WO2019174755A1 - Oral solutions comprising tramadol and acetaminophen - Google Patents

Oral solutions comprising tramadol and acetaminophen Download PDF

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Publication number
WO2019174755A1
WO2019174755A1 PCT/EP2018/057671 EP2018057671W WO2019174755A1 WO 2019174755 A1 WO2019174755 A1 WO 2019174755A1 EP 2018057671 W EP2018057671 W EP 2018057671W WO 2019174755 A1 WO2019174755 A1 WO 2019174755A1
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Prior art keywords
oral pharmaceutical
solution according
pharmaceutical solution
tramadol
acetaminophen
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PCT/EP2018/057671
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French (fr)
Inventor
Tsampikos Dimitrios PANAGIOTOPOULOS
Soultana Tziala
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Laboserve Pharmaceutical Company S.A.
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Publication of WO2019174755A1 publication Critical patent/WO2019174755A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions

Definitions

  • the present invention relates to oral pharmaceutical solutions comprising as active ingredient tramadol or a pharmaceutically acceptable salt thereof and acetaminophen.
  • Acetaminophen paracetamol or N-(4-hydroxyphenyl)acetamide
  • WO 1995/000133 describes acetaminophen suspensions where sweetening agents such as sugars (e.g. sucrose, glucose, fructose, lactose, and maltose), sugar alcohols (e.g. sorbitol, mannitol and maltitol), natural and semi-refined sweetening agents such as honey and corn syrups, which are mixtures of sugars with other related compounds, polymers of sugars such as maltodextrins, artificial sweeteners such as aspartame and saccharin are used for decreasing the solubility of acetaminophen in an aqueous medium.
  • sweetening agents such as sugars (e.g. sucrose, glucose, fructose, lactose, and maltose), sugar alcohols (e.g. sorbitol, mannitol and maltitol), natural and semi-refined sweetening agents such as honey and corn syrups, which are mixtures of sugars with other related compounds,
  • WO 03/047502 describes liquid formulations in which the bitter active ingredient is dissolved or dispersed in an aqueous medium containing polyvinylpyrrolidone and/or copolyvidone (a copolymer of vinylpyrrolidone and vinyl acetate) and a polyethylene glycol of high molecular weight.
  • the formulations containing acetaminophen are always described as suspensions, and include amounts of sugar sweeteners between 20 and 95 wt.%.
  • the pharmaceutical forms in which the active ingredient is in suspension present various disadvantages connected above all with sedimentation of the dispersed phase over time and with the instability of said dispersion. Sedimentation causes a change in the concentration of the active ingredient within the suspension. This leads to difficulty and uncertainty in the administration of the correct dose of active ingredient, especially bearing in mind that the end users, in particular in the case of elderly patients, do not take care or are not able to shake the container well before use to restore a homogeneous distribution of the active ingredient in the suspension.
  • US 5,154,926 describes a syrup containing 5 mg/ml to 50 mg/ml acetaminophen, 50 mg/ml to 300 mg/ml of a polyol (glycerol, propylene glycol) or a polymer thereof (polyethylene glycols or polypropylene glycols with molecular weight between 300 and 400), 5 mg/ml to 50 mg/ml of a water-soluble macromolecule (polyvinyl pyrrolidones) to reduce the bitterness of the composition, 100 mg/ml to 600 mg/ml sugar sweeteners, and water.
  • a polyol glycerol, propylene glycol
  • a polymer thereof polyethylene glycols or polypropylene glycols with molecular weight between 300 and 400
  • a water-soluble macromolecule polyvinyl pyrrolidones
  • WO 2010/040652 discloses an aqueous solution comprising 20 mg/ml to 40 mg/ml paracetamol, 150 mg/ml to 200 mg/ml polyethylene glycol as solubilizing agent, 3 mg/ml to 5 mg/ml xanthan gum as thickening agent, 0.8 mg/ml to 1.2 mg/ml sucralose, 80 mg/ml to 120 mg/ml glycerol, 80 mg/ml to 120 mg/ml sorbitol and 40 mg/ml to 60 mg/ml xylitol.
  • Acetaminophen is marketed under many brand names worldwide.
  • An example of commercially available oral liquid product is“Vetopar® 500 mg/5ml oral solution” which is marketed in several European countries, and contains 100 mg acetaminophen per 1 ml of solution.
  • This product also contains as excipients citric acid monohydrate, sodium citrate, glycerol, macrogol 400, propylene glycol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, raspberry flavor, saccharin sodium, erythrosine, purified water.
  • T ramadol ((1 RS,2RS)-2-(dimethylaminomethyl)-1 -(3-methoxyphenyl)cyclohexanol) is also a well-established active pharmaceutical ingredient disclosed in US 3,652,589, which is used as a non-narcotic analgesic medicament.
