WO2010143202A1 - Pharmaceutical composition - Google Patents

Abstract

A pharmaceutical matrix tablet comprising an admixture of pseudoephedrine or its pharmaceutically acceptable salts and a release rate controlling system which comprises one or more water insoluble diluents, one or more water insoluble polymers and one or more hydrophobic materials.

Description

PHARMACEUTICAL COMPOSITION

The present invention relates to the pharmaceutical matrix tablet comprising pseudoephedrine or its pharmaceutically acceptable salts; wherein the tablet releases pseudoephedrine over a long period of time.

BACKGROUND OF THE INVENTION

United States Patent Number US4892742A (hereinafter referred to as '742) discloses Pharmaceutical compositions for controlled release of water soluble drugs are disclosed. The compositions comprise a tablet core containing the drug and a water insoluble polymeric matrix surrounded with a rate controlling membrane coating. Although the '742 patent discloses the use of water insoluble polymeric matrix system, the system also requires the use of a rate controlling membrane coating to control the release of the water soluble drugs like potassium hydrochloride. The prior art does not teach to use a water insoluble diluent in substantial amount so that the rate controlling matrix comprising a water insoluble diluent, water insoluble polymer like ethyl cellulose, hydrophobic material like a wax are enough to control the release of the water soluble drug without the need to use a rate controlling membrane coating in amounts as high as 8 % of the total weight of the tablet.

PCT publication namely, WO2005065641 A2 (hereinafter referred to as '641 publication) discloses a non-eroding, non-bioadhesive and non-swelling oral controlled release pharmaceutical composition comprising at least one high dose water soluble active ingredient, at least one diluent, at least one binder, and a polymer system comprising at least one release controlling polymer, wherein the composition formulated into a suitable dosage form maintains its geometric shape even after the drug has diffused from the dosage form and provides the concentrations of active ingredients above effective levels for extended periods of time, optionally with other pharmaceutically acceptable excipients. The '641 publication discloses to use diluent selected from both water soluble excipients as well as water insoluble excipients such as lactose, cellulose, microcrystalline cellulose, mannitol, dicalcium phosphate, pregelatinized starch. However the publication indicates that lactose is more suitable.

Another PCT publication WO2008114280 Al (hereinafter referred to as '280 publication) a novel reduced dose pharmaceutical composition comprising combination of fexofenadine or salts thereof; and pseudoephedrine or salts thereof in therapeutically effective amount, for the treatment of allergic rhinitis and associated symptoms in pediatric population. The '280 publication discloses the use of melt granulation of pseudoephedrine with hydrophobic materials such as hydrogenated vegetable oil, but does not teach to use a novel rate controlling matrix system comprising one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials.

We have surprisingly found that when a water soluble drug is mixed with a release rate controlling system comprising one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials the release of the water soluble drug such as of pseudoephedrine can be effectively controlled. It is because of the novel combination of the three components of the release rate controlling system, the formulator can easily achieve the desired release of the very water soluble drug like pseudoephedrine effectively and by way of a simple technique of mixing the ingredients, granulating and compressing the blend into a tablet dosage form. Such a matrix system not only controls the release of the drug without any burst and but more importantly, without the need of applying additional functional coating which otherwise makes the process of making the tablet tedious, time consuming. When the content of the water soluble drug is high i.e about 30 % or more, the inventors found that when the release rate controlling system was activated by heating for a short duration of time, the desired release of the water soluble active ingredient could be achieved. Surprisingly, tablets in spite of being subjected to heating, it was found to show no deterioration of the active ingredients after heat treatment or upon storage for long period of time.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical matrix tablet comprising an admixture of pseudoephedrine or its pharmaceutically acceptable salts and a release rate controlling system which comprises one or more water insoluble diluents, one or more water insoluble polymers and one or more hydrophobic materials.

