FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(Sec section 10 and rule 13)
TITLE OF THE INVENTION: "PHARMACEUTICAL COMPOSITION"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.


Related applications:
This application is related to our earlier four Indian national patent applications serial no
994/MUM/2004 filed on 15/09/2004; 1077/MUM/2004 filed on
08/10/2004; 1356/MUM/2004 filed on 17/12/2004; 40/MUM/2005 filed on 14/01/2005
Technical field:
The present invention relates to a pharmaceutical composition of novel polymorphs of
therapeutically effective isomer of a betamimetic agent and a mucolytic agent for the
treatment of respiratory disorders characterized by bronchoconstriction and excessive
mucus production.
Background and prior art:
Respiratory diseases include Chronic Obstructive Pulmonary Disorder, pneumonia,
bronchitis, cystic fibrosis, allergic disorders, asthma and several such disorders, which
are characterized by bronchoconstriction accompanied by excessive mucus secretion.
Thus the pharmacotherapy is aimed providing symptomatic relief i.e. relieving the patient
of the excessive mucus secretion or the cough associated with it and dilating the
bronchial tubes so as to ensure easy breathing. The formulations therefore usually include
a mucolytic agent along with an-antibacterial or an anti-viral agent.
EP1437134 by Boehringer Ingelheim claims an anti-influenzal agent comprising
ambroxol, bromhexin or a pharmaceutically acceptable salt thereof as an effective
component.
Another patent GB2083749 relates to pharmaceutical compositions comprising,
ambroxol in combination, with an antibiotic such as erythromycin, doxycycline,
cephalexin, ampicillin or amoxicillin or a physiologically acceptable salt thereof
optionally in association with a pharmaceutical carrier or excipient for use in the
treatment of infections of the respiratory tract formulated as tablets, capsules, dry
granulates for syrups.
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Patent number WOO 174341 claims the use of a non-sedating anti-histaminics along with
a mucolytic agent i.e. ambroxol for the treatment and/or prevention of allergic and
inflammatory conditions with cough.
Mucolytics such as ambroxol is also combined with steroids to provide adequate
bronchodilatory effect as in patent number US 5,840,277 which claims inhibiting the
activation of nuclear transcription factor NF-.kappa.B in a mammal comprising
administering to a mammal an effective amount of tyloxapol and a steroid selected from
methylprednisolone, triamcinolone, beclomethasone dipropionate, flunisolides and
dexamethasone by aerosolisation.
Another patent application, WO2004041263 by Boehringer Ingelheim claims a
pharmaceutical composition comprising of bromhexin or ambroxol along with an anti-
cholinergic agent i.e. isopropamide iodide for treating sputum or runny nose.
Prior art, DE3530761 by Klinge Co Chem Pharm Fab (DE), claims a synergistic
combination of ambroxol and theophylline for treatment of Chronic Obstructive
Pulmonary Disorder.
Another prior art WO03068206 provides for a formulation comprising of a betamimtic
agent such as salbutamol sulphate and terbutaline in combination with guaiphenesin and
anti-histaminic agent.
It has been proved that racemic salbutamol, a commonly used bronchodilator, is an exact
50:50 mixture of two enantiomers, R- and S- isomers of salbutamol. In-vitro studies
suggest that the two enantiomers have different binding affinities for the beta-
adrenoreceptor, may exert opposing effects on inflammation, demonstrate different
effects on the mucociliary transport, and display differing pharmacokinetics. The R-
isorner has greater bronchodilatory effects than the racemate and may have anti-
inflammatory properties. S-isomer has markedly less affinity for the beta-adrenoreceptor.
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Several methods for preparation of levoalbuterol have been described in the prior arts
such as US patent application number 20040115136 by King Code which describes a
method of preparation of levalbuterol tartarate.
Patent application number CN1413976 by Suzhou Junning New Drug Dev CT (CM),
describes the synthesis of levosalbutamol and US patent application number
US2004054215 by CIPLA Limited which discloses a method for obtaining an optically
pure R-i somer of salbutamo 1.
Thus using a therapeutically effective isomer of a betamimetic agent has a distinct
advantage over using the racemic molecule. And further combining it with a mucolytic
agent makes it even more advantageous for use in respiratory conditions associated with
bronchoconstriction and excessive mucus secretion because the betamimetic agent helps
to dilate the bronchial tubes and the mucolytic agent helps releving the patient from the
excessive mucus secretion.