  • Tramadol is mainly used in the form of its hydrochloride salt.
  • Tramadol hydrochloride was launched and marketed as "Tramal®” by the German pharmaceutical company Grunenthal GmbH in 1977 in West Germany, and 20 years later it was launched in countries such as the UK, US, and Australia.
  • the currently commercially available“Tramal® oral drops, solution” contains 100 mg tramadol hydrochloride per 1 ml of solution.
  • Tramal® also contains as excipients potassium sorbate, glycerol, propylene glycol, 200 mg/ml sucrose, sodium cyclamate, saccharin sodium, 1 mg/ml polyoxyl 40 hydrogenated castor oil, mint oil, aniseed flavour and purified water.
  • Tramal® is packaged in a dropper container, consisting of an amber glass bottle with inserted plastic dropper container or in a container with dispenser pump.
  • Tramadol hydrochloride is also marketed under many brand names worldwide.
  • Another example of commercially available oral liquid product is“Tramadol 100 mg/ml oral drops, solution” which is marketed in several European countries, and contains 100 mg tramadol hydrochloride per 1 ml of solution.
  • This product also contains as excipients 200 mg/ml sucrose, saccharin sodium, potassium sorbate, polysorbate 20, aniseed oil, peppermint oil, hydrochloric acid (for pH adjustment) and purified water.
  • This product is packaged in a dropper container, consisting of an amber glass bottle with inserted plastic dropper applicator.
  • the solutions are administered in the form of oral drops, by means of a dropper container.
  • the drops should be diluted with water before administration.
  • the usual dose for adults and children aged 12 and over is 50 mg to 100 mg tramadol (20 to 40 drops), three to four times per day.
  • the maximum allowed dose of Tramadol oral drops is generally 400 mg (160 drops) per day.
  • a starting dose of 100 mg is generally required since the effect begins later than with other pain relievers.
  • oral drops can provide a useful means to administer medicinal products only in low doses or small volumes.
  • alternative measuring devices should be considered where the dose comprises more than 10 drops.
  • tolerable tramadol oral solutions that can be administered without first diluting them with a liquid carrier, since it is considered difficult to effectively taste mask the bad and very bitter taste of tramadol and its pharmaceutically acceptable salts, even at low concentrations.
  • the present invention addresses the problems of the prior art knowledge by advantageously providing an oral pharmaceutical solution which comprises tramadol or a pharmaceutically acceptable salt thereof and acetaminophen and which can be administered without first diluting it with a liquid carrier.
  • the present invention provides an oral pharmaceutical solution comprising as active ingredients tramadol or a pharmaceutically acceptable salt thereof and acetaminophen.
  • the oral pharmaceutical solution according to the invention comprises tramadol or a pharmaceutically acceptable salt thereof in a concentration of 5 mg/ml to 20 mg/ml, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml and a pharmaceutically acceptable liquid carrier.
  • the oral pharmaceutical solution according to the invention comprises from 5 mg/ml to 20 mg/ml tramadol or a pharmaceutically acceptable salt thereof, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml, a solubilizing agent and one or more polyols, wherein the total concentration of polyols is from 50 mg/ml to 175 mg/ml.
  • the oral pharmaceutical solution according to the invention presents excellent taste masking effect while at the same time allows the optimal selection of concentration of taste masking excipients, surfactants or cosolvents at the lowest feasible level.
  • concentration of taste masking excipients, surfactants or cosolvents at the lowest feasible level.
  • the use of these excipients at the lowest feasible level is very important, particularly in the case of formulations intended for paediatric population.
  • the oral pharmaceutical solution according to the invention does not have to be first diluted with a liquid carrier, prior to its administration.
  • the present invention provides an oral pharmaceutical solution comprising tramadol or a pharmaceutically acceptable salt thereof and acetaminophen, in association with a pharmaceutically acceptable liquid carrier.
  • a pharmaceutically acceptable liquid carrier e.g., water soluble saccharides, having sweet taste.
  • sugars include, but are not limited to sucrose, glucose, dextrose, fructose, and galactose.
  • the sugar is high fructose corn syrup.
  • polyol refers to pharmaceutical excipients containing multiple hydroxyl groups, which however are not sugars. Polyols are used as sweeteners and bulking agents. They occur naturally in foods and come from plant products such as fruits and berries. Typical examples of suitable polyols according to the invention are sugar alcohols such as, glycerol, maltitol, sorbitol, xylitol, erythritol, isomalt and lactitol as well as propylene glycol and polyvinyl alcohol.
