WO2024256956A1

WO2024256956A1 - Stable formulations of bilastine for nasal and ophthalmic use

Info

Publication number: WO2024256956A1
Application number: PCT/IB2024/055686
Authority: WO
Inventors: Chandrashekhar Kocherlakota; Nagaraju Banda; Anji Reddy KESHIREDDY; Naga Udaya Sankar PULLAGURA
Original assignee: Leiutis Pharmaceutials LLP
Current assignee: Leiutis Pharmaceutials LLP
Priority date: 2023-06-13
Filing date: 2024-06-11
Publication date: 2024-12-19
Anticipated expiration: 2025-12-13

Abstract

The present invention deals with the pharmaceutical formulations of bilastine and the methods of preparing such formulations for nasal and ophthalmic use. The formulations of present invention are stable and comprises of bilastine and other pharmaceutically acceptable excipients. These compositions may be used in treating different allergies and the associated conditions.

Description

STABLE FORMULATIONS OF BILASTINE FOR NASAL AND OPHTHALMIC USE

FIELD OF INVENTION

The present invention deals with stable pharmaceutical formulations of bilastine and the method of preparing such formulations for nasal and ophthalmic use. The formulations may be used to treat different allergies and the associated conditions.

BACKGROUND OF THE INVENTION

Defence mechanism of our body produces histamines and other substances from basophils and mast cells against foreign allergens. These histamines cause immune responses as a protective action. When the levels of histamine elevate in the body, they cause serious allergic conditions.

Nasal allergic symptoms such as sneezing, itchy nose, runny nose and blocked nose are observed in conditions like allergic rhinoconjunctivitis, allergic rhinitis, inflammation, nasal congestion and bronchial constriction causes difficulty in breathing. These may lead to headache, irritability, loss of sleep and inability to concentrate and ultimately compromising the patient’s quality of life.

Immune mediated reactions affect eyes resulting in redness, itching, burning, tearing and inflammation of eye. These symptoms contribute to various ocular allergies such as seasonal or perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, contact allergic conjunctivitis and giant papillary conjunctivitis. These allergic conditions worsen when left untreated and may even progress to cause serious secondary infections. Site- specific administration of drug is effective than systemic administration to treat these nasal and ophthalmic conditions as it has localized effect and provides rapid relief of symptoms.

The first line of treatment includes antihistamines which exert their biological effects by acting on Hl receptors, reducing allergic inflammation by directly interfering with histamine actions. Based on the current international guidelines, non- sedating second-generation antihistamines are recommended as first- line treatment for treating allergic conditions.

Bilastine is a potent non-sedative, a second-generation medication used in treating allergic rhinitis and urticaria, and various other diseases caused by allergens. It works by inhibiting histamine related immune system reactions. Bilastine was approved in Europe for treating allergic rhinitis and urticaria. Bilastine in its approved tablet form is instructed not to be given along with food but taken at least before 1 hour or after 2 hours of food intake, as the bioavailability of bilastine is reduced to 30 % when taken with food (such as grapefruit juice).

European Publication No. EP3725298 and U.S Patent No. US 11642309 to FAES FARMA disclose intranasal compositions of bilastine and combination of bilastine with mometasone which are formulated specifically using HPBCD and citric acid. These formulations essentially require preservatives to maintain their stability.

International Publication No. W02015174910A1 to Malin et al., discloses oilbased nasal spray compositions comprising lipophilic components, oils, surfactants and propellants.

U.S Patent Application No. US20210128544 to FAES FARMA discloses to ophthalmic formulations comprising at least 0.4% of bilastine in combination with hydroxypropyl-P-cyclodextrin specifically and at least one water soluble gelling agents, at least one viscosity agent and tonicity agent. Further it was concluded that the increase in the concentration of bilastine did not entail a notable improvement in terms of effectiveness and duration of the effect even in preclinical trials.

U.S Patent Application No. US20130344139 to Benjamin et al., discloses methods and formulations comprising non-drying antihistamine compounds for reducing dry eye symptoms and promoting tear secretion.

International Publication No. WO2014150899 to Chapin et al., discloses topical ophthalmic compositions of anti-histamine agents (0.025-0.5%) for treating migraine.

U.S Patent Publication No. US20180319766 to FAES FARMA discloses method for increasing the solubility of bilastine by forming co-crystals using glutaric acid, adipic acid, sorbic acid, succinic acid, benzoic acid, 4-aminobenzoic acid, L-malic acid, resorcinol, methyl 4-hydroxy benzoate and N-(4-hydroxyphenyl) acetamide.

U.S Patent Publication No. US2022339414 to James et al., discloses methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders by administering formulations comprising a corticosteroid and an antihistamine.

