FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE, 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
“ANTI-VERTIGO COMPOUND AND PHARMACEUTICAL
COMPOSITIONS THEREOF”
KASHIV BIOSCIENCES, LLC
20, New England Avenue,
Piscataway, New Jersey,
United States of America
08854
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES
THE INVENTION AND THE MANNER IN WHICH IT IS TO BE
PERFORMED
1
DESCRIPTION
Title: ANTI-VERTIGO COMPOUND AND PHARMACEUTICAL COMPOSITIONS
THEREOF
FIELD OF THE INVENTION
[0001] The present invention relates to method of treatment of vertigo and/or one or more
symptoms of vertigo or diseases associated with vertigo using levocloperastine. The invention,
further relates to composition comprising Levocloperastine and use thereof for the treatment
or prevention of one or more symptoms of vertigo or diseases associated with vertigo.
BACKGROUND OF THE INVENTION
[0002] Levocloperastine (I) is levorotatory isomer of DL-cloperastine. Levocloperastine is used
in reducing the intensity and frequency of cough. The antihistamine, antiserotonergic and
muscle-relaxant properties of Levocloperastine contribute to its overall efficacy in the
treatment of cough, bronchospasm and related symptoms
[0003] Figure 1
[0004] Peripheral vertigo is an abnormality of integration mechanisms of information in the
central nervous system resulting from rapid dysfunction of equilibrium nervous system
occurring in a vestibular nervous system and it is accompanied with various symptoms such
as dysesthesia of motion and position, nystagmus, dysequilibrium, head deviation, nausea,
vomiting, sweating, salivation and tachycardia. The percentage of people with Peripheral
vertigo is increasing.
[0005] The most common causes of Peripheral vertigo are inner ear infections or diseases of the
ear such as benign paroxysmal positional Peripheral vertigo (BPPV), vestibular neuritis, and
Meniere's disease. BPPV can occur when calcium builds up in canals of the inner ear, causing
brief dizziness that lasts from 20 seconds to one minute. It is usually brought on by trauma to
the head or by moving the head in certain positions. Vestibular neuritis is brought on by an
inner ear infection that causes inflammation around the nerves that help the body sense balance.
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It results in a severe bout of Peripheral vertigo that can last a day or more and sometimes
includes hearing loss. Meniere's disease (MD) is a disorder of the inner ear that is characterized
by episodes of feeling like the world is spinning (Peripheral vertigo), ringing in the ears
(tinnitus), hearing loss, and a fullness in the ear.
[0006] Meclizine, diphenhydramine, scopolamine, diazepam, lorazepam, betahistine, and
cinnarizine are commonly used medications for Peripheral vertigo, and the current antiPeripheral vertigo drugs cause drowsiness. Further, a faster onset of action is also preferable
for Peripheral vertigo patients.
[0007] There exists a need for an effective vertigo treatment or diseases associated with vertigo
that would avoid drowsiness and that would relieve the vegetative symptoms in shorter
duration of time period and provide a faster onset of action. Major patients suffering from
Peripheral vertigo need an effective treatment which can provide relief from Peripheral vertigo
and vegetative concomitant symptoms like nausea, vomiting, sweating, tachycardia. The
present invention provides best patient compliance by providing quick relief in shorter duration
of time without sedation to patients.
OBJECTS OF THE INVENTION
[0008] The primary object of the present invention is to provide treatment of vertigo and/or
prevention of one or more symptoms of vertigo or disease associated with Vertigo using
levocloperastine.
[0009] Another object of the present invention is to provide a treatment and quick relief for one
or more symptoms of peripheral vertigo using Levocloperastine.
[0010] Another object of the present invention is to use Levocloperastine for the treatment for
vertigo or clinical sign and symptom associated with vertigo.
[0011] Another object of the present invention is to use Levocloperastine for the treatment of
vertigo or clinical sign and symptom or vegetative concomitant symptoms associated with
vertigo, or disease associated with Vertigo within a shorter duration of time as compared to
standard of care therapy used.
[0012] Another object of the present invention is to provide a pharmaceutical composition for use
in the treatment of vertigo or clinical sign and symptoms associated with it or vegetative
concomitant symptoms within a shorter duration of time as compared to standard of care
therapy.
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[0013] Another object of the present invention is to provide a pharmaceutical composition of
Levocloperastine and use thereof for the treatment or prevention of one or more symptoms of
vertigo.
SUMMARY OF INVENTION
[0014] One embodiment of the invention is to use Levocloperastine for the treatment of vertigo
and/or prevention of one or more symptoms of vertigo.
[0015] Another embodiment of the invention is to use Levocloperastine for the treatment of
Peripheral vertigo and clinical sign and symptoms of Peripheral vertigo.
[0016] Another embodiment of the invention is administration of therapeutically effective dose of
Levocloperastine for the treatment of vertigo and/or one or more symptoms of vertigo.
[0017] Another embodiment of the invention is administration of therapeutically effective dose of
Levocloperastine for the treatment of peripheral vertigo.
[0018] Another embodiment of the invention is use of Levocloperastine for quicker relief of
vertigo symptoms compared to existent standard of care and also prompt relief of associated
vegetative concomitant symptoms and in turn contributing to a major extent towards treating
patients with vertigo plus increasing compliance of these patients.
[0019] Another embodiment of the invention is a novel pharmaceutical composition comprising
Levocloperastine for use in the treatment of vertigo or one or more symptom associated with
vertigo.
[0020] Another embodiment of the invention is to use Levocloperastine for the treatment of
vertigo or one or more symptom associated with vertigo or vegetative concomitant symptoms
or disease associated with it, within a shorter duration of time as compared to standard of care
therapy used.
[0021] Another embodiment of the invention is, method of treatment of vertigo and/or prevention
of one or more symptoms of vertigo or disease associated with vertigo in a human subject,
wherein the method comprises administering to the subject, a therapeutically effective amount
of Levocloperastine or a pharmaceutically acceptable salt thereof for a duration of time that is
shorter as compared to standard of care therapy used.
[0022] Another embodiment of the invention is a pharmaceutical composition for use in the
treatment of vertigo or diseases associated with vertigo or vegetative concomitant symptoms
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within a shorter duration of time as compared to standard of care therapy used for treatment
of vertigo or disease associated with vertigo.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The above general and further specific embodiments of the invention including the
examples, described hereinafter, are exemplary and in no way limits the scope of the inventions
to expressly or specifically disclosed embodiments only; and variations and/or modifications
thereof that are apparent to and obvious for a person skilled in the art are also included within
the scope of the invention.
[0024] Unless otherwise defined, all the technical and scientific terms used herein shall bear the
meaning as ordinarily understood by a person skilled in the field of the invention.
[0025] Processes, methods and techniques, which are commonly used and routinely practiced in
the field of the invention and/or easily understood by a person skilled in the art, are not
described in detail, for the sake of brevity.