  • the polyol is glycerol, maltitol, sorbitol or xylitol. More preferably, the polyol is maltitol or xylitol.
  • mg/ml refers to mg of the respective ingredient per 1 ml of the oral solution.
  • the oral pharmaceutical solution according to the invention comprises tramadol or a pharmaceutically acceptable salt thereof in a concentration of 5 mg/ml to 20 mg/ml, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml and a pharmaceutically acceptable liquid carrier.
  • the oral pharmaceutical solution according to the invention further comprises a solubilizing agent and one or more polyols, wherein the total concentration of polyols is from 50 mg/ml to 175 mg/ml.
  • the oral pharmaceutical solution according to the invention comprises one or more polyols, wherein the total concentration of polyols is from 100 mg/ml to 150 mg/ml.
  • the oral pharmaceutical solution according to the invention comprises from 6 mg/ml to 10 mg/ml of tramadol or a pharmaceutically acceptable salt thereof and from 60 mg/ml to 85 mg/ml of acetaminophen. More preferably, the oral pharmaceutical solution according to the invention comprises 7.5 of tramadol or a pharmaceutically acceptable salt thereof and 65 mg/ml of acetaminophen.
  • the solubilizing agent comprises, amongst others, low molecular weight polyethylene glycols i.e. liquid polyethylene glycols with average molecular weight lower than 600 and any combination thereof. More preferably, the solubilizing agent is polyethylene glycol 400.
  • the oral pharmaceutical solution according to the invention comprises 50 mg/ml to 100 mg/ml polyethylene glycol 400.
  • the pharmaceutically acceptable liquid carrier according to the invention comprises water.
  • the oral pharmaceutical solution according to the invention comprises as active ingredients tramadol hydrochloride and acetaminophen.
  • the oral pharmaceutical solution according to the invention optionally comprises one or more sugars, wherein the total concentration of sugars is lower than 100 mg/ml.
  • the oral pharmaceutical solution according to the invention is free of sugars.
  • the oral pharmaceutical solution according to the invention is also free of essential oils.
  • the oral pharmaceutical solution according to the invention is also free of essential oils, polyvinylpyrrolidone and/or copolyvidone, polyethylene glycols with molecular weight of at least 900 and xanthan gum.
  • the oral pharmaceutical solution according to the invention presents excellent taste- masking effect while at the same time allows the optimal selection of concentration of taste-masking excipients as well as non-ionic surfactants and solubilizing agents at the lowest feasible level.
  • the oral pharmaceutical solution of tramadol or its pharmaceutically acceptable salt and acetaminophen, according to the invention may also comprise additional excipients commonly used in preparing oral liquid compositions, such as antimicrobial preservatives, antioxidants, buffering agents, sweeteners and flavouring agents.
  • Antimicrobial preservatives may include but are not limited to sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts thereof, benzyl alcohol, parahydroxybenzoic acids and their alkyl esters, methyl, ethyl and propyl parahydroxybenzoates and their salts or mixtures thereof.
  • Antioxidants which may be used in the present invention comprise, amongst others, butylated hydroxytoluene, butylated hydroxyanisole, ethylenediamine tetraacetic acid (“EDTA”), ascorbic acid, sodium metabisulfite and propyl gallate or any combinations thereof.
  • EDTA ethylenediamine tetraacetic acid
  • ascorbic acid sodium metabisulfite and propyl gallate or any combinations thereof.
  • Buffering agents may include but are not limited to ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, sodium citrate, potassium citrate, sodium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, carbonated calcium phosphate, magnesium hydroxide or mixtures thereof.
  • Sweeteners may include but are not limited to aspartame, acesulfame potassium, thaumatin, saccharin and salts thereof, sodium cyclamate, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate or mixtures thereof.
  • Flavouring agents may include but are not limited to fruit flavours such as orange, banana, strawberry, cherry, wild cherry, lemon and the like and other flavourings, such as cardamom, anise, mint, menthol, vanillin, bubble gum or mixtures thereof.
  • the oral pharmaceutical solution according to the invention may be supplied as multidose preparation.
  • Each dose from a multidose container may be administered by means of a device suitable for accurately measuring the prescribed volume.
  • the device is usually a spoon or a cup for volumes of 5 ml. or multiples thereof, or an oral syringe for other volumes.
  • the device is an oral syringe.
  • the present invention provides an oral solution comprising tramadol or a pharmaceutically acceptable salt thereof and acetaminophen for use in a method of treatment wherein the solution is orally administered without first diluting it in a liquid carrier.
  • the oral pharmaceutical solution of the present invention may be prepared using methods well known in the prior art and using regular manufacturing equipment. For example, it may be prepared using the following process:
  • Purified water is added into a vessel.
  • the solubilizing agent and the preservatives are dissolved in purified water heated to 35 - 40°C.
  • Acetaminophen is added into the vessel under continuous stirring.
  • the temperature of the resultant solution is lowered to 25°C, then the polyols and the remaining taste masking agents are added into the vessel under continuous stirring.
  • Tramadol or its pharmaceutically acceptable salt is added under continuous stirring.
  • the pH of the solution formed in the previous step is adjusted to 5.5 - 7.0 with the addition of buffering solution. Finally, the volume is adjusted with purified water.
  • the final solution is optionally filtered over a 10 pm filter, and filled preferably in light-protective containers, such as amber type III glass 50 or 100 ml bottles sealed with child resistant, tamper evident screw caps.
  • light-protective containers such as amber type III glass 50 or 100 ml bottles sealed with child resistant, tamper evident screw caps.
  • composition A1 acetaminophen
  • the tramadol hydrochloride & acetaminophen compositions were then prepared in the following manner: Purified water was added into a vessel. Polyoxyl 40 hydrogenated castor oil, propylene glycol and potassium sorbate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then glycerol, sucrose, sodium cyclamate, sodium saccharin, mint oil and flavour were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
  • composition A1 found to be unacceptable resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
  • the solutions were also studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen.
  • the flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All solutions were administered by means of a cup and they were administered directly into mouth and swallowed i.e. without first diluting them with a liquid carrier prior to their administration.
  • Table 2 Volume administered Five out of five judges preferred composition A2 to composition A1 since they all noticed that the bitter aftertaste was more intense in case of A1.
  • composition A2 provides for the administration of the same dose a higher and more consistent palatability effect than solutions comprising lower or higher concentrations of tramadol hydrochloride and acetaminophen. It is assumed that bigger volumes give rise to a bitter aftertaste since some of the bitter tasting active ingredients is retained in the mouth long enough to contact the taste buds of the tongue.
  • a liquid carrier comprising high concentrations of taste masking agents such as sucrose, polyols, essential oils or sweeteners seems to magnify this unacceptable aftertaste effect.
  • composition AT the palatability and acceptability of compositions similar to those disclosed in WO 2010/040652 (i.e. composition AT), also including tramadol hydrochloride.
  • the tramadol hydrochloride & acetaminophen compositions were prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 6000 and sodium sorbate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then xanthan gum, glycerol, sorbitol, xylitol and sucralose were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The flavour was then added under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
  • composition A1’ found to be unacceptable resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
  • compositions were also studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen.
  • the flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All compositions were administered by means of a cup and they were administered directly into mouth and swallowed i.e. without first diluting them with a liquid carrier prior to their administration.
  • Table 4 Volume administered Five out of five judges preferred composition A2’ to composition AT since they all noticed that the bitter aftertaste was more intense in case of AT.
  • composition A2’ provides for the administration of the same dose a higher and more consistent palatability effect than solutions comprising lower or higher concentrations of tramadol hydrochloride and acetaminophen.
  • composition A1 commercial“Vetopar 500 mg/5ml oral solution” product
  • composition A1 also including tramadol hydrochloride.
  • the tramadol hydrochloride & acetaminophen compositions were then prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 400 and sodium methyl parahydroxybenzoate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then propylene glycol, glycerol and sodium saccharin were added and dissolved.
  • Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution.
  • the flavour was then added under continuous stirring until complete dissolution.
  • the pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
  • composition A1 found to be unacceptable resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
  • compositions were studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen.
  • the flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All compositions were administered by means of a cup and they were administered directly into mouth and swallowed i.e. without first diluting them with a liquid carrier prior to their administration.
  • composition A2 provides for the administration of the same dose a higher and more consistent palatability effect than solutions comprising lower or higher concentrations of tramadol hydrochloride and acetaminophen.
  • the tramadol hydrochloride & acetaminophen compositions of this example were prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 400 and potassium sorbate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then propylene glycol, glycerol, sorbitol and sodium saccharin were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The flavour was then added under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water. Table 7
  • compositions were studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen.
  • the flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis.
  • the solutions according to the invention i.e. B1 , B2 & B3 present excellent taste masking effect while at the same time allows the optimal selection of concentration of taste masking excipients, surfactants or cosolvents at the lowest feasible level.
  • Table 10 shows preferred oral solution compositions according to the present invention.

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Abstract

Oral pharmaceutical solution comprising tramadol or a pharmaceutically acceptable salt thereof in a concentration of 5 mg/ml to 20 mg/ml, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml and a pharmaceutically acceptable liquid carrier. The oral pharmaceutical solution does not have to be first diluted with a liquid carrier, prior to its administration.

