WO2006030221A1 - Composition pharmaceutique comportant un agent betamimetique et un agent mucolytique - Google Patents

Composition pharmaceutique comportant un agent betamimetique et un agent mucolytique Download PDF

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Publication number
WO2006030221A1
WO2006030221A1 PCT/GB2005/003563 GB2005003563W WO2006030221A1 WO 2006030221 A1 WO2006030221 A1 WO 2006030221A1 GB 2005003563 W GB2005003563 W GB 2005003563W WO 2006030221 A1 WO2006030221 A1 WO 2006030221A1
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WO
WIPO (PCT)
Prior art keywords
composition according
agent
levosalbutamol
ambroxol
therapeutically effective
Prior art date
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PCT/GB2005/003563
Other languages
English (en)
Inventor
Amar Lulla
Geena Malhotra
Original Assignee
Cipla Limited
Turner, Craig, Robert
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Application filed by Cipla Limited, Turner, Craig, Robert filed Critical Cipla Limited
Publication of WO2006030221A1 publication Critical patent/WO2006030221A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics

Definitions

  • the present invention relates to pharmaceutical compositions for the treatment of respiratory disorders, especially those characterized by bronchoconstriction and excessive mucus production.
  • 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.
  • the pharmacotherapy is aimed at 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.
  • many formulations usually include a mucolytic agent along with an-antibacterial or an anti- viral agent.
  • EP1437134 by Boehringer Ingelheim claims an anti-infiuenzal 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.
  • 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 WO0174341 claims the use of non-sedating anti-histaminics along with a mucolytic agent i.e. ambroxol for the treatment and/or prevention of allergic and inflammatory conditions with cough.
  • Mucolytics such as ambroxol are 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.
  • WO03068206 provides for a formulation comprising of a betamimetic agent such as salbutamol sulphate and terbutaline in combination with guaiphenesin and an anti- histaminic agent.
  • a betamimetic agent such as salbutamol sulphate and terbutaline in combination with guaiphenesin and an anti- histaminic agent.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent and mucolytic agent.
  • US patent application number US2004054215 by CIPLA Limited discloses a method for obtaining an optically pure R-isomer of albuterol.
  • Salmeterol is a potent, long lasting betamimetic agent commonly prescribed for the treatment of patients with obstructive airway disease such as asthma. Salmeterol is commonly marketed as a racemate mixture under the trademark SEREVENT. TM.
  • US patent application number 20040136918 claims a combination of R-salmeterol xinafoate and fluticasone propionate as a metered dose aerosol inhalation for the treatment of asthma, chronic obstructive pulmonary disorder, and respiratory tract disorders.
  • Formoterol has two chiral centers and therefore has possibility of 4 different isomeric combinations of material available. However, it has been found that R,R formoterol is 1000-times more potentially active than its S,S-isomer or any other available isomer. It is well described by prior arts such as US 6068833, US 5795564 and US 6299863.
  • betamimetic agent has a distinct advantage over using the racemic molecule. 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 to relieve excessive mucus secretion.
  • It is an object of the present invention to provide novel pharmaceutical compositions comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives or polymorphs thereof and a mucolytic agent or is salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof.
  • It is another object of the present invention to provide a novel pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives or polymorphs and a mucolytic agent or is salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof to treat respiratory disorders, in particular those characterized by bronchoconstriction and excessive mucus secretion.
  • It is yet another object of the present invention to provide a novel pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate an inhalation liquid for nebulisation.
  • Another object of the present invention is to provide for a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate a dry powder for inhalation or a metered dose inhaler.
  • It is still another object of the present invention to provide for novel pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate liquid oral formulations.
  • It is still another object of the present invention to provide for novel pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate solid oral formulations.
  • a pharmaceutical composition comprising a therapeutically effective isomer of a betamimetic agent or a salt, solvate, ester, prodrug, polymorph or derivative thereof substantially free of the less therapeutically effective isomer(s) of said agent, and a mucolytic agent or salt, solvate, ester, prodrug, polymorph, enantiomer or derivative thereof.
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.