[0026] The term “Levocloperastine” used throughout the specification includes the free base form
and pharmaceutically acceptable salts thereof; anhydrous forms, solvates, hydrates and cocrystalline forms thereof; and crystalline and amorphous polymorphic forms thereof.
[0027] The term “Patient or subject” means a human being in some diseased state.
[0028] The term “Pharmaceutical composition” for the purpose of the invention, means a
composition in the form of tablet, capsule, solution and suspension. The said pharmaceutical
composition comprises of Levocloperastine and one of more pharmaceutically acceptable
excipients.
[0029] One embodiment of the invention is, use of Levocloperastine or a pharmaceutically
acceptable salt thereof, for the treatment of vertigo and/or prevention of one or more symptoms
of vertigo.
[0030] Another embodiment of the invention is use of Levocloperastine or a pharmaceutically
acceptable salt thereof, for the treatment of and/or prevention of one or more symptoms of
vertigo or disease associated with vertigo. The vertigo associated disease includes but not
limited to Meniere’s disease and Giddiness.
[0031] Another embodiment of the present invention is to use Levocloperastine for the treatment
of peripheral vertigo.
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[0032] Another embodiment of the invention is use of Levocloperastine or a pharmaceutically
acceptable salt thereof, in the preparation of a pharmaceutically acceptable composition for
use in the treatment of vertigo and/or prevention of one or more symptoms of vertigo.
[0033] Another embodiment of the invention is administration of Levocloperastine or a
pharmaceutically acceptable salt thereof at a therapeutically effective dose for the treatment of
vertigo and/or prevention of one or more symptoms of vertigo.
[0034] Another embodiment of the invention is method of treatment of vertigo and/or prevention
of one or more symptoms of vertigo or disease associated with Vertigo in a human subject,
wherein the method comprises administering to the subject, a therapeutically effective amount
of Levocloperastine or a pharmaceutically acceptable salt thereof.
[0035] Another embodiment of the invention is method of treatment of Peripheral Vertigo,
Meniere's disease, Tinnitus, Hearing loss, Giddiness, Dysesthesia of motion and position,
Nystagmus, Dysequilibrium, Dizziness, Head deviation, Nausea, Vomiting, Sweating,
Salivation and Tachycardia, Dystasia and Walking unsteadiness, Staggering, Rotary sensation,
Tendency to fall, Lift sensation, Blackout, Change of position (lying), Bowing, Getting up,
driving, Head movements (inclination, twist), eye movement or one or more symptoms or
disease associated with it in a human subject, wherein the method comprises administering to
the subject, a therapeutically effective amount of Levocloperastine or a pharmaceutically
acceptable salt thereof.
[0036] Another embodiment of the invention is to use Levocloperastine in the treatment of vertigo
and/or prevention of one or more symptoms of vertigo or diseases associated with vertigo in a
human subject.
[0037] Another embodiment of the invention is to use Levocloperastine in the preparation of a
pharmaceutical composition for use in the treatment of vertigo and/or prevention of one or
more symptoms of vertigo or diseases associated with vertigo in a human subject.
[0038] Levocloperastine can be used at a daily dose of 5 to 1000 mg, preferably at a daily dose of
about 5 to 500 mg, more preferably at a daily dose of about 5 to 200 mg, or more preferably at
a daily dose of about 5-160 mg for the treatment or prevention of vertigo or disease associated
with vertigo.
[0039] The daily dosage of Levocloperastine can be administered as a single dose or multiple
divided doses.
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[0040] The daily dosage of Levocloperastine can be administered as about 5-80mg once daily, or
as about 5-40 mg twice a day, or as about 3-30 mg thrice a day.
[0041] The daily dosage of Levocloperastine can be administered as about 60-90 mg once daily,
or as about 30-45 mg twice a day, or as about 20-30 mg thrice a day.
[0042] The daily dosage of Levocloperastine can be administered as about 70-120 mg once daily,
or as about 35-60 mg twice a day, or as about 25-40 mg thrice a day.
[0043] The daily dosage of Levocloperastine can be administered as about 90-160 mg once daily,
or as about 45-80 mg twice a day, or as about 30-55 mg thrice a day.
[0044] The actual dosage of Levocloperastine can be calculated and adjusted according to the
pharmaceutically acceptable salt thereof used. e.g. 35.4 mg of Levocloperastine Fendizoate is
equivalent to 20 mg of Levocloperastine HCl.
[0045] Another embodiment of the invention is to use about 20-36 mg Levocloperastine or a
pharmaceutically acceptable salt thereof three times a day for the treatment of vertigo or and/or
prevention of one or more symptoms of vertigo.
[0046] Another embodiment of the invention is to use about 30-55 mg Levocloperastine or a
pharmaceutically acceptable salt thereof twice a day for the treatment of vertigo or and/or
prevention of one or more symptoms of vertigo.
[0047] Another embodiment of the invention is to use about 60-110 mg Levocloperastine or a
pharmaceutically acceptable salt thereof once a day for the treatment of vertigo or and/or
prevention of one or more symptoms of vertigo.
[0048] Another embodiment of the invention is to use about 30-55 mg Levocloperastine or a
pharmaceutically acceptable salt thereof three times a day for the treatment of vertigo or and/or
prevention of one or more symptoms of vertigo.
[0049] Another embodiment of the invention is to use about 45-85 mg Levocloperastine or a
pharmaceutically acceptable salt thereof twice a day for the treatment of vertigo or and/or
prevention of one or more symptoms of vertigo.
[0050] Another embodiment of the invention is to use about 90-160 mg Levocloperastine or a
pharmaceutically acceptable salt thereof once a day for the treatment of vertigo or and/or
prevention of one or more symptoms of vertigo.
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[0051] Another embodiment of the invention is use of Levocloperastine for the treatment or
prevention of vertigo or disease associated with vertigo, wherein vertigo symptoms scale of
patients is 0 to 5.
[0052] Effectiveness of Levocloperastine in the treatment or prevention of vertigo or disease
associated with vertigo has been evaluated as Improvement in vertigo symptoms based on
MVS score as primary efficacy end point Improvement in quality of life (QoL) associated with
Peripheral vertigo evaluated based on NVI and IGA score by means of a 5-point verbal rating
scale (very much improved, much improved, slightly improved, not improved, deteriorated)
rated by Investigator, Improvement in the severity of tinnitus assessed subjectively by THI on
a categorical 3-point scale (yes/no/sometimes), and Improvement in four vegetative
concomitant symptoms (nausea, vomiting, sweating, and tachycardia) based on their intensities
evaluated by subjective 5-point VAS (0: not present; 1: moderate; 2: medium; 3: strong; 4:
very strong).
