Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to an aqueous solution, comprising an acid addition salt of ambroxol.
• the aqueous solution of the present invention comprises an ambroxol content ranging from 0.1 % to 7% (w/v), a total content of polyalcohols selected from polyols and polyalkyleneglycols of at least 20% (w/v), an alcohol content lower than 1 % (w/v) and is free of benzoic acid and/or salts thereof with organic or inorganic bases, hereinbelow collectively referred to as "benzoates".
• Ambroxol hydrochloride [trans-4-(2-amino-3,5-dibromobenzyl amino)cyclohexanol hydrochloride] (Ph. Eur., Monograph 1489) is a well known mucolytic drug available in various compositions suitable for oral or parenteral administration. However, oral compositions are by far preferred.
• US2003/0171391 and US 2005/0014844 generally disclose a pharmaceutical composition containing ambroxol.
• Example G of both such patent applications discloses an oral solution comprising 1 .5% w/v of ambroxol, 6% w/v of a sorbitol solution at 70%, 2% w/v of glycerol, and minor amount of other additives and flavouring agents.
• US 2005/0266058, US 2003/01 13377, and US 2005/0075403 generally disclose a pharmaceutical composition containing ambroxol, in particular in the form of gels, hydrophilic pastes, lotions, solutions, suppositories, hydrophobic pastes, ointments, creams, lotions, sticks, lozenges, tablets, pastilles, and sweets.
• Example 1 of US 2005/0266058 discloses an aqueous solution comprising 1 % w/w of ambroxol, 20% w/w of a glycerol solution at 85%, 5% w/w of ethanol solution at 96%, and minor amount of flavouring and colouring agents.
• Examples 1 1 and 15 of US 2003/01 13377 disclose an aqueous solution comprising about 2.3% w/w of ambroxol, about 47% w/w of propylene glycol, and 10% w/w of ethanol.
• Formulation 3 of US 2005/0075403 discloses an aqueous solution comprising 1 % w/w of ambroxol, 30% w/w of sorbitol, 10% w/w of glycerol, 5% w/w of ethanol, and minor amount of flavouring agents.
• EP 1 543 826 describes an oral liquid formulation of ambroxol, characterized by high concentration (about 4-7% w/v) of the active ingredient.
• Example 1 of EP 1 543 826 discloses an aqueous solution comprising 5% w/v of ambroxol, 20% w/v of xylitol, 10% w/v of Solutol HS15, 2.9% w/v of glycerol, 0.50% w/v of sodium benzoate, and minor amount of flavouring agents.
• Such formulation is said to be stable for at least 12 months if it is stored in an amber glass bottle at 25 °C.
• preservatives like alcohols, benzoates, sorbates, and parabens is common in liquid formulations. Preservatives are effective in controlling mold, inhibiting yeast growth and protecting against bacterial proliferation, thus, finally, to allow compliance with the European Pharmacopoeia microbiological specifications (Ph. Eur. 6.7, ⁇ 5.1 .4) for "aqueous preparations for oral use” or "aqueous preparations for oromucosal use”. The use of preservatives is particularly recommended in aqueous compositions, wherein microorganisms can find favourable conditions for their propagation.
• impurity B trans-4-(6,8- dibromo-1 ,4-dihydroquinazolin-3(2H)-yl)cyclohexanol.
• impurity A (2-amino-3,5-dibromophenyl)methanol]
• impurity E (2-amino-3,5-dibromobenzaldeyde), but both can be controlled by operating in nitrogen atmosphere.
• aqueous oral ambroxol formulations known in the art both with low and high active ingredient concentration, contain benzoates or other specific antimicrobial preservatives.
• Benzoates are known to induce adverse reactions, both in adults and children, for example in asthmatic persons (see Petrus M. et al., Arch. Pediatr., 1996; 3(10): 984-7), fixed drug eruption (Vilaplana J. ei al., Contact Dermatitis, 2003; 49(6):290-1 ) and episodes of acute urticaria/angio-oedema. (Nettis E. et al., Br. J. Dermatol., 2004; 151 (4): 898-902). Further, recent studies have reported serious side effects associated with potassium sorbate and methyl hydroxybenzoate (methyl-paraben). Skin reactions, such as rash, urticaria, and contact dermatitis have been reported after topical application.
• the Applicant has found that, despite the absence of sodium benzoate and the very low, if any, amount of alcohols, when the total content of polyols and polyalkyleneoxides is at least 20% w/v. the "efficacy of antimicrobial preservation" (Eur. Ph. 6.6 Ed. ⁇ 5.1 .3) test in different severe conditions is maintained, so that the presence of additional preservatives, together with the side effects thereof, can be optionally avoided.
