FIELD OF INVENTION
5
The present invention relates to liquid pharmaceutical formulations of bilastine, free
of cyclodextrins and a process of preparing such formulations. These formulations
are used to treat conditions caused by allergens or foreign substances.
10 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 such as itching, sneezing, runny nose, and watery eyes as a protective
15 action. When the levels of histamine elevate in the body, they cause serious allergic
conditions.
In recent decades, there has been an increased prevalence of allergic conditions such
as asthma, allergic rhinoconjunctivitis, allergic rhinitis, eczema, urticaria,
20 dermatitis, pruritus, inflammation, nasal congestion, and bronchial constriction.
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.
30 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
first-line treatment for treating allergic rhinitis and urticaria.
5 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 is approved in Europe for treating allergic rhinitis and urticaria. The tablet
10 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
longer duration to show the therapeutic activity.
15 US Publication No. US2018319766 (A1) to Gonzalo et al., discloses methods to
increase solubility of bilastine by forming cocrystals using organic molecules such
as carboxylic acids and phenolic compounds. These were stable only for a few days.
US Publication No. US2018344854 (A1) to Gonzalo et al., discloses methods to
20 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 their mixtures. These supersaturated aqueous solutions
were stable up to 24 h under standard ambient conditions.
25 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)
distearoylphosphatidylethanolamine (PEG-DSPE); and ii) at least one of
phosphatidyl glycerol and phosphatidylcholine for oral, sublingual or subcutaneous
30 administration.
PCT Publication No. WO2023156559 (A1) discloses parenteral compositions of
bilastine comprising beta cyclodextrins (10% to 30% w/v) for once-daily
administration. These compositions require cyclodextrins in combination with
bilastine for optimal parenteral administration and also for showing prolonged
5 effect. The formulations described would be expensive to manufacture and may not
be a viable option for affordable healthcare.
PCT Publication No. WO2020212380 (A1) discloses a nasal spray composition
comprising bilastine, mometasone, a suspending agent, 2-hydroxypropyl-β10 cyclodextrin and at least two preservatives. HPβCD is not a safe choice of excipient
as it reportedly disrupts the blood-labyrinth barrier causing ototoxicity resulting in
hearing impairment and loss. The undesirable toxic effects of HPβCD are even
more evident if it is used in parenteral administration.
15 The presently marketed oral formulations of bilastine take longer time to alleviate
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
20 there is a need to formulate bilastine into a stable dosage form with a faster onset
of action and enhanced bioavailability that retard the allergic reaction readily and
provides improved quality of life.
SUMMARY OF THE INVENTION
25
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 liquid parenteral formulation
30 of bilastine free of cyclodextrins.
Yet another aspect of the present invention is to provide liquid parenteral
formulations of bilastine comprising bilastine, solubilizers selected from dextran,
PEG 400, alcohols, glycerol, Kolliphor RH 40, propylene glycol, PEG-PE, and
other pharmaceutical excipients.
5
Another aspect of present invention is to provide the parenteral compositions of
bilastine comprising of bilastine, one or more acids with pka less than 5, buffers,
water, and other excipients.
10 Yet another aspect of the present invention is to provide parenteral formulations of
bilastine comprising bilastine, solubilizers selected from dextran, PEG 400,
glycerol, Kolliphor RH 40, propylene glycol, PEG-PE, acids with pka less than 5
and other pharmaceutical excipients.

We claim,
1. A parenteral composition comprising:
(a) bilastine
(b) one or more acids with pka less than 5
(c) one or more excipients selected from the group comprising solubilizers
and chelating agents
(d) pharmaceutically acceptable excipients
wherein the formulation is free of cyclodextrins.
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
solubilizer ranges from 0.1 to 15% w/v of the formulation.
5. The formulation of claim 1, wherein the chelating agent is selected from the
group comprising (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid),
DTPA (diethylene triamine-N,N,N',N",N"-pentaacetate)/pentetic acid, EDTA
(ethylene diamine tetraacetic acid) and 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 3 months.