[0053] The MVS score, a 12-item composite score to measure the severity of vertigo symptoms,
is defined as the mean intensity of 6 (unprovoked) vertigo symptoms (dystasia and walking
unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, blackout) and vertigo
in consequence of 6 triggering factors [change of position (lying), bowing, getting up, driving
by car/train, head movements (inclination, twist), eye movement]. The intensity of each of the
12 single symptoms is rated by the patients by means of a 5-point VAS (0 = not present, 1 =
moderate, 2 = medium, 3 = strong, 4 = very strong). A mean MVS serving as a measure of
vertigo intensity, will be calculated by adding the scores on all 12 vertigo symptoms and
dividing by 12. The scale is rated by patients directly.
[0054] NVI is a 28-item questionnaire with a five-point Likert scale for each question (1: Never;
2: Rarely; 3: Sometimes; 4: Very often; 5: Always), for a total score ranging from 28 to 140
points. Higher scores indicate greater dysfunction. It assesses seven domains of cognition:
space perception, attention, time perception, memory, emotional, visual/oculomotor, and
motor. The scale is rated by patients.
[0055] Method of measurement for severity of tinnitus will be subjective evaluation by 25-item
questions of THI on a categorical 3-point scale (yes/no/sometimes). The total score reflects the
sum of all responses with a maximum score of 100 indicating the greatest impact on everyday
function.
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[0056] The CNS activity of Levocloperastine is highly selective; therefore, it avoids central
adverse effects such as sedation. Levocloperastine, at doses up to 450-fold higher than the
therapeutic doses, did not induce any clinically relevant sedation. Levocloperastine provides a
faster onset of action and also avoids adverse events such as sedition and excitement. As
treatment with Levocloperastine is not associated with any sedation, none of the symptoms
associated with vertigo would be masked and surprisingly, levocloperastine, even without any
sedative property, shows improvement in vertigo and vegetative concomitant symptoms
associated with vertigo.
[0057] Levocloperastine provides the treatment of Vertigo or Peripheral vertigo or disease
associated with vertigo or vegetative concomitant symptoms, within a shorter duration of time
as compared to standard of care therapy used. Levocloperastine achieves comparable
improvement in MVS score with a shorter duration of treatment compared to the standard of
care treatment. The comparable amount of improvement in Vegetative concomitant symptoms
severity is achieved by the standard of care treatment after about 28 days of treatment, is
achieved by Levocloperastine in a treatment of duration of as short as about 7 days only, i.e. a
remarkable reduction of the duration of the treatment to about 1/4th of the standard of care
treatment. Levocloperastine gives quick relief to Vertigo or its symptoms and improvement in
severity of vegetative concomitant symptoms associated therewith.
[0058] The faster onset of action and shorter duration of treatment, without causing clinically
relevant sedation of Levocloperastine aids in better patient compliance, better treatment
adherence and limited motor/movement restrictions for the patients.
[0059] Another embodiment of the invention is method of treatment of Vertigo and/or prevention
of one or more symptoms of Vertigo or vegetative concomitant symptoms or disease associated
with Vertigo in a human subject, wherein the method comprises administering to the subject,
a therapeutically effective amount of Levocloperastine or a pharmaceutically acceptable salt
thereof for a duration of time that is shorter as compared to standard of care therapy used.
[0060] Another embodiment of the invention is to use a therapeutically effective amount of
Levocloperastine or a pharmaceutically acceptable salt thereof for the treatment of Peripheral
Vertigo, Meniere's disease, Tinnitus, Hearing loss, Giddiness, Dysesthesia of motion and
position, Nystagmus, Dysequilibrium, Dizziness, Head deviation, Nausea, Vomiting, Sweating,
Salivation and Tachycardia, Dystasia and Walking unsteadiness, Staggering, Rotary sensation,
Tendency to fall, Lift sensation, Blackout, Change of position (lying), Bowing, Getting up,
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driving, Head movements (inclination, twist), eye movement or one or more symptoms or
disease associated with it for a duration of time that is shorter as compared to standard of care
therapy used.
[0061] Another embodiment of the present invention is a pharmaceutical composition for use in
the treatment of vertigo or diseases associated with vertigo or vegetative concomitant
symptoms within a shorter duration of time as compared to standard of care therapy used for
treatment of vertigo or disease associated with vertigo.
[0062] Another embodiment of the invention a pharmaceutical composition comprising
Levocloperastine or pharmaceutically acceptable salt thereof for use in the treatment of vertigo
and/or prevention of one or more symptoms of vertigo or disease associated with Vertigo in a
human subject.
[0063] The pharmaceutically acceptable composition of Levocloperastine can be suitable for oral,
buccal, sublingual, transdermal, intravenous, intraperitoneal, intramuscular or subcutaneous
administration.
[0064] Another embodiment of the invention is an oral pharmaceutical composition comprising
Levocloperastine for use in the treatment or prevention of vertigo or disease associated with
vertigo.
[0065] Another embodiment of the invention is an oral pharmaceutical composition comprising
Levocloperastine for use in the treatment or prevention of Peripheral vertigo or disease
associated with Peripheral vertigo.
[0066] Another embodiment of the invention is a pharmaceutical composition comprising
Levocloperastine for use in the treatment of vertigo and/or prevention of one or more
symptoms of vertigo.
[0067] The pharmaceutical dosage form for use in the treatment or prevention of vertigo or disease
associated with vertigo can be, but not limited to, a solid or liquid oral dosage form. The solid
oral dosage form can be, but not limited to, tablet, capsule, granules or powder; and the liquid
oral composition can be, but not limited to, solution, syrup, suspension or emulsion.
[0068] Another embodiment of the present invention is to use Levocloperastine for the treatment
or prevention of vertigo or disease associated with vertigo, wherein the pharmaceutical
composition used for the treatment or prevention of vertigo or disease associated with vertigo
comprises Levocloperastine and one or more pharmaceutically acceptable excipients, wherein
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the said composition is in the form of liquid dosage form, wherein the said liquid dosage form
is used for administration to paediatric as well as adult patients.
[0069] Another embodiment of the present invention is, Levocloperastine for the treatment of
vertigo or disease associated with vertigo be used in admixture with conventional
pharmaceutically acceptable carriers or diluents which are suitable for oral or parenteral
administration.
[0070] Another embodiment of the present invention is, a stable oral pharmaceutical composition
of Levocloperastine and one or more pharmaceutically acceptable excipients wherein the said
composition is in tablet, capsule, solution, syrup or suspension dosage form.
[0071] Another embodiment of the present invention is, a stable oral pharmaceutical composition
of Levocloperastine and one or more pharmaceutically acceptable excipients wherein the said
pharmaceutically acceptable excipients comprising, but not limited to, diluent, disintegrants,
binder, lubricants, anti-adherents, plasticizer, colouring agent, opacifier, chelating agents,
glidant, flavouring agent, sweetening agent, coating agent, wetting agents, buffering agent,
suspending agents, preservatives, surfactants, viscosity-modifying agents, tonicity adjusting
agent, anti-dusting agents, adsorbents, antioxidants, humectant, solvents, polymers, soft gel
capsule, hard gel capsule or mixture thereof.