Prior published literature on bilastine discloses formulations as combinations with various medications using different excipients such as alcohols, oils, lipophilic components, and preservatives. To achieve the required solubility of bilastine at required pH, HPBCD is used as an excipient. However, HPBCD is not a safe excipient due to its documented potential to compromise the blood-labyrinth barrier, leading to ototoxicity and hearing impairment.

The inventors of the current invention developed a pharmaceutical formulation of bilastine that improves drug release and addresses the drawbacks of earlier methods. SUMMARY OF THE INVENTION

One aspect of the present invention is to provide stable formulations of bilastine for nasal and ophthalmic administration.

Another aspect of the present invention is to provide a bilastine composition formulated for nasal and ophthalmic administration free of gelling agents.

Another aspect of the present invention is to provide stable formulations of bilastine comprising bilastine, SBECD and other pharmaceutical excipients.

Another aspect of the present invention is to formulate nasal and ophthalmic compositions of bilastine comprising bilastine, SBECD and an acid selected from the group comprising carboxylic acids and amino acids, wherein the formulation is free of gelling agents.

Yet another aspect of the present invention is to provide a stable formulation of bilastine administered for nasal and/ ophthalmic administration with total impurities less than 5% when placed at recommended storage conditions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable nasal and ophthalmic formulations of bilastine and processes to prepare the said formulations. The invention further relates to a method of using such stable formulations of bilastine for treating symptoms related to nasal and ophthalmic allergic conditions.

The term "bilastine" is intended to include any of the alternative forms in which bilastine can be administered such as salts, esters, anhydrous, hydrates such as monohydrate or dihydrate, solvates, crystalline or amorphous polymorphs, racemic mixtures, enantiomeric isomers and so on. “Stable” means that bilastine composition has physical and chemical stability and can be stored for commercially significant periods, such as at least 3 months, 6 months, 1 year, or 2 years or 3 years, at 2-8°C or at ambient conditions (e.g., 25° or 30°C) or elevated temperatures (e.g., 40°C). Stable means that there is no significant physical instability and chemical degradation. The degradation in the product may be determined by analyzing for impurities by suitable analytical method.

The term “composition or formulation” in the context of present invention refers to combination of bilastine along with at least one pharmaceutically acceptable excipient. Any excipient that is considered to be safe and non-toxic may be used.

Formulations of present invention contain bilastine ranging from 0.2 to 1.2% (w/v) of the total weight of the formulation. Preferred range is from 0.5 to 1% (w/v).

The term “SBECD” in the present invention refers to sulfobutylether beta cyclodextrin. It has the following structure:

Further formulations of present invention contain SBECD ranging from 2% to 20% (w/v) of the total weight of the formulation.

The permeating agents or enhancers in the present invention refers to the agents that promote the penetration of drugs through membranes. These include but not limited to sodium carbonate, sodium caprate, sodium caprylate, poloxamer-188, poloxamer-407, PEG-PE, PEG-400, Kolliphor EL and Kolliphor RH40 ranging from 0.1% to 1% of the total weight of the formulation. Using these enhancers in the formulations improve the bioavailability thereby increasing therapeutic response of ophthalmic and nasal preparations.

The chelating agents in the present invention refers to but not limited to (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid), DTPA (diethylene triamine- N,N,N',N",N"-pentaacetate)/pentetic acid, EDTA (ethylene diamine tetra acetic acid), calcium disodium edetate or their salts. The concentration of chelating agent if present, may vary from 0 to 0.5 % by weight of the formulation.

The amino acids and carboxylic acids may be selected from the group comprising L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, lysine, sodium acetate, acetic acid, citric acid, boric acid, tartaric acid and lactic acid. The formulations may additionally contain Tris (tromethamine), sodium carbonate and sodium bicarbonate. The concentration of amino acids and carboxylic acids, may range from 0.01 to 1 % by weight of the formulation.

Unlike the formulations of the prior art, the present invention formulations do not contain any gelling agents. Use of gelling agents often causes nasal and ocular irritation thereby compromising patient compliance.

The present invention formulations are administered in the form of solutions, suspensions, emulsions and so on. These formulations are supplied in single use or multi use component system that can be in the form of a container or vial, drop bottle, spray container, and squeeze bottles made of robust and inert materials to ensure the stability of the formulation throughout the shelf life.

In one embodiment, the formulations of present invention are intended to be administered nasally. In another embodiment, the formulations of present invention are intended to be administered ophthalmically.

It is essential to obtain the required concentration of bilastine in solution to make an effective composition. The excipient selection plays an important role as they also have to be safe and approved for nasal and ophthalmic use.