The present invention also provides a process of preparing the pharmaceutical matrix tablet, the process comprising steps of a. first granulating the mixture of pseudoephedrine or its pharmaceutically acceptable salts and the ingredients of a release rate controlling system by non aqueous wet granulation b. drying the granules c. compressing the granules into a compressed tablet e. optionally, coating the tablet. d. heating the tablets at a temperature above the melting point of the hydrophobic material of the release rate controlling system for a period of about one hour

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical matrix tablet comprising an admixture of pseudoephedrine or its pharmaceutically acceptable salts and a release rate controlling system which comprises one or more water insoluble diluents, one or more water insoluble polymers and one or more hydrophobic materials. In one preferred embodiment, the pharmaceutical matrix tablet is not coated with any functional coating, hi another embodiment, the tablet is a bilayer tablet, wherein the first layer comprises pseudoephedrine and the release rate controlling system and the second layer comprising another active agent that is released immediately.

In one embodiment, when the pharmaceutical matrix tablet is a bilayer tablet, the first layer comprises more than 30 % of the pseudoephedrine or its pharmaceutically acceptable salts and the release rate controlling system comprising one or more water insoluble diluent, one or more^' water insoluble polymers and one or more hydrophobic materials, wherein the release rate controlling system is activated by heat treatment and the second layer comprises antihistaminic agent and one or more diluent that causes rapid release of the antihistaminic agent wherein pseudoephedrine is released over a period of time and the antihistaminic is released immediately upon of the bilayer tablet with the aqueous environment.

In most preferred embodiment of the present invention, the release rate controlling system comprises dicalcium phosphate as the water insoluble diluent, ethyl cellulose as the water insoluble polymer and the stearic acid as the hydrophobic material.

The present invention provides a pharmaceutical matrix tablet comprising an admixture of pseudoephedrine or its pharmaceutically acceptable salts and a release rate controlling system which comprises one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials.

The present invention further provides a pharmaceutical matrix tablet consisting essentially of an admixture of pseudoephedrine or its pharmaceutically acceptable salts and a release rate controlling system which comprises one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials. The pharmaceutical matrix tablet of the present invention does not require the functional coating that controls the release of the water soluble drug in the core. The use of novel, inventive release rate controlling system is advantageous in that it allows the formulator to avoid the complicated, functional coating process which is not only tedious and time consuming, but is an additional step during the manufacturing. Moreover, such coatings also cause lot of variations in the coating weight gain and therefore, it is always desirable to make a composition without the addition of the functional coating.

The release rate controlling system present in the pharmaceutical matrix tablet of the present invention comprising three components namely, water insoluble diluents, water insoluble polymers and hydrophobic materials.

The water insoluble diluents used in the release rate controlling system of the present invention are water insoluble and non swellable in contrast to the water insoluble diluents such as pregelatinized starch or microcrystalline cellulose or any other water insoluble cellulose derivative. The examples of the water insoluble diluents that may be used in the pharmaceutical matrix tablet of the present invention, include, but are not limited to, dicalcium phosphate, calcium sulphate, calcium carbonate, calcium silicate, tribasic calcium phosphate and the like and mixtures thereof. The amount of the water insoluble excipient ranges from about 20 % to about 50 % by weight of the layer comprising pseudoephedrine, when the tablet of the present invention is a bilayer tablet.

The examples of water insoluble polymers that may be used include, but are not limited to, ethyl cellulose, methacrylic acid derivatives such as ammoniomethacrylate copolymer (EUDRAGIT® RL or EUDRAGIT® RS), methacrylic acid ester neutral copolymer (EUDRAGIT® NE30D), Kollicoat SR30D) [containing 27 wt % polyvinyl acetate, 2.5 wt % polyvinyl pyrrolidone and the like and mixtures thereof.

In one preferred embodiment, ethyl cellulose is used as the water insoluble polymer. In preferred embodiment, the viscosity of ethyl cellulose suitable for the present invention may range from about 5 cps to 25 cps. The amount of the water insoluble polymer present in the pseudoephedrine portion of the tablet ranges from about 5 % to about 25 % by weight, preferably about 10 % to about 20 % by weight of the pseudoephedrine portion of the tablet.

The examples of the hydrophobic materials that may be used includes, but are not limited to, waxes, carnauba wax, vegetable wax, fruit wax, microcrystalline wax, bees wax, hydrocarbon wax, paraffin wax, cetyl esters wax, nonionic emulsifying wax, anionic emulsifying wax, candelilla wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, a hydrogenated vegetable oil, a hydrogenated castor oil, a fatty acid, a fatty acid ester, or mixtures thereof. The hydrophobic material that is preferred is the one having the melting point in the range of about 50⁰C -70° C. Generally, the amount of the hydrophobic material present in the pseudoephedrine portion of the tablet ranges from about 5 % to about 25 % by weight. Preferably, the amount of hydrophobic material present in the rate controlling system is about 15 % by weight.

In preferred embodiment, the hydrophobic material is stearic acid and the water insoluble polymer is ethyl cellulose. The stearic acid and ethyl cellulose are present in the ratio of about 1:1, preferably about 0.8:1.2.

The present invention also provides a pharmaceutical matrix tablet comprising an admixture of pseudoephedrine or its pharmaceutically acceptable salts in amounts more than 30 % of the tablet, and a release rate controlling system which comprises one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials, wherein the hydrophobic material is activated by heat treatment.

In the preferred embodiment, the pharmaceutical matrix tablet is in the form of a bilayer tablet wherein the two layers are arranged in the form of lamina, the bilayer tablet comprising a. first layer comprising admixture of pseudoephedrine and a release rate controlling system which comprises one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials b. second layer comprising one or more other active ingredient that is released immediately.

In one embodiment, the pharmaceutical matrix tablet of the present invention is a bilayer tablet wherein the first layer comprises more than 30 % of the pseudoephedrine by weight of the layer and the release rate controlling system comprising one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials, wherein the hydrophobic material is activated by heat treatment and the second layer comprises antihistaminic agent and one or more diluent that causes rapid release of the antihistaminic wherein pseudoephedrine is released over a period of time and the antihistaminic agent is released immediately upon of the bilayer tablet with the aqueous environment. One or more diluents present in the second layer of the matrix tablet of the present invention that causes rapid release of the antihistaminic agent can be a disintegrants such as for example crospovidone, sodium starch glycolate, sodium croscarmellose or a wicking agent such as silicified microcrystalline cellulose, microcrystalline cellulose or a water soluble excipient such as for example, lactose, mannitol, sugars, dextrose and the like and mixtures thereof or a low viscosity molecular weight polymers such as Opadry polymers that are used for aesthetic coating and are known not to hinder in the quick release of the active ingredient if present in the layer.

hi yet another embodiment, the pharmaceutical matrix tablet is in the form of a bilayer tablet wherein the two layers are arranged in the form of lamina, the bilayer tablet comprising a. First layer comprising pseudoephedrine present in amount more than 30 % of the first layer, wherein the layer comprises admixture of pseudoephedrine and a release rate controlling system which comprises one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials c. Second layer comprising one or more other active ingredient that is released immediately wherein the hydrophobic material is activated by heat treatment.

hi one embodiment, where the amount of pseudoephedrine was more than 30% by weight of the pseudoephedrine layer, the tablets when manufactured at a small scale, such as for example 1000- 2000 tablet batch size, the heating of the granules to activate the hydrophobic material provided a satisfactory control over the release of pseudoephedrine. Without wishing to be bound by any theory, the applicants believe that the addition of the stearic acid at the semi granulation stage instead of at the dry-mix stage would essentially allow more solvent available for solubilization of ethyl cellulose to exert its hydrophobic matrix effect. When stearic acid would be added to semi-wet mass during granulation process and then granulation would be completed by adding more of solvent mixture. This would also ensure homogenous distribution of stearic acid. Drying process would be made simpler from further scale-up point of view and heat treatment for activation of stearic acid would be given after completion of coating process.

However, when the same process was adopted for a large scale-up, there were observed some scale up problems. The term large scale as used herein indicates the batch size of the manufacturing of tablet in the range of 50,000 to about 150,000 units. While drying of the granules in fluid bed dryer at 60⁰C, the mass became heavy and resistant to effective fluidization. The inventors believed that this could be due to melting of stearic acid and making mass stickier. This could be potential problem for further scale-up.

In an embodiment, where the pseudoephedrine is present in more than 30 % of the first layer, when the bilayer tablets are manufactured in large scale, it was found that when a significantly less quantity of solvent mixture was used to get end point, that could result in inadequate solubilization of water insoluble polymer present in dry-mix. Therefore, during a large scale manufacturing, the addition of hydrophobic material was done into semi-granulated mass instead of adding the hydrophobic material in the dry-mix. Alternatively, it was possible to add the hydrophobic component during granulation just prior to completion of granulation process. In yet another embodiment, it was possible to dry the wet mass at 45°C while not applying any heat treatment to granules during drying stage but subjecting the coated tablets to the heat treatment to coated tablets during drying phase in coating pan at 60⁰C bed temperature.

In one preferred embodiment, the activation of the hydrophobic material is carried out after the compression of the bilayer tablet by heating the bilayer tablets at 60° C for a period of about 60 minutes in the coating pan. The present invention provides a pharmaceutical matrix tablet is prepared by steps of a. first granulating the mixture of pseudoephedrine and the ingredients of a release rate controlling system by wet granulation b. drying the granules c. heating the granules at a temperature above the melting point of the hydrophobic material of the release rate controlling system for a period of about one hour, and subsequently cooling and milling d. compressing the milled granules into a compressed tablet

The present invention provides a pharmaceutical matrix tablet is prepared by steps of a. first granulating the mixture of pseudoephedrine and the ingredients of a release rate controlling system by wet granulation b. drying the granules c. compressing the granules into a compressed tablet e. optionally, coating the tablet. d. heating the tablets at a temperature above the melting point of the hydrophobic material of the release rate controlling system for a period of about 15 minutes to one hour.

Further, the incorporation of a hydrophobic component into the release rate controlling system allows the formulator to make sure that the release of the drug was adequately controlled. The tablets of the present invention are not required to be prepared by conventional melt granulation technique, but by simply by heating the granules or curing the compressed tablets at a temperature above the melting point of the hydrophobic component for a short period of time as much as 60 minutes or less.

Without wishing to be bound by any theory, the inventors have found that upon curing the tablets at a temperature above the melting point of hydrophobic material for a short period for example, 10 minutes to about not more than 2 hours, the hydrophobic material gets melted and gets redistributed in matrix thereby reducing the porosity of the compressed material. While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.

Example 1

The pharmaceutical tablet of the present invention was prepared as follows.

Table 1 : composition of the matrix tablet

All the excipients of the pseudoephedrine hydrochloride layer were sieved through 40 # sieve. The ethyl cellulose was sifted through 16 #. Stearic acid was sifted through 40 # sieve separately. The materials were loaded into a rapid mixer granulator. The sieved ingredients were dry mixed. The dry, powder blend was granulated with a solvent mixture of isopropyl alcohol and dichloromethane. The wet granules were air dried and then the granules were further dried for 1 hour at 60 ° C. The dried granules showed moisture content of below 2 %. The dried granules were allowed to cool to room temperature for 2 hours and then passed through mesh and milled the granules. The sized granules were lubricated with magnesium stearate and the lubricated granules were compressed along with the fexofenadine layer into a bilayer tablet. The tablets produced according to Example 1 at a laboratory scale of around 1000-2000 tablets per batch. The tablets showed a desired control over the release of pseudoephedrine. The in vivo studies indicated. that the bilayer tablets of Example 1 were bioequivalent to the commercially available tablet dosage form available under the brand name of Allegra^® Example 2

The pharmaceutical tablet of the present invention was prepared as follows.

Table 2: composition of the tablets

Pseudoephedrine hydrochloride (40#), dicalcium phosphate dihydrate (40#), Iron oxide yellow along with some part of dicalcium phosphate (80#) and Ethocel Std 10 (20#) were mixed in 5L capacity for 5 min and then solvent mixture was added at "slow/off' settings. Wet mass was kneaded at "slow/slow" settings for 1 min 45 sec, stearic acid was added to wet mass and kneaded for 30 sec at "slow/slow" settings. Additional solvent mixture was added at "slow/slow" settings and kneaded further to get desired end point. About 31.26% w/w of solvent mixture was consumed during the process. Wet mass was milled through clitt-mill fitted with 8 mm screen at knives forward settings at slow speed. Wet milled mass was first air-dried for 10 min and at 45⁰C for 50 min to remove solvents. Loss on drying of 0.89%w/w (6O⁰C for 15 minutes) was achieved. Dried mass was allowed to cool at room temperature for 1 hour and then milled through clitt- mill fitted with 1.5 mm screen at medium speed. Milled granules were blended for 5 min with magnesium stearate (40#). Lubricated granules of pseudoephedrine HCl were compressed into bilayer tablet with the fexofenadine HCl IR granules having the ingredients listed in Table 2. Bilayer core tablets were coated with HPMC based Opadry clear to a weight gain of 3.0%w/w. Coating was carried out at inlet temperature 60-65⁰C and bed temperature was maintained at 35- 36°C. After achieving target weight gain, coated tablets were dried at bed temperature of 60⁰C (Stearic acid melting temperature 56-58°C) for one hour to activate the stearic acid. The dissolution profiles of pseudoephedrine HCl of core tablets, coated tablets and heat-treated tablets for different exposure period are compiled in table 3.

The tablets produced according to Example 2 could be manufactured at a scale of about 67,000 tablets with the slight process modification. The tablets were found to a desired control over the release of pseudoephedrine. The in vivo studies indicated that the bilayer tablets of Example 2 were bioequivalent to the commercially available tablet dosage form available .under the brand name of Allegra^®

Example 3

The tablets prepared according to example 1, example 2 with variation in the heating time were subjected to in vitro dissolution studies to monitor the ability of the rate controlling matrix to control the release of pseudoephedrine. The example 1 tablets, tablets of example 2, tablets of example 2 with Opadry coating but without heating, coated tablets prepared according to example 2 with heating the tablets for 15 minutes, 30 minutes, 45 minutes and 60 minutes were compared for the in vitro dissolution. The in vitro dissolution data is presented below.

Table 3: In vitro dissolution indicating release of pseudoephedrine

Claims

Claims:

1. A pharmaceutical matrix tablet comprising an admixture of pseudoephedrine or its pharmaceutically acceptable salts and a release rate controlling system which comprises one or more water insoluble diluents, one or more water insoluble polymers and one or more hydrophobic materials.

2. A pharmaceutical matrix tablet as claimed in claim 1 wherein the tablet is not coated with any functional coating.

2. A pharmaceutical matrix tablet as claimed in claim 1 wherein the tablet is a bilayer tablet, wherein the first layer comprises pseudoephedrine or its pharmaceutically acceptable salt and the release rate controlling system and one more pharmaceutically acceptable excipients and the second layer comprising another active agent that is released immediately.

3. A pharmaceutical matrix tablet as claimed in claim 2 wherein the first layer comprises more than 30 % of the pseudoephedrine or its pharmaceutically acceptable salts and the release rate controlling system comprising one or more water insoluble diluent, one or more water insoluble polymers and one or more hydrophobic materials, wherein the release rate controlling system is activated by heat treatment and the another active agent is an antihistaminic agent and one or more diluent that causes rapid release of the antihistaminic agent wherein pseudoephedrine is released over a period of time and the antihistaminic is released immediately upon of the bilayer tablet with the aqueous environment.

4. A pharmaceutical matrix tablet as claimed in claim 3 wherein the antihistaminic agent is fexofenadine hydrochloride.

5. A pharmaceutical matrix tablet as claimed in claim 1 wherein water insoluble diluent is dicalcium phosphate, the water insoluble polymer is ethyl cellulose and the hydrophobic material is stearic acid.

6. A pharmaceutical matrix tablet as claimed in claim 3 wherein the matrix tablet is prepared by steps of a. first granulating the mixture of pseudoephedrine and the components of the release rate controlling system by wet granulation b. drying the granules c. compressing the granules into a compressed tablet d. heating the compressed tablets at a temperature above the melting point of the hydrophobic material of the release rate controlling system for a period of about one hour e. optionally, coating the tablet.

7. A pharmaceutical matrix tablet as claimed in claim 6 wherein the wet granulation is done by using non aqueous solvents such as dichloromethane, isopropyl alcohol and mixtures thereof.