  • Preferred betamimetics include levosalbutamol, R-salmeterol and R, R formoterol, and any one of these may be used in combination with any one of the preferred mucolytic agents ambroxol, tyloxapol, carbocysteine, mecysteine, bromhexine, or N-acetylcysteine.
  • compositions of the invention may, for example, be in the form of an inhalation liquid for eg inhalation solution or suspension, a dry powder for inhalation, an oral liquid, an oral solid dosage form such as a tablet or capsule, or as a metered dose inhaler.
  • a method of treatment for respiratory disorders characterized by bronchoconstriction and excessive mucus secretion comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
  • compositions • of the invention are provided for use as medicaments, particularly for treating respiratory disorders including those characterized by bronchoconstriction and excess mucus production.
  • a particularly preferred combination of actives is levosalbutamol sulphate and ambroxol hydrochloride.
  • the invention employs the most active, therapeutically speaking, isomer of a betamimetic agent.
  • substantially free of the less therapeutically effective isomer(s) means that these isomers will not be present in any significant amount.
  • such isomers will be present at no more than 10% w/w of betamimetic, more preferably 1% w/w or less.
  • compositions containing levosalbutamol, (R) -salmeterol or R, R- formoterol are substantially free of the S-isomers of these compounds.
  • a therapeutically effective isomer of betamimetic agent includes a combination of two or more therapeutically effective isomers of one or more betamimetic agents
  • reference to" a pharmaceutical composition includes of two or more pharmaceutical compositions
  • reference to" a mucolytic agent includes combinations of two or more mucolytic agents
  • reference to" a pharmaceutically acceptable carrier includes combinations of two or more pharmaceutically acceptable carriers, and the like.
  • Betamimetic agents are known to provide a bronchodilatory effect to patients by acting on the ⁇ -2 adrenergic receptors in the airway smooth muscles and the bronchial smooth muscles, resulting in relief from the symptoms of breathlessness. More particularly, betamimetic agents have been shown to increase the conductance of potassium channels in airway muscle cells, leading to membrane hyperpolarization and relaxation. Therefore being very selective in their activity, they are preferred class of bronchodilators. This class comprises of compounds such as salbutamol, salmeterol, formoterol, rimeterol, acebutolol.
  • the present invention advantageously employs the therapeutically effective isomers of these compounds.
  • Compounds such as salbutamol, salmeterol and formoterol are known to exist as their R- and S-isomers and in all the three cases the R-isomers are more active than the S-isomers. Difference in activity is such that the S-isomer has markedly less affinity for the beta-adrenoreceptors than the R-isomers. Also the R-isomer has greater bronchodilatory effects and has anti-inflammatory properties. Therefore, the R-isomers are much more therapeutically active, and are therefore the preferred drug of choice.
  • the preferred betamimetic according to the present invention is levosalbutamol or its salts, solvates, prodrugs, esters, polymorphs or derivates thereof.
  • the salts of levosalbutamol may include levosalbutamol sulphate, levosalbutamol tartrate, levosalbutamol hydrochloride or other suitable salts however the preferred salt is levosalbutamol sulphate, levosalbutamol tartrate, levosalbutamol hydrochloride
  • mucolytic agents help to liquefy the thick, tenacious secretions.
  • 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 helps to open the airways and thus facilitate expectoration.
  • the dense - mucus may also impair penetration of levosalbutamol into the bronchiole during a rescue therapy during acute attacks of asthma.
  • a mucolytic agent like ambroxol which helps in clearing up the airways by removal of the mucus, enhances the penetration of bronchodilator into the bronchioles.
  • a mucolytic agent like ambroxol which helps in clearing up the airways by removal of the mucus
  • both the drugs are very effective in respiratory conditions associated with bronchoconstriction and excessive mucus production.
  • a bronchodilator such as levosalbutamol, R-salmeterol and R, R-formoterol helps to open the airways and thus facilitate expectoration.
  • Phospholipase A 2 is an enzyme, which is activated during inflammatory and allergic reactions and it reduces the number of ⁇ 2 -receptors in the lung thereby reducing the spasmolytic activity of betamimetic agents.
