A solid pharmaceutical composition comprising bilastine

Abstract

The present invention relates to a pharmaceutical composition comprising bilastine or a pharmaceutically acceptable salt thereof and a superdisintegrant wherein bilastine or pharmaceutically acceptable salt thereof is used in the specific d90 values to obtain an improved solubility and dissolution properties.

Description

[0001]DESCRIPTION A SOLID PHARMACEUTICAL COMPOSITION COMPRISING BILASTINE Field of Invention The present invention relates to a pharmaceutical composition comprising bilastine or a 5 pharmaceutically acceptable salt thereof and a superdisintegrant wherein bilastine or pharmaceutically acceptable salt thereof is used in the specific d90values to obtain an improved solubility and dissolution properties. Background of the Invention 10 Bilastine has a chemical name as 2-[4-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidin-1- yl]ethyl]phenyl]-2-methylpropanoic acid and its chemical structure is shown below, which is developed by Faes Farma. Bilastine has molecular weight of 463.6 g / mol. 15 Bilastine The brand name of bilastine is Bilaxten, which is used to relieve the symptoms of hayfever (sneezing, itchy, runny, blocked-up nose and red and watery eyes) and other forms of allergic rhinitis. It may also be used to treat itchy skin rashes (hives or urticaria). 20 It is also approved for children from 6 years of age with a body weight of at least 20 kg and also indicated in adults and adolescents. Histamine has a very common role to treatment allergic-type diseases, such as allergic rhinitis, conjunctivitis, rhinoconjunctivitis, dermatitis, urticaria and asthma for a long time. EP3453384 relates to a pharmaceutical composition in the form of a tablet, comprising a 25 crystalline form of bilastine. EP3470062 relates to a pharmaceutical tablet composition, comprising bilastine and magnesium aluminometasilicate, wherein bilastine is present in crystalline form. A pharmaceutical composition may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients examples can be filler, disintegrant, superdisintegrants, binder, surfactant, lubricant, solvent, antiadherent, flavor, glidant, preservative, sweetener, suspending / viscosity agent, diluent, colorant and the mixtures thereof. 5 According to the United States Pharmacopeia (USP / NF), superdisintegrants are defined as “highly effective disintegrants that, when used at low levels, provide rapid disintegration and dissolution of the tablet or capsule dosage form” (USP 41-NF 36 General Chapter <2040> Superdisintegrants). The oral dispersible tablet dosage form is a solid dosage form containing medicinal substances that disintegrate rapidly, usually within a few seconds, when placed on the tongue. The oral 10 dispersible tablet is designed to rapidly disintegrate or dissolve upon contact with saliva. This eliminates the need to chew the tablet, swallow a solid tablet or take the tablet with liquid. This application was initially expected to benefit paediatric and geriatric patients, people with swallowing disorders and the treatment of patients where compliance may be difficult (e.g. for psychiatric disorders). Subsequently, the use of oral dispersible tablets became widespread due 15 to their ease of use. Characteristics exhibited by early products included low tablet weight, small tablet size, highly soluble ingredients and rapid disintegration. These characteristics support the intended use of these products. Brief Description of the Invention The present invention relates to a pharmaceutical composition comprising bilastine or a 20 pharmaceutically acceptable salt thereof and a superdisintegrant, wherein bilastine or pharmaceutically acceptable salt thereof is used in the specific d90 values and superdisintegrant presents in a specific ratio in the total tablet weight. The present invention relates to an oral dispersible tablet composition comprising bilastine or a 25 pharmaceutically acceptable salt thereof and a superdisintegrant, characterized in that the particle size distribution of the bilastine or a pharmaceutically acceptable salt thereof is 10 µm ≤ d (90) ≤ 90 µm and superdisintegrant having a concentration of 5-25% (w / w). 30 More preferably particle size distribution of bilastine or a pharmaceutically acceptable salt thereof can be 20 µm ≤ d (90) ≤ 70 µm. A process for preparing solid pharmaceutical composition of the present invention, said process comprises the steps below: a. Sieving bilastine or a pharmaceutically acceptable salt thereof, filler, superdisintegrant and a flavour, b. Mixing the substances from step a, c. Adding aroma and lubricant to step b, 5 d. Tablet compression. Detailed Description of the Invention The present invention relates to preparation of pharmaceutical compositions comprising bilastine 10 in the treatment of allergic-type diseases. The present invention relates to preparation of pharmaceutical compositions comprising bilastine or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients. 15 The present invention relates to preparation of pharmaceutical compositions comprising bilastine and one or more pharmaceutically acceptable carriers or excipients, wherein the particle size distribution of the bilastine is in the specific values. 