Pharmaceutical composition containing lamotrigine

 

(57) Abstract:

The inventive pharmaceutical composition contains, wt%: 0.5 to 50 levels of lamotrigine, or its pharmaceutically acceptable acid additive salt, 15-50 lactose, 15-50 starch, 0.5 to 15 crystalline cellulose and 5-15 polyvinylpyrrolidone. The composition is in the form of freely-current powder in the form of granules. The granules have a particle size of not more than 850 μm. At least 90 wt.% the granules have a particle size 75-850 μm. Method of preparation of specified pharmaceutical composition is that lamotrigine, lactose, corn starch and crystalline cellulose is subjected to spray granulation in the presence of polyvinylpyrrolidone as a binder. The pellets disintegrate within 30 minutes At least 90 wt.% levels of lamotrigine in the pellet is dissolved within 30 minutes New members with lamotrigina is stable under conditions of high temperature and high humidity. 2 S. and 6 C.p. f-crystals, 8 PL.

The invention relates to pharmaceutical drug levels of lamotrigine and its pharmaceutically acceptable salts formed by the addition of acid. This invention also relates to the preparation of such a drug.

La is remaneat for the treatment of epilepsy. Powder drugs levels of lamotrigine or any of its salts are not currently available.

Pharmaceutical preparations in powder form can be prepared by way zhidkostnogo granulation or spray granulation. However, such methods are complex interaction of technological parameters.

To date, we have prepared several powder drugs levels of lamotrigine. However, only one type of drug was found to be completely satisfactory. Accordingly, the present invention features a pharmaceutical preparation, which includes:

(a) from 0.5 to 50 wt.% levels of lamotrigine, or its pharmaceutically acceptable salts formed by addition of acid,

(b) from 15 to 50 wt.% lactose,

(C) from 15 to 50 wt.% starch,

(d) from 0.5 to 15 wt.% crystalline cellulose, and

(d) from 5 to 15 wt.% polyvinylpyrrolidone

and that is in the form of freely-current powder of granules having the following properties:

(1) the granules have a particle size of not more than 850 μm,

(2) at least 90 wt.% the granules have a particle size from 75 to 850 μm,

(3) the granules disintegrate within 30 minutes according to the Disintegration Test of the Pharmacopoeia of Japan, igina or salt levels of lamotrigine in the pellet is dissolved within 30 min according to the results of the Dissolution Test, method 2 (paddle method) of the Pharmacopoeia of Japan, twelfth edition, 1991 (Test for dissolution, method 2 (method of mixing). The Pharmacopoeia of Japan, 12th edition, 1991).

The proposed drug is produced in a way that includes a spray granulation:

(a) from 0.5 to 50 wt.% levels of lamotrigine or salt levels of lamotrigine,

(b) from 15 to 50 wt.% lactose,

(C) from 15 to 50 wt.% starch, and

(d) from 0.5 to 15 wt.% crystalline cellulose in the presence of a binder,

(d) from 5 to 15 wt.% polyvinylpyrrolidone.

The granules that make up the proposed powder, are agglomerate. Features lamotrigine or salt levels of lamotrigine on the particles of lactose and starch, which act as the increasing volume of the adsorbing agent. A homogeneous powder mixture containing the components (a) through (g), can be prepared in the form of prespeci before beginning the process of spray granulation. The presence of lactose promotes the formation of such presmise. Crystalline cellulose gives the granules properties disintegrability and solubility. Polyvinylpyrrolidone acts as a binding agent.

Can be used with any suitable salt levels of lamotrigine, which was before the mi are methansulfonate and isethionate salt. These salts can be obtained by the interaction of levels of lamotrigine in free base form with an appropriate acid.

Preferably, up to 98 wt.% the offered granules had a particle size of from 75 to 850 μm. At least 92 wt.% granules can have such a particle size, for example from 92 to 95 wt.% granules. Preferably, not more than 5 wt.% the granules had a particle size of more than 500 μm, for example not more than 3 wt.%. It is desirable that the size of the granules do not exceed more than 500 μm. Particle size is determined according to the Particle Size Distribution for Powders, The Farmacopoeia of Japan, twelfth edition, 1991 (the size Distribution of particles for powder. The Pharmacopoeia of Japan, 12th edition, 1991).