  • Mucolytic agent being an inhibitor of PLA 2 has a sparing action on the ⁇ 2 -receptors. Mucolytics act on the phospholipase and reducing its acticvity thus enhancing the activity of betamimetic agents. With the bronchial tubes being more dilated, the drainage of thick mucus is much more faster. Thus the two drugs act additively to each other and providing quicker relief.
  • the mucolytics can be suitably selected from N-acetylcysteine, bromhexine, tyloxapol, carbocysteine, mecysteine and ambroxol or their salts, solvates, , esters, derivatives, enanatiomers, polymorphs or prodrugs thereof.
  • the preferred compounds are ambroxol hydrochloride and bromhexine hydrochloride.
  • Ambroxol to be used for pharmaceutical compositions of the present invention, has 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.
  • acid addition salts including hydrobromate, oxalate, nitrate, sulphonate, fumarate, maleate, sulfate phosphate, and the like or freebase can also be used.
  • Ambroxol hydrochloride may preferably be administered in the dosages of 1 mg to 90 mg whereas bromhexine hydrochloride can be administered in the dosages of 4 mg to 30 mg in order to be therapeutically effective
  • Commercially available formulations comprising Salbutamol typically have the doses as 2.5 mg of salbutamol sulphate or any such other salt of salbutamol.
  • therapeutically effective isomer i.e.
  • the dosage of the betamimetic agent to be administered is reduced to half or even less. Due to lesser-administered dosage, there are lesser cardiovascular complications, which are associated with higher doses of bronchodilators. Therefore the use of such a combination involving a therapeutically effective isomer results in increase patient compliance.
  • the combination may further be combined with pharmaceutically acceptable excipients in order to provide a suitable formulation.
  • preferred ranges for the amount of betamimetic agent and the amount of mucolytic agent (separately), preferably levosalbutamol and ambroxol (separately), include lmg to 4mg and 5mg to 70mg for oral dosage forms; 0.3 mg to 1.25 mg and 5 to 30 mg and more preferably 15mg for inhalation liquid (respules), and 25mcg/spray to 200mcg/spray and lmg/spray to 7.5 mg/spray for metered dose inhalers, 25 meg to 400mcg and lmg to 15mg for dry powder for inhalation.
  • betamimetic agent is used in the entire specification and the claims in a broad sense to include not only betamimetic per se but also its salts, solvates, prodrugs, esters, derivatives, enantiomers, or polymorphs thereof, and to combinations of more than one betamimetic agent.
  • mucolytic agent is used in the entire specification and claims in a broad sense to include not only mucolytic per se but also its salts, solvates, prodrugs, esters, derivatives, enantiomers, or polymorphs thereof, and to combinations of more than one mucolytic agent.
  • the combination may be formulated as an inhalation liquid for nebulisation, as a liquid oral dosage form or as a dry powder for inhalation, as a metered dose inhaler, and in solid oral dosage forms, or in other suitable dosage forms.
  • the different dosage forms may be formulated using known pharmaceutically acceptable excipients using techniques known in the art.
  • a pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate an inhalation liquid.
  • the therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof may be combined with one or more of suitable excipients such as but not limited to tonicity adjusting agents, pH regulators, chelating agents, antimicrobials and the like in a suitable vehicle to form an inhalation liquid.
  • 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 is very effective in assisting 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 respiratory disorders 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 patients or otherwise unable to use hand-held inhalers or also to acute respiratory disorder patients requiring oxygen therapy.
  • isotonicity- or tonicity-adjusting agents include, one or more of 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.
  • the isotonicity-adjusting agent is sodium chloride.
  • the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt.
  • the present invention comprises 0.9 wt % of an isotonicity-adjusting agent, which is preferably sodium chloride
  • the pH is adjusted by the addition of pharmacologically acceptable pH adjusting agents.
  • the pH adjusting agents or pH regulators may be selected from one or more of pharmacologically acceptable inorganic acids or organic acids; sodium hydroxide, sodium carbonate, sodium bicarbonate, magnesium carbonates, aluminium hydroxide, aluminum carbonate, aluminium bicarbonate, calcium carbonate and calcium hydroxide, calcium bicarbonate and the like may be used for this purpose.
  • preferred inorganic acids are one or more of inorganic acids selected from the group consisting of but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid.
  • organic acids are one or more of organic acids selected from the group consisting of but not limited to 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.
  • ascorbic acid, fumaric acid and citric acid are preferred.
  • suitable buffering agents may also be employed for this purpose.
  • a inhalation liquid for nebulisation as provided by the present invention has a pH in the range of 3 to 8.5 and more preferably in the range of 3 to 5
  • the formulations according to the invention may contain complexing agents as other ingredients in suitable amounts.
  • 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 EDTA or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate, as complexing agent.
  • EDTA or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate, as complexing agent.
  • disodium EDTA is used in a range of 0.005% to 0.1%, preferably 0.01 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 salts, solvates or derivatives thereof such as sodium benzoate, potassium benzoate, sorbic acid or salts, solvates or derivatives thereof such as potassium sorbates in the concentration known in the art.
  • therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof may be provided in a variety of pharmaceutically acceptable vehicles, including, but not limited to, water or any other aqueous solution comprising a pharmaceutically acceptable amount of an isotonicity adjusting agent.
  • the liquid vehicles include, but are not limited to, polar solvents, including, but not limited to, compounds that contain hydroxyl groups or other polar groups.
  • solvents include, but are not limited to, water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols.
  • the inhalation liquid comprising therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof.
  • the process comprises dissolving the drugs, optionally chelating agents, isotonicity adjusting agents and any other suitable ingredients in the vehicle and adjusting the pH using a suitable pH adjusting agent.
  • the inhalation liquid of the present invention may be administered by nebulizer.
  • nebulizer including, but not limited to, a jet nebulizer, ultrasonic nebulizer and breath actuated nebulizer.
  • 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.
  • a nebulizer (with face mask or mouthpiece) connected to a compressor may be used to deliver the inhalation liquid of the present invention to a patient.
  • a pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate liquid oral formulations.
  • the liquid formulation may preferably comprise one or more suitable ingredients for liquid formulations like but not limited to thickeners, humectants, sweeteners, buffering agents, preservatives, colors, chelating agents/sequestering agents, stabilisers and flavours and any other suitable ingredients.
  • the liquid formulations are useful for patients unwilling or unable to take inhaled medications.
  • the liquid formulation may act as an alternative therapy for mild intermittent asthma, as an option in case of exercise-induced asthma, add-on to inhaled medication.
  • the liquid formulation is a convenient dosage form for pediatric as well as geriatric patients who have difficulty in swallowing tablets.
  • thickeners may be used which are stable over a wide pH range and may be selected from one or more of but not limited to the group consisting celluloses viz methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose hydroxy ethyl cellulose; natural gums like xanthan gum, acacia gum, gum tragacanth, carrageen gum; pectin, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol, and mixtures thereof.
  • the thickeners may be present in the range of 0.1 to 2% by weight.
  • the present invention may include one or more of ingredients like but not limited to propylene glycol, medium chain triglycerides, glycerol, maltitol, sorbitol and the like, in the range of about 10 to 70% w/v, based on the formulation that impart viscosity to the formulation.
  • ingredients like glycerol, sugar syrup, fructose corn syrup, maltitol, sorbitol and others of their class act as sweetening agents as well can be added.
  • the preservatives may be selected from one or more of but not limited to the group consisting of benzoic acids or their salts , solvates derivative thereof for eg potassium benzoate, sodium benzoate, sorbic acids or their salts , solvates derivative thereof for eg potassium sorbate, methyl parahydroxy benzoate, propyl parahydroxy benzoate, ethyl parahydroxy benzoate, butyl parahydroxy benzoate and/or mixtures thereof.
  • the preservatives may be present in the range of 0.001% to 0.5% by weight.
  • the formulation may also comprise buffering agents selected from one or more of but not limited to the group consisting phosphates, citrates and their salts and derivatives thereof, such as but not limted to sodium citrate, citric acid, hydrochloric acid , organic acids like succinic acid, fumaric acid, tartaric acid.
  • buffering agents selected from one or more of but not limited to the group consisting phosphates, citrates and their salts and derivatives thereof, such as but not limted to sodium citrate, citric acid, hydrochloric acid , organic acids like succinic acid, fumaric acid, tartaric acid.
  • the formulation of the present invention preferably has a pH in the range of 3.0 to 5.0.
  • Sequestering agent like aminopolycarboxylic acids and salts thereof which are safe for ingestion and have sufficient solubility in the formulations to make a stable single phase composition can be used.
  • Commercially available compounds which could be used include iminodiacetic acid, methyliminodiacetic acid, nitrilotriacetic acid, ethylenediaminetetraacetic acid ("EDTA”), diethylenetriaminepentaacetic acid, 1,2- diaminocyclohexane-tetraacetic acid, N-hydroxyethylenediaminetriacetic acid and related compounds.
  • the preferred salts are alkali metal salts of EDTA in an amount of from 0.05% to about 1% by weight of the formulation. Coloring agents may be added for aesthetic appearance.
  • Sweeteners and flavoring agents may be added, to increase palatability of the formulation.
  • the color and the flavor added may be complementary to each other.
  • Sodium chloride may optionally be added to the formulation which further enhances the taste of the formulation. Any such other suitable ingredients that contribute to make palatable syrup may also be included in the present formulation.
  • the vehicles used according to the present invention may be selected from but are not limited to water or liquid polyols like maltitol, lactitol, sorbitol, and glycerol.
  • the vehicle used is water.
  • a process for manufacture of a pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, prodrugs, or polymorphs thereof and a mucolytic agent or its salts, solvates, esters, derivatives, prodrugs, enantiomers or polymorphs thereof in a suitable liquid carrier.
  • the manufacturing process comprises dissolving preservative, sequestering agent and buffers in specified amount of purified water followed by addition of the drug. This is followed by the addition of other ingredients to the above solution. The pH is checked and finally the volume is made up.
  • the therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof according to the present invention may also be formulated as any other suitable liquid oral dosage forms.
  • a pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients may also be formulated as solid oral dosage formulation.
  • a tablet formulation can be manufactured by granulating the therapeutically effective isomer of betamimetic agent and mucolytic agent with one or more diluents and/or binders, mixing the granulated therapeutically effective isomer of betamimetic agent and mucolytic agent with other pharmaceutically acceptable excipients, and compressing to form a tablet.
  • the granules can be filled into a capsule with pharmaceutically acceptable excipients.
  • the therapeutically effective isomer of betamimetic agent and mucolytic agent may be mixed with suitable pharmaceutical excipients and encapsulated or compressed.
  • therapeutically effective isomer of betamimetic agent and mucolytic agent can also be formulated as extended release capsules/tablets , bilayered tablets, core-coated tablet or any other suitable oral solid dosage form.
  • the therapeutically effective isomer of betamimetic agent and mucolytic agent can be blended with one or more of but not limited to diluents, binders, disintegrants, glidants, lubricant or other suitable pharmaceutically acceptable ingredients and may be formulated into suitable solid oral dosage forms using known techniques in the art, for example wet granulation, dry granulation, and direct compression.
  • the therapeutically effective isomer of betamimetic agent and mucolytic agent can be formulated as an extended release tablet.
  • the extended release tablets can be made by techniques known in the art.
  • the extended release tablets may include but are not limited to matrix tablets, sustain release-coated tablets, sustain release tablets by OROS technology, MUPS.
  • Suitable tablet formulations of the present invention may be in coated or uncoated form, as desired.
  • Suitable diluents include one or more of but not limited to calcium phosphate-dibasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents thereof.
  • the diluents can be added in a quantity ranging from 15 to 90% by weight of the formulation.
  • Suitable binders include one or more of but not limited to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, starch, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof.
  • the binders can be added in a quantity ranging from 1 to 15% by weight of the formulation.
  • Suitable disintegrants include one or more of but not limited to hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, starch, crystalline cellulose, sodium starch glycollate, hydroxypropyl starch, partly pregelatinized starch, crospovidone and equivalents thereof.
  • the disintegrants can be added in a quantity ranging from 5 to 20% by weight of the formulation.
  • Suitable lubricants/glidants include one or more of but not limited to stearic acid or its salts, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, colloidal silicon dioxide and equivalents thereof.