20 The present invention relates to preparation of pharmaceutical compositions comprising bilastine and one or more pharmaceutically acceptable carriers or excipients, comprising a superdisintegrant. The present invention relates to preparation of pharmaceutical compositions comprising bilastine 25 and one or more pharmaceutically acceptable carriers or excipients, comprising a superdisintegrant in a specific ratio on the total weight of the tablet. In this invention, an oral dispersible tablet composition comprising bilastine or a pharmaceutically acceptable salt thereof and a superdisintegrant, 30 characterized in that the particle size distribution of the bilastine or a pharmaceutically acceptable salt thereof is 10 µm ≤ d (90) ≤ 90 µm and superdisintegrant having a concentration of 5-25% (w / w). In this invention, it is obtained pharmaceutical compositions comprising bilastine wherein the 35 particle size distribution of the bilastine is 10 µm ≤ d (90) ≤ 90 µm. In this invention, it is obtained pharmaceutical compositions comprising bilastine wherein the particle size distribution of the bilastine is 20 µm ≤ d (90) ≤ 70 µm. The aspects and disclosures according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to the bilastine or a pharmaceutically acceptable salt thereof as defined hereinbefore and hereinafter. 5 As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic 10 properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. In this invention, it is obtained pharmaceutical compositions comprising bilastine and a 15 superdisintegrant having a minimum concentration of 5% (w / w). In this invention, it is obtained pharmaceutical compositions comprising bilastine and a superdisintegrant having a concentration from 5.0% to 25% (w / w). 20 The present invention relates to preparation of pharmaceutical compositions comprising bilastine and one or more pharmaceutically acceptable carriers or excipients, comprising a superdisintegrant may be selected from croscarmellose sodium, alginic acid and its derivatives, L-Hydroxy propyl cellulose, crospovidone, sodium starch glycolate and other materials known to one of ordinary skill in the art. 25 The present invention relates to preparation of pharmaceutical compositions comprising bilastine and one or more pharmaceutically acceptable carriers or excipients, comprising croscarmellose sodium as a superdisintegrant. 30 The present invention relates to a process for pharmaceutical composition comprising bilastine or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fillers, disintegrants, superdisintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof. 35 The value d90 refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d90 value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, in the d90 describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size. One can determine the average particle size of a solid from a knowledge of its surface area per unit weight and its density. The term “(w / w)” as used herein, refers to a percentage by weight compared to the total weight 5 of the composition considered. A pharmaceutical composition according to the invention is considered "stable", if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of bilastine, is maintained over said period of time. 10 As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. 15 Lubricants can also be used in the process. Lubricants are used for preventing adhesion of the tablet material to the surfaces of the die and punches. This helps to reduce the wear and tear on the tableting equipment and to prevent the formation of tablet defects, such as cracks or chips. Suitable lubricants according to the present invention include, but are not limited to, calcium 20 stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol. The preferred lubricant is sodium stearyl fumarate. Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium 25 phosphate, tricalcium phosphate, magnesium trisilicate, lactose such as example the anhydrous form or the hydrate form such as the monohydrate form, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non-hygroscopic are preferred, with non- 30 hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries. The preferred filler is mannitol. The present invention is described in the following example in more details. This example is not limiting the scope of the present invention and is to be considered under the light of the foregoing 35 detailed description. Superdisintegrants can also be used in the process. Superdisintegrants are used for disintegrating tablets into fine particles in gastric and intestinal fluid, so that the other components of the composition can be quickly dissolved and absorbed to have a desired effect. Most of these substances have good water absorption and expansion, so as to achieve the disintegration of tablets. Suitable superdisintegrants for this inventive formulation can be selected from the group, but are 5 not limited to, alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, sodium starch glycolate, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinized starch, sodium alginate, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used. 10 The preferred disintegrant is croscarmellose sodium. Preferably, active ingredient in the present invention composition is bilastine or a pharmaceutically acceptable salt thereof. More preferably is bilastine. 15 The particle size of bilastine or a pharmaceutically acceptable salt thereof can be 10 µm ≤ d (90) ≤ 90 µm. More specifically it can be 20 µm ≤ d (90) ≤ 70 µm. Even more specifically, it can be 30 µm ≤ d (90) ≤ 60 µm. In this invention, bilastin D90 value and superdisintegrant are very critical. Superdisintegrant and 20 bilastin D90 value should be selected with given ratio and properties. In this invention, manufacturing process generally consisting of four stages: a) Sieving and mixing, b) Mixing, c) Adding aroma and lubricant, d) Tablet compression. 