Sustained-release composition comprising venlafaxin hydrochloride as active substance

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to sustained-release medicinal formulation composition comprising venlafaxin hydrochloride as an active component. In this formulation venlafaxin hydrochloride in common with a binding agent is applied on inert core as lozenge form (nonpareil) followed applying with a cover-insulating polymeric layer for providing stability and additional cover with external polymeric layer providing the sustained-release of venlafaxin hydrochloride.

EFFECT: improved and valuable properties of composition.

18 cl, 1 tbl, 4 ex

 

The present invention relates to compositions comprising as active compound venlafaxine hydrochloride.

Venlafaxine hydrochloride is an antidepressant of the formula 1

having the chemical name (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride or (±) -1-[and](dimethylamino) methyl] para-methoxybenzyl-cyclohexanol hydrochloride empirical formula C17H27NO2hydrochloride and molecular weight 313,87.

Venlafaxine hydrochloride is a white or almost white crystalline substance with a solubility of 572 mg/ml (adjustment of ionic strength 0.2 M solution is sodium chloride).

Its distribution coefficient octanol: water is 0.43 (0.2 M solution using sodium chloride). The product with the trade name of Effexor XR release in the form of a capsule extended release for oral use 1 time per day.

The release of the medication until the present time was regulated by diffusion through the membrane covering the spherical particles, which does not depend on pH. Known capsules contain venlafaxine hydrochloride, currently used in doses equivalent to 37.5 mg, 75 mg or 150 mg of venlafaxine. Inactive ingredients in them are what I mainly cellulose, ethylcellulose, gelatin, hypromellose, iron oxide and titanium dioxide.

Pharmaceutical dosage forms with controlled or slow release of these medicines traditionally receive in the form of tablets based on the matrix obtained by hydrogel technology. In accordance with this technology the dosage form with controlled release is obtained directly by mixing the active ingredient at a corresponding rate of flow of the polymer and then the mixture is pressed into tablets with the desired controlled release of her active component. Polymers regulating the speed of vysvobozhdeny, usually referred to as hydrogels. As examples of such polymers can serve ethers of cellulose, such as ethylcellulose or hydroxypropylcellulose. Famous patented methods for such dosage forms are described, for example, in the description of the patent US 4,966,768 or 4,389,393.

In some cases, for example, with very high solubility of active substances and their relatively high doses of this technology unsuitable to obtain tablets that can ensure the proper regulation of the release of medicinal substances. This applies, for example, to venlafaxine hydrochlo the go.

In this situation, a suitable method involves encapsulating drugs and getting the dosage forms as capsules slow release of active substances. The preferred method for such dosage forms as believe, is that the active ingredient is mixed with at least one binder to form a homogeneous mixture, which is then moistened with water or an appropriate organic solvent to form a plastic mass which can be sprecavati, then ekstragiruyut drug / matrix in the form of cylinders of small size (1 mm in diameter), which are then cut into segments of appropriate length and give them a spherical shape with the use of equipment for spiritali. The obtained spherical particles are dried and then coated with a suitable polymer with the formation of a film with the desired release profile. The most widely used filler in the process of extrusion is microcrystalline cellulose of different varieties. Usually in the process of wetting water use.

As polymers, are widely used to produce coatings may serve ethylcellulose or Eudragit (amniotically copolymer, type a or b). Water-soluble ingredients are usually mixed with E. what intellisol or other hydrophobic polymers, such as the pore to help control the drug release through the hydrophobic coating layer. Water-soluble ingredients, such as hydroxypropylcellulose or polyethylene glycol can also serve as plasticizers.

Venlafaxine hydrochloride on the date received in the pharmaceutical dosage form with controlled release, which can provide in a single dose of a therapeutic level of the medication in the serum within twenty-four hours. With this method the technique to ensure stricter control of therapeutic level in the plasma and thus avoid repeated daily administration of the drug. In addition, this method allows to avoid the sharp peaks and troughs of the curve in the levels of drug in plasma.