Typically, at least 90 wt.% levels of lamotrigine or salt levels of lamotrigine in granules dissolved within 15 min according to the results of the Dissolution Test, method 2 (puddle method). The quantity of dissolved levels of lamotrigine is determined using the appropriate physico-chemical methods, for example by ultraviolet (UV) analysis or by liquid chromatography high pressure (ghvd).

The offered powder is usually free from dust. Its color is preferably white, although it may vary from white to not-quite-white. Mogavero, bulk density of the powder is from 0.3 to 0.6 g/cm3for example from 0.35 to 0.50 g/cm3or from 0.36 to 0.40 g/cm3. The values of the residual moisture content is usually from 0.5 to 5 wt.%, for example, from 1 to 3 wt.%.

Preferred preparations contain from 0.5 to 30 wt.% levels of lamotrigine or salt levels of lamotrigine. So, the preparations may contain from 0.5 to 20 wt.%, for example from 0.5 to 15 wt.% or from 1 to 10 wt.% levels of lamotrigine or salt levels of lamotrigine. Most preferred are preparations containing 1, 2, 5 or 10 wt.% levels of lamotrigine or salt levels of lamotrigine.

The amount of lactose and starch in medicines exceed present fewer levels of lamotrigine or salt levels of lamotrigine. The starch is preferably corn starch. Acceptable amounts of lactose and starch can be from 15 to 45 wt.%, for example from 30 to 45 wt.% or from 35 to 45 weight. %, or from 40 to 45 wt.%. Preferably, the amount of lactose ranged from 70 to 130%, for example from 90 to 110%, from the amount of starch. Usually amounts of lactose and starch are the same.

The proposed powders can contain from 3 to 8 wt.%, for example from 3.5 to 6 wt.%, crystalline cellulose. Preferred are powders containing 5 wt.% crystallizes the lo from 5 to 10 wt.%, for example, from 6 to 9 wt.% from the drug. Preferred are powders containing 8 wt.% polyvinylpyrrolidone.

The preferred proposed product contains:

(a') from 0.5 to 15 wt.% levels of lamotrigine or salt levels of lamotrigine,

(b) from 35 to 45 wt.% lactose,

(in') from 35 to 45 wt.% starch,

(g') of from 3.5 to 6 wt.% crystalline cellulose, and

(d') from 6 to 9 wt.% polyvinylpyrrolidone.

The most preferred product contains 1 wt.% levels of lamotrigine, 43 weight. % lactose and starch, 5 wt.% crystalline cellulose and 8 wt.% polyvinylpyrrolidone. Another most preferred product contains 10 weight. % levels of lamotrigine, a 38.5 wt.% lactose and starch, 5 wt.% crystalline cellulose and 8 weight. % polyvinylpyrrolidone.

The proposed drug is prepared in a way that includes a spray granulation levels of lamotrigine or salt levels of lamotrigine, lactose, starch, crystalline cellulose in the presence of polyvinylpyrrolidone as a binder. Salt levels of lamotrigine, lactose, starch and crystalline cellulose are available each in the form of a powder having a particle size, for example, the average particle size, significantly smaller than 850 μm, in fact, below 200 μm. These caterine.

As a binder solution to prepare a solution of polyvinylpyrrolidone. This solution can be an aqueous or aqueous-ethanolic solution. Weight part of polyvinylpyrrolidone, for example from 30 to 60 wt.%, or, more specifically 50 wt.%, can be pre-mixed with lamotrigine or salt levels of lamotrigine, lactose, starch and crystalline cellulose.

To obtain the offered powder is used the way zhidkostnogo granulation. Usually use liquid granulator rotary type. Lamotrigine or salt levels of lamotrigine, lactose, starch and crystalline cellulose is introduced into the granulator in powder form, for example in the form of a pre-mixed mixture. The current powder sprayed binder solution. Particles of the current powder stick one to another. Form the desired granules. The conditions in which carry out granulation, can be adjusted accordingly.

Thus obtained granules can be sifted in order to make sure that you meet the requirements of the appropriate particle size. So, in order to ensure that there are no granules, the size of particles greater than 850 μm, the granules may be sieved through a sieve to make sure no more than 5 wt.% the granules have a particle size greater than 500 microns. The pellets can be sifted through a sieve with openings of 75 μm. Almost pellets obtained from the pelletizer may be passed through a set of sieves at 850, 500 and 75 microns. Material larger and smaller cast.