Our inventors have now found out novel polymorphs of levosalbutamol that are stable,
reproducible and useful for formulating pharmaceutical formulations.
The present invention therefore provides a pharmaceutical composition comprising novel
polymorphs of levosalbutamol and a mucolytic agent,
Object of the invention:
Therefore, it is an object of the present invention to provide for a pharmaceutical
composition comprising of a combination of novel polymorphs of levosalbutamol and a
mucolytic agent.
It is another object of the present invention to provide for pharmaceutical compositions
comprising of novel polymorphs of levosalbutamol and a mucolytic agent thereby
providing an additive effect in treatment of respiratory disorders characterized by
bronchoconstriction and excessive mucus secretion.
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It is yet another object of the invention to provide for a method of preparation of
pharmaceutical compositions according to the present invention.
Summary of the invention:
According to one aspect of the present invention there is provided pharmaceutical
composition comprising novel polymorphs of levosalbutamol and ambroxol or its salts,
solvates, derivatives, prodrugs, enantiomers or polymorphs thereof in a suitable liquid
carrier.
According to yet another aspect of the present invention there is provided method of
preparation of pharmaceutical composition comprising novel polymorphs of
levosalbutamol and ambroxol or its salts, solvates, derivatives, prodrugs, enantiomers or
polymorphs thereof in a suitable liquid carrier.
According to yet another aspect of the present invention there is provided method of
treatment for respiratory disorders characterized by broncho constriction and excessive
mucus secretion which method comprises administration of a therapeutically effective
amount of pharmaceutical compositions according to the present invention,
Detailed description:
Salbutamol is available as a racemic mixture comprising R and S form. But only the R-
enantiomer (levosalbutamol) is a potent p2 -adrenoceptor stimulant, whereas the S-
enantiomer (dextrosalbutamol) shows little or no adrenoceptor activity. The
bronchodilatory property of racemic salbutamol is attributable entirely to (R)-
salbutamol, which has an approximately 100 fold greater binding affinity for beta2
receptors as compared to (S)- salbutamol. This divergent pharmacology accentuates the
need of levosalbutamol over racemic salbutamol in the treatment of asthma and other
airway diseases. Levosalbutamol is a more potent bronchodilator when administered as
the single enantiomer compared with the same amount in a racemic mixture.
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Levosalbutamol produces comparable efficacy at nearly one-fourth the dose of racemic
salbutamol, simultaneously reducing the beta-mediated side effects.
In respiratory tract diseases, a number of conditions are accompanied by dense mucus or
mucopurulent secretions, which are difficult to expectorate. Viscosity of the secretions
increase and they tend to stagnate, thereby constituting an ideal medium for exacerbation
or persistence of infectious processes.
Since most of the respiratory conditions are associated with 'bronchoconstriction' and
'excessive mucus production', mucolytic agents help to liquefy the thick, tenacious
secretions. However, due to inflammation of the bronchial tubes, the airways are
constricted resulting in the expectoration of these mucus secretions being hampered. This
leads to deposition of mucus in the airways forming mucus plugs thereby increasing the
secondary infections and further complications. A. bsonchodilator: such as levosalbutamol
helps to open the airways and thus facilitate expectoration. The dense mucus may also
impairs penetration of levosalbutamol into the bronchiole during a rescue therapy during
acute attacks of asthma. Hence co-administration of a mucolytic agent like ambroxol
which helps in clearing up the airways by removal of the mucus, enhances the penetration
of levosalbutamol into the bronchioles. Thus both the drugs are very effective in
respiratory conditions associated with bronchoconstriction and excessive mucus
production. Also phospholipase A2 (PLA2) enzyme, which is activated during
inflammatory and allergic reactions reduces the number of β2-receptors in the lung
thereby reducing the spasmolytic activity of levosalbutamol. Mucolytic agent, being an
inhibitor of PLA2 has a sparing action on the β2-receptors. Thus administration of
ambroxol with levosalbutamol improves the spasmolytic activity of levosalbutamol.
The mucolytics can be selected from N-acetylcysteine, bromhexine, tyloxapol and
ambroxol, their derivatives, salts, isomers and prodrugs thereof. The preferred
compounds are ambroxol hydrochloride.