When venlafaxine hydrochloride in traditional medicinal dosage forms with immediate-release (tablet) peak levels in plasma appeared after 2-4 hours after his admission as opposed to the form prolonged release when the levels of venlafaxine hydrochloride in plasma was initially increased after his admission in the range from 5 to 8 hours (average is 6 hours), and then began to fall through the sprawling, no essence, a linear decrease from the peak level of the drug is in the plasma during the remaining time twenty-four hour period, thereby maintaining a therapeutic level of medication during the entire 24-hour period.

In the international application WO 99/22724 (ANR, Sherman) provides a detailed description of the encapsulated drug dosage form of venlafaxine hydrochloride (spherical particles, coated). In accordance with the method described in this application, the core of the spherical particles produced by the method of extrusion-spheronization mixture consisting of specified drugs with microcrystalline cellulose, which is then covered with a mixture consisting of ethyl cellulose and hydroxypropylcellulose.

This dosage form provides a slow release product, which has the following indicators of dissolution in vitro:

Time (hours)Average % release venlafaxine HCL
2<30
430-55
855-80
1265-90
24>80

These characteristics of dissolution is a value independent of pH and RPM.

In the course of developing the present invention was developed alternative structure for the reception of 1 times a day, the biosimilar Effexor XR described in international application WO 99/22724).

As mentioned earlier, the beam receive product with a very high solubility in water and high doses of it in drug form, such as venlafaxine hydrochloride (150 mg), standard preferred method of encapsulation is carried out by obtaining a granulate in the form of "spherical particles" cover their shell, using the method of extrusion-spheronization.

In the present invention proposes a modified method microencapsulation, i.e. microincision carried out by applying a layer of medicine on an inert core in the form of pills (nonpareil), and covered so the core is then coated with the appropriate polymer mixture.

Thus, in the present invention claimed prolonged release composition comprising as active compound venlafaxine hydrochloride, characterized by the fact that venlafaxine hydrochloride is applied to the inert core in the form of pills, and then covered so the core is covered by a polymeric layer, which allows you to provide controlled release of venlafaxine hydrochloride.

The composition in accordance with the present invention preferably contains 30 to 60% of venlafaxine hydrochloride based on the total weight of the dosage form.

In a preferred embodiment of the present invention venlafaxine hydrochloride is associated with the binder, which may be, for example, polyvinylpyrrolidone (the ovidon), hydroxypropylcellulose, hypromellose, and the like. The composition according to the present invention preferably contains from 0.5% to 10% binder based on the total weight of the dosage form.

As the inert core in the form of pills is preferred core obtained from an inert material, such as sucrose, microcrystalline cellulose, etc. Composition contains 30-60% inert cores based on the total weight of the dosage form.

In an alternative embodiment of the invention the specified medication can be sprayed directly on such a nucleus with the subsequent use of water as an agent that increases the cohesive ability.

Preferably, coated with medicine, the core was covered with the insulating / protective / separating layer, and to obtain such a layer can be used polymers, such as polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, carrageenan, glycerylmonostearate (GMS), etc. the Composition according to the present invention preferably contains from 0.5% to 10% of the insulation layer based on the total weight of the dosage form.

The core or the insulating layer is then coated with an additional polymer layer, which allows to provide control Studio strobe, flash is radiated release from the dosage form of venlafaxine hydrochloride. This additional polymer layer, for example, consists of a hydrophobic polymer, mixed with an appropriate hydrophobic or hydrophilic plasticizer. The specified polymer layer can be sprayed on layer-covered core in the form of pills or an insulating layer.

Suitable polymers for receiving the coating can be, for example, Eudragit, derivatives of cellulose, such as hypromellose, ethylcellulose, cellulose acetate, and the like. As suitable plasticizers can be, for example, castor oil, dibutylsebacate, glycerylmonostearate, diethylphthalate, glyceryltrinitrate, triethylcitrate and so on.

As the covering polymer layer can also be used based coating of wax.

The composition according to the present invention preferably contains from 2 to 15% of a hydrophobic polymer based on the total weight of the dosage form, and preferably from 0.1 to weight 2% hydrophobic plasticizer based on the total weight of the dosage form.

The above methods are traditional technological methods in the production of dosage forms that can be implemented in an apparatus for coating in the fluidized bed with the use of spray from the bottom pushing.

In the oppozitsii according to the present invention preferably is released from the dosage form is not more than 40% of the drugs two hours, no more than 60% is released after four hours and not more than 80% is released after 8 hours.

The obtained compositions can, for example, to fill hard gelatin capsules or compressed into tablets.

This recipe drug medication is identical in vitro dissolution profiles as Effexor XR (see Sherman, WO 99/22724). The proposed composition is not sensitive to any changes in the terms of dissolution. They are bio-equivalent to 150 mg capsules with Effexor XR.

The method of coating used to obtain the compositions according to the present invention, more effective than the method disclosed in the patent Sherman. In addition, it allows you to get this drug on only one type of hardware, for example on the installation for coating in the fluidized bed.

The present invention is illustrated by the following examples which should not, however, limit its scope.

The method of obtaining the composition according to the present invention, respectively, is as follows (all temperatures are given in degrees Celsius):

A. When venlafaxine hydrochloride is associated with the binder, the binding of venlafaxine hydrochloride with the binder is well-known in this field methods.

b. Stud is I 1

Floor venlafaxine hydrochloride kernel in the form of pills (mostly linked with the binder) is carried out at a temperature at the entrance to the interval from 45° to 55° preferably at a temperature of 50°) and the outlet temperature of 35° to 45° preferably at a temperature of 40°).

At the end of the spraying composition is dried for 10 minutes without nozzle with flow of air 30 Kubratovo/min

C. stage 2

Coated core obtained in Stage 1, the cover insulating layer at a temperature at the inlet 60±3°and the outlet temperature 50±2°C.

d. Stage 3 (in the case of the insulating layer in Stage 2).

The core cover additional auxiliary layer, but such coverage is obtained when the following conditions are met:

Inlet temperature: - 50≤±2°C;

Outlet temperature: - 40≤±5°C.

Example 1 (without the use of binders)

Stage 1: components of the kernel in the form of pills - 25/30 - 150,

Venlafaxine hydrochloride 37.5 g; H2O - 150,

Stage 2: components - 150 g covered venlafaxine granulate from Stage 1

Atiel - 45 centipoise (Wed) - 15 year

Metozel - 5 centipoise (CP) - 1,

Ethanol BP - 300,

At the end of the spraying composition is dried for 10 minutes without nozzle with flow of air 30 Kubratovo/ min

Por what measures 2

Stage 1: components of the kernel in the form of pellets (granules of inert sugar - 150 g).

Povidone K-30 - 3,3,

Venlafaxine hydrochloride - 165,

Ethanol BP - 670,

Stage 2: components - 150 g covered venlafaxine granulate from Stage 1

Atiel - 45 centipoise (Wed) - 15 year

Metozel - 5 centipoise (CP) - 1,

Ethanol BP - 300,

The coating process is carried out in an apparatus for coating in the fluidized bed modification 4 manufactured by Coating Place Inc., USA.

Example 3:

Stage 1: components of the kernel in the form of pills - 25/30 - 150,

Venlafaxine hydrochloride, 37,5,

Povidone K-30 - 0,75,

Stage 2: components - 150 g covered venlafaxine granulate from Stage 1

Eudragit RS 30 D - 150,

Triethylcitrate - 9,

Glycerylmonostearate 2,25,

Polysorbate - 80-1,

Water - 150g

The coating process is carried out in an apparatus for coating in the fluidized bed modification 4 manufactured by Coating Place Inc., USA.

Example 4:

Stage 1: components of the kernel in the form of pills - 25/30 - 150,

Povidone K-30 - 0,75,

Venlafaxine hydrochloride, 37,5,

Ethanol BP - 160,

Stage 2: components - 150 g of granulate from Stage 1

Eudragit RS 30 D - 150,

Eudragit RL 30 D - 15,

Triethylcitrate - 9,

Glycerylmonostearate 2,25,

Polysorbate - 80-1,

Water - 140,

All processes perform the installation for applying pokrytiyu fluidized bed modification 4. manufactured by Coating Place Inc., USA.