  • the lubricants can be added in a quantity ranging from 0.5 to 5% by weight of the formulation.
  • suitable coloring agents may be added.
  • suitable ingredients giving extended release may include one or more of but not limited to Eudragit, cellulose derivatives such as hydroxypropylmethylcellulose, ethyl cellulose, and cellulose acetate, polyvinyl acetate polymers.
  • Other ingredients that are suitable for extended release formulations like Osmogens eg. Sodium chloride, potassium chloride, lactose, fructose, glucose, mannitol, calcium sulfate, polyethylene oxide etc. or any other suitable pharmaceutically acceptable excipients or techniques giving extended release.
  • a pharmaceutical composition comprising a therapeutically effective isomer of betamimetic agent or its salts, solvates, prodrugs, esters, derivatives, or polymorphs thereof and a mucolytic agent or its salts, solvates, prodrugs, esters, derivatives, enantiomers or polymorphs thereof along with suitable pharmaceutically acceptable excipients in order to formulate dry powder for inhalation or and a metered dose inhaler or any other suitable dosage form for inhalation.
  • the drugs may be separately micronised and mixed with pharmaceutically acceptable carrier or may optionally be micronised together with a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be chosen from materials such as one or more of but not limited to saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.
  • An especially preferred carrier is lactose.
  • the dry powder may be in capsules of gelatin or hydroxypropyl methyl cellulose or alternatively, the dry powder may be contained as a reservoir or multiple unit doses in a multi-dose dry powder inhalation device.
  • the particle size of the active ingredient, and that of the carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray-drying, lyophilisation or recrystallisation from supercritical media. Size reduction of the active ingredient is desired since it is seen that lower the particle size better is the respirable fraction.
  • the formulation is therefore developed to meet the following criteria:
  • the blend i.e. drug + pharmaceutically acceptable carrier
  • the blend should be such that it has a satisfactory flow while filling on machine. It should give a high respirable fraction. The blend should not exhibit cohesive property, which could result in agglomeration of blend in capsule.
  • the drug used may be micronised (eg 95 % ⁇ 2.5 ⁇ and 5 % between 2.5 - 5 ⁇ ).
  • the drugs may be added together or separately in solution or suspension in a propellant.
  • An aerosol formulation according to present invention may optionally comprise in addition to the drugs , at least one propellant, other pharmaceutically acceptable agents such as cosolvents, antioxidants, bulking agents and/or surfactants.
  • Suitable propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons such as monofluorotrichloromethane, dichlorodifluoromethane and halogen-substituted hydrocarbons, for example fluorine- substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, particularly 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227) or mixtures of two or more such halogen-substituted hydrocarbons.
  • hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons such as monofluorotrichloromethane, dichlorodifluoromethane and halogen-substituted hydrocarbons,
  • the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art.
  • suitable aerosol compositions include surfactant-free or substantially surfactant- free aerosol compositions.
  • the bulking agent and surfactant may be in an amount up to 1 to 500% and 0.005 to 5% respectively by weight of the active .
  • the bulking agents may be selected from but not limited to saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.
  • the preferred bulking agent is lactose.
  • the aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition.
  • the surfactants may be selected from those known in the art like oils such as but not limited to corn oil, olive oil, cottonseed oil & sunflower oil, mineral oil like liquid paraffin, oleic acid, phospholipids such as lecithin and citric acid, sorbitan trioleate, glycerol, glycol , magnesium stearate and the like.
  • a process for the manufacture of an aerosol composition which comprises I) addition of drugs to a suitable canister, II) crimping the canister with the metered valve, III) charging with the suitable propellant.
  • the process also optionally comprises dissolution of surfactant in a co-solvent or addition of bulking agent after addition of the drugs.
  • the present invention may also be formulated as parenteral preparations or other suitable dosage forms as may be desired.
  • 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 1 mg to 90 mg whereas levosalbutamol may be administered in the doses of - 0.3mg to 6 mg.
  • Levosalbutamol may be administered in the doses of 0.63 meg to 1.5 mg up to 3-4 times daily whereas R-salmeterol can be administered upto 8 mg one to four times daily and R, R-formoterol can be administered in doses between 8 meg to 25 meg daily.
