DESCRIPTION
Filed of the Invention
The present invention is related to the novel oral combination comprising
Acebrophylline, Levocetirizine and Montelukast for the treatment of asthma and
airway inflammation due to allergy and other pathological condition. The
combination is also useful in treating the cough and airway blockage due to
allergy.
Related Prior Art for the invention
CA2701956 (A1) discloses inhalation compositions comprising montelukast
acid and a second active agent selected from a PDE4 inhibitor and an inhaled
corticosteroid. Also provided is a method for the treatment of respiratory
disorders such as asthma using such compositions.
JP2010001295 (A) relates the medical drug or a pharmaceutical composition
contains, separately or together, (A) formoterol or a pharmaceutically
acceptable salt thereof or a solvate of formoterol or a solvate of the salt and (B)
mometasone furoate, for their simultaneous, sequential or separate
administration.
NZ532279 (A) discloses the pharmaceutical combinations comprising the PDE4
inhibitor Roflumilast, and a leukotriene receptor antagonist selected from
Atreleuton, Acitazanolast, Zileuton, Zafirlukast, Pranlukast, and Montelukast.
The combinations are used for the manufacture of medicaments for treating
respiratory tract disorders, such as asthma.
US2006134217 (A1) provides novel solid pharmaceutical dosage forms for oral
administration comprising a therapeutically active amount of montelukast, or a
pharmaceutically acceptable salt thereof, a therapeutically effective amount of
N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine-2
(diethylamino) ethyl ester, or a pharmaceutically acceptable thereof, and one or
more pharmaceutically acceptable excipients. These novel solid pharmaceutical
dosage forms are useful in the treatment or control of asthma. The present
invention also provides a method for treating asthma employing the solid
pharmaceutical dosage forms and a method for preparing the pharmaceutical
dosage forms.
WO2005089761 (A1) relates to a pharmaceutical compostion containing a
combination of a leukotriene receptor antagonist and a histamine H3 receptor

antagonist, wherein the leukotriene receptor antagonist is particularly selected from montelukast, pranlukast and zafirlukast. The composition can be Used for treating an allergic and/or inflammatory condition, such as seasonal and perennial allergic rhinits, non-allergic rhinitis, asthma, sinusitis, colds, dermatitis and urticaria.
WO2005037245 (A2) reveals a multiple route medication for the prophylactic and/or therapeutic treatment of rhinitis and asthma based on the concept of "one airway-one disease". A first preset amount of an active composition for the oral route is given together with preset amount of a second active composition for the nasal route and optionally also with a third preset amount of a third active composition for the pulmonary route. The first active composition can include an antihistamine, such as loratidine, desloratidine, fexofenadine, HCI, ebastine, mizolastine, mequitazine or ceterizine, an anti-leukotriene, such as montelukast, zafirlukast or pranlukast or a combination of an- antihistamine and a anti-leukotriene. The second active composition can include a coticosteroid such as budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide or ciclesonide.; The third active composition can include a corticosteroid of the same type or a combination of such corticosteroid with a beta2-agonist, such as salmeterol and formoterol. US2002137785 (A1) proposes the use of a leukotriene antagonist, particularly a montelukast sodium compound such as SINGULAIR, in combination with cystine to combat inflammatory disease and hopefully reduce the necessary use of SINGULAIR. Combination with other anti-inflammatory agents and anti¬asthmatic agents is proposed. Selenium to assure glutathione pathway benefit is suggested. The addition of a selective COX-2 inhibitor is suggested. WO03101434 (A2) discloses a pharmaceutical composition in the intranasal delivery to the nasal mucosa for prevention and treatment of symptoms of allergic rhiities and problems like nasal polyps comprising of Loratadine or Desloratadine which are potent antihistamine and solubilised at pharmaceutically acceptable pH of 4 to 8 which does not cause any irritation in the nose and permits the application of potent antihistamine at the site of action the nasal mucosa in lesser doses and without any side effect with immediate onset of action. Montelukast Sodium in combination with Loratadine would be

very effective and gives some effect as intranasal steroids that without any side
effects.
CN101352415 (A) discloses a formulation of oral solution of acebromine
theophylline and a preparation and belongs to the western medicine formulation
field; the oral solution of acebromine theophylline has pH value of 3.0 to 6.5 and
consists of the following ingredients with percentage: 0.1 to 2 percent (W/V) of
acebromine theophylline, 0 to 30 percent (V/V) of glycerin and/or propylene
glycol, moderate pH regulator, 0.001 to 50 percent of corrigent, 0.002 to 0.5
percent of bacteriostat and the solvent is water.
CN 101596173 (A) The invention discloses a capsule capable of stabilizing
acebrophylline, comprising an active ingredient acebrophylline/stabilizing agent
and a pharmaceutically acceptable accessory. The capsule with the
acebrophylline of the invention solves the problem that the acebrophylline and
monosaccharide or polysaccharide, in particular to lactose, are mixed and react
unstably, has simple operation, saves cost and is more suitable for large-scale
industrialized production.
CN 101607960 (A) The invention relates to a crystal form of acebrophylline,
surfolase and a preparation method thereof. The invention also relates to a
pharmaceutical composition containing the crystal form and the application of
the new crystal form in the preparation of medicine which is used for relieving
cough and eliminating phlegm as well as has double functions of bronchiectasis
and mucolysis.
WO 2010/107404 provides an effective combination for the prevention and/or
treatment of allergic and inflammatory diseases of skin or the upper and lower
respiratory tract such as seasonal allergic rhinitis, perenial allergic rhinitis,
allergic sinusitis, atopic dermatitis, urticaria, allergic asthma, aspirin mediated
asthma, exercise mediated asthma and elimination of symptoms which are
associated with these diseases.
Objectives of the Invention
The objective of the present invention is to provide a combination which is
highly effective in allergy.
Yet another objective of the invention is to provide patient's compliance by
combining the drugs which are generally used for co-morbid indications.

Another objective of the present invention is to combine two drugs which are not interacting with each other and have a different mechanism of action, used for similar indications. Detailed description of the invention
Allergy is a disorder of the immune system which is a form of hypersensitivity. Allergic reactions occur to normally harmless environmental substances known as allergens; these reactions are acquired, predictable, and rapid. Strictly, allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. It is characterized by excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma attacks, food allergies, and reactions to the venom of stinging insects such as wasps and bees. Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a major role in conditions such as asthma. In some people, severe allergies to environmental or dietary allergens or to medication may result in life-threatening anaphylactic reactions.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy. The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage. Proteins have unique properties that allow them to become allergens. Specifically, stabilizing forces in the tertiary and quaternary structure of the proteins resist degradation. Subsequently, they interact improperly with IgE immune cells. Most potentially allergenic proteins cannot survive the destructive environment of the digestive tract; similarly, others that are harmless but have strong structure resist the acidic environment of the digestive system and are sometimes tagged by the immune system as harmful. In other reactions, toxins

attach to an existing protein. The immune system considers the protein as harmful to the organism, and rejects the protein, causing a dermatological or systemic response.
Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLTI receptor. Montelukast inhibits physiologic actions of LTD 4 at the CysLTI receptor without any agonist activity. It therefore acts as a leukotriene receptor antagonist.
Ambroxol theophylline-7-acetate (ACE) is the salt obtained by reaction of equimolar amounts of ambroxol (AMB), a drug showing mucolytic and expectorant properties, and theophylline-7-acetic acid (TAA), a xanthine derivative with specific bronchodilator activity.
Acebrophylline is an airway mucus regulator with antiinflammatory action. The drug's approach involves several points of attack in obstructive airway disease. The molecule contains ambroxol, which facilitates various steps in the biosynthesis of pulmonary surfactant, theophylline-7 acetic acid whose carrier function raises blood levels of ambroxol, thus rapidly and intensely stimulating surfactant production. The resulting reduction in the viscosity and adhesivity of the mucus greatly improves ciliary clearance. By deviating phosphatidylcholine towards surfactant synthesis, making it no longer available for the synthesis of inflammatory mediators such as the leukotrienes, acebrophylline also exerts an inflammatory effect. This is confirmed in vivo by the reduction in aspecific bronchial hyper-responsiveness in patients with stable bronchial asthma. On a clinical level, acebrophylline is therapeutically effective in patients with acute or chronic bronchitis, chronic obstructive or asthma-like bronchitis and recurrence of chronic bronchitis; it reduces the frequency of episodes of bronchial obstruction and reduces the need for beta2-agonists, and improves indexes of ventilatory function.
Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that levocetirizine has high affinity for human H1 -receptors (Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociates from H1 -receptors with a half-life of 115 ± 38

min. After single administration, levocetirizine shows receptor occupancy of 90% at 4 hours and 57% at 24 hours.
The present invention discloses the oral dosage formulation comprising Acebrophylline, Levocetirizine and Montelukast. Furthermore, the invention also relates to a bilayer tablet comprising Acebrophylline sustained release, Levocetirizine immediate release and Montelukast immediate release.
The particles of the invention are obtained by wet granulation method. For
granulation pharmaceutically acceptable organic solvents or mixtures thereof,
or binder dispersion in an organic solvent are used. Preferred solvents include
acetone, ethanol and acetonitrile, in particular acetone. The particles may be
spherical or irregular in shape.
Montelukast may be in the form of Montelukast Sodium. The range of
Montelukast varies from 1 mg to 20 mg, preferably 10 mg and the range of
Levocetirizine is 3 mg to 12 mg more preferably 5 mg while the range of
Acebrophylline varies from 50 mg to 400 mg preferably 100mg to 200mg, most
preferably 200mg sustained release in the combination.
The release of Acebrophylline , Levocetirizine and Montelukast from the
pharmaceutical formulations of the present invention can be immediate or
modified, controlled, delayed, sustained, and extended. The release rate for
active drugs can be the same or different.
The pharmaceutical formulations of the present invention may comprise formed
particles with the same composition or formed particles with different
composition and different release rate of Acebrophylline, Levocetirizine and
Montelukast.

CLAIMS
1) A pharmaceutical formulation, useful for the treatment of asthma and
airway inflammation due to allergy and other pathological condition,
comprising Acebrophylline in the range 50 mg to 400 mg, preferably
100mg to 200mg, more preferably 200 mg in sustained release form,
while the range of Monteleukast varies from 1 mg to 20 mg preferably
10mg and Levocetirizine is in the range of 3 mg to 12 mg preferably 5
mg with pharmaceutically acceptable excipients.
2) The pharmaceutically acceptable excipients as claimed in claim 1 are
selected from diluents, disintegrants, and lubricants.
3) The diluents as claimed in claim 2 can be selected from lactose, sucrose,
glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.
4) The disintegrants as claimed in claim 2 can be selected from
polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl
cellulose (croscarmellose sodium) and sodium starch glycolate.
5) The lubricants as claimed in claim 2 can be selected from talc or silica,
and fats, e.g. vegetable stearin, magnesium stearate or stearic acid.
6) The formulation as claimed in claim 1 can be coated with Hydroxypropyl
Methyl Cellulose, along with suitable plasticizer, opacifier, coloring agent
and the solvent.
7) The formulation as claimed in claim 1 is preferably oral.
8) The oral formulation as claimed in claim 7 may be immediate release tablets, capsules, liquid orals, disintegrating tablets, or dry syrups.