[0072] The diluents or fillers can be selected from a group comprising but not limited to Lactose
Monohydrate, Maize Starch, mannitol, dibasic calcium phosphate anhydrous, microcrystalline
cellulose, Silicified MCC, corn starch, sucrose or other sugar or sugar derivatives, low
substituted HPC, pregelatinized starch or mixture thereof, more preferably mannitol and
microcrystalline cellulose. The fillers or diluents can be present in a concentration of from
about 20% to about 80% by weight of the total weight of the composition.
[0073] The binder can be selected from a group comprising but not limited to pregelatinized starch,
polyvinylpyrrolidone, Vinylpyrrolidone-vinyl acetate copolymer, povidone, copovidone,
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, maize starch, microcrystalline
cellulose or mixture thereof. The binder can be present in a concentration of from about 0.5%
to about 5% by weight of the total weight of the composition.
[0074] The disintegrant can be selected from a group comprising but not limited to
crosscarmellose sodium, crospovidone, sodium starch glycolate, starch, corn starch,
pregelatinized starch or mixture thereof. The disintegrant can be present in a concentration of
from about 1% to about 10% by weight of the total weight of the composition.
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[0075] The lubricant can be selected form the group comprising of agar, calcium stearate, ethyl
oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil,
magnesium oxide, magnesium stearate, sodium stearyl, sorbitol, stearic acid, talc, and zinc
stearate or mixture thereof. The lubricant can be present in a concentration of from about 0.2%
to about 2% by weight of the total weight of the composition.
[0076] The plasticizer can be selected from a group comprising Acetyltributyl Citrate,
Acetyltriethyl citrate, Benzyl Benzoate, Chlorobutanol, Cellulose acetate phthalate compatible,
Dextrin, Dibutyl Phthalate, DibutylSebacate, Diethyl Phthalate, Dimethyl Phthalate, Glycerin,
Glycerinmonostearate, Hypromellose phthalate compatible, Mannitol, Mineral Oil and
Lanolin Alcohols, Petrolatum and Lanolin Alcohols, Polyethylene Glycol, Propylene Glycol,
Pyrrolidone, Sorbitol, Triacetin, Tributyl Citrate, Triethyl Citrate, Palmitic acid,
Polymethacrylate compatible, Polyvinyl acetate phthalate, Stearic acid, Triethanolamine or
mixture thereof.
[0077] The colouring agent can be selected from a group comprising Red 3 (Erythrosine), Red 40
(Allura red AC), Yellow 5 (Tartrazine), Yellow 6 (Sunset Yellow), Blue 1(Brilliant Blue),
Blue 2 (Indigotine), Green 3 (Fast Green), Iron Oxides or mixture thereof.
[0078] The opacifier can be selected from a group comprising AluminumMonostearate, Calcium
Carbonate, Calcium Silicate, Ceresin, Titanium Dioxide, Zinc Acetate, Coloring agents,
Ethylene glycol palmitostearate, Octyldodecanol, Zinc stearate or mixture thereof.
[0079] The chelating agents can be selected from a group comprising Calcium Acetate,
HydroxypropylBetadex, Potassium Citrate, Citric acid, Citric Acid Monohydrate, Disodium
Edetate, Edetic Acid, Malic Acid, Pentetic Acid, Phosphoric acid, Sodium Citrate Dihydrate,
Dibasic Sodium Phosphate, Monobasic Sodium Phosphate, Tartaric Acid, Potassium citrate,
Fumaric acid, Maltol, Pentetic acid or mixture thereof.
[0080] The glidant can be selected from a group comprising colloidal silicon dioxide, magnesium
silicate, starch, talc, tribasic calcium phosphate, stearic acid, palmitic acid, polyethylene glycol,
carnauba wax or mixtures thereof. The glidant can be present in a concentration of from about
0% to about 2% by weight of the total weight of the composition.
[0081] The flavouring agent can be selected from a group comprising Adipic Acid, n-butyl lactate,
Confectioner’s sugar, Citric Acid Monohydrate, Dibutylsebacate, Denatonium Benzoate,
Ethyl Acetate, Ethyl Lactate, Ethyl Maltol, Ethyl Vanillin, Ethylcellulose, Fructose, Fumaric
Acid, Leucine, Malic Acid, Maltol, Menthol, Methionine, Monosodium Glutamate,
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NeohesperidinDihydrochalcone, Neotame, Sodium Acetate, Sodium Lactate, Triethyl citrate,
Tartaric Acid, Thaumatin, Thymol, Trehalose, Vanilla, Phosphoric acid, Propionic acid,
Sodium propionate or mixture thereof
[0082] The sweetening agent can be selected from a group comprising Acesulfame Potassium,
Alitame, Aspartame, Dextrose, Erythritol, Fructose, Glucose Liquid, Glycerin, Inulin, Isomalt,
Lactitol,Maltitol, Maltitol Solution, Maltose, Mannitol, NeohesperidinDihydrochalcone,
Neotame, Saccharin, Saccharin Sodium, Sodium Cyclamate, Sorbitol, Sucralose, Sucrose,
Compressible Sugar, Confectioner’s Sugar, Tagatose, Thaumatin, Trehalose, Xylitol or
mixture thereof
[0083] The Antiadherent can be selected from a group comprising Magnesium stearate, Calcium
Stearate, Leucine, Colloidal Silicon Dioxide, Talc, Starch, Cellulose Microcrystalline, Leucine
or mixture thereof
[0084] The Polymers can be selected from a group comprising hydroxypropyl methylcellulose,
polyethylene glycol, hydroxypropyl cellulose and its derivative, polysorbate, Soluplus®
(polyvinyl caprolactam-polyvinyl acetate-polyethylene), sodium carboxy methyl cellulose,
Talc, Titanium dioxide, simethicon, Eudragit, purified water and colorant. The polymers can
be used in the film coating material or as excipient,can be present in a concentration of from
about 1% to about 5% by weight of the total weight of the composition.
[0085] The Surfactants can be selected from a group comprising anionic surfactants such as
sodium lauryl sulfate and docusate sodium, cationic surfactants such as cetrimide, ampholytic
surfactants such as N-dodecyl- N, N-dimethylbetaine, non-ionic surfactants such as sorbitan
fatty acid esters, polysorbates, polyoxyethylene alkyl ethers, poloxamers, medium-chain
triglycerides, polyoxylglycerides, polyoxyethylene castor oil derivatives and combinations
thereof. The surfactants can be present in a concentration of from about 0% to about 5% by
weight of the total weight of the composition.
[0086] The Anti-dusting agents are Edible oils.
[0087] The Adsorbents can be selected from a group comprising Bone Gelatin (Type B), Skin
Gelatin (Type A) or mixture thereof. Gelatine also works as suspending agent.
[0088] The solubilizer or emulsifier or dispersing agent can be selected from a group comprising
Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, Capmul
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MCM, Capmul PG-12, Captex 355, gelucire, lecithine, vitamin E TOPS or other acceptable
solubilizer, emulsifier or dispersing agents.