Description

ORAL SOLUTIONS COMPRISING TRAMADOL AND ACETAMINOPHEN
FIELD OF THE INVENTION
The present invention relates to oral pharmaceutical solutions comprising as active ingredient tramadol or a pharmaceutically acceptable salt thereof and acetaminophen.
BACKGROUND OF THE INVENTION
Acetaminophen (paracetamol or N-(4-hydroxyphenyl)acetamide) is a well established therapeutic agent having both analgesic and antipyretic activity. Acetaminophen' s relatively poor solubility in water and its bitter taste, however, make it difficult to formulate into consumer acceptable oral liquid dosage forms.
WO 1995/000133 describes acetaminophen suspensions where sweetening agents such as sugars (e.g. sucrose, glucose, fructose, lactose, and maltose), sugar alcohols (e.g. sorbitol, mannitol and maltitol), natural and semi-refined sweetening agents such as honey and corn syrups, which are mixtures of sugars with other related compounds, polymers of sugars such as maltodextrins, artificial sweeteners such as aspartame and saccharin are used for decreasing the solubility of acetaminophen in an aqueous medium.
WO 03/047502 describes liquid formulations in which the bitter active ingredient is dissolved or dispersed in an aqueous medium containing polyvinylpyrrolidone and/or copolyvidone (a copolymer of vinylpyrrolidone and vinyl acetate) and a polyethylene glycol of high molecular weight. The formulations containing acetaminophen are always described as suspensions, and include amounts of sugar sweeteners between 20 and 95 wt.%.
However, it is generally preferable to administer liquid pharmaceutical forms in which the active ingredient is completely dissolved; the pharmaceutical forms in which the active ingredient is in suspension present various disadvantages connected above all with sedimentation of the dispersed phase over time and with the instability of said dispersion. Sedimentation causes a change in the concentration of the active ingredient within the suspension. This leads to difficulty and uncertainty in the administration of the correct dose of active ingredient, especially bearing in mind that the end users, in particular in the case of elderly patients, do not take care or are not able to shake the container well before use to restore a homogeneous distribution of the active ingredient in the suspension.
US 5,154,926 describes a syrup containing 5 mg/ml to 50 mg/ml acetaminophen, 50 mg/ml to 300 mg/ml of a polyol (glycerol, propylene glycol) or a polymer thereof (polyethylene glycols or polypropylene glycols with molecular weight between 300 and 400), 5 mg/ml to 50 mg/ml of a water-soluble macromolecule (polyvinyl pyrrolidones) to reduce the bitterness of the composition, 100 mg/ml to 600 mg/ml sugar sweeteners, and water.
WO 2010/040652 discloses an aqueous solution comprising 20 mg/ml to 40 mg/ml paracetamol, 150 mg/ml to 200 mg/ml polyethylene glycol as solubilizing agent, 3 mg/ml to 5 mg/ml xanthan gum as thickening agent, 0.8 mg/ml to 1.2 mg/ml sucralose, 80 mg/ml to 120 mg/ml glycerol, 80 mg/ml to 120 mg/ml sorbitol and 40 mg/ml to 60 mg/ml xylitol.
Acetaminophen is marketed under many brand names worldwide. An example of commercially available oral liquid product is“Vetopar® 500 mg/5ml oral solution” which is marketed in several European countries, and contains 100 mg acetaminophen per 1 ml of solution. This product also contains as excipients citric acid monohydrate, sodium citrate, glycerol, macrogol 400, propylene glycol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, raspberry flavor, saccharin sodium, erythrosine, purified water.
T ramadol ((1 RS,2RS)-2-(dimethylaminomethyl)-1 -(3-methoxyphenyl)cyclohexanol) is also a well-established active pharmaceutical ingredient disclosed in US 3,652,589, which is used as a non-narcotic analgesic medicament. Tramadol is mainly used in the form of its hydrochloride salt.
Tramadol hydrochloride was launched and marketed as "Tramal®" by the German pharmaceutical company Grunenthal GmbH in 1977 in West Germany, and 20 years later it was launched in countries such as the UK, US, and Australia. The currently commercially available“Tramal® oral drops, solution”, contains 100 mg tramadol hydrochloride per 1 ml of solution. Tramal® also contains as excipients potassium sorbate, glycerol, propylene glycol, 200 mg/ml sucrose, sodium cyclamate, saccharin sodium, 1 mg/ml polyoxyl 40 hydrogenated castor oil, mint oil, aniseed flavour and purified water. Tramal® is packaged in a dropper container, consisting of an amber glass bottle with inserted plastic dropper container or in a container with dispenser pump.