25 In another preferred embodiment, the pharmaceutical composition according to invention: Table 1: Bilastine compositions Ingredients % weight Bilastine or a pharmaceutically acceptable salt thereof 5.00%-15.00% One or more fillers 60.00%-90.00% One or more superdisintegrants 5.00%-25.00% One or more flavours 0.10%-1.00% One or more aromas 0.10%-1.00% One or more lubricants 0.50%-2.50% Total 100.00% A process for preparing solid pharmaceutical composition of the present invention, said process comprises the steps below: a. Sieving bilastine or a pharmaceutically acceptable salt thereof, filler, superdisintegrant and a flavour, 5 b. Mixing the substances from step a, c. Adding aroma and lubricant to step b, d. Tablet compression. In other embodiment solid pharmaceutical compositions of the present invention are prepared 10 by direct compression, dry granulation or wet granulation. Preferably, by direct compression. A process for preparing solid pharmaceutical composition of the present invention, said direct compression process comprises the steps below: a. Sieving bilastine or a pharmaceutically acceptable salt thereof, filler, 15 superdisintegrant and a flavour, b. Mixing the substances from step a, c. Adding aroma and lubricant to step b d. Tablet compression. Dispersion time 20 Superdisintegrant ratio is critical for this composition comprising bilastine. It effect dispersion time of this pharmaceutical product. Rapid dispersion feature is an important criterion for orally dispersible tablets. When superdisintegrant is used below 5% (w / w) in the composition, the dispersion time is over one minute. (Table 2) 25 Table 2: Pharmaceutical composition comprising bilastine and relevant excipients Ingredients % weight Bilastine or a pharmaceutically acceptable salt thereof 5.00%-15.00% One or more fillers 60.00%-90.00% One or more superdisintegrants 4.00% One or more flavours 0.10%-1.00% One or more aromas 0.10%-1.00% One or more lubricants 0.50%-2.50% Total 100.00% However, if superdisintegrant is used above 5% (w / w), the dispersion time is at the desired value, that is, less than a minute. (Table 3) The present invention provides rapid disintegration time using a superdisintegrant used at above 5% (w / w) in the composition. (Table 3) 5 Table 3: Pharmaceutical composition comprising bilastine and relevant excipients Ingredients % weight Bilastine or a pharmaceutically acceptable salt thereof 5.00%-15.00% One or more fillers 60.00%-90.00% One or more superdisintegrants 5.00%-25.00% One or more flavours 0.10%-1.00% One or more aromas 0.10%-1.00% One or more lubricants 0.50%-2.50% Total 100.00% In another preferred embodiment, the pharmaceutical composition according to invention: Table 4: Pharmaceutical composition comprising bilastine and relevant excipients Ingredients % weight Bilastine or a pharmaceutically acceptable salt thereof 5.00%-15.00% One or more fillers 60.00%-90.00% Croscarmellose sodium 10.00% One or more flavours 0.10%-1.00% One or more aromas 0.10%-1.00% One or more lubricants 0.50%-2.50% Total 100.00% 10 Advantages The major obstacle to be overcome in the development of an oral pharmaceutical composition of the bilastine product is to improve the solubility of the composition. However, the developed pharmaceutical composition must be able to be maintained solubility properties and stability throughout the shelf life. 15 In this invention, using suitable superdisintegrant with specific concentration in the composition, the oral dispersible tablet could be dispersed as desired, and the desired solubility was achieved with the desired dispersion. These ideal dispersion and solubility properties ensure that the desired product performance is achieved both in-vitro and in-vivo. In this invention, by selecting bilastin D90 value smaller than 90 microns, the contact surface of Bilastine with water is increased, thus it is aimed to obtain faster dissolution. In this invention, by selecting bilastin d90value greater than 10 microns, possible homogeneity 5 problems that may be observed in the product were prevented. The pharmaceutical compositions of the invention are particularly shows similar property in the stability and dissolution, it is extremely useful as a pharmaceutical product preparation technique. It effects on many specifications during determining and designing manufacturing process for pharmaceutical products. 10 When the physical and chemical test results of the pharmaceutical composition obtained by using specific PSD value of bilastin and superdisintegrant are evaluated, it has been observed that it has positive effect on the manufacturing process. The pharmaceutical compositions of the invention are particularly suited for the oral administration. 15 The pharmaceutical compositions of the invention are particularly shows similar property in the stability and dissolution, it is extremely useful as a pharmaceutical product preparation technique. The present invention provides pharmaceutical composition comprising bilastine and relevant excipients, characterized by i) A simple and exclusive manufacturing process 20 ii) Stable formulation Dispersible tablet dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance. Dissolution Test 25 In this invention, the dissolution test has been performed for Bilastine 20 mg Dispersible Tablet in pH 4.5 acetate buffer. It is shown in Table 5. Drug release for the test product were found to be satisfactory. Table 5: Summary of Dissolution Result of Bilastine 20 mg Dispersible Tablet in pH 4.5 acetate buffer Time Mean % Drug Release (min.) Bilastine 20 mg Dispersible Tablet (Test Product) 5 80 10 94 30 100 45 100 60 100 Stability data Pharmaceutical products comprising bilastine prepared according to the invention were tested for stability in below storage conditions: 5 25°C ± 2°C / %60 RH ± %5 RH 30°C ± 2°C / %65 RH ± %5 RH 40°C ± 2°C / %75 RH ± %5 RH Result of the stability study indicates that present bilastine composition in accordance with the present invention exhibits excellent storage stability. 10 During the stability period, the product was found to comply with specifications.