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The present invention discloses pharmaceutical compositions containing novel
polymorphs of the levosalbutamol and ambroxol. The novel polymorphs are the
polymorphs of levosalbutamol sulfate. These polymorphs have been identified as Form-I,
Form-II and Form-Ill. They have been found to be stable, reproducible and suitable for
pharmaceutical preparations. The polymorphs I, II, III of levosalbutamol sulfate are
micronisable, have good flow properties and bulk density and hence may be combined
with pharmaceutical diluents and/or carriers to provide pharmaceutical compositions
suitable for use in therapy.
Ambroxol, to be used for pharmaceutical compositions of the present invention, chemical
name: trans-4-[2-amino-3,5-dibromobenzyl]amino]cyclohexanol, is an expectorant
classified as a mucosal lubricant drug, which, by the increase in production of pulmonary
surfactant, has the effect of lubricating the membrane of the airway. Ambroxol is a
metabolite of bromhexine. In the present invention, preferably ambroxol hydrochloride is
used. However, other acid addition salts including hydrobromate, oxalate, nitrate,
sulphonate, fumarate, maleate, sulfate phosphate, and the like or freebase can also be
used.
The present invention therefore provides a liquid formulation comprising novel
polymorphs of the levosalbutamol sulfate namely Form-I, Form-II and Form-Ill and
ambroxol or its salts, solvates, derivatives, prodrugs, enantiomers or polymorphs thereof
in a suitable liquid carrier.
The term novel polymorphs of levosalbutamol are used in the entire specification in a
broad sense to include either form I, form II, and form III of levosalbutamol sulfate or
mixtures thereof.
The term Ambroxol is used in the entire specification in a broad sense to include not only
ambroxol per se but also its salts, solvates, derivatives, prodrugs, enantiomers or
polymorphs thereof.
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The liquid formulation comprises one or more of suitable ingredients for liquid
formulation like thickeners, sweeteners, buffering agents, preservatives, artificial colors,
chelating agents/sequestering agents and flavours and any other suitable ingredients.
The liquid formulation is useful for patients unwilling or unable to take inhaled
medications. The liquid formulation may act as an alternative therapy for mild
intermittent asthma, as an option in case of exercise-induced asthma, add-on to inhaled
medication. In addition to all these, the liquid formulation is a convenient dosage form
for pediatric as well as geriatric patients who have difficulty in swallowing tablets.
In the present invention thickeners may be used which are stable over a wide pH range
and may be selected from but are not restricted to the group consisting celluloses viz
methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose
hydroxy ethyl cellulose; natural gums like xanthan gum, acacia gum, gum tragacanth,
carrageen gum; pectin, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol, and mixtures
thereof. The thickeners may be present in the range of 0.1 to 2%. Additionally the present
invention may include ingredients like propylene glycol, glycerol, maltitol, sorbitol and
the like, in the range of about 10 to 70% w/v, based on the formulation that impart
viscosity to the formulation. In addition ingredients like glycerol, maltitol, sorbitol and
others of their class act as sweetening agents as well can be added.
The preservatives may be selected from but are not restricted to the group consisting of
potassium benzoate, sodium benzoate, potassium sorbate, methyl parahydroxy benzoate,
propyl parahydroxy benzoate and/or mixtures thereof. The preservatives may be present
in the range of 0.001% to 0.5%.
The formulation may also comprise of buffering agents selected from but are not
restricted to the group consisting phosphates, citrates and their salts and derivatives
thereof, such as but not limted to sodium citrate, citric acid monohydrate, organic acids
like hydrochloric acid, succinic acid, fumaric acid, tartaric acid,
The formulation of the present invention has a pH in the range of 3.0 to 5.0,
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Sequestering agent like aminopolycarboxylic acids and salts thereof, which are safe for
ingestion and have sufficient solubility in the formulations to make a stable single phase
composition can be used. Commercially available compounds which could be used
include iminodiacetic acid, methyliminodiacetic acid, nitrilotriacetic acid,
ethylenediaminetetraacetic acid ("EDTA"), diethylenetriaminepentaacetic acid, 1,2-
diaminocyclohexane-tetraacetic acid, N-hydroxyethylenediaminetriacetic acid and related
compounds. The preferred salts are alkali metal salts of EDTA 0,05% to about 1%,
Coloring agents are added for aesthetic appearance. Sweeteners and flavoring agents are
added to increase palatability of the formulation. The color and the flavor added may be
complementary to each other. Sodium chloride may optionally be added to the
formulation which further enhances the taste of the formulation. Any such other suitable
ingredients that contribute to make palatable syrup may also be included in the present
formulation.
The vehicles used according to the present invention may be selected from water or liquid
polyols like maltitol, lactitol, sorbitol, and glycerol. Preferably the vehicle used is water.
In a further aspect of the present invention, there is provided a process for manufacture of
a pharmaceutical composition comprising novel polymorphs of levosalbutamol and
ambroxol or its salts, solvates, derivatives, prodrugs, enantiomers or polymorphs thereof
in a suitable liquid carrier that can be made according to the techniques known in the art.
According to one embodiment of the present invention the manufacturing process
comprises, dissolving preservative, sequestering agent and buffers in specified amount of
purified water followed by addition of the drug. This is followed by the addition of other
ingredients to the above solution. The pH is checked and finally the volume is made up.
The Novel polymorphs of levosalbutamol according to the present invention may also be
formulated as other liquid oral dosage forms.
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In a further aspect of the present invention there is provided method of treatment for
respiratory disorders characterized by bronchoconstriction and excessive mucus secretion
which method comprises administration of a therapeutically effective amount of
pharmaceutical compositions according to the present invention. Ambroxol may be
administered in the dosages of 5 mg to 90 mg whereas the novel polymorphs of
levosalbutamol may be administered in the doses of 0.3mg to 5 mg
It will be readily apparent to one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the
scope and spirit of the invention. Thus, it should be understood that although the present
invention has been specifically disclosed by preferred embodiments and optional
features, modification and variation of the concepts herein disclosed may be resorted to
by those skilled in the art, and that such modifications and variations are considered to be
falling within the scope of the invention.
The following examples are for the purpose of illustration of the invention only and are
not intended in any way to limit the scope of the invention.
Example: 1:

Name of the ingredient Quantity (%w/v)
Levosalbutamol sulphate form I* 0.0241
Ambroxol hydrochloride 0.3
Sodium benzoate 0.2
Hydroxy propyl methyl cellulose 0.3
Disodium edetate 0.05
Sodium citrate 0.10
Citric acid monohydrate 0.20
Sodium chloride 0.10
Sweet Orange No.l 0.20
Sodium Saccharin 0.10
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Sunset Yellow FCF 0.004
Purified water Qs to 100ml,
Process:
1. Sodium benzoate, disodium edetate, sodium citrate, citric acid monohydrate were
dissolved in purified water.
2. Levosalbutamol sulphate form 1* and ambroxol hydrochloride were then dissolved in
the solution as obtained in step 1
3. Sodium saccharin and Sodium chloride were then added to the solution as obtained in
step 2.
4. Hydroxy propyl methyl cellulose was then added to the solution as formed in step 3.
5. Color and flavor was then added and finally the volume was made up
Example 2

Name of the ingredient Quantity (%w/v)
Levosalbutamol sulphate form I* 0.01
Ambroxol hydrochloride 0.3
Menthol 0.02
Sodium benzoate 0.1
Potassium sorbate 0.06
Disodium edetate 0.50
Sodium saccharin 0.10
Sodium citrate 0.46
Citric acid monohydrate 0.40
Sorbitol solution 20.00
Propylene glycol 10.00
Color tartrazine 0.001
Flavour pineapple no 1 0.25
Citric acid monohydrate Upto pH 3 to 5
Purified water Qs to 100 ml.
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1. EDTA, sodium saccharin, sodium benzoate was dissolved in boiling water.
2.To this solution sorbitol solution was added and cooled.
3.citric acid, Ambroxol hydrochloride, and sodium citrate was added to the above
solution and then levosalbutamol sulfate form I* was added to the above solution.
4.The flavour pineapple no 1 and menthol were dissolved in propylene glycol was added
to the above solution.This was followed by the addition of color tartarazine mixed in
water.
5.The pH was adjusted to a pH between 3 to 5 using citric acid
6.Potassium sorbate was added to water and this was added to the above solution and
finally the volume was made up using water.
* Levosalbutamol sulfate form I can be suitably substituted by levosalbutamol form II
and levosalbutamol form III or mixture of levosalbutamol form II, levosalbutamol form
III, levosalbutamol form I.
Dated this 18th day March 2005

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