  • the R-isomer has shown improvement in Fine Particle Dose (FPD) compared to racemic salbutamol sulphate.
  • FPD Fine Particle Dose
  • levosalbutamol sulfate is more free flowing than the racemate and has the advantage of giving better suspension and dispersion characteristics.
  • Example: 1 As inhalation solution.
  • step 2 To the solution prepared in step 1, ambroxol hydrochloride was added and dissolved under stirring.
  • 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.
  • step 2 To the solution prepared in step 1, ambroxol hydrochloride was added and dissolved under stirring.
  • 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.
  • step 2 To the solution prepared in step 1, ambroxol hydrochloride was added and dissolved under stirring.
  • 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.
  • step 4 levosalbutamol sulfate solution (prepared in purified water) was added and the volume was made up with purified water.
  • Example: 4 As dry powder for inhalation.
  • citric acid, Ambroxol hydrochloride, and sodium citrate was added to the above solution and then levosalbutamol sulfate was added to the above solution.
  • flavour pineapple no 1 and menthol were dissolved in propylene glycol was added to the above solution. This was followed by the addition of color tartarazine mixed in water.
  • step 2 was added to that of step 1

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Abstract

La présente invention se rapporte à une composition pharmaceutique comportant un isomère thérapeutiquement actif d'un agent bêtamimétique ou d'un sel, d'un solvate, d'un ester, d'un promédicament, d'un polymorphe ou d'un dérivé de cet agent, ne contenant sensiblement aucun autre(s) isomère(s) moins thérapeutiquement efficace(s) dudit agent, et un agent mucolytique ou un sel, un solvate, un ester, un promédicament, un polymorphe, un énantiomère ou un dérivé de celui-ci. L'invention se rapporte à une composition préférée comportant du R-salbutamol et de l'ambroxol. L'invention se rapporte également à des procédés de fabrication de ces compositions ainsi qu'à leur utilisation à des fins thérapeutiques.
PCT/GB2005/003563 2004-09-15 2005-09-15 Composition pharmaceutique comportant un agent betamimetique et un agent mucolytique WO2006030221A1 (fr)

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IN994MU2004 2004-09-15
IN994/MUM/2004 2004-09-15
IN297MU2005 2005-03-18
IN298/MUM/2005 2005-03-18
IN297/MUM/2005 2005-03-18
IN298MU2005 2005-03-18

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CN101099729B (zh) * 2006-07-03 2010-08-25 天津康鸿医药科技发展有限公司 含盐酸氨溴索与沙丁胺醇活性成分的口服固体制剂
JP2017516849A (ja) * 2014-05-23 2017-06-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング アンブロキソール塩酸塩を含む咳止めシロップ
IT201800006909A1 (it) * 2018-07-04 2020-01-04 Polvere secca di ambroxolo per uso inalatorio con target bronchiale
WO2020022975A3 (fr) * 2017-12-29 2020-02-27 Neutec Ar-Ge Sanayi Ve Ticaret Anonim Sirketi Nouvelles compositions pharmaceutiques dans le traitement de la bpco
CN113018444A (zh) * 2020-01-09 2021-06-25 海南斯达制药有限公司 治疗呼吸系统疾病的药物组合物及其制备方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101099729B (zh) * 2006-07-03 2010-08-25 天津康鸿医药科技发展有限公司 含盐酸氨溴索与沙丁胺醇活性成分的口服固体制剂
JP2017516849A (ja) * 2014-05-23 2017-06-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング アンブロキソール塩酸塩を含む咳止めシロップ
WO2020022975A3 (fr) * 2017-12-29 2020-02-27 Neutec Ar-Ge Sanayi Ve Ticaret Anonim Sirketi Nouvelles compositions pharmaceutiques dans le traitement de la bpco
IT201800006909A1 (it) * 2018-07-04 2020-01-04 Polvere secca di ambroxolo per uso inalatorio con target bronchiale
CN113018444A (zh) * 2020-01-09 2021-06-25 海南斯达制药有限公司 治疗呼吸系统疾病的药物组合物及其制备方法

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