• an object of this invention to provide an aqueous solution comprising an acid addition salt of ambroxol, wherein the ambroxol content is ranging from 0.1 % to 7% (w/v), the total content of polyalcohols selected from polyols and/or polyalkyleneglycols is at least 20% (w/v), the total content of alcohols is lower than 1 % (w/v), and said aqueous solution is free of benzoates.
• the term “benzoates” shall refer to both the benzoic acid and the salt thereof with organic or inorganic bases.
• the term “free of” referred to the amount of “benzoates” as defined herein shall mean that the amount of benzoates is below 0.001 % (w/v).
• alcohols shall refer to any of a class of pharmaceutically acceptable organic compounds bearing only one hydroxy (-OH) group attached to a carbon atom of an alkyl group (hydrocarbon chain). Specific examples of alcohols within the above mentioned definition are: ethanol, propanol and isopropanol.
• the acid addition salt of ambroxol is hydrochloride salt.
• the ambroxol content is from 0.2 to 6% (w/v), more preferably is from 0.3 to 5% (w/v), and most preferably from 1 .0% to 4.0% (w/v).
• the formulation comprises polyalcohols selected from polyols and/or polyalkyleneglycols having solubilising, surfactant and sweetening properties as main functions.
• said polyols are selected from glycols, such as ethylene glycol, propylene glycol, 1 ,3-propanediol, trimethylene glycol, 1 ,2- butanediol, 1 ,3-butanediol, 1 ,4-butanediol, 1 ,2-pentanediol, 1 ,4- pentanediol, 1 ,5-pentanediol, 1 ,6-hexanediol, 1 ,7-heptanediol, diethylene glycol, dipropylene glycol, glycerol, 1 , 1 , 1 -trimethylolpropane, 1 ,1 ,1 -trimethylolethane, 1 ,2,6 hexanetriol, etohexadiol, 2-methyl-2,4- pentanediol, 1 ,8-octanedi
• the polyols useful in the present invention are selected from glycerol, propylene glycol, xylitol, sorbitol, sucrose, glucose, and mixture thereof.
• said polyalkylene glycols are selected from polyethylene glycol, polypropylene glycol, esters thereof with organic acids, or ethers thereof with alcohols, and mixture thereof.
• the polyalkylene glycols useful in the present invention are selected from esters of polyethylene glycols having a molecular weight ranging from 200 to 1500 (PEG 200, PEG 300, PEG 400, PEG 600, PEG 660, PEG 1000, PEG 1500) with hydroxy fatty acids, such as, for example hydroxylauric acid, hydroxymyristic acid, hydroxypalmitic acid, hydroxystearic acid, and hydroxyarachidic acid.
• the polyalkylene glycol ester useful in the present invention is SolutolTM HS 15 (Macrogol 15 hydroxystearate, Ph. Eur., Monograph 2052), a polyethylene glycol 660 hydroxystearate manufactured by BASF (Parsippany, N.J.).
• the total content of the above described polyols and polyalkylene glycols amounts to at least 20% by weight based on the total volume of the aqueous solution (w/v).
• the total content of the above described polyols and polyalkylene glycols ranges from 25% to 75% w/v, more preferably from 30% to 70% w/v, and most preferably from 35% to 65% w/v.
• the total content of alcohols is lower than 0.7% (w/v), and more particularly, the presence of alcohols can also be totally avoided.
• the aqueous solution is preferably free of additional preservatives represented by sorbic acid, sorbates (salts of sorbic acid) and parabens (esters of para-hydroxybenzoic acid).
• additional preservatives represented by sorbic acid, sorbates (salts of sorbic acid) and parabens (esters of para-hydroxybenzoic acid).
• the term "free of” referred to the amount of "additional preservatives" as defined herein shall mean that the amount of any of such preservatives is below 0.001 % (w/v).
• the pH value of the formulation is from 6 to 7 and more preferably it is about 6.4.
• a pH value of from 6 to 7 is obtained by adding an inorganic or organic base, such as sodium or potassium hydroxide, sodium or potassium bicarbonate, triethanolamine, tris [tris(hydroxy methyl)aminomethane], N-methylglucosamine, lysine, arginine and the like.
• an inorganic or organic base such as sodium or potassium hydroxide, sodium or potassium bicarbonate, triethanolamine, tris [tris(hydroxy methyl)aminomethane], N-methylglucosamine, lysine, arginine and the like.
• the aqueous solution of this invention may comprise further pharmacologically active ingredients whose concurrent administration is useful, provided they do not interfere with the solubility of the acid addition salt of ambroxol in the solution of this invention.
