COMPLETE DESCRIPTION
Filed of the Invention
The present invention is related to the novel oral combination comprising Acebrophylline 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 antiinflammatory 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 (VA/) 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.
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 two 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.
Acute response
Degranulation process in allergy. 1 - antigen; 2 - IgE antibody; 3 - FceRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)ln the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FCERI) on the surface of other kinds of immune cells called
mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.
If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.
Late-phase response
After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction. Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of TH2 cells.
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.
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLTi) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis.
In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLTi receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLTi receptor without any agonist activity.
Absorption:
After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning. For the 4-mg chewable tablet, the mean Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. The safety and efficacy of Montelukast in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablets were administered in the evening without regard to the time of food ingestion. The safety of montelukast in patients with asthma was also demonstrated in clinical trials in which the 4-mg chewable tablets were administered in the evening without regard to the time of food ingestion. The safety and efficacy of montelukast in patients with seasonal allergic rhinitis were demonstrated in
clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.
Distribution:
Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.
Metabolism:
Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro studies using human liver microsomes indicate that cytochromes P450 3A4 and 2C9 are involved in the metabolism of montelukast. Clinical studies investigating the effect of known inhibitors of cytochromes P450 3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on montelukast pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. However, in vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme.
Elimination:
The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5 day fecal collections and <0.2% was
recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast is nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%).
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.
The present invention discloses the oral dosage formulation comprising Acebrophylline and Montelukast. Furthermore, the invention also relates to
a bilayer tablet comprising Acebrophylline sustained release and Montelukast immediate release.
The particles of the invention are obtained by wet granulation method. For granulation pharmaceutical^ 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, 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 particles of the present invention may comprise, in addition to the active substances, also excipients such as fillers, binders, disintegrants, glidants and lubricants. Suitable fillers are microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc and others, preferably microcrystalline cellulose and lactose. Suitable binders are starch, pregelatinized starch, gelatine, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glucose syrup, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, potassium polacrilinin, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate,
colloidal silicon dioxide, guar gum, magnesium aluminium silicate and others, preferably sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone. Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycol of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch and others, preferably colloidal silicon dioxide. Suitable lubricants are steraic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc and others. Preferred lubricants are magnesium and calcium stearate, and stearic acid.
The formed particles of the present invention have good flow and compressible properties.
Formed particles of the invention may optionally be coated with a release controlling coating or with a protective coating. The coating may be prepared from polymer or nonpolymer substances. Suitable polymers that may be used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxymethyl cellulose phthalate, polyvinyl alcohol, methylhydroxyethyl cellulose, polymers of acrylic and methacrylic acid, maltodextrin and others. Nonpolymer substances that may be used are carnauba wax, cetyl alcohol, sucrose, glucose, shellac and others. The coating may optionally comprise other coating agents conventionally used in coating such as fillers, e.g. talc, lactose, polysaccharides and others, plasticizers, e.g. dibutyl sebacate, triethyl citrate, polyethylene glycol, adipic acid, coconut oil, oleic acid and others, colourants, e.g. titanium dioxide, lakes, pigments and others, antioxidants and others.
The object of the present invention are also pharmaceutical compositions comprising the above described formed particles. Coated and/or uncoated particles may be used. They may be filled into sachets or capsules, they may be compressed together with suitable excipients into tablets or they mey be used for reconstitution into suspension. Tablets may be single- or multilayer, dispersible, orodispersible, effervescent, chewing, pastilles. The tablets of the invention are hard and have suitable physical technological properties. By the addition of suitable excipients the release of the active substance from the tablet may be controlled. Excipients to be added to the formed particles for the preparation of the previously stated pharmaceutical compositions may be different fillers, binders, disintegrants, glidants and lubricants.
Suitable fillers may be microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc and others, preferably microcrystalline cellulose and lactose.
Suitable binders are starch, pregelatinized starch, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glucose syrup, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, potassium polacrilinin, cross-
linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate and others, preferably sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch and others, preferably, colloidal silicon dioxide.
Suitable lubricants are stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate and others. Preferred lubricants are calcium or magnesium stearate and stearic acid.
Capsules and tablets may optionally be coated with a coating which may be applied from an aqueous or non-aqueous medium. A coating may control the release or it is only a protective coating. The coating may be prepared from polymer or nonpolymer substances. Suitable polymers that may be used are polyethylene glycol, hydroxyl propyl cellulose, hydroxyl propyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyl ethyl cellulose, sodium carboxy methylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxymethyl cellulose phthalate, polyvinyl alcohol, methylhydroxyethyl cellulose, polymers of acrylic and methacrylic acid, maltodextrin and others. Nonpolymer substances may be carnauba wax, cetyl alcohol, sucrose, glucose, shellac and others.
The coating may also comprise other conventionally used coating agents such as fillers, e.g. talc, lactose, polysaccharides and others, plasticizers, e.g. dibytil sebacate, trietyl citrate, polyethylene glycol and others; colorants, e.g. titanium dioxide, lakes, pigments and others, antioxidants and others.
The formed particles are suitable for the preparation of multiple unit forms such as capsules or tablets with the primary formed particles wherein a multiple unit form disintegrates to individual primary formed particles from which the active substance is released. The formed particles are also suitable for the preparation of multiple unit forms such as sachets and dozers for multiple unit systems and others. Uncoated and/or coated particles may be used.
The release of Acebrophylline and Montelukast from the pharmaceutical formulations of the present invention can be immediate or modified, controlled, delayed, sustained, and extended. The release rate for both 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 and Montelukast.
The present invention also relates to the process for the preparation of the formed particles regular and irregular in shape. They are prepared by the wet granulation with organic solvent. For granulation either a solvent or binder dispersion in an organic solvent may be used.
The present invention can be formulated, but not limited to, in the following manner-
1) Weigh the following ingredients For upper laver-
Montelukast- 26.6gm Microcrystalline cellulose- 85gm Lactose- 90gm Starch- 56gm
Col. Quinoline yellow lake- 1gm Polyvinyl Pyrrolidone- 5.6gm Isopropyl alcohol-100ml Talcum- 5.6gm Magnesium Stearate- 3.3gm
Sodium Starch Glycollate- 15gm Colloidal Silicon dioxide- 1.1gm Sodium metabisulphite- 1.1 gm
For Lower layer
Acebrophylline- 459gm Methoceal k 100 LV- 112.5gm MCC pH 102-46.7gm Polyvinyl pyrrollidone K-30- 19.6gm Isopropyl alcohol- 300ml Purified water- 130ml Methoceal k4 M- 76gm MCC pH 102-45gm Magnesium stearate- 8.5gm Colloidal Silicon dioxide- 4gm
2) The following materials are taken, dried and sifted-
(Table Removed)
The sifted materials of step 2 are transferred in RMG and the RMG is rn for 10 minutes.
3) For binding, dissolve PVPK-30 5.6 gm in isopropyl alcohol with stirring.
4) The binding agent is mixed with the sifted material.
5) The wet mass so obtained is passed through sieve # 8 manually.
6) Dry the wet milled material in FBD/Tray drier at a temperature 50-57°C. Air dry for 60 minutes to get moisture content between 1-2%.
7) Sift the dried granules through sieve # 24.
8) Lubricate the granules obtained in step 8 with the following material
Ingredients Sieved Number
Talcum #80
Magnesium stearate #40
Sod. Starch Glycollate #80
Coll. Silicon dioxide #80
Sodium meta bi sulphate #80
10)The lubricated granules are compressed using required dies and punches.

WE CLAIM:
1. A blood collection device comprising:
a cannula (10) hub defining a chamber (28);
an inlet cannula (12) defining an axis and having a distal end and a lumen extending therethrough, the inlet cannula (12) being mounted to the cannula hub (10) such that the distal end of the inlet cannula (12) is external of the cannula hub (10) and such that the lumen through the inlet cannula (12) communicates with the chamber (28);
an outlet cannula (14) having a proximal end and a lumen extending therethrough, the outlet cannula (14) being mounted to the cannula hub (10) such that the proximal end of the outlet cannula (14) is external of the cannula hub (10) and such that the lumen of the outlet cannula (14) communicates with the chamber (28);
a closed sleeve (34) mounted over a portion (32) of the outlet cannula (14) disposed externally of the cannula hub (10); and
a venting mechanism (38) providing communication between the chamber (28) and ambient surroundings,
characterized in that
the venting mechanism (38) comprises a tubular insert (40) defining a fluid passage (42) therethrough and a membrane (44) extending across the fluid passage (42), wherein the membrane (44) is made from a material permeable for air and substantially impermeable for blood.
2. A blood collection device in accordance with claim 1,
characterized in that
the tubular insert (40) of the venting mechanism (38) is received in a tubular projection (50) extending from the cannula hub (10).
3. A blood collection device in accordance with claim 2,
characterized in that
the tubular projection (50) extends in a direction transverse, in particular perpendicular, to the axis of the inlet cannula (12).

4. A blood collection device in accordance with claim 2 or 3,
characterized in that
the tubular projection (50) is integral with the cannula hub (10), in particular with a first part (16) of the cannula hub (10) carrying the inlet cannula (10).
5. A blood collection device in accordance with anyone of claims 2 to 4,
characterized in that
the tubular insert (40) of the venting mechanism (38) is fixed in the tubular projection (50) by means of a press fit.
6. A blood collection device in accordance with anyone of claims 2 to 5,
characterized in that
the tubular insert (40) of the venting mechanism (38) has an outer collar (52) formed at its outer surface adjacent an end facing away from the cannula hub (10).
7. A blood collection device in accordance with claim 6,
characterized in that
an outer diameter of the outer collar (52) is substantially equal to an outer diameter of the tubular projection (50).
8. A blood collection device in accordance with anyone of claims 2 to 7,
characterized in that
in the region of the tubular projection (50) adjacent the chamber (28) of the cannula hub (10), the fluid passage is diminished by an inner collar (54).
9. A blood collection device in accordance with anyone of the preceding
claims,
characterized in that
the cannula hub (10) is formed from first and second parts (16, 18), the first part (16) carrying the inlet cannula (12) and the second part (18) carrying the outlet cannula (14).

10. A blood collection device in accordance with claim 9,
characterized in that
the first part (16) comprises a grip portion (20) and a tubular portion (22) extending proximal therefrom in the direction of the cannula axis.
11. A blood collection device in accordance with claim 10,
characterized in that
the second part (18) is of generally tubular shape and partly received in the tubular portion (24) of the first part by means of a press fit.
12. A blood collection device in accordance with anyone of claims 9 to 11,
characterized in that
the second part (18) and at least the tubular portion (22) of the first part (16) are made from a transparent plastic material.