Experiments were carried out to identify the excipients that may be used for preparing the stable formulations. Solubility studies were conducted to determine the saturation solubility of bilastine in various carboxylic acids, amino acids and solubilizers.

Table 1: Solubility of bilastine with or without SBECD in various carboxylic acids, amino acids and solubilizers

It is surprising to note that the solubility of bilastine remarkably improved when SBECD is used in combination with aspartic acid. Same observation is made with other acids like acetic acid, lactic acid and citric acid. Solubility improvement can also be seen in combination of SBECD with sodium carbonate, arginine, meglumine etc.

The pH of the composition of the present invention is between 4.5 and 7.5. In one embodiment, the compositions comprise bilastine, SBECD and other pharmaceutical excipients and may have pH between 5.0 and 6.5.

Thus, in one embodiment, the formulations of bilastine for nasal and/ ophthalmic administration comprise:

(a) bilastine,

(b) sulfobutylether beta cyclodextrin (SBECD) and

(c) an acid selected from the group comprising carboxylic acids or amino acids or combinations thereof, wherein the formulation is free of gelling agents.

In another embodiment, the formulations of bilastine for nasal and/ ophthalmic administration comprise:

(a) bilastine in a concentration of 0.2- 1.2% w/v,

(b) sulfobutylether beta cyclodextrin (SBECD) in a concentration of 2-20% w/v,

(c) a carboxylic acid selected from the group comprising acetic acid and lactic acid wherein the formulation is free of gelling agents. In another embodiment, the formulations of bilastine for nasal and/ ophthalmic administration comprise:

(a) bilastine in a concentration of 0.2- 1.2% w/v,

(b) sulfobutylether beta cyclodextrin (SBECD) in a concentration of 2 -20 %^IN,

(c) an amino acid selected from L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, and lysine. wherein the formulation is free of gelling agents.

(a) bilastine in a concentration of 0.2- 1.2% w/v,

(b) sulfobutylether beta cyclodextrin (SBECD) in a concentration of 2 -20% w/v,

(c) a carboxylic acid selected from the group comprising acetic acid and lactic acid; and

(d) an amino acid selected from L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, and lysine. wherein the formulation is free of gelling agents.

The formulations of present invention are subjected to accelerated stability. These formulations have not more than 0.5% of known individual impurities and not more than 0.2% of unknown individual impurities. The total impurities are not more than 5%.

Drug release studies:

The evaluation of effect of permeation enhancers helps in estimating drug concentration at target site. Thus, this study was conducted using potential permeation enhancers to investigate influence of the enhancers’ concentration on drug release. Drug release study was conducted using USP IV dissolution apparatus with 20 KD Float- A-Lyzer® Device. This device has a total length of 5cm with a Biotech Grade Cellulose acetate membrane of 10 mm size. The sample volume of this device is 1ml and flow rate is maintained at 4 mg/min. A phosphate buffer of pH 7.4 was taken as media and bilastine solution (10 mg/ml) with different permeating agents were employed as samples in the study. Bilastine was taken as such in buffer as control sample (Example 4). Further the obtained results were compared with control.

Duration of the drug release is considered for 12 hours or till at least 50 % of the drug should be dissolved through the screened formulations for comparable evaluation. The release rate constant of drug was measured for all the formulations with the respect to time intervals and percentage drug release from the linearity.

Table 2: Drug release rate constant

From the above data, it is clear that the present invention formulations have more than 2 fold increase in release rate compared to as such bilastine (control).

Below are few exemplary formulations of bilastine which do not limit the scope of the present invention and are only for the purpose of illustration. Example 1

Manufacturing Procedure:

1. About 80 % of the weighed quantity of Milli-Q water is taken into a compounding vessel.

2. Then weighed quantity of L-aspartic acid was added to the above vessel followed by addition of required quantity of SBECD and subjected for stirring.

3. To the above vessel required quantity of EDTA was added and stirred well.

4. Then weighed quantity of bilastine was added into the above compounding vessel and subjected for stirring.

5. To the above vessel weighed quantity of poloxamer 188 (if required) was added and stirred well, followed by addition of Tris buffer and subjected for stirring.

6. Final volume of the solution was made up to 100% with Milli-Q water while stirring.

7. The above prepared final bulk solution was filtered with 0.22pm nylon syringe filter, filled into USP Type-I clear tubular glass vials (Fill volume 10 mF), stoppered using 13 mm bromobutyl unlaminated stoppers and sealed the vials using 13 mm aluminum seals.

