FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003PROVISIONAL SPECIFICATION(See section 10 and rulel3)
TITLE OF THE INVENTION: "PHARMACEUTICAL COMPOSITION"
2. APPLICANT(a) NAME: CIPLA LTD.(b)NATIONALITY: Indian Company incorporated under the IndianCompanies 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.

1 8 MAR 2005

Related applications:
This application is related to our earlier three Indian national patent applications serial no 994/MUM/2004 filed on 15/09/2004; 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.
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.
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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 anticholinergic 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-isomer has greater bronchodilatory effects than the racemate and may have antiinflammatory 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 (CN), describes the synthesis of levosalbutamol and US patent application number
US2004054215 by CIPLA Limited which discloses a method for obtaining an optically pure R-isomer of salbutamol.
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 for inhalation comprising novel polymorphs of levosalbutamol and a mucolytic agent in a suitable liquid carrier.
It is another object of the present invention to provide for pharmaceutical composition for inhalation comprising 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 for inhalation comprising novel polymorphs of levosalbutamol and ambroxol or its salts, solvates, derivatives, enantiomers, prodrugs 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 for inhalation comprising novel polymorphs of levosalbutamol and ambroxol or its salts, solvates, derivatives, enantiomers, prodrugs 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 bronchoconstriction 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 β2 -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 beta 2 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 bronchodilator such as levosalbutamol, helps to open the airways and thus facilitate expectoration. On the other hand 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 P2-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 for inhalation 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 an inhalation formulation comprising novel polymorphs of the levosalbutamol sulfate namely Form-I, Form-II, Form-III and ambroxol or its salts, solvates, derivatives, enantiomers, prodrugs 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 say but also its salts, solvates, derivatives, enantiomers, prodrugs or polymorphs thereof.
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The novel polymorphs of levosalbutamol and ambroxol may be combined with suitable excipients such as tonicity agents, pH regulators, chelating agents in a suitable vehicle to form an inhalation solution.
Nebulised levosalbutamol has been reported to increase the mucociliary clearance by upto 36%; thereby helping in effective expectoration of mucus by ambroxol. Therefore this combination has an additive effect on expectoration.
Nebulisers are devices that aid to deliver medicines to the lungs and also help to administer the drugs directly to the target organs. They are useful in asthma when large amounts of medicines need to be rapidly delivered to the lungs. It is of great help to patients too ill, short of breath, young children, the elderly, asthmatics who have sudden frequent attacks of asthma or otherwise unable to use hand-held inhalers or also to acute asthma patients requiring oxygen therapy.
Nebulisation therapy has an advantage over other inhalation therapy, since it is easy to use and does not require co-ordination or much effort .It also works much more rapidly than medicines taken by mouth.
In the present invention, isotonicity-adjusting agents, which may be used, include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other isotonicity-adjusting agents may also include, but are not limited to, mannitol, glycerol, and dextrose and mixtures thereof. Preferably the isotonicity-adjusting agent is Sodium chloride. In an alternative embodiment, the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt. Preferably, the present invention comprises 0.9 of sodium chloride wt % of an isotonicity-adjusting agent.
The pH is adjusted by the addition of pharmacologically acceptable acids. Pharmacologically acceptable inorganic acids or organic acids may be used for this purpose. Examples of preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid. Examples of particularly suitable organic acids are selected from the group consisting of
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ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid. Preferred inorganic acids are hydrochloric acid and sulphuric acid, of which sulphuric acid is particularly preferred according to the invention. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. Preferably a nasal inhalation formulation as provided by the present invention has a pH in the range of 3 to 5.
The formulations according to the invention may contain complexing agents as other ingredients. Complexing agents meant within the scope of the present invention mean molecules that are capable of entering into complex bonds. Preferably, these compounds should have the effect of complexing cations, most preferably metal cations. The formulations according to the invention preferably contain editic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate), as complexing agent. Preferably, disodium EDTA is used in a range of 0.005% to 0.05%
Anti-microbial preservative agent may be added for multi-dose packages. Suitable preservatives are those known from the prior art, particularly benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate, potassium benzoate, sorbic acid or sorbets such as potassium sorbates in the concentration known from the prior art.
In the present invention, the novel polymorphs of levosalbutamol and ambroxol or its salts, solvates, derivatives, enantiomers, prodrugs or polymorphs thereof may be provided in a variety of pharmaceutical^ acceptable vehicles, including, but not limited to, water or any other aqueous solution comprising a pharmaceutically acceptable amount of an isotonicity adjusting agent.
Further according to the present invention there is also provided a process for manufacture of the inhalation solution comprising novel polymorphs of levosalbutamol and ambroxol, which can be made according to the techniques known in the art.
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In one embodiment of the present invention the process comprises dissolving the drugs, chelating agents, isotonicity adjusting agents and any other suitable ingredient in the vehicle and adjusting the pH using suitable pH adjusting agent.
In another alternative embodiment, the inhalation solution of the present invention may be administered by nebulizer. Such nebulizer including, but not limited to, a jet nebulizer, ultrasonic nebulizer and breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow. The nebulizer being equipped with a mouthpiece or suitable face mask. Specifically, a nebulizer (with face mask or mouthpiece) connected to a compressor may be used to deliver the inhalation solution of the present invention to a patient.
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.
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Example: 1: As inhalation solution.

Name of ingredients Quantity (%w/v)
Ambroxol hydrochloride 0.60
Levosalbutamol sulfate form I* 0.06
Disodium edetate 0.05
Sodium chloride 0.77
Hydrochloride acid QS
Sodium hydroxide QS
Purified water QS to 100. ml
Process:
1. The pH of freshly boiled and cooled purified water was adjusted to 3.5 to 4.1 using hydrochloric acid.
2. To the solution prepared in step 1, ambroxol hydrochloride was added and dissolved under stirring.
3. The solution of step 2 was added to a solution of disodium edetate and sodium chloride and the pH was adjusted to 4.1 to 4.6 with sodium hydroxide.
4. To the solution prepared in step 3, levosalbutamol sulfate form I* solution (prepared in purified water) was added and the volume was made up with purified 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 March 2005