WO2013058721A1

WO2013058721A1 - Pharmaceutical granules and production method

Info

Publication number: WO2013058721A1
Application number: PCT/TR2012/000172
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-10-13
Filing date: 2012-10-12
Publication date: 2013-04-25

Abstract

The present invention relates to pharmaceutical granules having maximum 1% of moisture content by weight and production method thereof.

Description

PHARMACEUTICAL GRANULES AND PRODUCTION METHOD

Background of the Invention Levocetirizine which has the chemical name of 2-[2-[4-[(R)-(4-chlorophenyl)-phenyl- methyl]piperazine-l-yl]ethoxy] acetic acid as shown with the following formula (I) is a nonsedating, long-acting Hl-antihistaminic:

Formula (I) Cetirizine was first disclosed in the patent numbered EP0058146 A 1.

Piperazine derivative of levocetirizine which is the R-enantiomer of cetirizine is a potent and selective HI receptor antagonist. Levocetirizine is a new antihistaminic which binds to HI receptors with high affinity, even two times higher as compared to cetirizine. Levocetirizine competes with histamine and inhibits histamine from binding to HI receptors. This antagonism blocks the effects of histamine on the gastrointestinal tract, uterus, large blood vessels and bronchial smooth muscle. The blockage of HI receptors suppresses histaminic activities such as oedema, flare and itching. The facts that levocetirizine enters the central nervous system in little amounts and has little affinity to HI receptors explain its non-sedative nature to some extent. Levocetirizine has anti-allergic and anti-inflammatory activity. The studies have shown that levocetirizine inhibits a comprehensive series of reactions that induce and disseminate allergic inflammation.

Levocetirizine formulations existing in the prior art are in oral solution, oral drop and film tablet forms. The production method existing in the prior art related to levocetirizine formulations is wet granulation method which is generally implemented by spraying a granulation solution on the active agent mixture. The granulation solution can comprise other excipients such as filling agent, binder in addition to various pharmaceutically acceptable solvents. The solvents used in pharmaceutical technology for this purpose are the solvents such as water, deionized water, toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol (for instance ethyl alcohol) and/or alcohol mixtures.

However, in degradation studies of levocetirizine granules produced by wet granulation method, the inventors have observed an increase in impurity concentration (impurity A) of piperazine derivative after the product was kept in 60% of relative humidity at 25°C for 12 weeks. (See Table I). Degradation studies were analysed by HPLC device.

Table I. Degradation Study Results

In addition, moisture content of levocetirizine granules produced by wet granulation method was measured by Karl Fischer method (with Metrohm, Karl Fischer reactive, at 25 °C) and the results of the analysis implemented on the samples taken by 5 different production lines are given below; % moisture content was measured according to total granule weight (See Table II).

5 1.8

Average (~) 1.24

Table II. Moisture content results

As a result of the moisture analysis study conducted, it has been found that the average moisture content of levocetirizine granule samples produced in 5 different production lines is 1.24% in proportion to total granule weight.

The inventors have found that the fact that moisture content of the granules produced by wet granulation method is more than 1% by weight causes degradation of the formulations independent from storage conditions.

The studies conducted in the scope of the present invention have shown that this high moisture content is closely associated with the content of the granulation solution used in wet granulation production method and granulation/drying temperature.

However, this problem related to levocetirizine granules was not disclosed in the prior art and therefore a solution offer was not made.

The inventors have found an improved formulation and production method in order to obtain stable levocetirizine granules as a solution for this problem.

In another aspect, the present invention discloses pharmaceutical granule formulations having a maximum granule moisture content of 1% and comprising levocetirizine as the active agent.

Moisture content of the granule formulations of the present invention is maximum 1% by weight, preferably in the range of 0.1% to 1% by weight. The term "levocetirizine" used throughout the text refers to levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof.

Levocetirizine used in the formulations of the present invention is preferably its dihydrochloride salt, polymorphically is in its crystalline form.

The granule formulations according to the present invention comprise levocetirizine dihydrochloride in the range of 0.1 to 10% by weight, preferably in the range of 0.1% to 5% by weight. In one aspect, the present invention discloses pharmaceutical granules comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention discloses pharmaceutical granules having a maximum moisture content of 1% in proportion to total granule weight, comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention discloses pharmaceutical granules having moisture content in the range of 0.1 to 1% in proportion to total granule weight, comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention discloses use of these granules in production of a dosage form suitable for oral use.

Oral dosage forms of the present invention can be solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet; modified, fast, slow, controlled, prolonged release tablets; orodispersible tablet, mini tablet, microtablet, pellet, as well as multiple dosage forms comprising one or more of these dosage forms or liquid dosage forms such as suspension dosage forms.

The excipients that can be used in the granule formulations according to the present invention can be selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavouring agents, taste masking agents, diluents, binders, glidants, wetting agents, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners or combinations thereof.

The disintegrants that can be comprised in the present invention can be selected from highly dispersive polymers, for instance cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicone dioxide, alginic acid, sodium alginate, corn starch.

