WO2011146032A2

WO2011146032A2 - Effervescent formulations

Info

Publication number: WO2011146032A2
Application number: PCT/TR2011/000112
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2010-05-18
Filing date: 2011-05-16
Publication date: 2011-11-24
Also published as: WO2011146032A3; EP2571484A2

Abstract

The present invention relates to stable levocetirizine effervescent formulations flavor and taste of which is improved, and method for preparation of said formulations.

Description

EFFERVESCENT FORMULATIONS

The present invention relates to stable levocetirizine effervescent formulations flavor and taste of which has been improved in order to be used in the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, chronic idiopathic urticaria, and the methods for preparation of said formulations.

Background of the Invention

Levocetirizine is a non-sedating, long-acting HI anti-histaminic displayed in formula (I) below which has the chemical name 2-[2-[4-[(i?)-(4-chlorophenyl)-phenyl-methyl]piperazin- l-yl]ethoxy] acetic acid (Formula I).

(I)

Cetirizine was first disclosed in the patent numbered EP0058146 Al.

Levocetirizine which is an R-enantiomer of cetirizine is a piperazine derivative, potent and selective HI receptor antagonist. Levocetirizine is a new anti-histaminic that binds to HI receptors with high affinity, even twelve times higher than cetirizine. Levocetirizine competes with histamine and prevents histamine to bind to HI receptors. This antagonism blocks the effects of histamine on gastrointestinal channel, uterus, large blood vessels and bronchial smooth muscle. Blockage of HI receptors impedes histaminic activities such as edema, warmness and itchiness. The facts that levocetirizine does not enter the central nervous system in significant amounts and its affinity to HI receptors there is low can explain its non-sedating characteristics to some extent.

Levocetirizine has antiallergic and anti-inflammatory activity. The studies conducted have presented that levocetirizine inhibits the wide range of chain of events starting and spreading out the allergic inflammation. Levocetinzine formulations existing in the prior art are in oral solution, oral drop and film tablet form. As it is known, solid dosage forms such as tablets have lower bioavailability than solution forms and they generally pose difficulty of use for geriatric, pediatric and physically handicapped patients who have swallowing difficulties. Oral solution and suspension forms produced as an alternative to these forms, on the other hand, are not preferable much as the stability of active agents cannot be maintained for long in these forms and they have short shelf life. Another disadvantage of these forms is that they have a risk of high and/or uncontrolled dose intake in pediatric and geriatric patients.

Another alternative in terms of dosage forms is effervescent forms which satisfy the expectations of bioavailability, shelf life, ease of use and carrying and accurate dosing.

Effervescent forms are more advantageous than conventional forms owing to fast dispersion.

Effervescent formulations disperse fast; emit the component/components simultaneously and rapidly into aqueous liquid. The time which passes between adding the formulation into water and swallowing the solution is relatively short. Consumption of the formulations in a short time prevents the degradation of the active agent with water and thus, this type of formulations that are consumed in a short time do not require high amounts of stabilizing agent.

Another significant problem about levocetirizine formulations is that it is hard to formulate them due to the bitter taste of the active agent and its difficulty of use by patients. There exist some propositions for solution of this problem. These propositions are generally on use of various pharmaceutical excipients such as sweeteners, flavoring agents or aroma in formulations of levocetirizine. Most often, use of sweeteners only is not enough to mask the bitter taste in the formulations. To this end, some other excipients are used in addition to sweeteners. The most frequently used excipients for this purpose are sugar alcohols such as mannitol, sorbitol; sugars such as sucrose, fructose; polyols such as cyclodextrins. However, as the use of polyol was clearly explained in the European patent application numbered EP 0 811 375, it reacts with levocetirizine and conduces to production of undesirable by-products especially in the presence of water and/or at high temperature. This brings along the necessity to select the suitable excipient combination and production method in order to prevent disintegration of levocetirizine caused by its reaction with said excipients, in other words, to provide stability of levocetirizine in the pharmaceutical form of the present invention. Consequently, there is need for pharmaceutical formulations comprising levocetinzine and/or pharmaceutically acceptable salts thereof which are easy to use and carry; have high bioavailability and long shelf life.

Description of the Invention The present invention relates to user-friendly levocetirizine formulations having high bioavailability bitter taste of which are masked and which can be produced without conducing to undesirable by-products, and the production method of said formulations. The inventors have surprisingly masked the bitter taste by using at least one polyol and/or derivative thereof in the formulations and managed to produce stable formulations of levocetirizine. The formulations of the present invention are characterized in being in effervescent form.

A characteristic feature of formulations of the present invention is that polyol derivative excipients can be included in the formulations of the present invention without conducing to any stability problem resulting from their interaction with cetirizine derivatives.

Use of the polyol derivative excipients utilized in the formulations of the present invention for different purposes such as bulking agent is also known in the prior art in addition to their sweetening and/or taste masking functions. Polyol derivatives used in the formulations of the present invention can fulfill one or more functions at the same time.

The formulations of the present invention comprise levocetirizine or pharmaceutically acceptable salt, ester, solvate, derivative, polymorph or hydrate thereof as the active agent. The formulations of the present invention are used in the treatment of allergic rhinitis (including seasonal allergic rhinitis comprising ocular symptoms), persistent allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria.

The purpose of the present invention is to produce an effervescent tablet which provides ease of administration by the oral route in aqueous solution form. The formulation rapidly disperses in the aqueous liquid and it can be administered by the oral route, by spoon or dropper where necessary. This type of formulations are more advantageous for use especially in physically handicapped and elderly patients. The formulations of the present invention comprise the following constituents:

• Active agent in an amount in the range of 0.1 % to 80% by weight,

• At least one effervescent couple in an amount in the range of 60% to 90% by weight,

• At least one pharmaceutically acceptable polyol and/or derivative thereof in an amount in the range of 1 % to 30% by weight,

• At least one pharmaceutically acceptable sweetener in an amount in the range of 5% to 30% by weight,

• At least one pharmaceutically acceptable flavoring agent in an amount in the range of l% to 10% by weight,

· At least one pharmaceutically acceptable solvent in an amount in the range of 5% to 20% by weight,

Polyol derivative excipients which can be used in the formulations of the present invention can be selected from a group comprising xylitol, mannitol, sorbitol, dextrose, sucrose, lactose, maltodextrin, alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins and polysaccharides. The polyol derivative excipients used in the formulations of the present invention are preferably sorbitol and maltodextrin.

The sweeteners which can be used in the formulations of the present invention can be selected from a group comprising synthetic and natural sugars; sucrose, sucralose, saccharine, aspartame, acesulfame, thaumatin, dextrose, mannitol, maltitol, lactose, xylitol, isomalt, isomaltol, lactitol, eryhtrol, maltodextrin, alpha, beta and gamma cyclodextrins, dihydrochalcone, alitam, sorbitol, sodium cyclamate, miraculin, monellin, steviocide and/or pharmaceutically acceptable salts thereof. The sweeteners used in the formulations of the present invention are preferably aspartame and acesulfame potassium.

The pharmaceutical formulations of the present invention comprise other pharmaceutically acceptable additives and excipients selected from a group comprising disintegrants, viscosity enhancers, filling materials, drying agents, lubricants, diluents, binders, glidants, anti-foam agents, wetting agents, effervescent mixtures, sweeteners and flavoring agents.

Effervescent formulations of the present invention comprise levocetirizine in an effective amount, an effective effervescent couple, at least one sweetener and at least another excipient. The term of "effervescent couple" used throughout text refers to a mixture which comprises at least one pharmaceutically acceptable effervescent acid and at least one effervescent base. The effervescent acids which can be used in the formulations of the present invention comprise citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid and/or their pharmaceutically acceptable salts, hydrates, anhydrates or optionally a mixture thereof.

The effervescent bases which can be used in the formulations of the present invention comprise sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.

The effervescent couple used in the formulations of the present invention is preferably composed of hydrogen carbonate and citric acid.

The disintegrant which can be used in the present invention can be selected from polymers having high disintegrating characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, the products known as Crospovidone®, Polyplasdone® or Kollidon® XL, alginic acid, sodium alginate.

The binders which can be used in the present invention can be selected from a group comprising potato starch, wheat starch or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, sorbitol, hydroxyethyl cellulose; hydroxypropylmethyl cellulose, for instance hydroxypropylmethyl cellulose- Type 2910 USP; hypromellose and polyvinylpyrrolidone.

The flavoring agents which can be used in the formulation of the present invention can be banana, strawberry, lemon, orange, peach, vanilla, blackberry or a similar natural fruit or an aromatic plant flavor. The flavoring agent used in the effervescent formulations of the present invention is preferably blackberry flavor.

The filling materials which can be used in the formulations of the present invention can be selected from a group comprising talc, calcium carbonate, microcrystalline cellulose, powderized cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, maltodextrin or a combination thereof.

The lubricants which can be used in the present invention can be selected from a group comprising one or more components selected from the group comprising metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearil fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.

The effervescent formulations of the present invention can be produced by methods known in the prior art. However, said substances are added into the formulation in particular steps and at specified ratios and manufacturing conditions are selected carefully in order not to cause side reactions of the active agent with polyol group excipients.

The method proposed for production of the formulations of the present invention is preferably wet granulation method and it basically comprises the following steps: a. Preparation of the granulation solution,

b. Granulation,

c. Drying and sieving,

d. Tablet compression.

The granulation solution to be used in the production of the formulations of the present invention comprise a pharmaceutically acceptable solvent in an effective amount and at least one polyol derivative excipient.

Polyol derivative excipients used in the granulation solution are preferably sorbitol and maltodextrin.

10%-50%, preferably %10-%20 of total amount of the maltodextrin and 5%-50%, preferably %10-%30 of total amount of sorbitol by weight used in the formulations are used in the first step as mixed with a pharmaceutically acceptable solvent for preparation of the granulation solution.

The pharmaceutically acceptable solvent used in the granulation solution is preferably deionized water and it is present in the granulation solution in an amount in the range of 10%- 80%, preferably 10% to 70%, more preferably 10% to 60 by weight.

In the second step, an effective amount of levocetirizine dihydrochloride, at least one effervescent couple, rest of maltodextrin and sorbitol some of which are used in the first step and at least one sweetener are mixed. This mixture comprising the active agent is granulated with the granulation solution obtained in the first step. The granules obtained are dried so as to obtain granules having moisture content of the up to % 0.5 by weight and sieved. Preferred temperature for drying is 50-80 °C, preferably 50- 70°C.

At least one flavoring agent is added into the sieved granules and the blend is mixed again. The final mixture is prepared and sent to tablet compression machine.

Not all of the polyol derivative compounds used in the effervescent levocetirizine formulations of the present invention are directly mixed with the active agent. Some part of the polyol derivative compounds is absorbed in the granulation solution and included in the formulation this way. It is seen from the present invention that the content of the granulation solution and also conditions of the granulation play an important role on the preparation of the stable levocetirizine formulations.

Thus, direct contact of the active agent with polyol derivative excipient is impeded in the effervescent levocetirizine formulation of the present invention and gelling of the medicament formulation as a result of undesirable reaction is successfully prevented. The examples below are given to explain the present invention. These examples are evaluated with the description part given in detail hereinabove but they do not restrict the scope of said invention.

EXAMPLES

Example 1. Effervescent formulation comprising levocetirizine

Claims

1. A pharmaceutical formulation comprising levocetirizine and/or a pharmaceutically acceptable salt thereof as the active agent characterized in that said formulation is in effervescent form.

2. The effervescent formulation according to claim 1, wherein said formulation comprises levocetirizine dihydrochloride in an effective amount.

3. The effervescent formulation according to claim 1, wherein said formulation is composed of levocetirizine dihydrochloride in an effective amount, at least one effervescent couple, at least one pharmaceutically acceptable polyol derivative excipient, at least one sweetener, at least one flavoring agent, at least one binder and at least another excipient.

4. The pharmaceutically acceptable polyol derivative excipient according to claim 3, wherein said pharmaceutically acceptable polyol derivative excipient is selected from a group comprising xylitol, mannitol, sorbitol, dextrose, sucrose, lactose, maltodextrin, alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins and polysaccharides and/or combinations thereof.

5. The pharmaceutically acceptable polyol derivative excipient according to claim 4, wherein said pharmaceutically acceptable polyol derivative excipient is maltodextrin and sorbitol.

6. The effervescent formulation according to claim 1, wherein said formulation comprises maltodextrin and sorbitol preferably in the range of 1% to 30%, more preferably in the range of 1% to 20% by weight.

7. The effervescent couple according to claim 3, wherein said effervescent couple comprises citric, monosodium citrate, tartaric acid, fumaric acid, malic acid and/or their pharmaceutically acceptable salts, hydrates, anhydrates or preferably a mixture thereof as the organic acid; and comprises sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate as the basic agent.

8. The effervescent couple according to claim 7, wherein said effervescent couple is preferably citric acid and sodium bicarbonate.

9. The sweetener according to claim 3, wherein said sweetener is seleceted from a group comprising synthetic and natural sugars; sucrose, sucralose, saccharine, aspartame, acesulfame, thaumatin, dextrose, mannitol, maltitol, lactose, xylitol, isomalt, isomaltol, lactitol, eryhtrol, maltodextrin, alpha, beta and gamma cyclodextrins, dihydrochalcone, alitam, sorbitol, sodium cyclamate, miraculin, monellin, steviocide and/or pharmaceutically acceptable salts thereof.

10. The sweetener according to claim 9, wherein said sweetener is preferably aspartame and acesulfame potassium.

11. A production method for an effervescent formulation according to any preceding claims, wherein said method comprises the following steps respectively:

a. Preparation of the granulation solution by mixing an organic solvent in an effective amount with some part of sorbitol and maltodextrin

b. Granulation of the mixture obtained by mixing levocetirizine dihydrochloride, at least one effervescent couple, the rest of maltodextrin and sorbitol remained from the first step with the granulation solution obtained in the first step c. Drying and sieving the granules obtained

d. Loading the dry granules in tablet compression machine and compression of effervescent tablets.

12. The production method according to claim 11, wherein said method comprises granulation solution, 10%-50% of total amount of maltodextrin and 5%-50% of total amount of sorbitol by weight used in the pharmaceutical formulations.

13. The effervescent formulation according to any one of preceding claims, wherein said formulation is used in production of a medicament so for treatment of allergic rhinitis (including seasonal allergic rhinitis comprising ocular symptoms), persistent allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria.