Claims:WE CLAIM:

1. Stable pharmaceutical composition of Bilastine, wherein the composition comprises Bilastine crystalline Form 3, water insoluble diluent, disintegrant and one or more pharmaceutically acceptable excipients.

2. Stable pharmaceutical composition of Bilastine according to Claim 1, wherein water insoluble diluent is selected from the group comprising of microcrystalline cellulose, dicalcium phosphate, starch and its derivatives like powdered starch, corn starch, wheat starch, maize starch, potato starch, pregelatinized starch, calcium silicate and combinations thereof.

3. Stable pharmaceutical composition of Bilastine according to Claim 1, wherein one or more pharmaceutically acceptable excipients are selected from binder, lubricant and glidant.

4. Stable pharmaceutical composition of Bilastine according to Claim 1, wherein the composition is free of water soluble excipient.

5. Stable pharmaceutical composition of Bilastine according to Claim 1, wherein Bilastine crystalline Form 3 is present in an amount of about 4-8% w/w, water insoluble diluent in an amount of about 60-90% w/w, disintegrant in an amount of about 1-10% w/w, lubricant in an amount of about 0.1 to 4.0 % w/w and glidant in an amount of about 0.1-4.0 % w/w.

5. A process for preparing stable pharmaceutical composition of Bilastine, wherein the process is direct compression process and bilastine is crystalline Form 3.

6. A process according to Claim 5, wherein the composition is free of water soluble excipient.

7. Stable pharmaceutical composition of Bilastine according to Claim 3, wherein lubricant is selected from the group comprising of stearic acid, magnesium stearate, sodium stearyl fumarate, fumaric acid, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, and combinations thereof.

8. Stable pharmaceutical composition of Bilastine according to Claim 3, wherein glidant is selected from the group comprising of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof. , Description:FILED OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of H1 receptor antagonist. Specifically the invention relates to stable pharmaceutical compositions of Bilastine and method of preparing them. The invention further relates to stable pharmaceutical composition in the treatment of allergic rhino-conjunctivitis and/or urticaria.
BACKGROUND OF INVENTION
Bilastine is a second generation non-sedating, long-acting antihistamine with selective peripheral Hi receptor antagonist affinity. Bilastine effectiveness is similar to cetirizine, fexofenadine and desloratadine.
Chemically Bilastine is 2-[4-(2-(4-(1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropionic acid, having molecular formula of C28H37N3O3 and molecular mass of 463.622 g·mol-1 . It has the following chemical structure:

Bilastine can be classified into the same chemical group as many of the new antihistamines on the market, although it is not structurally derived, nor is it a metabolite or enantiomer of any of them, but an original molecule designed with the intent of fulfilling all the requirements of a second-generation antihistamine.
Bilastine was developed by FAES Farma. Bilastine is approved in Europe in August 2010 for the treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria. It is available under the brand name of Bilaxten®/Bellozal® in tablets, orodispersible tablets and oral liquid dosage forms.

EP0818454 patent discloses Bilastine as product and also discloses process for preparing Bilastine. This patent also discloses the use of Bilastine to treat allergic reactions in mammals
EP1505066 patent discloses bilastine exist in three polymorphic forms Form 1, 2 and 3. Form 1 is more stable having melting point of 200.3°C. Polymorph 2 has a melting point of 205.2°C. Polymorph 3 has a melting point of 197.0°C. This patent discloses The polymorphic forms 1 and 2 are stable. Also discloses the process described in US patent no. 5,877,187 generates a mixture of polymorphs 2 and 3. Further disclosed, they have discovered in selected experimental conditions, the mixture of the polymorphic forms 2 and 3, obtained according to US patent no. 5,877,187, is surprisingly transformed into polymorph 1. Also discovered that polymorph 1 of bilastine is very stable and is not transformed into any of the other polymorphs 2 and 3. Similarly, in the same experimental conditions, the pure polymorphic form 2 of bilastine is surprisingly transformed into the pure polymorphic form 1. Polymorphic form 3, which is the most unstable, undergoes the same transformation in the same conditions. Polymorph 1 of bilastine is a very stable polymorph at room temperature and accelerated conditions.

As per BfARM public assessment report of Bilaxten®, the active substance is crystalline polymorph form 1 have been used in Bilaxten® tablets.

WO2017017301 publication discloses various bilastine crystalline polymorphic forms Alpha, Beta, Gamma A & B, Delta, Zeta and Eta forms. Also discloses compositions containing these crystalline polymorphic forms.

WO2019097090 publication discloses tablet composition of bilastine containing magnesium aluminometasilicate as stabilizer. Also discloses magnesium aluminometasilicate shows unexpected effect in stabilization of polymorphic form conversion. Polymorhic conversion is not observed during stability in presence of magnesium aluminometasilicate. Crystalline polymorphs Form 2 or Form 3 of Bilastine is used in the tablet composition. In addition to magnesium aluminometasilicate the tablet composition contains water soluble diluent, optionally water insoluble diluent, disintegrant, lubricant and glidant. Tablet composition is prepared by either dry granulation or direct compression process.

WO2019097091 publication discloses tablet composition of bilastine containing water soluble diluent, optionally water insoluble diluent, disintegrant, lubricant and glidant. Crystalline polymorph Form 3 of Bilastine is used in the tablet composition. Tablet composition is prepared by either dry granulation or direct compression process.

It has been observed some of the patients in European region are prone to lactose intolerance, due to that while approving any product in Europe, regulatory agencies ask to put lactose intolerance in the label if the product contains lactose. Hence, there is need to develop stable Bilastine tablets without water soluble excipient. The present inventors during their continuations efforts developed stable tablet dosage form of Bilastine using unstable crystalline polymorph Form 3.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides stable pharmaceutical composition of bilastine crystalline Form 3 comprising water insoluble diluent, disintegrant and one or more pharmaceutically acceptable excipients, wherein the composition is free of water soluble diluent.

In another embodiment, the present invention provides process for preparing stable pharmaceutical composition of crystalline bilastine Form 3, wherein the process is direct compression process.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention provides stable pharmaceutical composition of bilastine crystalline Form 3 comprising water insoluble diluent, disintegrant and one or more pharmaceutically acceptable excipients, wherein the composition is free of water soluble diluent.

"Stable" according to the present invention is defined as the there is no polymorphic conversion of bilastine or its salt or hydrates thereof from one crystalline polymorphic form to another crystalline polymorphic form or from crystalline polymorphic form to amorphous form during manufacturing and shelf-life of finished product. Alternatively "Stable" may also be defined as crystalline polymorphic form used as starting material in the pharmaceutical composition remain maintains the same form during manufacturing and shelf-life of finished product.

“Crystalline Form of 3 of Bilastine” according to the present invention is same as specified in US 7,612,095 patent having melting point of 197.0°C and specific Infrared absorption Spectrum. It can also be characterized by X-ray crystallography having at least two or more characteristic peaks at 6.35, 9.19, 9.52, 10.83, 12.71, 13.46, 14.77, 15.60, 16.05, 17.66, 18.29, 18.80, 20.07, 22.35, 27.32 ± 0.2?.

"Water insoluble diluent" according to the present invention selected from the group comprising of microcrystalline cellulose, dicalcium phosphate, starch and its derivatives like powdered starch, corn starch, wheat starch, maize starch, potato starch, calcium silicate, pregelatinized starch and combinations thereof. Preferably water insoluble diluent is microcrystalline cellulose. Water insoluble diluent is present in an amount of about 60%-90% w/w.

“Free of Water soluble diluent” according to the present invention, wherein the composition is substantially free of water soluble diluent. Substantially free means completely absence of water soluble diluent like mannitol, lactose, sorbitol, xylitol and the like in the composition.

"Disintegrant" according to the present invention is selected from the group comprising of sodium starch glycolate, Crospovidone, low substituted hydroxypropyl cellulose, croscarmeltose sodium, croscarmellose potassium, starch, silicified microcrystalline cellulose, polacriiin potassium and combinations thereof. Preferably disintegrant is sodium starch glycolate. Disintegrant is present in an amount of about 1 %-10% w/w.

One or more pharmaceutically acceptable excipients according to the present invention are selected from the group of binder, glidant, lubricant etc.

Suitable binders used according to the present invention are selected from the group comprising of povidone, microcrystalline cellulose, alginic acid, starch, potato starch, wheat starch, corn starch, hydroxy propyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.

Suitable lubricants used according to the present invention are selected from the group comprising of stearic acid, magnesium stearate, sodium stearyl fumarate, fumaric acid, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, and combinations thereof. Preferably lubricant is magnesium stearate. Lubricant is present in an amount of about 0.1%-4.0% w/w.

Suitable glidants used according to the present invention are selected from the group comprising of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof. Preferably glidant is colloidal silicon dioxide. Glidant is present in an amount of about 0.1%-4.0% w/w.

In another aspect of the present invention provides process for preparing stable pharmaceutical composition of bilastine crystalline Form 3, wherein the process is direct compression process.

Direct compression process according to the present comprising steps of optionally sifting all the excipients, loading bilastine, water insoluble excipient, disintegrant, optionally glidant in a blender and blended for some time, adding lubricant to the blend, again blended for some time. Finally unload the blend and compress into tablets.

In another aspect of the present invention provides stable pharmaceutical composition of bilastine crystalline Form 3 comprising bilastine in an amount of about 4-8% w/w, water insoluble diluent in an amount of about 60-90% w/w, disintegrant in an amount of about 1-10% w/w, and one or more pharmaceutically acceptable excipients.

In another aspect of the present invention provides stable pharmaceutical composition bilastine crystalline Form 3 comprising bilastine in an amount of about 4-8% w/w, water insoluble diluent in an amount of about 60-90% w/w, disintegrant in an amount of about 1-10% w/w, lubricant in an amount of about 0.1 to 4.0 % w/w and glidant in an amount of about 0.1-4.0 % w/w.

In another aspect of the present invention provides stable pharmaceutical composition bilastine crystalline Form 3 comprising bilastine in an amount of about 4-8% w/w, water insoluble diluent in an amount of about 75-85% w/w, disintegrant in an amount of about 2-5% w/w, lubricant in an amount of about 0.2 to 2.0 % w/w and glidant in an amount of about 0.2-2.0 % w/w.

The % weight by weight as mentioned in the specification is based on the total weight of the composition.

In another aspect of the present invention provides use of stable pharmaceutical composition of bilastine crystalline Form 3 for the treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria.

The invention is further illustrated by following non-limiting examples:

Example 1:

Sr.No Name of the ingredient mg/tablet
1 Bilastine crystalline Form 3 20.0
2 Microcrystalline cellulose 96.2
3 Sodium starch glycolate 2.8
4 Colloidal silicon dioxide 0.6
5 Magnesium stearate 0.4
Total tablet weight 120mg

Manufacturing process:
1. Bilastine, microcrystalline cellulose, Sodium starch glycolate and Colloidal silicon dioxide was passed through #40 ASTM mesh and mixed for 10 min in blender at 10 rpm.
2. Magnesium stearate sifted through #60 mesh ASTM and add to the above blend and lubricated for 5 min in blender at 10 rpm.
3. Compressed the above blend into tablets.
4. Tablets are packed in Al/Al blister.