Claims

CLAIMS 1. An oral dispersible tablet composition comprising bilastine or a pharmaceutically acceptable salt thereof and a superdisintegrant, characterized in that the particle size distribution of the bilastine or a pharmaceutically 5 acceptable salt thereof is 10 µm ≤ d (90) ≤ 90 µm and superdisintegrant having a concentration of 5-25% (w / w).

2. The pharmaceutical composition according to claim 1, characterized in that the particle size distribution of the bilastine or a pharmaceutically acceptable salt thereof is 20 µm ≤ d (90) ≤ 70 µm.

3. The pharmaceutical composition according to any preceeding claims, wherein the particle size of the bilastine is 30 µm ≤ d (90) ≤ 60 µm.

4. The pharmaceutical composition according to any of the preceding claims, wherein superdisintegrant having a concentration from 5.0% to 15% (w / w).

5. The pharmaceutical composition according to any preceeding claims, wherein said superdisintegrant is selected from crospovidone, sodium starch glycolate and croscarmellose sodium or mixture thereof.

6. The pharmaceutical composition according to claim 1, for use in the treatment of allergic-type diseases.

7. Method for preparing the composition according to Claim 1 comprising steps of a. Sieving bilastine or a pharmaceutically acceptable salt thereof, filler, superdisintegrant and a flavour, b. Mixing the substances from step a, c. Adding aroma and lubricant to step b, d. Tablet compression.

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