Lamotrigine or salt levels of lamotrigine, used as starting material, typically have a particle size of 125 μm or less. The original lactose usually has a particle size less than 250 microns, usually 200 μm or less, for example from 50 to 200 μm. Lactose can be an anhydrous lactose, such as lactose direct pressing, such as lactose DCL21, or lactose monohydrate.

Lactose DCL21 and lactose another brand, usable, lactose DMV200 have particle sizes are presented in table. A.

The starch may be rice, wheat or corn. Corn starch is also called maize, and it is preferred. Usually the quality of the source material used starch powder with a particle size of from 30 to 150 μm. The starch may be a partially pregelatinized starch, such as starch 1500, manufactured use, Indianapolis, Indiana 46218, US, or complete the Wallpaper powder, for example with an average particle size of from 40 to 100 μm, in particular from 50 to 90 μm. Suitable crystalline cellulose is Avicel PH102, having an average particle size of 90 μm. Crystalline cellulose otherwise referred to as microcrystalline cellulose.

Can be used any suitable polyvinylpyrrolidone, capable of acting as a binder. The polyvinylpyrrolidone may be a linear polymer of 1-vinyl-2-pyrrolidone having an average molecular weight of about 40,000, for example povidone K30. On the other hand, can be used a linear polymer of 1-vinyl-2-pyrrolidone having an average molecular weight of about 1200000, such as povidone K90.

The powder, which is obtained in the spray granulation and, if necessary, subsequent screening, then placed in the container, which is then closed. The container can be sealed. This can be a container for a single dose or mnogorazovyj container. The container can be a jar, bottle or package. The most convenient packages, particularly packages of foil.

The following examples illustrate the invention.

Example 1

Through spray is th, wt.%:

Composition A (comparison)

Lamotrigine 125 μm to 1.0

Lactose (Fastflo - 91,0

Povidone K30 British Pharmacopoeia (BP) - 8,0

Lamotrigine 125 μm represents lamotrigine having a particle size of up to 125 microns. Lactose (Fastflo is a waterless spray dried lactose production Wisconsin Dairies, Baraboo, Wisconsin 53913, U. S.

Composition B (comparison)

Lamotrigine 125 μm to 1.0

Lactose (Fastflo - 43,0

Lactose DCL21 - 43,0

Povidone K30 BP - 8,0

Hydroxypropylcellulose with a low degree of substitution (LHPC-11) - 5,0

Part C (suggested)

Lamotrigine 125 μm to 1.0

Lactose DCL21 - 43,0

Pregelatinized maize (corn) starch BP/USNF (starch 1500) - 43,0

Microcrystalline cellulose BP (Avicel PH102) - 5,0

Povidone K30 BP - 8,0

Composition D (comparison)

Lamotrigine 125 μm to 1.0

Pregelatinized maize (corn) starch BP/USNF (starch 1500) - 86,0

Hydroxypropylcellulose with a low degree of substitution (LHPC-11) - 5,0

Povidone K30 BP - 8,0

Composition E (comparison)

Lamotrigine 125 μm to 1.0

Pregelatinized maize starch - 91,0

BP/USNF (starch 1500) - 91,0

Povidone K30 BP - 8,0

Composition C was subjected to spray granulation in the form of podprte 2 x 5 kg next">

2. Pregelatinized starch was passed through a 250 μm sieve to remove large agglomerates.

3. Lamotrigine, lactose, starch and Avicel PH102 subjected to preliminary mixing in the mixer Colette in the form of precautionary measures to facilitate homogeneous distribution of levels of lamotrigine.

4. The powder was subjected to spray granulation in the Glatt granulator GPCG5 using Schlick spray orifice of the nozzle 1.2 mm, using a spray air pressure of 2 bar. The feed rate of the binder solution was approximately 90 ml in 1 min. Temperature at the inlet was maintained equal to 72oC, and to ensure fluidity sufficient for simultaneous drying and granulation, supported the flow of air between 150-250 cm3in 1 hour Drying capacity was shaken to remove fine powder for 6 with intervals of 1.5 min.

5. During granulation was detected temperature of the product. This temperature was usually 32-34oC, but soon after spraying it increased to 45-50oC, testified to the completion of drying. The whole process was about 1 h per supporti.

6. Two supportive granules sea roar of 710 μm and 100 μm to remove components of the granules excessively large or excessively small sizes.

Compositions A, B, D and E were subjected to spray granulation in the same way. In the case of compositions A to C and E were obtained powders of freely-current white granules. Composition D was given powder, which is highly Komsomolka. A significant proportion of particles exceeded the allowable size. Therefore, the powder was found to be unsatisfactory and was not tested. The properties of powders obtained from compositions A to C and E, are presented in table. B.

Originally 9.8 wt.% powder obtained from composition B, is not passed through a sieve of 500 μm. Then more powder was sifted through a sieve of 500 μm. Subsequent sieve analysis showed that only 1.2% of the powder in this case is not passed through a sieve of 500 μm. For repeated screening and the subsequent analysis used different sieve of 500 μm, which allowed to establish why some of the powder and was experienced through a sieve of 500 μm.

Example 2

A common part

It was studied the effect of temperature, humidity and artificial lighting on the stability of the powders obtained in example 1 according to the formulations A to C and E. the Powders were stored for two months at 40oC and 75% relative humidity (R. H.) in closed plastic lids, so is in closed plastic caps glass bottles amber color. In addition, the powders were kept at 25oC in light (1000 Lux) up to 1.2 million Lux/h total exposure.

The tested variables

To assess the stability of the preparations was recorded the following parameters.

1. Appearance

2. Losses during drying

Conditions for compositions A and B were the following: 60oC in vacuum for 3 hours Conditions for compositions C and E: 60oC in vacuum for 6 hours These experimental conditions were chosen in accordance with experimental conditions for lactose and starch (Pharmacopoeia of Japan, twelfth edition, 1991).

3. (Quantitative) analysis and related compounds

(Quantitative) analysis of the levels of lamotrigine and test for purity was performed using liquid chromatography high pressure (hplc).

4. The test for dissolution

The dissolution of the powders was studied, by using Dissolution Test, method 2 (paddle method) of The Pharmacopoeia of Japan, twelfth edition, 1991. Temporary sampling points was 15, 30 and 45 min, and the test solution was applied in 0.1 N hydrochloric acid solution. Lamotrigine was determined by UV absorption.

Results

1. Appearance

When 40oC and 75% R. H. all powders in open glass bottles under conditions of high humidity formed lumps, etc what about the comparison with the color of other particles. The results are presented in table. 1-5.

2. Losses during drying

Composition E was the most hygroscopic powder. The results are presented in table. 1-5.

3. (Quantitative) analysis and related compounds

From the point of view of degradation under conditions of high humidity, at 40oC and 75% R. H. in open glass bottles are the most stable was the powder of composition E, and the most unstable powder of composition A.

4. The test for dissolution

All the formulations showed rapid dissolution. Over 90% levels of lamotrigine in each powder was dissolved within 15 minutes

Conclusion

Composition A (comparison)

The powder of the drug was stable under conditions of high temperature in the absence of moisture. However, in conditions of high humidity, it is slightly lost stability.

Composition B (comparison)

The powder of the drug was stable under conditions of high temperature in the absence of moisture. However, it is easier all changed color. In conditions of high humidity, it is slightly lost stability.

Part C (suggested)

The powder of the drug was stable under conditions of high temperature in the absence of moisture. He also stabilen under conditions of high temperature in the absence of moisture. He was also stable in high humidity conditions. However, in conditions of high humidity, it absorbed the greatest amount of moisture.

Example 3

Powders were prepared by spray granulation of each of the compositions shown in table. 6.

50 g levels of lamotrigine 125 μm and 2150 g of lactose DMV grit 200 and starch 1500 (composition 1) or 500 g levels of lamotrigine 125 μm and 1925 lactose DMV grit 200 and starch 1500 (composition 2) was mixed with 250 g of Avicel PH102 and 200 g of povidone K30 in the mixer Colette Planetary for 3 minutes So got practically homogeneous presmise powders.

Separately in 600 ml of demineralized water was dissolved 200 g of povidone K30, the second half of povidone K30. Then the solution was brought to 1000 ml with 20% aqueous solution of solid substances. It was used as a granulating solution.

Presmise powders were put in a rotary granulator Freund SFC. It is a type of zhidkostnogo granulator, which has on powders pseudoviruses the impact of rotational type in order to achieve an acceptable distribution of granules. Granulating solution was sprayed on the current powders in the form of a fine mist through the spray system works is of granular particles of a suitable size. This process continued until, until he was introduced all granulating solution and granules have not purchased the appropriate size.

More specifically on the granulator Freund SFC used the following parameters.

1. The temperature of the inlet air 80oC.

2. The rotor speed of 300 rpm

3. Speed agitator 450 rpm

4. The speed of the chopper 1500 rpm

5. The volume of air entering 2.9 m3/PM

6. The spraying air pressure of 4 kg/cm2.

7. The size of the spray nozzles of 1.8 mm

8. The spray rate of 45 g/min

The required granules were obtained by applying the above and the following parameters.

1. The temperature of the inlet air 75-80oC.

2. The air temperature at the outlet 28-32oC.

3. Temperature prodcat 28-35oC.

4. The volume of air 2,9-3,0 m3/PM

5. Speed spray 40-43 g/min

6. Duration granulating powders 22 minutes

7. The duration of drying of the granules 11 minutes

The resulting granules are then passed through a screen with sieves with apertures 850, 500 and 75 microns. The granules were screened in accordance with the requirements of which had a particle size of from 75 to 850 μm. Not more than 5 wt.% the granules had a particle size greater than 500 microns. Used granules aggregates and podkrkonosi faction.

Each powder had the following properties:

(1) the granules disintegrate within 30 minutes according to the Disintegration Test of The Pharmacopoeia of Japan, twelfth edition, 1991, and

(2) at least 90 wt.% levels of lamotrigine is dissolved within 30 min according to the Dissolution Test, method 2 (paddle method) of The Pharmacopoeia of Japan, twelfth edition, 1991.

1. Pharmaceutical composition containing: (a) 0.5 to 50 wt.% levels of lamotrigine, or its pharmaceutically acceptable acid salt additive, (b) 15 to 50 weight. % lactose, (b) 15 to 50 wt.% starch, (d) 0.5 to 15 wt.% crystalline cellulose, and (d) 5 to 15 wt.% polyvinylpyrrolidone, and are in the form of freely-current powder in the form of granules having the following properties: (1) the granules have a particle size of not more than 850 μm, (2) at least 90 weight. % of the granules have a particle size of 75 to 850 μm, (3) the granules disintegrate within 30 min Test according to the disintegration of the Pharmacopoeia of Japan, 12th edition, 1991, and (4) at least 90 wt.% levels of lamotrigine or salt levels of lamotrigine in the pellet is dissolved within 30 min according to the Test results on the dissolution method 2 (method of mixing) in accordance with the Pharmacopoeia of Japan, 12th issued the levels of lamotrigine, (b') 35 - 45 wt.% lactose (') 35 - 45 weight. % corn starch (g') of 3.5 to 6 wt.% crystalline cellulose, and (d') 6 - 9 wt.% polyvinylpyrrolidone.

3. The composition according to p. 2, characterized in that it contains 1 wt.% levels of lamotrigine, 43 weight. % lactose and starch, 5 wt.% crystalline cellulose and 8 wt.% polyvinylpyrrolidone.

4. The composition according to p. 2, characterized in that it contains 10 wt.% levels of lamotrigine, a 38.5 wt.% lactose and starch, 5 wt.% crystalline cellulose and 8 weight. % polyvinylpyrrolidone.

5. The composition according to any one of paragraphs.1 to 4, characterized in that not more than 5 wt.% the granules have a particle size of more than 500 microns.

6. The composition according to any one of paragraphs.1 to 5, characterized in that the powder has a bulk density of 0.36 - 0.40 g/cm3.

7. The composition according to any one of paragraphs.1 - 6, characterized in that the starch is corn starch.

8. The method of preparation of a pharmaceutical composition containing (a) 0.5 to 50 wt.% levels of lamotrigine, or its pharmaceutically acceptable acid salt additive, (b) 15 to 50 wt.% lactose, (b) 15 to 50 wt.% starch, (d) 0.5 to 15 weight. % crystalline cellulose, and (d) 5 to 15 wt.% polyvinylpyrrolidone, and are in the form of freely-current powder in the form of granules having the following properties: (1) granules are R iroute for 30 min according to the disintegration Test according to the Pharmacopoeia of Japan, 12th edition, 1991, and (4) at least 90 wt.% levels of lamotrigine or salt levels of lamotrigine in the pellet is dissolved within 30 min according to the Test results on the dissolution method 2 (method of mixing) in accordance with the Pharmacopoeia of Japan, 12th edition, 1991, when lamotrigine or the salt levels of lamotrigine, lactose, corn starch and crystalline cellulose is subjected to spray granulation in the presence of polyvinylpyrrolidone as a binder.

 

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