The anti-adhesive agents that can be comprised in the present invention are used in order to prevent the mixture comprising active agent from forming rough surfaces by adhering to device and machine surfaces during the process. Substances which can be used for this purpose can comprise one or more components selected from the following group comprising talc, colloidal silicon dioxide, magnesium stearate and corn starch.

The binders that can be comprised in the present invention comprise one or more components selected from the group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropyl methylcellulose, polyvinylpyrrolidone, lactose, guar gam, pectin, gelatine, sodium alginate.

The formulations according to the present invention comprise at least one pharmaceutically acceptable binder of minimum 1% by weight, preferably in the range of 1 to 10% by weight, more preferably in the range of 1 to 5% by weight. The preferred binder is sorbitol. The lubricants that can be comprised in the present invention can comprise one or more components selected from the group comprising highly metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.

The diluents that can be comprised in the present invention can comprise one or more components selected from the group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, directly compressible lactose, lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates and/or derivatives thereof.

The sweetening agents that can be used in the formulations of the present invention can comprise one or more components selected from the group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, acesulphame, maltose, saccharin and/or pharmaceutically acceptable salts or combinations thereof.

The solvents that can be comprised in the present invention can comprise one or more components selected from the group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol mixtures.

The film coating agent according to the present invention is composed of the following components and/or combinations thereof such as lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol. The inventors have found that components of the formulation have also an important effect on degradation of the end product.

In the case that the product is particularly an effervescent formulation, the type and amount of the filling agent and effervescent acid-base comprised in the formulations have a role in stability of the end product.

The effervescent acids that can be comprised in the formulations prepared in the scope of the present invention can be citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid and/or pharmaceutically acceptable salts, hydrates, anhydrates thereof or preferably a combination thereof. Effervescent base, on the other hand, can be sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.

The particularly preferred effervescent acid-base couple is sodium hydrogen carbonate and citric acid wherein the weight ratio of citric acid: sodium hydrogen carbonate is minimum 1, preferably in the range of 1 to 2.

The filling agents that can be comprised in the present invention can be selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol or combinations thereof.

The formulations of the present invention comprise at least one pharmaceutically acceptable filling agent of minimum 5% by weight, preferably in the range of 5 to 15% by weight, more preferably in the range of 8 to 15% by weight. The preferred filling agent is maltodextrin.

In another aspect, the present invention discloses a method developed in order to produce a pharmaceutical granule formulation comprising levocetirizine.

The method according to the present invention comprises granulating the active agent mixture with the granulation solution comprising minimum 50% of deionised water by weight, drying and sieving the granules obtained.

The present invention also comprises drying the granules obtained effectively.

One characteristic feature of the production method of the present invention is that said method is wet granulation method. Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises minimum 50% of water in proportion to total solution weight.

Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises minimum 50% of water in proportion to total weight of the solution, a pharmaceutically acceptable filling agent and/or a binder.

Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises water in the range of 50% to 70% in proportion to total weight of the solution, a pharmaceutically acceptable filling agent and/or a binder.

One characteristic feature of the production method of the present invention is that said method is composed of the following steps:

1. Preparing the active agent mixture,

2. Preparing the granulation solution by mixing minimum 50% of water by weight and a pharmaceutically acceptable binder and/or a filling agent,

3. Wet granulating the mixture obtained in the first step with this granulation solution,

4. Drying and sieving the granules.

Another characteristic feature of the production method of the present invention is that said method is composed of the following steps:

1. Obtaining the active agent mixture by mixing levocetirizine and/or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient,

2. Preparing the granulation solution by mixing minimum 50% of deionised water by weight and a pharmaceutically acceptable binder and/or a filling agent,

3. Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator preferably at a temperature in the range of 20 °C to 60 °C, more preferably at a temperature in the range of 30 °C to 50 °C,

4. Drying and sieving the granules obtained in a fluid bed dryer at a drying temperature in the range of 50 °C to 90 °C, preferably in the range of 50 to 70 °C

5. Sending the dry granules to tablet compression machine for tablet compression. Moisture content of the granules obtained this way has been measured by Karl Fischer method (Metrohm, Karl Fischer reactive 25 °C) and it has been found that moisture content of said granules is 0.16 on average in proportion to total granule weight (See Table III).

Table III. Moisture content results-II

Levocetirizine granules produced by the production method according to the present invention and stored under specific conditions (at 25 °C and under 60% of relative humidity for 12 weeks) and average impurity values of piperazine derivative of said granules are given below (See Table IV).

Table IV. Degradation Study Results - II

As seen, the granules produced according to the present invention can surprisingly remain stable longer than the granules produced by wet granulation method existing in the prior art.

In the scope of the present invention, it has also been found that granulation and granule drying temperatures have an important effect on stability of the end product. It has been found that it is advantageous to have the drying temperature of the granule product is more than 50 °C during granulation process. When very high temperatures are used in order to vaporize the granulation solution used especially after granulation process, additional degradations are observed in the active agent and other excipients.

In one aspect, the present invention discloses wet granulation of the mixture comprising levocetirizine as the active agent and at least one other excipient in fluid bed granulator at a temperature in the range of 20 °C - 60 °C, more preferably in the range of 30 °C - 50 °C.

In one aspect, the present invention discloses drying the granules obtained at a drying temperature in the range of 50 °C to 90 °C, preferably in the range of 50 to 70 °C.

The temperature is generally in the range of 50 °C -90 °C, preferably in the range of 50 °C - 70° C for obtaining a stable levocetirizine granule according to the production method of the present invention.

The formulations according to the present invention can be combined with a second active agent. Nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants can be listed as the second active agent.

Dosage forms can be taken separately, together or successively as well as taken in a single dosage form combining levocetirizine with the other active agent or agents for combined treatment.

The antihistaminics that can be used in the formulations of the present invention are selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, tripleamine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastin, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.

The leukotriene receptor antagonists that can be used in the formulations of the present invention are selected from a group comprising montelukast, zafirlukast and zileuton or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof, preferably montelukast sodium.

The examples of the formulation of the present invention are given below. These examples are given in order to elucidate the subject of the present invention. Yet the present invention is not limited to these examples. EXAMPLES

Example 1. Effervescent levocetirizine dihydrochloride granules a. Active Agent Mixture

b. Granulation Solution

The method to be followed in order to prepare effervescent levocetirizine dihydrochloride granules is preferably as follows:

1. Mixing levocetirizine dihydrochloride and sweetener, flavouring agent and at least one pharmaceutically acceptable excipient and preparing active agent mixture by adding an effervescent mixture into this mixture,

2. Preparing the granulation solution by mixing deionised water and binder and filling agent in the amounts given in order to prepare the granulation solution,

3. Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator at 40 °C,

4. Drying the granules obtained in a fluid bed dryer at the drying temperature of 65°C,

5. Sending the dried granules to tablet compression machine for tablet compression.

Example 2. Levocetirizine dihydrochloride granules

a. Active Agent Mixture

a. Granulation solution

The method to be followed for preparation of levocetirizine dihydrochloride granules is preferably as follows:

1. Mixing levocetirizine dihydrochloride, at least one pharmaceutically acceptable diluent and anti-adhesive agent,

2. Granulating the mixture obtained with the granulation solution in the composition given above,

3. Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator (Fluid Bed Dryer) at 45 °C,

4. Drying the granules obtained in a fluid bed dryer at 60 °C,

5. Compressing the dry granules in tablet form.

Claims

1. Pharmaceutical granules comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof and at least one pharmaceutically acceptable excipient, characterized in that moisture content of the granules is maximum 1% in proportion to total granule weight.

2. The pharmaceutical granules according to claim 1, characterized in that moisture content of the granules is in the range of 0.1 to 1% by weight in proportion to total granule weight.

3. The pharmaceutical granules according to claim 1, characterized in that said granules comprise levocetirizine dihydrochloride in the range of 0.1 to 10% by weight.

4. The pharmaceutical granules according to claim 3, characterized in that said granules comprise levocetirizine dihydrochloride in the range of 0.1 to 5% by weight.

5. The pharmaceutical granules according claim 1, characterized in that pharmaceutically acceptable excipients are selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavouring agents, taste masking agents, diluents, binders, glidants, wetting agents, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners or combinations thereof.

6. The pharmaceutical granules according to any preceding claims, characterized in that said granules are used in production of a pharmaceutical dosage form appropriate for oral intake.

7. The pharmaceutical granules according to claim 6, characterized in that said granules are in solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet, modified, fast, slow, controlled, prolonged release tablets, orodispersible tablet, mini tablet, microtablet, pellet; or in multiple dosage forms comprising one or more of these dosage forms or in liquid dosage forms such as suspension dosage forms.

8. A production method for the pharmaceutical granules according to any preceding claims, characterized in that said production method is composed of the following steps:

a) Preparing the active agent mixture, b) Preparing a granulation solution by mixing minimum 50% of water in by weight and at least one pharmaceutically acceptable binder and/or a filling agent,

c) Wet granulating the mixture obtained in the first step with this granulation solution,

d) Drying and sieving the granules.

9. The production method according to claim 8, characterized in that said method is composed of the steps of:

a) Preparing the active agent mixture by mixing levocetirizine and /or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient,

b) Preparing the granulation solution by mixing minimum 50% of deionised water by weight and a pharmaceutically acceptable binder and/or a filling agent, c) Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator at a temperature in the range of 20 °C to 60 °C,

d) Drying and sieving the granules obtained in a fluid bed dryer at a temperature in the range of 50 °C to 90 °C,

e) Sending the dry granules to tablet compression machine for tablet compression.

10. The method according to claims 8-9, characterized in that granulation solution comprises water in the range of 50 to 70% by weight.

1 1. The method according to claims 8-9, characterized in that the temperature of the fluid bed granulator is preferably in the range of 30 °C - 50 °C.

12. The method according to claims 8-9, characterized in that drying temperature is in the range of 50 to 70 °C.

13. The pharmaceutical granule according to any preceding claims, characterized in that said granule is used in combined form with a second active agent.

14. The pharmaceutical granule formulation according to claim 13, characterized in that the second active agent is selected from a group comprising nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants.

15. The granules according to claim 1, characterized in that said granules are used in production of a drug for treatment of allergic rhinitis, persistent allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria.