendresume agents that are compatible with the "agent", can be added to the composition to increase the period of time during which the composition remains as a suspension in aqueous media. Examples suspendida agents include glycolate, sodium starch, starch, guar gum and povidone. However, it was found that the composition dissolves or is very well suspended without the use of suspendida agents or thickeners, and it is another feature of this image is the shadow. For example, 25 mg of granulated compositions described in the examples below, unexpectedly form a solution in 30 ml of water for approximately 15-20 seconds. 150 mg of granulated compositions described in the examples below, form a suspension in 30 ml of water for approximately 10 seconds with mild stirring and remain in suspension for about 10 minutes. It is easy to resuspendable for a few seconds with mild stirring in a circular motion capacity.

Unexpectedly, it was found that, as a rule, are not only not required suspendisse agent, but also that ordinary suspendisse agent, xanthan gum, is not suitable as a suspending agent in the compositions of the present invention.

Preferably, the composition does not include suspendisse agent.

Likewise, the composition can be added surfactants that are compatible with the "agent", such as Polysorbate, monooleate glycerol and esters sorbitan, but it was found that the composition works well, without the need for specified substances.

Preferably, the composition does not include a surfactant.

Preferably, the present invention relates to a granular composition consisting of 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo[b,f][1,4]thiazepine or its pharmaceutically when mlemos salt, easy or very soluble in water binding agent and sweetener, in which the granules have a bulk density in the range of 0.15 g/ml to 0.60 g/ml, and the density after utracki in the range of 0.20 g/ml to 0.70 g/ml, and 80% of the granules have a size in the range from 75 to 850 μm. In a preferred embodiment, 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo-[b,f][1,4]diazepin is in salt form fumarata.

Granules of the present invention is easily dissolved or suspendered in aqueous media. Water environment does not necessarily represent the water; it includes substances with sufficient water content, such as fruit/vegetable juices, sauces or purees, such as desserts.

Preferably, the pH of the resulting solution and/or suspension is from 4 to 9. More preferably, the pH of the resulting solution and/or suspension is from 5 to 6.

In another aspect, the present invention relates to a granular composition as defined above, dissolved or suspended in aqueous media.

The dose of a compound of the present invention, which is administered will necessarily vary in accordance with principles well known in the art, taking into account the route of administration, duration of treatment, severity of psychotic condition, weight and age of the patient, the effectiveness of the act the main component and the response of the patient. Effective dose of the active component, thus, can easily determine the attending physician, taking into account all criteria and their concerns relating to the welfare of the patient. Usually the connection will enter a warm-blooded animal (such as man) in such a way that the patient received an effective dose, usually, the daily dose is in the range from about 0.01 to about 40 mg/kg of body weight. For example, when administered orally it is usually administered in a range of about from about 0.1 to about 40 mg/kg of body weight.

Preferably, the compound of the present invention is administered during the maintenance of the drug is approximately 25, 50, 100, 125 or 150 mg

The specialist will be understood that the composition can be entered in conjunction with other therapeutic or prophylactic agents and/or drugs that are compatible with them. The compound of the present invention usually does not show obvious signs of toxicity when tested on laboratory animals using several series of the minimum effective dose of the active ingredient.

According to another aspect, the present invention relates to a granular composition as described above, for use as pharmaceuticals.

According to another aspect, the present invention relates to a method of treating psychosis, especially sizofrenik is, by introducing an effective amount of a granular composition, as described above, the mammal that needs specific treatment.

The present invention is used is illustrated by the following non-limiting examples, in which temperature values are in degrees Celsius. "Agent" can be obtained as described in European patents EP 240 228 or 282 236, as well as in U.S. patent No. 4 879 288.

Examples

Example 1

Prepared two compositions with different content of active agent. The first contained 25 mg of free base of quetiapine (composition 25 mg), and the second to 150 mg free base of quetiapine (composition 150 mg).

The compositions shown below:

Ingredient25 mg (mg/dose)150 mg (mg/dose)
Of quetiapine fumarate28,8172,7
Maltodextrin, NF950,0767,3
Aspartame NFof 21.230,0
MagnaSweet 135® 30, 0
Purified water, USPq.s. (≈ of 186.0)q.s. (≈ of 186.0)

Of quetiapine fumarate equivalent to 86.8% of the free base of quetiapine. Purified water was sprayed in sufficient quantity and appropriate ways is om, to obtain pellets with a water content of 5.6%.

Maltodextrin can be purchased as Maltrin M-100, for example, a company Grain Processing Corporation. MagnaSweet 135® can be purchased from the company MAFCO Worldwide Corporation.

The composition produced by the method fluidized bed. Used the installation of fluidized bed Glatt GPCG-60 when loading 15 kg and 50 kg Installation fluidized bed Glatt GPCG-300 is used when loading 225kg Installation of fluidized bed was designed for fluidized bed granulation using a spray top and described below:

DeviceGlatt GPCG-60Glatt GPCG-300
Water pumpPeristalticPeristaltic
The dew point of the incoming10°10°
air  
Inlet1.2 mm1.5 m
The number of inputs in the nozzle head36
The height of the nozzle#4#4
Bottom sieve100 mesh100 mesh
Mode shakingGPCGGPCG
The interval is l shaking 30 sec60 sec
The duration of shaking3 sec5 sec

Used the following process conditions:

Glatt GPCG-60

The process parameters
SeriesThe content agentThe pace. on entry

(°)
Air volume (ft3/min)The air pressure in the atomization (bar)Pump speed (g/min) spray rate of added water
And25 mg658502,0360
In150 mg658502,0360
150 mg658501,7360
D150 mg65850-7501,5360

Glatt GPCG-300

The process parameters
SeriesContent

agent
The pace. input (°)Air volume (ft3/min)Air pressure

when atomization (bar)
Speed n is Sosa (g/min) spray rate of added water
And25 mg≈ 7018502,0800
In25 mg≈ 7018502,0800
150 mg≈ 7018001,5800
D150 mg≈ 7018001,5800

All the ingredients are loaded into the hopper of a fluidized bed granulator. Then the material was given fluidity. After approximately 2-3 minutes sprayed water (186 ml per 1 g of the components in the camera extension. The total time for each series was less than one hour.

The results from GPCG-60 (load 50 kg)

Data after SITA1- % delay (µm)Density (g/ml)Humidity2,

%
Series85042525018015075Palletin massAfter utrackiEOS3End4
and0,44,819,821,8/td> 11,131,610,50,290,399,3of 5.4
b0,322,013,720,011,738,913,20,360,357,9the 3.8
0,23,318,2of 21.910,833,112,50,340,417,44,3
d1,612,228,920,07,719,110,50,310,426,75,9

The results from GPCG-300 (load 225 kg)

Data after SITA1- % delay (µm)Density (g/ml)Humidity2,

%
Series85042525018015075palletin massafter utrackiEOS3end4
and2,813,1the 33.42,8 the 10.113,0the 3.80,260,356,26,0
b1,712,232,9to 25.39,915,72,30,260,287,56,7
2,517,633,619,59,511,36,00,360,426,75,3
d5,823,932,717,28,38,04,10,290,377/46,6
1Data were obtained when using 100 grams of sample, the last shake for 5 minutes on the sieve apparatus Tyier.

2Moisture was determined using the installation Computrac Moisture Balance set 105°C.

3Finish spray (End of Spray).

4The level of moisture in the granules after drying.

Example 2

The compositions of example 1, above, filled the bags in the usual way.

1. Granulated composition for the manufacture of a medicinal product for the treatment of diseases of the Central nervous system, such as psychosis is, in particular schizophrenia, including 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo[b,f][1,4]thiazepine or its pharmaceutically acceptable salt and easy or very soluble in water binding agent, in which the granules have a bulk density in the range of 0.15 g/cm3to 0.60 g/cm3and the density after utracki in the range from 0.20 to 0.70 g/cm3and 80% of the granules have a size in the range from 75 to 850 microns.

2. The composition according to claim 1, in which 11-[4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinil]dibenzo[b,f][1,4]diazepin is in the form of fumarata.

3. Composition according to any one of claim 1 or 2, in which it is easy or very soluble in water binding agent includes maltodextrin, mannitol, xylitol, pregelatinized starch, sucrose or poly[1-(2-oxo-1-pyrrolidinyl)ethylene].

4. The composition according to claim 3, in which the binding agent is a maltodextrin.

5. Composition according to any one of claims 1 to 4, in which the bulk density is in the range from 0.26 to 0.400 g/cm3and the density after utracki within 0,342 to 0.500 g/cm3.

6. Composition according to any one of claims 1 to 5, which further includes a sweetener.

7. A granular composition consisting of 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo[b,f][1,4]thiazepine and its pharmaceutically acceptable salts, easy or very soluble in water linking tasks, sweetener, in which the granules have a bulk density in the range from 0.15 to 0.60 g/cm3the density after utracki in the range from 0.20 to 0.70 g/cm3and 80% of the granules have a size in the range from 75 to 850 microns.

8. The composition according to claim 7, in which 11-[4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinil]dibenzo[b,f][1,4]diazepin is in the form of fumarata.

9. Composition according to any one of claims 1 to 8, in which the moisture content of the granules is from 1.5 to 15%.

10. The composition according to claim 9, in which the moisture content of the granules is from 4 to 8%.

11. The composition according to claim 1 for use in a method of therapeutic treatment of a patient who needs it.

12. The method of preparation of the composition according to claim 1, which includes:

i) giving a yield of one or more components on a layer of air in the fluidized bed,

ii) adding to the fluid layer of water, optionally containing one or more components

iii) drying.

13. The method according to item 12, which is 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinil]dibenzo[b,f][1,4]thiazepine or its pharmaceutically acceptable salts and easily or very soluble in water binding agent to impart fluidity to the layer of air.

14. A method of treatment of diseases of the Central nervous system, such as psychoses, in particular schizophrenia, which includes the introduction of an effective amount of the composition is about to claim 1 to a patient who need it.

15. The set includes:

i) granular composition according to any one of claims 1 to 10,

ii) the water environment,

iii) optionally, instructions for use, so that the granules can be dissolved or suspended in a specified aqueous medium for injection.

16. Sachet containing granular composition according to any one of claims 1 to 10.



 

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SUBSTANCE: invention relates to treatment of patients with post-infarct cardiosclerosis with circulation insufficiency of functional class 2. Method involves using diltiazem with individual setting doses. Method involves carrying out the simplified 2 h oral tolerance test to glucose. Diltiazem is prescribed in the initial dose 90 mg and in the maintenance dose 45 mg in positive result of test. In negative result of test diltiazem is prescribed in the initial dose 180 mg and in the maintenance dose 90 mg. Method provides enhancing effectiveness in treatment of patients with post-infarct cardiosclerosis with circulation insufficiency due to the more precise individual setting dose of the preparation and reducing frequency in arising adverse effects.

EFFECT: improved method for setting, enhanced effectiveness of treatment.

2 tbl, 2 ex

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