FIELD OF INVENTION
5 The present invention relates to liquid pharmaceutical formulations of bilastine and
a process of preparing such formulations. These formulations are used to treat
conditions caused by allergens or foreign substances.
BACKGROUND OF THE INVENTION
10
Defence mechanism of our body produces histamines and other substances from
basophils and mast cells against foreign allergens. These histamines cause immune
responses such as itching, sneezing, runny nose, and watery eyes as a protective
action. When the levels of histamine elevate in the body, they cause serious allergic
15 conditions.
In recent decades, there has been an increased prevalence of allergic conditions such
as asthma, allergic rhinoconjunctivitis, allergic rhinitis, eczema, urticaria,
dermatitis, pruritus, inflammation, nasal congestion, and bronchial constriction.
20 This rise is attributed to a heightened sensitivity to external stimuli, including
certain foods, dust, harmful substances, microorganisms, and environmental
pollutants. Autoimmunity may also play a role in these conditions, leading to
symptoms that can make it difficult to breathe and impacting overall quality of life.
25 Globally these conditions are reported to affect approximately 25% and 40% of
children and adults respectively. These allergic conditions lead to loss of sleep,
irritability, and inability to concentrate and ultimately compromising the patient’s
quality of life.
These allergic conditions are generally treated with antihistamines which exert their
biological effects by acting on H1 receptors, reducing allergic inflammation by
directly interfering with histamine actions. Based on the current international
guidelines, non-sedating second-generation antihistamines are recommended as
5 first-line treatment for treating allergic rhinitis and urticaria.
One such drug is bilastine, 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.
10
Bilastine is approved in Europe for treating allergic rhinitis and urticaria. The tablet
is not meant to be given along with food but taken at least before 1 hour or after 2
hours of food intake. This is because the bioavailability of bilastine is reduced by
30 % when taken with food (such as grapefruit juice). The tablets also require a
15 longer duration to show the therapeutic activity.
US Publication No. US2018319766 (A1) to Gonzalo et al., discloses methods to
increase solubility of bilastine by forming co-crystals using organic molecules such
as carboxylic acids and phenolic compounds, which were stable only for few days.
20
US Publication No. US2018344854 (A1) to Gonzalo et al., discloses methods to
increase the solubility of bilastine by forming co-crystals using organic carboxylic
acid selected from glutaric acid, citric acid, α-cetoglutaric acid, tartaric acid, acetic
acid, propionic acid and mixtures. These supersaturated aqueous solutions were
25 stable up to 24 h under standard ambient conditions.
PCT Publication No. WO2017048860 (A1) to Konduri et al., discloses methods for
treatment of food allergy and eosinophilic esophagitis using liposome carrier
compositions comprising: i) poly (ethylene glycol)
30 distearoylphosphatidylethanolamine (PEG-DSPE); and ii) at least one of phosphatidylglycerol and phosphatidylcholine for oral, sublingual or subcutaneous
administration.
PCT Publication No. WO2023156559 (A1) discloses parenteral compositions of
5 bilastine comprising beta cyclodextrins (10% to 30% w/v) for once-daily
administration. The formulations described would be expensive to manufacture
because of the high quantity of cyclodextrin required and may not be a viable option
for affordable healthcare.
10 PCT Publication No. WO2020212380 (A1) discloses a nasal spray composition
comprising bilastine, mometasone, a suspending agent, 2-hydroxypropyl β
cyclodextrin and at least two preservatives.
HPβCD is not a safe choice of excipient as it reportedly disrupts the blood-labyrinth
15 barrier causing ototoxicity resulting in hearing impairment and loss. The
undesirable toxic effects of HPβCD may be more evident if it is used in parenteral
administration.
The presently marketed oral formulations of bilastine take longer time to alleviate
20 unpleasant and irritating symptoms that result in prolonging patient’s discomfort
and incomplete symptomatic relief due to its form and food interactions. Also, there
is no patented literature that discloses a dosage form of bilastine, for immediate
relief of allergic symptoms, free of preservatives, solvents and surfactants. Hence
there is a need to formulate bilastine into a stable dosage form with a faster onset
25 of action and enhanced bioavailability that retard the allergic reaction readily and
provides improved quality of life.
SUMMARY OF THE INVENTION
30 One aspect of the present invention is to provide liquid formulations of bilastine for
parenteral administration.
Another aspect of the present invention is to provide a process for preparing stable
parenteral formulations of bilastine.
5 Yet another aspect of the present invention is to formulate stable parenteral
formulations of bilastine comprising bilastine, cyclodextrin selected from SBECD
or sugammadex, buffers or amino acids or pH adjusting agents and optionally other
pharmaceutical excipients.
10 Another aspect of the present invention is to formulate stable parenteral
formulations of bilastine comprising bilastine, cyclodextrin selected from SBECD
or sugammadex and other pharmaceutical excipients.
Yet another aspect of the present invention is to formulate stable parenteral
15 formulations of bilastine comprising bilastine, cyclodextrin selected from SBECD
or sugammadex, an acid with pka less than 5 and other pharmaceutical excipients.

We claim,
1. A parenteral composition comprising:
(a) bilastine
(b) cyclodextrin selected from sulfobutylether beta cyclodextrin and
modified gamma-cyclodextrin
(c) one or more acids with pka less than 5 and
(d) pharmaceutically acceptable excipients
2. The parenteral formulation of claim 1, wherein the acid with pka less than 5 is
selected from the group comprising acetic acid, ascorbic acid, citric acid, lactic
acid, tartaric acid, glutamic acid, aspartic acid and succinic acid
3. The parenteral formulation of claim 1, wherein the concentration of the acid
ranges from 0.01 to 5% w/v of the formulation.
4. The parenteral formulation of claim 1, wherein the concentration of the
cyclodextrin is less than 10% w/v of the formulation.
5. The formulation of claim 1, wherein pharmaceutically acceptable excipient
such as the chelating agent is selected from the group comprising (1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylene triamineN,N,N',N",N"-pentaacetate)/pentetic acid, EDTA (Ethylene diamine tetra
acetic acid), calcium disodium edetate or their salts.
6. The formulation of claim 5, wherein the concentration of chelating agent ranges
from 0.1 to 0.5 %w/v
7. The formulation of claim 1, further comprising water as the solvent.
8. The formulation of claim 1, wherein the content of the drug is not less than 90%
when stored at 40°C for 6 months.