8. The above vials were subjected to terminal sterilization in autoclave for 30 minutes at 121°C and 15 lb. pressure and analyzed. Table 3: Stability study

*CCS - clear colourless solution

Example 2

Manufacturing procedure:

1. About 80 % of the weighed quantity of Milli-Q water was taken into a compounding vessel.

2. Followed by addition of weighed quantities of L-aspartic acid and SBECD to the above vessel and subjected for stirring. 3. To the above vessel weighed quantity of EDTA was added and stirred well.

4. Then weighed quantity of bilastine was added into the above vessel and subjected for stirring.

5. To the above vessel specified permeating agent (PEG-PE, PEG-400) at a concentration of 0.5% w/v (5mg/ml) was added and stirred well. 6. Weighed quantity of Tris buffer was added and subjected for stirring.

7. Final volume of the solution was be made up to 100% with Milli-Q water while stirring.

8. The above prepared final bulk solution was filtered with 0.22pm nylon syringe filter, filled into USP Type-I clear tubular glass vials (Fill volume 10 mL), stoppered using 13 mm bromobutyl unlaminated stoppers and sealed the vials using 13 mm aluminium seals.

9. The above vials were subjected to terminal sterilization in autoclave for 30 minutes at 121°C and 15 lb. pressure and analyzed.

Example 3

Manufacturing procedure:

2. Followed by addition of weighed quantities of L-aspartic acid and SBECD to the above vessel and subjected for stirring.

3. To the above vessel weighed quantity of EDTA was added and stirred well.

5. To the above vessel specified permeating agent (sodium caprylate and sodium caprate) at a concentration of 0.5% w/v (5mg/ml) was added and stirred well.

6. Weighed quantity of Tris buffer was added and subjected for stirring. 7. Final volume of the solution was be made up to 100% with Milli-Q water while stirring.

Example 4: Control sample

Manufacturing procedure:

1. To prepare the control sample required quantity of pH 7.4 phosphate buffer was taken in to a manufacturing vessel and required quantity of bilastine was added in to it.

2. The above contents are stirred well.

Example 5

Manufacturing procedure:

1. About 80 % of the weighed quantity of Milli-Q water was taken into a compounding vessel. 2. Followed by addition of weighed quantities of L-aspartic acid and SBECD to the above vessel and subjected for stirring.

3. To the above vessel weighed quantity of EDTA was added and stirred well.

5. To the above vessel weighed quantity of poloxamer 188 was added and stirred well followed by addition of required quantity of benzalkonium chloride.

6. Weighed quantity of Tris buffer was added and subjected for stirring.

7. Final volume of the solution shall be made up to 100% with remaining amount of Milli-Q water while stirring.

8. The above prepared final bulk solution was filtered with 0.22pm nylon syringe filter, filled into USP Type-I clear tubular glass vials (Fill volume 10 mL), stoppered using 13 mm bromobutyl unlaminated stoppers and sealed the vials using 13 mm aluminum seals.

Table 4: Stability data

*CCS - clear colourless solution Example 6

Manufacturing procedure:

2. Followed by addition of weighed quantities of aspartic acid and SBECD to the above vessel and subjected for stirring.

3. To the above vessel weighed quantity of EDTA was added and stirred well.

5. Final volume of the solution was be made up to 100% with Milli-Q water while stirring.

Example 7 :

Manufacturing procedure:

2. Followed by addition of weighed quantities of aspartic acid or lactic acid and SBECD to the above vessel and subjected for stirring.

3. To the above vessel weighed quantity of EDTA was added and stirred well.

Claims

We claim,

1. A formulation of bilastine for nasal or ophthalmic administration comprising

(a) bilastine

(b) sulfobutylether beta cyclodextrin (SBECD)

2. The formulation of claim 1, wherein the concentration of bilastine ranges from 0.2 to 1.2% w/v.

3. The formulation of claim 1, wherein the concentration of SBECD ranges from 2 to 20% w/v.

4. The formulation of claim 1, wherein the total impurities are less than 5%.

5. A formulation of bilastine for nasal or ophthalmic administration comprising

(a) bilastine in a concentration of 0.2- 1.2% w/v

(b) sulfobutylether beta cyclodextrin (SBECD) in a concentration of 2 -20% w/v

(c) a carboxylic acid selected from the group comprising acetic acid and lactic acid in a concentration of 0.01 to 1% w/v wherein the formulation is free of gelling agents.

6. The formulation of claim 5, further comprising an amino acid selected from the group comprising L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, and lysine.

7. The formulation of claim 5, further comprises an excipient selected from the group comprising sodium carbonate, sodium caprate, sodium caprylate, poloxamer-188, poloxamer-407, PEG-PE, PEG-400, Kolliphor EL, and Kolliphor RH40.