[0089] The Solvent can be selected from a group comprising purified water, Water for Injection,
Arometic water, Alcohol, Glycerol, Propylene Glycol USP, Ether (Diethyl ether),
Polyethylene glycol and derivatives, Diethlyene glycol monemethyl ether and its derivative,
Dimethylacetamide, Fixed oil form plant source or mixture thereof.
[0090] The Wetting agents can be selected from a group comprising Benzalkonium Chloride,
Benzethonium chloride, Cetylpyridinium Chloride, Docusate Sodium, Glycine, Glycofurol,
Hypromellose, Poloxamer, Phospholipids, Polyoxyethylene Alkyl Ethers, Polyoxyethylene
Castor Oil Derivatives, PolyoxyethyleneSorbitan Fatty Acid Esters, Polyoxyethylene Stearates,
Sodium Lauryl Sulfate, Sorbitan Esters (Sorbitan Fatty Acid Esters), Tricaprylin or mixture
thereof.
[0091] The Buffering agent can be selected from a group comprising Adipic Acid, Ammonia
solution, Boric Acid, Calcium Carbonate, Calcium hydroxide, Calcium Lactate, Calcium
Phosphate(Tribasic), Citric Acid Monohydrate, Dibasic sodium phosphate, Diethanolamine,
Glycine, Maleic Acid, Malic Acid, Methionine, Monosodium Glutamate, Monoethanolamine,
Monosodium glutamate, Potassium Citrate, Sodium Acetate, Sodium Borate, Sodium
Carbonate, Sodium Citrate Dihydrate, Sodium Hydroxide, Sodium Lactate, Sodium
Phosphate(Dibasic), Sodium Phosphate (Monobasic), Propionic Acid, Phosphoric acid,
Sodium bicarbonate, Triethanolamine or mixture thereof.
[0092] The Suspending Agents can be selected from a group comprising Acacia, Agar, Alginic
Acid, Bentonite, Carbomer, Calcium stearate, Carboxymethylcellulose Calcium,
Carboxymethylcellulose Sodium, Carrageenan, Microcrystalline cellulose,
Carboxymethylcellulose Sodium, Cellulose Powdered, Ceratonia, Colloidal Silicon Dioxide,
Dextrin, Gelatin, Guar Gum, Hydrophobic Colloidal Silica, Hydroxyethyl Cellulose,
Hydroxyethylmethyl Cellulose, Hydroxypropyl Cellulose, Hypromellose, Kaolin, Magnesium
Aluminum Silicate, Maltitol Solution, Medium-chain Triglycerides, Methylcellulose,
Phospholipids, Polycarbophil, PolyoxyethyleneSorbitan Fatty Acid Esters, Potassium Alginate,
Povidone, Propylene Glycol Alginate, Sodium Alginate, Saponite, Sesame oil, Sorbitan Esters
(Sorbitan Fatty Acid Esters), Sucrose, Tragacanth, Vitamin E Polyethylene Glycol Succinate,
Xanthan Gum, Ceratonia, Hectorite or mixture thereof.
14
[0093] The Viscosity-modifying Agents can be selected from a group comprising Acacia, Agar,
Alginic Acid, Bentonite, Carboxymethylcellulose Calcium, Carboxymethylcellulose Sodium,
Carrageenan, Ceratonia, Cetostearyl Alcohol, Chitosan, Colloidal Silicon Dioxide,
Cyclomethicone, Ethylcellulose, Gelatin, Glycerin, GlycerylBehenate, Guar Gum, Hectorite,
Hydrophobic Colloidal Silica, Hydroxyethyl Cellulose, Hydroxyethylmethyl Cellulose,
Hydroxypropyl Cellulose, Hydroxypropyl Starch, Hypromellose, Magnesium Aluminum
Silicate, Maltodextrin, Methylcellulose, Myristyl Alcohol, Polydextrose, Poly(methyl vinyl
ether/maleic anhydride), Polyvinyl Alcohol, Propylene Glycol, Propylene Glycol Alginate,
Saponite, Sodium Alginate, Sodium chloride, Starch, Sulfobutylether b-Cyclodextrin,
Tragacanth, Xanthan Gum or mixture thereof.
[0094] The Preservatives can be selected from a group comprising Alcohol, Benzalkonium
Chloride, Benzethonium Chloride, Benzoic Acid, Benzyl Alcohol, Boric Acid, Bronopol,
Butylene Glycol, Butylatedhydroxyanisole, Butylparaben, Calcium Acetate, Calcium Chloride,
Calcium Lactate, Cetrimide, CetylpyridiniumChloride, Chlorhexidine , Chlorobutanol ,
Chlorocresol, Chloroxylenol, Citric Acid Monohydrate, Cresol, Dimethyl ether, Ethylparaben,
Glycerin, Hexetidine, Imidurea, Isopropyl alcohol, lactic acid, Methylparaben,
Monothioglycerol, Pentetic Acid, Phenol, Phenoxyethanol, Phenylethyl Alcohol,
Phenylmercuric Acetate , Phenylmercuric Borate, Phenylmercuric Nitrate, Potassium
Benzoate, Potassium Metabisulfite, Potassium Sorbate, Propionic Acid, Propylene Glycol,
Propyl gallate, Propylparaben, Propylparaben Sodium, Sodium Acetate, Sodium Benzoate,
Sodium Borate, Sodium Lactate, Sodium Metabisulfite, Sodium Propionate, Sodium Sulfite,
Sorbic Acid, Sulfur Dioxide, Thimerosal, Sulfobutyletherb-cyclodextrin, Xylitol, Edetic acid
or mixture thereof.
[0095] The Antioxidants can be selected from a group comprising Alpha / beta / delta / gamma
tocopherols , Ascorbic Acid, AscorbylPalmitate, ButylatedHydroxyanisole,
ButylatedHydroxytoluene, Citric Acid Monohydrate, Erythorbic Acid, Ethyl oleate, Fumaric
Acid, Malic Acid, Methionine, Potassium Metabisulfite, Propionic Acid, Propyl Gallate,
Sodium Ascorbate, Sodium Formaldehyde Sulfoxylate, Sodium Metabisulfite, Sodium Sulfite,
Sodium Bisulfite, Sodium Thiosulfate, Sulfur Dioxide, Thymol, Vitamin E Polyethylene
Glycol Succinate, Monothoglycerol, Phosphoric acid or mixture thereof.
[0096] The Tonicity adjusting agent can be selected from a group comprising Dextrose, Glycerin,
HydroxypropylBetadex, Mannitol, Potassium Chloride, Sodium Chloride or mixture thereof.
15
[0097] The humectant can be selected from a group comprising Ammonium Alginate, Butylene
Glycol, Cyclomethicone, Glycerin, Polydextrose, Propylene Glycol, Sodium Hyaluronate,
Sodium Lactate, Sorbitol or mixture thereof.
[0098] Dicom DC SP®, F-Melt Type C® etc are used as excipients.
[0099] In one of the preferred embodiments of the present invention a pharmaceutical composition
comprising Levocloperastine or pharmaceutically acceptable salt thereof, wherein the
composition is a tablet composition comprising Levocloperastine 1-5%, diluent 20-80%,
disintegrant 1-10%, binder 0.5-5%, lubricant 0.2-2%, glidant 0-2% and surfactant 0-5%, by
total weight of the tablet composition.
[0100] In one of the preferred embodiments of the present invention a pharmaceutical composition
comprising Levocloperastine or pharmaceutically acceptable salt thereof, wherein the
composition is a solution composition comprising Levocloperastine 1-5%, anti-oxidant 1-10%
and preservative 0.01-10% by total weight of the solution composition, and further comprising
buffer, and optionally flavouring and sweetening agent.
[0101] In other embodiments of the present invention a pharmaceutical composition comprising
Levocloperastine or pharmaceutically acceptable salt thereof, wherein the composition is a
hard gel capsule composition, comprising Levocloperastine, surfactant, binder, polymer,
diluent, and solvent.
[0102] In other embodiments of the present invention a pharmaceutical composition comprising
Levocloperastine or pharmaceutically acceptable salt thereof, wherein the composition is a soft
gel capsule composition, comprising Levocloperastine, solubilizer, stabilizer, lubricant, and
optionally other excipients.
[0103] The pharmaceutical composition described herein may be prepared by conventional
technology well known to those skilled in the art such as wet granulation, dry granulation and
direct compression and the like.
[0104] In one of the preferred embodiments, present invention is to provide a process for
preparation of a stable pharmaceutical composition comprising Levocloperastine or its
pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients
comprising following steps:
1) Mixing Levocloperastine or its salt with diluent and disintegrants to obtain a blend.
2) Disperse binder in solvent under stirring to obtain a binder solution.
16
3) Granulate the blend obtained in step 1 in a granulator with binder solution to obtain wet
granules. Dry the wet granules.
4) Size the dried granules and add desired amount of lubricant to obtain a lubricated granule.
5) Compress the lubricated granules of step 6 to obtain compressed tablets.
6) Optionally, coat the compressed tablets using coating solution.
[0105] In one of the preferred embodiments, present invention is to provide a process for
preparation of a stable pharmaceutical composition comprising Levocloperastine or its
pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients
comprising following steps:
1) Mixing Levocloperastine or its salt with diluent and disintegrants to obtain a blend.
2) Disperse binder in solvent under stirring to obtain a binder solution.
3) Granulate the blend obtained in step 1 in a granulator with binder solution to obtain wet
granules. Dry the wet granules.
4) Size the dried granules and add desired amount of lubricant to obtain a lubricated granule.
5) Fill the lubricated granule into the suitable sized capsule.
[0106] In one of the preferred embodiments, present invention is to provide a process for
preparation of a stable pharmaceutical composition comprising Levocloperastine or its
pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients
comprising following steps:
1) Mixing Levocloperastine or its salt with diluent and disintegrants to obtain a blend.
2) Mixing remaining excipients to obtained blend
3) Mixing blend of step 1 to the blend of step 2
4) Compress the dry blend to obtained tablet or fill into the capsule.
5) optionally coating the compress tablets.
[0107] In one of the preferred embodiments, present invention is to provide a process for
preparation of a stable pharmaceutical composition comprising Levocloperastine or its
pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients
wherein said Levocloperastine is mixed with suitable pharmaceutically acceptable excipients
and filled in to soft gel capsule.
17
[0108] In one of the preferred embodiment, present invention is to provide a process for
preparation of a stable pharmaceutical composition comprising Levocloperastine or its
pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients
wherein said Levocloperastine or its pharmaceutically acceptable salt thereof undergoes a size
reduction process and adding buffer, suspending agent, anti-oxidant, preservative, co solvent,
preservative, sweetening agent or flavouring agent to obtain suspension dosage from.
[0109] In one of the preferred embodiments, present invention is to provide stable pharmaceutical
composition comprising Levocloperastine or its pharmaceutically acceptable salt thereof and
one or more pharmaceutical acceptable excipients, wherein the content uniformity of the said
composition is in between 95% and 105%.
[0110] In one of the preferred embodiments, present invention is to stable pharmaceutical
composition comprising Levocloperastine or its pharmaceutically acceptable salt thereof and
one or more pharmaceutical acceptable excipients, wherein the dissolution rate of
Levocloperastine is not less than 90% at 45 minutes when the composition is subjected to the
dissolution test using paddle method at a rotation of 50 rpm in 900 ml of purified water.
[0111] In yet another embodiment, the present invention is to provide a stable pharmaceutical
composition comprising Levocloperastine and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of tablet, capsule, solution or
suspension, and the said composition can be used as single dose or multi dose administration
formulation in adult as well as paediatric patients for the treatment of Vertigo, Peripheral
vertigo, Meniere's disease and giddiness.
[0112] Examples
[0113] One or more general or specific embodiments are further described in detail in the
following examples, which are not intended, in any way, to limit the scope of the invention to
the specifically disclosed embodiments only. It is readily apparent to those of ordinary skill in
the art in light of the teachings of this invention that certain changes and modifications may be
made thereto without departing from the scope of the invention.
[0114] Example - 1: Levocloperastine Tablet
Sr. No. Ingredients % w/w
1 levocloperastine 1-5
2 Diluent 20-80
18
3 Disintegrant 1-10
4 Binder 0.5-5
5 Lubricant 0.2-2
6 Glidant 0-2
7 Surfactant 0-5
8 Solvent Qs
9 Film Coating material 1-5
Process of preparation of tablet:
1. Levocloperastine was mixed with diluent and disintegrants to obtain a blend.
2. The binder was dispersed in the solvent under stirring to obtain a binder solution.
3. The blend obtained in step 1 was granulated in granulator with the binder solution.
4. The wet granules were dried in fluid bed dryer then seived the dried granules.
5. The granules were mixed with the lubricant and compressed into tablets and coated with the
coating solution prepared by dissolving the film coating material in the solvent.
[0115] Example – 2: Levocloperastine Hard Gel Capsule
Sr.
No
Ingredient % (w/w)
1. Levocloperastine Fendizoate 35
2. Sodium Lauryl Sulfate 0.5-2.5
3. Polyvinylpyrrolidone 0.5-25.0
4. Vinylpyrrolidone-vinyl acetate copolymer 0.5-5.0
5. Polysorbate 80 1-15
6. Silicified MCC 0-5.0
7. Lactose Monohydrate + Maize Starch 0-2.0
8. Ethanol Q.S.
Process of preparation of capsule:
1. Levocloperastine Fendizoate was mixed with lactose monohydrate, maize starch,
vinylpyrrolidone-vinyl acetate copolymer rand silicified MCCto obtain a blend.