Tramadol hydrochloride is also marketed under many brand names worldwide. Another example of commercially available oral liquid product is“Tramadol 100 mg/ml oral drops, solution” which is marketed in several European countries, and contains 100 mg tramadol hydrochloride per 1 ml of solution. This product also contains as excipients 200 mg/ml sucrose, saccharin sodium, potassium sorbate, polysorbate 20, aniseed oil, peppermint oil, hydrochloric acid (for pH adjustment) and purified water. This product is packaged in a dropper container, consisting of an amber glass bottle with inserted plastic dropper applicator.
According, to the Patient Information Leaflet (PIL) of marketed tramadol hydrochloride oral liquid products, the solutions are administered in the form of oral drops, by means of a dropper container. Importantly, the drops should be diluted with water before administration. The usual dose for adults and children aged 12 and over is 50 mg to 100 mg tramadol (20 to 40 drops), three to four times per day. The maximum allowed dose of Tramadol oral drops is generally 400 mg (160 drops) per day. For acute pain, a starting dose of 100 mg is generally required since the effect begins later than with other pain relievers.
However, according to the“Guideline on pharmaceutical development of medicines for paediatric use” of the European Medicines Agency, oral drops can provide a useful means to administer medicinal products only in low doses or small volumes. Importantly, according to the guideline there is a risk of counting the incorrect number of drops, and the accuracy and precision of the volume administered should always be justified in relation to the criticality of the dose. In order to avoid counting errors, alternative measuring devices should be considered where the dose comprises more than 10 drops. Apparently, this lack of convenience due to excessive number of drops required to deliver the extremely high doses of tramadol, as well as due to the rather inconvenient reconstitution procedure, may result in high incidence of non- compliance and ineffective therapy.
Thus, as a means of both ensuring flexibility in dose titration and advanced patient compliance, the development of oral pharmaceutical solutions which may also be administered by means of a device suitable for accurately measuring the prescribed volume, such as an oral syringe, a spoon or a cup, and which may also be administered without first diluting them with a liquid carrier, is definitely an existing need.
However, it is extremely challenging to formulate tolerable tramadol oral solutions that can be administered without first diluting them with a liquid carrier, since it is considered difficult to effectively taste mask the bad and very bitter taste of tramadol and its pharmaceutically acceptable salts, even at low concentrations.
According, for example, to US 6,723,343 despite the excellent efficacy of tramadol in pain control, the active ingredient tramadol and its readily soluble salts have an intensely bitter taste. As a consequence, available formulations of tramadol are poorly accepted and patients fail to observe the dosage instructions.
In these cases, the prior art indicates that high concentrations of taste masking agents such as sucrose, sugar alcohols, essential oils and sweeteners are necessary for masking the bitterness of the active ingredient. But even such high quantities are not proved sufficient to provide an effectively taste masked formulation. Thus, tramadol or its pharmaceutically acceptable salts are inevitably formulated in the form of oral drops that should be first diluted with a liquid carrier, such as water, prior to their administration.
Therefore, it is considered even more challenging to develop palatable oral solutions of the combination of tramadol or its pharmaceutical acceptable salts and acetaminophen since both active ingredients are extremely bitter and especially acetaminophen exhibits high solubility problems. The present invention addresses the problems of the prior art knowledge by advantageously providing an oral pharmaceutical solution which comprises tramadol or a pharmaceutically acceptable salt thereof and acetaminophen and which can be administered without first diluting it with a liquid carrier.
SUMMARY OF THE INVENTION
The present invention provides an oral pharmaceutical solution comprising as active ingredients tramadol or a pharmaceutically acceptable salt thereof and acetaminophen.
The oral pharmaceutical solution according to the invention comprises tramadol or a pharmaceutically acceptable salt thereof in a concentration of 5 mg/ml to 20 mg/ml, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml and a pharmaceutically acceptable liquid carrier.
Preferably, the oral pharmaceutical solution according to the invention comprises from 5 mg/ml to 20 mg/ml tramadol or a pharmaceutically acceptable salt thereof, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml, a solubilizing agent and one or more polyols, wherein the total concentration of polyols is from 50 mg/ml to 175 mg/ml.
The oral pharmaceutical solution according to the invention presents excellent taste masking effect while at the same time allows the optimal selection of concentration of taste masking excipients, surfactants or cosolvents at the lowest feasible level. The use of these excipients at the lowest feasible level is very important, particularly in the case of formulations intended for paediatric population.
The oral pharmaceutical solution according to the invention does not have to be first diluted with a liquid carrier, prior to its administration.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an oral pharmaceutical solution comprising tramadol or a pharmaceutically acceptable salt thereof and acetaminophen, in association with a pharmaceutically acceptable liquid carrier. As used throughout this description and claims, the term "sugar" refers to water soluble saccharides, having sweet taste. Examples of sugars include, but are not limited to sucrose, glucose, dextrose, fructose, and galactose. Preferably, the sugar is high fructose corn syrup.
As used throughout this description and claims, the term“polyol” (polyhydric alcohol) refers to pharmaceutical excipients containing multiple hydroxyl groups, which however are not sugars. Polyols are used as sweeteners and bulking agents. They occur naturally in foods and come from plant products such as fruits and berries. Typical examples of suitable polyols according to the invention are sugar alcohols such as, glycerol, maltitol, sorbitol, xylitol, erythritol, isomalt and lactitol as well as propylene glycol and polyvinyl alcohol. Preferably, the polyol is glycerol, maltitol, sorbitol or xylitol. More preferably, the polyol is maltitol or xylitol.
The term“mg/ml” refers to mg of the respective ingredient per 1 ml of the oral solution.
In the prior art, attempts have been made to mitigate or reduce the bad and very bitter taste and aftertaste imparted by tramadol and its pharmaceutically acceptable salts and by acetaminophen when taken in the form of an oral liquid. These attempts include use of taste masking agents such as sucrose, sugar alcohols, essential oils and sweeteners in relatively high concentrations or reformulation of tramadol or its pharmaceutically acceptable salts in extremely low concentrations.
The inefficient use of high quantities of taste masking agents in the oral liquid formulations described in the prior art, proved not only insufficient to effectively taste mask the bitter taste and aftertaste of tramadol or its pharmaceutically acceptable salts and acetaminophen so that to be feasible for these oral liquids to be administered without diluting them with a liquid carrier prior to their administration, but also proved to overwhelm bitterness with an unpleasant sweetness.
Now, it has been unexpectedly found that extremely low concentrations of tramadol or its pharmaceutically acceptable salts and acetaminophen cannot be administered in the form of an oral solution without first diluting it with a liquid carrier. It is assumed that the bigger volumes of solution required in this case to be administered directly to mouth give rise to a bitterer aftertaste that lasts longer, since some of the bitter tasting active ingredients are retained in the mouth long enough to contact the taste buds of the tongue. In this case, the relatively high concentrations of taste masking agents that are necessary for masking the bitterness of the bitter tasting active ingredients cause a negative effect on solubility, resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
Hence, disclosed herein is the unexpected finding that, for the administration of a specific dose, oral solutions in a certain concentration range of tramadol or its pharmaceutically acceptable salts and acetaminophen provide, an improved palatability effect compared to solutions comprising tramadol or a pharmaceutically acceptable salt thereof and acetaminophen outside this concentration range. This unexpected finding allows on the one hand the use of lower concentrations of excipients, including taste masking agents and solubilizing agents, and on the other hand allows the administration of the solutions without first diluting them with a liquid carrier.
The oral pharmaceutical solution according to the invention comprises tramadol or a pharmaceutically acceptable salt thereof in a concentration of 5 mg/ml to 20 mg/ml, acetaminophen in a concentration of 50 mg/ml to 100 mg/ml and a pharmaceutically acceptable liquid carrier.
Preferably, the oral pharmaceutical solution according to the invention further comprises a solubilizing agent and one or more polyols, wherein the total concentration of polyols is from 50 mg/ml to 175 mg/ml.
More preferably, the oral pharmaceutical solution according to the invention comprises one or more polyols, wherein the total concentration of polyols is from 100 mg/ml to 150 mg/ml.
Preferably, the oral pharmaceutical solution according to the invention comprises from 6 mg/ml to 10 mg/ml of tramadol or a pharmaceutically acceptable salt thereof and from 60 mg/ml to 85 mg/ml of acetaminophen. More preferably, the oral pharmaceutical solution according to the invention comprises 7.5 of tramadol or a pharmaceutically acceptable salt thereof and 65 mg/ml of acetaminophen.
Preferably, the solubilizing agent comprises, amongst others, low molecular weight polyethylene glycols i.e. liquid polyethylene glycols with average molecular weight lower than 600 and any combination thereof. More preferably, the solubilizing agent is polyethylene glycol 400.
Preferably, the oral pharmaceutical solution according to the invention comprises 50 mg/ml to 100 mg/ml polyethylene glycol 400.
Preferably, the pharmaceutically acceptable liquid carrier according to the invention comprises water.
Preferably, the oral pharmaceutical solution according to the invention comprises as active ingredients tramadol hydrochloride and acetaminophen.
The oral pharmaceutical solution according to the invention optionally comprises one or more sugars, wherein the total concentration of sugars is lower than 100 mg/ml. Preferably, the oral pharmaceutical solution according to the invention is free of sugars.