Example 5:

Stage 1: components - 150 g of the cores in the form of pills 25/30

Povidone K - 90 - 4,5,

Venlafaxine hydrochloride - 150,

Ethanol BP - 670,

Water - 110,

Stage 2: components - 150 g of granulate from Stage 1

Povidone K-30 - 3,75,

Ethanol absolute - 160,

Stage 3: the components of the Granules of stage 2

Atiel - 100 centipoise (Wed) - 8,

Dibutylsebacate - 1,

Ethanol absolute - 300g

1. The prolonged release composition comprising as active compound venlafaxine hydrochloride, properly bound with a binder, with venlafaxine hydrochloride together with a binder initially deposited on an inert core in the form of pills (nonpareil), followed by coating an insulating polymer layer, which is optionally covered with the outer polymer layer, which provides controlled release of venlafaxine hydrochloride.

2. The composition according to claim 1, characterized in that the binder is chosen from the group consisting of polyvinylpyrrolidone (povidone), hydroxypropylcellulose and hydroxypropylmethylcellulose.

3. The composition according to claim 1, characterized in that it contains from 0.5 to 10% binder based on the total weight of the dosage form.

4. Composition according to any one of claims 1 to 3, characterized in that as the inert core in the form of tablets IP is result the core of inert material such as sucrose, microcrystalline cellulose, or the like.

5. Composition according to any one of claims 1 to 3, characterized in that it contains 30-60% of a core of inert material based on the total weight of the dosage form.

6. The composition according to claim 1, characterized in that the insulating layer is 0.5-10 wt.% insulating based on the total weight of the dosage form.

7. The composition according to claim 6, characterized in that an insulating layer made of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, carrageenan, glycerylmonostearate.

8. The composition according to claim 1, characterized in that it contains 30-60% of venlafaxine hydrochloride based on the total weight of the dosage form.

9. The composition according to claim 8, characterized in that the binder is chosen from the group consisting of polyvinylpyrrolidone (povidone), hydroxypropylcellulose and hydroxypropylmethylcellulose.

10. The composition according to claim 9, characterized in that it contains 0.5 to 10% binder based on the total weight of the dosage form.

11. Composition according to any one of p-10, characterized in that as the inert core in the form of pills use a core of inert material, such as sucrose, microcrystalline cellulose, or the like.

12. The composition is according to any one of p-10, characterized in that it contains 30-60% of a core of inert material based on the total weight of the dosage form.

13. The composition according to claim 8, characterized in that the insulating layer is 0.5-10 wt.% based on the total weight of the dosage form.

14. The composition according to item 13, wherein the insulating layer is made of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, carrageenan, glycerylmonostearate.

15. The composition according to claim 1 or 8, characterized in that the composition covers the additional polymer layer.

16. The composition according to item 15, characterized in that the said additional polymer layer comprises a hydrophobic polymer, mixed with an appropriate hydrophobic or hydrophilic plasticizer.

17. The composition according to item 16, characterized in that the polymers used for coating selected from Eudragit, cellulose derivatives, such as hypromellose, ethylcellulose, cellulose acetate, and a plasticizer selected from castor oil, dibutylsebacate, glycerylmonostearate, diethylphthalate, glyceryltrinitrate, triethylcitrate.

18. The composition according to item 16 or 17, characterized in that it contains 2-15% of a hydrophobic polymer based on the total weight of the dosage form is and 0.1-2 wt.% hydrophobic plasticizer based on the total weight of the dosage form.



 

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6 cl, 6 ex

FIELD: medicine, gastroenterology, surgery, endoscopy.

SUBSTANCE: method involves injection of adrenaline hydrochloride 0.01% solution that is administrated in the amount 10 ml and injection is carried out from 4-6 points in the dose 1.6-2.5 ml per a point, and dalargin in the dose 1 mg diluted in 2 ml of physiological solution, and the preparation is injected from 4 points in the dose 0.5 ml per a point. These medicinal agents are administrated into submucosa periulcerogenic zone wherein the preparation "TakhoKomb" is used for application that is pressed to the bottom of ulcer defect for 2 min, not less. Invention promotes to diminish the amount of bleeding relapses in early post-hemorrhagic period due to the combined effect of "TakhoKomb", adrenaline and dalargin. Invention can be used in carrying out the endoscopic hemostasis in bleeding-complicated chronic gastroduodenal ulcers.

EFFECT: improved method for hemostasis.

2 ex

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