• an acid addition salt of ambroxol is the sole pharmacologically active ingredient in the aqueous solution of this invention.
• the solution of this invention preferably comprises a taste masking agent.
• the taste masking agent is an ammonium salt of glycyrrhizic acid.
• the preferred salt is ammonium monoglycyrrhizinate.
• ammonium monoglycyrrhizinate with menthol has been found to be particularly effective.
• the preferred ammonium monoglycyrrhizinate:menthol weight ratio is of from 0.5:10 to 5:10.
• the preferred ammonium monoglycyrrhizinate:ambroxol weight ratio is of from 0.001 :1 to 0.1 :1 . More preferably, said weight ratio is of from 0.01 :1 to 0.05:1 and even more preferably, it is of from 0.01 1 :1 to 0.025:1 .
• the solution of this invention is suitable for mucolytic therapy in place of known ambroxol-based compositions. Moreover, the most concentrated (> 5%) solutions of this invention are also effective in the treatment of sore throat symptoms when administered in the form of sprays or mouth washes.
• the solution of the present invention is for oral use.
• Preferred dosage forms of the solution of this invention are, therefore, syrups, drops, sprays and mouthwashes.
• the following examples further illustrate the invention, without limiting it.
• Formulation 1 5% ambroxol solution, comparative formulation according to EP 1 543 826 (100 mL).
• Formulation 2 5% ambroxol solution, formulation according to the present invention (100 mL).
• a standard solution of impurity B was prepared by weighing exactly 10 mg of the product, in a 100 mL volumetric flask. The product was dissolved with acetonitrile and the solution thus obtained was brought to volume (100 mL) with acetonitrile.
• a standard solution of ambroxol HCI was prepared by weighing exactly 50 mg of the product, in a 25 mL volumetric flask. The product was then dissolved with 10 mL of acetonitrile and then, 0.5 ml of the standard solution of impurity B, prepared as described above, was added. The solution thus obtained was brought to volume (25 ml_) with acetonitrile.
• Two sample solutions were prepared for both Formulations 1 and 2.
• the sample solutions to be used in the HPLC analysis were prepared by transferring 1 g of each Formulation 1 and Formulation 2, into two 25 ml_ volumetric flasks. The solutions thus obtained were brought to volume (25 ml_) with acetonitrile.
• Accelerated stability tests are performed by storing a product in stress conditions.
• the accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/122/02, rev 1 ), i.e. by maintaining the product in its container at a temperature of 40 °C ⁇ 2°C and 75% + 5 %RH (Relative Humidity) for six months.
• Formulation 3 0.3% ambroxol solution, comparative formulation prepared in substantial agreement with that of Mucosolvan (100 ml_).
• Formulation 4 0.3% ambroxol solution, as Formulation 3, modified according to the present invention (100 ml_). Table 4
• Formulation A and B correspond to Formulations 2 and 4.
• Formulation C has the composition of the following Table 7.
• pH 6.4 Formulations A to C were subjected to a test to verify the preservative properties.
• the test for efficacy of anti-microbial preservation was performed in accordance with the EU Ph. 6.6, ⁇ 5.1 .3.
• the test verified that the limits related to the concentration of bacteria and fungi in oral preparations were in accordance with Table 5.1 .3-3 of the European Pharmacopoeia.
• Formulations A to C demonstrated that the preservative properties of the preparations were maintained, although the absence of a specific excipient acting as preservative agent.

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• 2011
  • 2011-12-22 AR ARP110104880A patent/AR084537A1/es not_active Application Discontinuation
  • 2011-12-22 KR KR1020137013725A patent/KR20130140042A/ko not_active Application Discontinuation
  • 2011-12-22 NZ NZ609742A patent/NZ609742A/en not_active IP Right Cessation
  • 2011-12-22 MX MX2013005500A patent/MX2013005500A/es not_active Application Discontinuation
  • 2011-12-22 CN CN2011800583550A patent/CN103269685A/zh active Pending
  • 2011-12-22 BR BR112013012815A patent/BR112013012815A2/pt not_active Application Discontinuation
  • 2011-12-22 CA CA2817453A patent/CA2817453A1/en not_active Abandoned
  • 2011-12-22 EA EA201300535A patent/EA201300535A1/ru unknown
  • 2011-12-22 JP JP2013545397A patent/JP2014503542A/ja active Pending
  • 2011-12-22 EP EP11799722.1A patent/EP2654719A1/en not_active Withdrawn
  • 2011-12-22 WO PCT/EP2011/073754 patent/WO2012085185A1/en active Application Filing
  • 2011-12-22 AU AU2011347257A patent/AU2011347257A1/en not_active Abandoned
• 2013
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