2. Polyvinylpyrrolidone was dispersed in solvent under stirring to obtain a binder solution.
19
3. The blend obtained in step 1 was granulated in the granulator with the binder solution.
4. The wet granules were dried in fluid bed dryer then seived the dried granules.
5. The granules were mixed with sodium lauryl sulfate and polysorbate 80, and filled in capsules.
[0116] Example – 3: Levocloperastine Soft Gel Capsule
Sr. No. Ingredients
mg per
capsule
1 Levocloperastine Fendizoate 35
2 Labrafac 15
3 Polyoxyl castor oil 15
4 Lecithine 20
5 Gelatine 20
Levocloperastine Fendizoate and the excipients as per above table were mixed and filled in a soft
gel capsule.
[0117] Example - 4: Levocloperastine Solution
Sr. No. Ingredients % w/w
1 Levocloperastine 1-5
2 Buffer
Q.S. to adjust
pH 4.0 to 8.0
3 Anti-oxidant 0-10
4 Preservative 0.01-10
5 Co solvent 0.01 - 50
6 Sweetening agent 0.01-5.0
7 Flavoring agent 0.01-5.0
8 Water Q.S.
Amount of solution 100
Process of preparation of solution:
1. Take purified water in SS vessels.
2. Add preservative, buffer, sweetening agent, and anti-oxidant to it and stir up to uniform
mix.
3. Add Levocloperastine, flavoring agent, and co-solvent; and stir up to uniform mix.
4. Make up final volume by purified water.
20
[0118] Example - 5: Levocloperastine Suspension
Sr. No. Ingredients % w/w
1 Levocloperastine 1-5
2 Buffer
To make pH 4.0 to
8.0
3 Suspending agent 0.01-10
4 Flocculating agent 0.01-10
5 Anti-oxidant 0-10
6 Preservative 0.01-10
7 Co solvent 0.01 - 50
8 Preservative 0.01-10
9 Sweetening agent 0.01-5.0
10 Flavouring agent 0.01-5.0
11 Water Q.S.
Amount of suspension 100
Process of preparation of suspension:
1. Take 60% of purified water in SS vessels.
2. Add preservative, buffer, sweetening agent, anti-oxidant, suspending agent and
flocculating agent, and stir up to uniform mix.
3. Add Levocloperastine and stir up to uniform mix.
4. Add flavoring agent and co-solvent and stir up to uniform mix.
5. Make up final volume by purified water.
[0119] Example – 6: Levocloperastine Capsule
Sr. No. Ingredients Qty./Unit
01 Levocloperastine Fendizoate 20.0-35.0 mg
02
Soluplus® (polyvinyl
caprolactam-polyvinyl acetatepolyethylene)
30-45 mg
03 Dimethylacetamide 0.1-0.3mL
04 Dicom DC SP® 230-260 mg
05 Talc Powder 1-3 mg
21
06 Magnesium Stearate 1-3 mg
Process for preparation of Capsule: Wet granulation method
1. Dimethylacetamide and Soluplus® were stirred in a glass vessel.
2. Levocloperastine Fendizoate was added and stirred up to uniform mix.
3. Dicom DC SP® was sifted through #40 sieve and added to above mix and stirred up to
uniform mix.
4. The mix was granulated in a granulator.
5. The granules were dried in hot air oven at 50° C
6. The dried granules were sifted through #40 sieve, and mixed with talc powder (sifted
through #80 sieve) and magnesium stearate (sifted through #80 sieve).
7. The obtained mix was filled in Size ‘0’ capsule
[0120] Example – 7: Levocloperastine Capsule
Sr. No. Ingredients Qty./Unit
01 Levocloperastine Fendizoate 20.0 mg
02 Dicom DC SP 227.0 mg
03 Talc Powder 2.0 mg
04 Magnesium Stearate 1.0 mg
Process for preparation of Capsule: Dry Mix method
Dicom DC SP® (sifted through #40 sieve), Levocloperastine Fendizoate (sifted through #40
sieve), talc powder (sifted through #80 sieve) and magnesium stearate (sifted through #80 sieve)
were blended in a blender up to uniform mix; and filled in Size ‘0’ capsule.
[0121] Example – 8: Levocloperastine Tablet
Sr. No. Ingredients Qty./Unit
01 Levocloperastine Fendizoate 20.0 mg
02 F-Melt Type C® 94.6 mg
03 Crosscarmellose Sodium 10.0 mg
04 Magnesium Stearate 5.0 mg
Process for preparation of Tablet: Dry Mix method
F-Melt Type C®(sifted through #40 sieve), Levocloperastine Fendizoate (sifted through #40
sieve), Crosscarmellose Sodium (sifted through #40 sieve) and magnesium stearate (sifted
22
through #80 sieve) were blended in a blender up to uniform mix; and compressed in8/32 or 9/32
concave punch.
[0122] Example – 9: Levocloperastine HCl Solution (20mg/0.1mL)
Sr. No. Ingredients mg/0.1mL
01 Levocloperastine Hydrochloride 20.0 mg
02 Polyethylene Glycol 300 30.0 mg
03 Polypropylene glycol 10.0 mg
04 Glycerin 0.1mg
05 Hydroxypropyl Methylcellulose E15 0.1 mg
06 Purified Water Q.S to 0.1mL
Process for preparation of Levocloperastine HCl solution
1. About 20% of total required quantity of purified water was taken in a glass vessel and
Polyethylene Glycol 300, Polypropylene glycol were added and stirred up to uniform
mix.
2. Levocloperastine HCl was added and stirred up to uniform mix.
3. Glycerin and Hydroxypropyl methylcellulose E15 were added and stirred up to uniform
mix.
4. Final volume was made-up by purified water.
[0123] Example – 10: Levocloperastine HCl Solution (20mg/0.1mL)
Sr. No. Ingredients mg/0.1mL
01 Levocloperastine Hydrochloride 20.0 mg
02 M- Polyethylene Glycol 350 30.0 mg
03 Polypropylene glycol 6.0 mg
04 Polyethylene Glycol 400 17.0 mg
05 Dehydrated Alcohol 7.0 mg
06 Purified Water Q.S to 0.1mL
Process for preparation of Levocloperastine HCl solution
1. About 10% of total required quantity of purified water was taken in a glass vessel and
Polyethylene Glycol 400, Polypropylene glycol, Dehydrated Alcohol and MPolyethylene Glycol 350 were added and stirred up to uniform mix.
2. Levocloperastine HCl was added and stirred up to uniform mix.
23
3. Final volume was made-up by purified water.
4. The solution was filtered through 0.45µ Nylon filter.
[0124] Example –11: Treatment of Peripheral vertigo: The current study was designed as an
open label, two-treatment arm, active comparator controlled, Clinical trial in patients with
Peripheral vertigo. This study involved a screening phase, randomization and treatment phase
as mentioned below:
• Screening phase (Visit 1): -14 to -1 day
• Baseline visit and day of randomization (Visit 2): Day 0/1
• Treatment phase: Day 1 to Day 28
• End of treatment (Visit 4): Day 29 ± 2 days
[0125] Patients with Peripheral vertigo, meeting the mentioned eligibility criteria were identified
and shortlisted patients underwent screening within 14 days prior to randomization. A total of
16 patients were randomized in the ratio of 3:1 to receive the test and active comparator
products (12 patients received test product and 4 patients received active comparator product).