Example 2:

Sr.No Name of the ingredient mg/tablet
1 Bilastine crystalline Form 3 20.0
2 Dicalcium phosphate anhydrous 93.00
3 Croscarmellose sodium 4.00
4 Colloidal silicon dioxide 1.00
5 Magnesium stearate 2.00
Total tablet weight 120mg

Manufacturing process:

1. Bilastine, Dicalcium phosphate anhydrous, Croscarmellose and Colloidal silicon dioxide was passed through #40 ASTM mesh and mixed for 10 min in blender at 10 rpm.
2. Magnesium stearate sifted through #60 mesh ASTM and add to the above blend and lubricated for 5 min in blender at 10 rpm.
3. Compressed the above blend into tablets.
Example 3:

Sr.No Name of the ingredient mg/tablet
1 Bilastine crystalline Form 3 20.0
2 Pregelatinized starch 95.50
3 Sodium starch glycolate 3.00
4 Colloidal silicon dioxide 0.50
5 Magnesium stearate 1.00
Total tablet weight 120mg

Manufacturing process:
1. Bilastine, pregelatinized starch, Sodium starch glycolate and Colloidal silicon dioxide was passed through #40 ASTM mesh and mixed for 10 min in blender at 10 rpm.
2. Magnesium stearate sifted through #60 mesh ASTM and add to the above blend and lubricated for 5 min in blender at 10 rpm.
3. Compressed the above blend into tablets.
Example 4:

Sr.No Name of the ingredient mg/tablet
1 Bilastine crystalline Form 3 20.0
2 Dicalcium phosphate anhydrous 91.30
3 Sodium starch glycolate 5.00
4 Colloidal silicon dioxide 1.20
5 Magnesium stearate 2.50
Total tablet weight 120mg

Manufacturing process:

1. Bilastine, Dicalcium phosphate anhydrous, Sodium starch glycolate and Colloidal silicon dioxide was passed through #40 ASTM mesh and mixed for 10 min in blender at 10 rpm.
2. Magnesium stearate sifted through #60 mesh ASTM and add to the above blend and lubricated for 5 min in blender at 10 rpm.
3. Compressed the above blend into tablets.

Example 5:

Sr.No Name of the ingredient mg/tablet
1 Bilastine crystalline Form 3 20.0
2 Pregelatinized starch 95.50
3 Crospovidone 3.00
4 Colloidal silicon dioxide 0.50
5 Magnesium stearate 1.00
Total tablet weight 120mg

Manufacturing process:
1. Bilastine, pregelatinized starch, Crospovidone and Colloidal silicon dioxide was passed through #40 ASTM mesh and mixed for 10 min in blender at 10 rpm.
2. Magnesium stearate sifted through #60 mesh ASTM and add to the above blend and lubricated for 5 min in blender at 10 rpm.
3. Compressed the above blend into tablets.

In-vitro dissolution:
Tablets of Example 1 are tested in 0.1N HCl dissolution media, Apparatus II, 900ml volume, 50 rpm and compared with Reference Product BELLOZAL®. The results of the same are given below:

Time in minutes BELLOZAL® Example 1
5 95 91
10 100 96
15 101 97
30 102 98
45 102 99

The dissolution of Example 1 is comparable with that of Reference Product and meeting Regulatory requirements.

Stability studies: Further tablets of Example 1 are tested during stability for observing the polymorphic stability of the tablets. XRD test is used for testing polymorphic form conversion. XRD results of tablets at initial and after 6 months of storage at 40 ± 2°C/75 ± 5% RH are given below:

Bilastine drug substance crystalline form 3 Example 1 tablets
Initial Example 1 tablets
40°C/75 ± 5% RH -6M
6.33 6.35 6.32
9.15 9.19 9.16
9.47 9.52 9.50
10.76 10.83 10.78
12.66 12.71 12.67
13.40 13.46 13.43
14.72 14.77 14.72
15.55 15.60 15.57
16.08 16.05 16.01
17.61 17.66 17.62
18.24 18.29 18.25
18.71 18.80 18.76
20.01 20.07 20.04
22.24 22.35 22.27
27.23 27.32 27.20

The results from XRD data is evident that Example 1 tablets are stable and no polymorphic conversion was observed.

In-vivo Bioequivalency study: Further tablets of Example 1 also tested for Bioequivalence studies in healthy human volunteers in fasting condition. Example 1 tablets data is compared with Reference Product (BELLOZAL®) data. Results of the same given below:

The results from Bioequivalency data evident that the test tablets of Example 1 are bioequivalent with reference product.