FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"PHARMACEUTICAL PRODUCT COMPRISING A BETA-2 ADRENOCEPTOR AGONIST AND AN ANTIHISTAMINE"
CIPLA LIMITED of 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India.
The following specification particularly describes the invention and the manner in which it is to be performed.
68/mumnp/2006
19/01/2006

WO 2005/007145 PCT/GB2004/003004
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PHARMACEUTICAL PRODUCT COMPRISING A BETA-2 ADRENOCEPTOR AGONIST AND AN
ANTIHISTAMINE
The present invention is concerned with pharmaceutical combinations comprising agents such as β-2 adrenoreceptor agonists and antihistamines. In particular, the present invention is concerned with pharmaceutical formulations comprising β-2 adrenoreceptor agonists and antihistamines, useful in the prophylaxis and treatment of respiratory diseases.
The path physiology of asthma or related disorders involves bronchoconstriction resulting from bronchial smooth muscle spasm and airway inflammation with muscle edema. Treatment of asthma and other related disorders have been known to employ β-2 agonists, also known as β-2 adrenoreceptor agonists. Such β-2 adrenoreceptor agonists are known to provide a bronchodilator effect to patients, resulting in relief from the symptoms of breathlessness. More particularly, β-2 adrenoreceptor agonists have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation.
Examples of β-2 adrenoreceptor agonists include terbutaline, saibutamol, lev-albuterol, R, R-formoterol, metaproterol sulfate, pirbuterol acetate, bitolterol jnesylate, fenoterol, procaterol, salmeterol, bambuterol hydrochloride, clenbuterol and forraoterol Of these, salmeterol, fonnoterol and bambuterol hydrochloride are long acting β-2 adrenoreceptor agonists, of which bambuterol, a biscarbamate ester prodrug of the β-2 adrenoreceptor agonist terbutaline, has been recently approved for the treatment of asthma. The long acting subgroup of β-2 adrenoreceptor agonists act via relaxation of airway smooth muscles and consequent bronchodilation. Drugs of this long acting subgroup may have delayed onset of action, so are used for long-term regular treatment of reversible airways

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obstruction in asthma and in particular are bronchodilators used for the management of persistent asthma symptoms.
Histamine, acting through preceptors, produces smooth muscle contraction, an increase in vascular permeability, and stimulation of parasympathetic nerves, all of which are pathophysiological features of asthma. It is also known from the literature that antihistamines may be effective in the treatment of asthma. Antihistamines have, however, generally been used in the treatment of allergic symptoms, for example they have been seen to possess potent activity in treating seasonal and perennial allergic rhinitis, the symptoms of allergic asthma, chronic idiopathic urticaria, certain types of physical urticaria, and other disorders benefiting from an inhibitory action on eosinophil function. Examples of antihistamines include H1eceptor antagonists such as cetirizine, levocetirizine and functional derivatives thereof.
Cetirizine inhibits eosinophil chemotaxis and function, and the generation of cytotoxic mediators by blood platelets, providing therapy in immunologically induced asthma. Racemic cetirizine dihydrochloride is an oral, potent, long acting peripheral histamine Hireceptor antagonist and is an example of the second generation of H1 histamine receptor antagonists, which generally offer some significant advantages beyond the first generation compounds. The main advantages associated with the second generation of H1 histamine receptor antagonists include less sedation, little anticholinergic activity and longer duration which improve patient compliance. In addition to being competitive inhibitors of histamine, second generation H1 histamine inhibitors appear to have other anti-allergic pharmacological mechanisms, which have led to their use in bronchial asthma, as well as in seasonal and perennial rhinitis and chronic urticarias. There are, however, some adverse effects associated with racemic cetirizine dihydrochloride as reported in the literature, including, but not limited to, sedation

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and somnolence, headache, gastrointestinal disturbance, anticholinergic effects, dizziness, cardiac arrhythmias and other cardiovascular effects.
Cetirizine is the international non- proprietary name of 2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl) ethoxyacetic acid. "Cetirizine" as referred to herein denotes racemic 2-[4-[(4-chIorophenyl)phenylmethylH-piperaziny]) ethoxyacetic acid. The active isomer is the (-) isomer of cetirizine and the optically pure (-) isomer of cetirizine, known as levocetirizine, has been seen to be an effective agent for treating seasonal and perennial allergic rhinitis, the symptoms of allergic asthma, chronic idiopathic urticaria, certain physical urticaria., and other disorders, including those that would benefit from an inhibitory action on eosinophilia, and eosinophil function. Levocetirizine provides an effective treatment, whilst avoiding the above discussed adverse effects including, but not limited to, sedation and somnolence., headache, gastrointestinal disturbance, dizziness, nausea, cardiac arrhythmias and other cardiovascular effects.
An antiallergic and antiurticaric composition known from the literature for the treatment of allergic asthma, chronic idiopathic urticaria and certain types of physical urticaria, comprises an amount of (-) cetirizine, or a pharmaceutically acceptable salt thereof; substantially free of its (+) isomer, the amount being sufficient to alleviate or palliate said disorder but insufficient to cause adverse effects associated with the administration of racemic cetirizine.
The chemical synthesis of the racemic mixture of cetirizine can be carried out as described in US 4,525,358 or by an improved procedure disclosed in GB 2,225,320. Levocetirizine may be obtained from its racemic mixture by resolution of the enantiomers of cetirizine, or precursors thereto, using conventional means such as an optically active resolving acid. For example, GB 2,225,321 discloses a method for resolving 1- [(4-chlorophenyl) phenylmethyl] piperazine using tartaric acid in ethanol. Other standard methods of resolution known to those skilled in the art including, but not limited to, simple crystallization and chromatographic

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resolution, can be used. Additionally, levocetirizine can be prepared from its racemic mixture by enzymatic biocatalytic resolution, as reported in US 5,057,427 and 5,077,217.
WO 94/06429 and WO 94/06430 describe methods and compositions for treating allergic disorders using optically pure (-) cetirizine and optically pure (+) cetirizine respectively.
US 6,521,254 describes pharmaceutical compositions for oral administration comprising an antihistamine, preferably cetirizine and derivatives thereof, together with a decongestant, for the treatment of allergic rhinitis.
WO 98/27981, WO 98/18827, US 6,258,814, LU 90898 and LU 90870 describe pharmaceutical compositions comprising either β-2 agonists or antihistamines (such as cetirizine and functional derivatives thereof) respectively for the treatment of allergic rhinitis, allergic asthma and related disorders.
Despite the large number of known treatments of respiratory diseases, there continues to exist a clinical need for therapies of respiratory diseases which exhibit advantageous profiles of action. To this end, it has now surprisingly been found that a combination of β-2 adrenoreceptor agonists, with antihistamines, provides an enhanced, synergistic therapeutic effect in terms of treatment of respiratory
diseases, such as asthma, allergic respiratory disorders and related disorders. Also,
such combination therapy is a patient-friendly combination, which results in enhanced patient compliance and better control of respiratory diseases, such as asthma, allergic respiratory disorders and related disorders.
Accordingly, it is an object of the present invention to provide methods of treating asthma, allergic respiratory disorders and related disorders. It is a further object of the present invention to provide a pharmaceutical formulation comprising pharmaceutically active agents for the treatment of asthma, allergic respiratory disorders and related disorders.

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According to a first aspect of the present invention, therefore, there is provided a pharmaceutical product comprising (i) bambuterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and (ii) at least one of cetirizine and levocetirizine or pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof, as a combined preparation, for simultaneous, separate or sequential use in the treatment of respirator}' diseases.
It will be appreciated from the above, that the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical formulations, or separately or sequentially. If there is separate or sequential administration, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time scale so as to achieve, or more particularly optimize, the above referred to advantageous synergistic therapeutic effect of a combined preparation as present in a pharmaceutical product according to the present invention.
Also, according to the present invention, there is provided a pharmaceutical formulation comprising (i) bambuterol or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and (ii) at least one of cetirizine and levocetirizine or pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof, for use in the treatment of respiratory diseases, together with a pharmaceutically acceptable carrier or excipient therefor.
The p-2 adrenoreceptor agonist employed according to the present invention is bambuterol. especially bambuterol hydrochloride.
Bambuterol. the bis-dimethyl carbamate prodrug of terbutaline, namely 5-[2-(tertbutylamino)-l -hydroxyethyl]-m-phenylene-bis(dimethylcarbamate), or a pharmaceutically acceptable salt thereof, is described in EP 0043807B.

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Bambuterol has been used in the treatment of asthmatic patients, with no observable effect of lipoprotein metabolism having been reported. Bambuterol can provide a significantly prolonged duration of action compared to terbutaline, for example 24 hours versus 8 hours for conventional terbutaline tablets. It is especially preferred to use the hydrochloride salt of bambuterol according to the present invention.
In the pharmaceutical products or formulations according to the present invention, the antihistamine is selected from the group consisting of, cetirizine and levocetirizine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably cetirizine hydrochloride or levocetirizine hydrochloride, is employed according to the present invention.
Particularly preferred is the combination of (i) bambuterol hydrochloride together with (ii) cetirizine hydrochloride or levocetirizine hydrochloride.
The term "physiologically functional derivative" as used herein denotes a chemical derivative of any of the specific therapeutic agents described herein having the same or similar physiological function as the free base therapeutic agent and, for example, being convertible in the body thereto.
Suitable pharmaceutically acceptable salts for use according to the present invention include those formed with both organic and inorganic acids and are well known to one of ordinary skill in the art.
There is also provided by the present invention a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more β-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical product according to claim 1 as a combined preparation for simultaneous, separate or sequential use in the treatment of such respiratory diseases.

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The present invention also provides a method for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more β-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, which method comprises administration of a therapeutic ally effective amount of a pharmaceutical formulation according to claim 2.

Preferred therapeutic agents for use in a method according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein can include in particular asthma, allergic respiratory disorders and other related disorders.

There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more β-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, a pharmaceutical product according to claim 1, as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases.

There is also provided by the present invention for use in the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more β-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, a pharmaceutical formulation according to claim 2, together with a pharmaceutically acceptable carrier or excipient therefor.

Preferred therapeutic agents for such prophylactic or therapeutic use according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein can include in particular asthma, allergic respiratory disorders and other related disorders.

There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more β-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, a pharmaceutical product

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according to claim 1 as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases.

There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment of a respiratory disease in a mammal, such as a human, for which one or more β-2 adrenoreceptor agonists, and / or one or more antihistamines is indicated, a pharmaceutical formulation according to claim 2.

Preferred therapeutic agents for such use in the manufacture of a medicament according to the present invention are substantially as hereinbefore described with reference to pharmaceutical products and pharmaceutical formulations according to the present invention. The term respiratory disease as used herein can include in particular asthma, allergic respiratory disorders and other related disorders.

There is further provided by the present invention a process of preparing a pharmaceutical product substantially as hereinbefore described, which process comprises providing as a combined preparation for simultaneous, separate or sequential use in the treatment of respiratory diseases (i) bambuterol or a physiologically acceptable salt, solvate or functional derivative thereof, and (ii) at least one of cetirizine and levocetirizine or pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

The present invention also provides a process of preparing a pharmaceutical formulation substantially as hereinbefore described, which process comprises admixing a pharmaceutically acceptable carrier or excipient with (i) bambuterol or a physiologically acceptable salt, solvate or functional derivative thereof, and (ii) at least one of cetirizine and levocetirizine or pharmaceutically acceptable salts, solvates or physiologically functional derivatives thereof.

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The pharmaceutical formulations according to the present invention are preferably in the form of tablets, but it is also possible according to the present invention to use other preparations, such as capsules, oral solutions, injection solutions or the like. Suitably, according to the literature, 20-30 mg of anti-asthmatics administered once daily generally provides effective anti-asthmatic treatment. Conventionally, this may be achieved by administration of inhaled preparations. Whilst inhaled long-acting β-2 adrenoreceptor agonists are less likely to have systemic adverse effects, there are, however, theoretical concerns that regular β -2 adrenoreceptor agonist inhalation treatment may lead to tolerance and failure to respond to emergency asthma treatment. Pharmaceutical formulations according to the present invention can be advantageous, therefore, by providing a combination of β-2 adrenoreceptor agonists with antihistamines, whereby administration thereof can alleviate allergic rhinitis and mild to moderate asthma symptoms.

In particular, the present invention provides tablet formulations (suitably compressed tablet formulations) comprising at least one antihistamine and at least one β-2 adrenoreceptor agonist. A tablet according to the present invention may further comprise a combination of one or more further ingredients, including one or more diluents, binders, disintegrants and lubricants.

Suitably, a diluent or a bulking agent should be selected to provide an increase in tablet size. The artisan can utilize known methods to select a bulking agent, which provides hardness, friability and disintegration time required for pharmaceutical usage. A preferred diluent is lactose or microcrystalline cellulose. Various forms of lactose are appropriate for such formulations, including anhydrous, hydrous and spray dried forms. The most desired form of lactose for use according to the present invention can be selected based on desired dissolution, content uniformity, hardness, friability and disintegration time. The artisan can use known techniques to achieve the desired physical properties.

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The artisan may further select appropriate dry binders and disintegrants using known methods. Most preferably used dry binders and disintegrants are starch, sodium starch glycollate and microcrystalline cellulose; however, other appropriate dry binders and disintegrants may be selected.
A tablet formulation according to the present invention may also include lubricants and glidants to prevent sticking and picking of the tablets to the compression tooling. Suitable agents include talc, fatty acids and salts of fatty acids, mineral oil, and hydrogenated vegetable oils. An example of a suitable fatty acid material is stearic acid or its magnesium salt The most preferred lubricants are talc and magnesium stearate.
The tablets may be coated with film forming materials, which can include cellulose polymers such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose and other salts and derivatives thereof, acrylic acid polymers, and other known film forming polymers.
Substantially as hereinbefore described the tablets of the present invention can be prepared by using direct compression, or by dry or wet granulation processes to achieve homogeneous distribution of the drug within the formulation. The tablets of the invention are orally administered in the amounts necessary to achieve a particular blood level and an optimum dosage size may be determined by observing the therapeutic results achieved and the side effects encountered and / or by blood serum analysis.
The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in anyway.
EXAMPLE I

Sr. No. Ingredients Mg/Tablet
Bambuterol Hydrochloride 10.0
Cetirizine Hydrochloride 10.0

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Lactose 100,20
Starch 50,00
Colloidal silicon dioxide 2.00
Microcrystalline cellulose 14.50
Talc 1.80
Magnesium stearate 1.50
Film coating
Opadry white™ 6.00
Purified water q.s.
Film coated tablets employing the above ingredients were prepared by techniques well known in the art.
EXAMPLE

Sr, No. Ingredients Mg/Tablet
Bambuterol Hydrochloride 10.0
Cetirizine Hydrochloride 5.0
Lactose 43.00
Starch 10.50
Sodium starch glycollate 5.00
Microcrystalline cellulose 50.00
Talc 1.00
Magnesium stearate 0.50
Tablets employing the above ingredients were prepared by techniques well known in the art.
CLAIMS
1. A pharmaceutical product comprising (i) bambuterol or a pharmaceutically
acceptable salt, solvate or physiologically functional derivative thereof and (ii) at
least one of cetirizine and levocetirizine or pharmaceutically acceptable salts,
solvates or physiologically functional derivatives thereof, as a combined
preparation, for simultaneous, separate or sequential use in the treatment of
respiratory diseases.
2. A pharmaceutical formulation comprising (i) bambuterol or a
pharmaceutically acceptable salt, solvate or physiologically functional derivative
thereof or a pharmaceutically acceptable salt solvate or physiologically functional
derivative thereof and (ii) at least one of cetirizine and levocetirizine or
pharmaceutically acceptable salts, solvates or physiologically functional
derivatives thereof, for use in the treatment of respiratory diseases, together with a
pharmaceutically acceptable carrier or excipient therefor.
3. A pharmaceutical product or formulation according to claim 1 or 2,
wherein said pharmaceutically acceptable salt of bambuterol is bambuterol
hydrochloride.
4. A pharmaceutical product or formulation according to claim I, 2, or 3,
wherein said pharmaceutically acceptable salt of cetirizine or levocetirizine, is
cetirizine hydrochloride or levocetirizine hydrochloride.
5. A pharmaceutical product or formulation according to claim I, 2, 3 or 4,
comprising bambuterol hydrochloride and either cetirizine hydrochloride or
levocetirizine hydrochloride.
6. A pharmaceutical product or formulation according to any preceding claim,
for oral administration.

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7. A pharmaceutical product or formulation according to claim 6, in tablet
form.
8. A pharmaceutical product or formulation according to 7, wherein said
tablet comprises lactose as a carrier or diluent.
9. A pharmaceutical product or formulation according to claim 7 or 8,
wherein said tablet comprises one or more of talc, colloidal silicon dioxide and
derivatives thereof, fatty acids and salts of fatty acids, mineral oil, and
hydrogenated vegetable oils.
10. A pharmaceutical product or formulation according to claim 9, which
comprises colloidal silicon dioxide, talc and magnesium stearate.
11. A process of preparing a pharmaceutical product according to claim 1, or
any of claims 3 to 10, which process comprises providing as a combined
preparation for simultaneous, separate or sequential use in the treatment of
respiratory diseases (i) bambuterol or a pharmaceutically acceptable salt, solvate
or physiologically functional derivative thereof, and (ii) at least one of cetirizine
and levocetirizine or pharmaceutically acceptable salts, solvates or physiologically
functional derivatives thereof.
12. A process of preparing a pharmaceutical formulation according to any of
claims 2 to 11, which process comprises admixing a pharmaceutically acceptable
carrier or excipient with (i) bambuterol or a pharmaceutically acceptable salt,
solvate or physiologically functional derivative thereof, and (ii) at least one of
cetirizine and levocetirizine or pharmaceutically acceptable salts, solvates or
physiologically functional derivatives thereof.
13. A method for the prophylaxis or treatment of a respiratory disease in a
mammal, such as a human, for which one or more β-2 adrenoreceptor agonists,

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and / or one or more antihistamines is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical product according to claim 1, or any of claims 3 to 10, or a pharmaceutical formulation according to any of claims 2 to 10.
14. A method according to claim 13, wherein the respiratory disease is asthma,
an allergic respiratory disorder or a related disorder.
15. For use in the prophylaxis or treatment of a respiratory disease in a
mammal, such as a human, for which one or more β-2 adrenoreceptor agonists,
and / or one or more antihistamines is indicated, a pharmaceutical product
according to claim 1, or any of claims 2 to 10, or a pharmaceutical formulation
according to any of claims 2 to 10.
16. For use in the manufacture of a medicament for the prophylaxis or
treatment of a respiratory disease in a mammal, such as a human, for which one or
more β-2 adrenoreceptor agonists, and / or one or more antihistamines is
indicated, a pharmaceutical product according to claim 1, or any of claims 3 to 12,
or a pharmaceutical formulation according to any of claims 2 to 12.
17. A pharmaceutical product, pharmaceutical formulation and a process of preparation of pharmaceutical product and formulation substantially as herein described with reference to the foregoing.

Dated this 17th day of January 2006 VIBHA SHUKLA
OF K & S PARTNERS Agent for the Applicants
18. A method of treatment and use in prophylaxis treatment substantially as herein described with reference to the foregoing.