Test product was consumed as 20mg Levocloperastine orally three times a day for 28 days.
Active comparator (standard of care) was consumed by the patients as per the investigator’s
sole discretion and medical judgement. The standard of care treatment included Betahistine 16
mg tablets three times daily OR Betahistine 16 mg tablets three times daily plus Acetazolamide
125 mg tablets two time daily OR Cinnarizine 25 mg tablets three times daily which was given
to patient.
[0126] MVS Score: Mean change in MVS score from baseline score was compared between two
treatment arms. The absolute data and mean changes from baseline data are presented in
Table1:
Table 1
MVS Score Test treatment
Mean ± SD (Min, Max)
Standard of care
Mean ± SD (Min, Max)
Baseline (Day 0/1) 2.2 ± 0.29 (1.7, 2.8) 2.2 ± 1.4 (2.1, 2.4)
Interim visit [Day 7+ 3] 1.5 ± 0.49 (1.1, 2.8) 1.7 ± 0.35 (1.3, 2.1)
Change from baseline -0.7 ± 0.33 (-1.1, 0.0) -0.5 ± 0.33 (-0.9, -0.2)
24
MVS Score Test treatment
Mean ± SD (Min, Max)
Standard of care
Mean ± SD (Min, Max)
Change as % 31.81% 22.72%
A/28 Days [Day 29 ±2] 1.1 ± 0.58 (0.3, 2.2) 1.1 ± 0.35 (0.7, 1.5)
Change from baseline -1.1 ± 0.45 (-1.8, -0.3) -1.1 ± 0.35 (-1.5, -0.8)
Change as % -50.00% -50.00%
[0127] Levocloperastine is found to be equally efficacious in comparison to standard of care
treatment with regards to primary efficacy endpoint i.e. MVS score and similar trend while
evaluating other co secondary endpoints, NVI score, THI severity & IGA as well.
[0128] Additionally, mean change in composite score of vegetative concomitant symptoms from
baseline score was compared between two treatment arms. The absolute data and mean
changes from baseline data are presented below in Table 2.
[0129] Score of vegetative concomitant symptoms
Table 2
Data presentation
Test treatment
(N = 12)
Standard of care
(N = 4)
Baseline
Absolute data
Mean ± SD (Min,
Max)
1.3 ± 1.05 (0.0, 4.0) 1.6 ± 0.81 (0.0, 3.0)
7 days after treatment onset [Interim visit: Day 7 +3]
Absolute data
Mean ± SD (Min,
Max)
0.6 ± 0.73 (0.0, 2.0) 1.2 ± 0.91 (0.0, 3.0)
Change from
baseline
Mean ± SD (Min,
Max)
-0.6 ± 0.81 (-3.0, 1.0) -0.4 ± 0.50 (-1.0, 0.0)
Change as % -46.15 -25.00
28 days after treatment onset [end of treatment: Day 29 ±2]
Absolute data
Mean ± SD (Min,
Max)
0.2 ± 0.47 (0.0, 2.0) 0.6 ± 0.63 (0.0, 2.0)
Change from Mean ± SD (Min, -1.1 ± 0.98 (-3.0, -1.0) -1.0 ± 0.52 (-2.0, 0.0)
25
Data presentation
Test treatment
(N = 12)
Standard of care
(N = 4)
baseline Max)
Change as % -84.62 -62.50
[0130] Study Data confirms that Levocloperastine is able to control vegetative concomitant
symptoms more rapidly and more significant way compared to existent standard of care
therapy. Levocloperastine is statistically better in alleviating the vegetative concomitant
symptoms than the standard of care treatment even though both the treatment showed clinical
improvement.
Further, as shown statistically in table 1 and 2 within shorter duration of time drug is acting more
superior than standard of care. The study shows favourable response and well tolerability in all
patients. Levocloperastine is found to be equally efficacious in comparison to standard of care
treatment

We claims:

[Claim 1] A pharmaceutical composition comprising Levocloperastine or pharmaceutically
acceptable salt thereof for use in the treatment of vertigo and/or prevention of one or more
symptoms of vertigo or disease associated with Vertigo in a human subject.
[Claim 2] The pharmaceutical composition according to claim 1, wherein the composition
is an oral composition.
[Claim 3] The pharmaceutical composition according to claim 2, wherein the oral
composition is a tablet, capsule, granules, powder, solution, syrup, emulsion or suspension
composition.
[Claim 4] The pharmaceutical composition according to claim 1, wherein the composition
provides treatment of vertigo or diseases associated with vertigo or vegetative concomitant
symptoms, within a shorter duration of time as compared to standard of care therapy used
for treatment of vertigo or disease associated with vertigo.
[Claim 5] The pharmaceutical composition according to claim 1, wherein composition is
used in treatment of Peripheral Vertigo, Meniere's disease, Tinnitus, Hearing loss,
Giddiness, Dysesthesia of motion and position, Nystagmus, Dysequilibrium, Dizziness,
Head deviation, Nausea, Vomiting, Sweating, Salivation and Tachycardia, Dystasia and
Walking unsteadiness, Staggering, Rotary sensation, Tendency to fall, Lift sensation,
Blackout, Change of position (lying), Bowing, Getting up, driving, Head movements
(inclination, twist), Eye movement or one or more symptoms or disease associated with it.
[Claim 6] A pharmaceutical composition comprising Levocloperastine or pharmaceutically
acceptable salt thereof, wherein the composition is a tablet composition comprising
Levocloperastine 1-5%, diluent 20-80%, disintegrant 1-10%, binder 0.5-5%, lubricant 0.2-
2%, glidant 0-2% and surfactant 0-5%, by total weight of the tablet composition.
[Claim 7] A pharmaceutical composition comprising Levocloperastine or pharmaceutically
acceptable salt thereof, wherein the composition is a solution composition comprising
Levocloperastine 1-5%, anti-oxidant 1-10% and preservative 0.01-10% by total weight of
the solution composition, and further comprising buffer, and optionally flavouring and
sweetening agent.
27
[Claim 8] A pharmaceutical composition comprising Levocloperastine or pharmaceutically
acceptable salt thereof, wherein the composition is a hard gel capsule composition,
comprising Levocloperastine, surfactant, binder, polymer, diluent, and solvent.
[Claim 9] A pharmaceutical composition comprising Levocloperastine or pharmaceutically
acceptable salt thereof, wherein the composition is a soft gel capsule composition,
comprising Levocloperastine, solubilizer, stabilizer, lubricant, and optionally other
excipients.