Lower concentrations or even absence of sugars, essential oils, polyvinylpyrrolidone and/or copolyvidone, polyethylene glycols with molecular weight of at least 900 and xanthan gum relieve the oral solutions of the“heavy” oily texture, disagreeable “syrupy” mouthfeel which is prominent in the solutions described in the prior art. It is assumed that lower concentrations or even absence of these excipients, which increase the viscosity of the solution, helps bitter tasting tramadol or its pharmaceutically acceptable salts and/or acetaminophen to be retained less time in the mouth.
Thus, in a preferred embodiment, the oral pharmaceutical solution according to the invention is also free of essential oils. In a preferred embodiment, the oral pharmaceutical solution according to the invention is also free of essential oils, polyvinylpyrrolidone and/or copolyvidone, polyethylene glycols with molecular weight of at least 900 and xanthan gum.
The oral pharmaceutical solution according to the invention presents excellent taste- masking effect while at the same time allows the optimal selection of concentration of taste-masking excipients as well as non-ionic surfactants and solubilizing agents at the lowest feasible level.
The oral pharmaceutical solution of tramadol or its pharmaceutically acceptable salt and acetaminophen, according to the invention may also comprise additional excipients commonly used in preparing oral liquid compositions, such as antimicrobial preservatives, antioxidants, buffering agents, sweeteners and flavouring agents.
Antimicrobial preservatives may include but are not limited to sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts thereof, benzyl alcohol, parahydroxybenzoic acids and their alkyl esters, methyl, ethyl and propyl parahydroxybenzoates and their salts or mixtures thereof.
Antioxidants which may be used in the present invention comprise, amongst others, butylated hydroxytoluene, butylated hydroxyanisole, ethylenediamine tetraacetic acid ("EDTA"), ascorbic acid, sodium metabisulfite and propyl gallate or any combinations thereof.
Buffering agents may include but are not limited to ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, sodium citrate, potassium citrate, sodium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, carbonated calcium phosphate, magnesium hydroxide or mixtures thereof.
Sweeteners may include but are not limited to aspartame, acesulfame potassium, thaumatin, saccharin and salts thereof, sodium cyclamate, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate or mixtures thereof. Flavouring agents may include but are not limited to fruit flavours such as orange, banana, strawberry, cherry, wild cherry, lemon and the like and other flavourings, such as cardamom, anise, mint, menthol, vanillin, bubble gum or mixtures thereof.
The oral pharmaceutical solution according to the invention may be supplied as multidose preparation. Each dose from a multidose container may be administered by means of a device suitable for accurately measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml. or multiples thereof, or an oral syringe for other volumes. Preferably, the device is an oral syringe.
In a preferred embodiment, the present invention provides an oral solution comprising tramadol or a pharmaceutically acceptable salt thereof and acetaminophen for use in a method of treatment wherein the solution is orally administered without first diluting it in a liquid carrier.
The oral pharmaceutical solution of the present invention may be prepared using methods well known in the prior art and using regular manufacturing equipment. For example, it may be prepared using the following process:
Purified water is added into a vessel. The solubilizing agent and the preservatives are dissolved in purified water heated to 35 - 40°C. Acetaminophen is added into the vessel under continuous stirring. The temperature of the resultant solution is lowered to 25°C, then the polyols and the remaining taste masking agents are added into the vessel under continuous stirring. Tramadol or its pharmaceutically acceptable salt is added under continuous stirring. The pH of the solution formed in the previous step is adjusted to 5.5 - 7.0 with the addition of buffering solution. Finally, the volume is adjusted with purified water.
The final solution is optionally filtered over a 10 pm filter, and filled preferably in light-protective containers, such as amber type III glass 50 or 100 ml bottles sealed with child resistant, tamper evident screw caps. EXAMPLES
EXAMPLE 1
The purpose of this experiment was to evaluate the palatability and acceptability of compositions similar to commercial “Tramal® oral drops, solution” product (i.e. composition A1 ), also including acetaminophen.
The quantitative composition of commercial“Tramal® oral drops, solution” product was approached by a set of laboratory studies, including inter alia an HPLC measurement for assessing the concentration of propylene glycol, potassium sorbate and glycerol as well as organoleptic tests for the assessment of the concentration of the remaining flavouring and sweetening agents. Information regarding concentration of sucrose and polyoxyl 40 hydrogenated castor oil is publically available through the SmPC of the product.
The tramadol hydrochloride & acetaminophen compositions were then prepared in the following manner: Purified water was added into a vessel. Polyoxyl 40 hydrogenated castor oil, propylene glycol and potassium sorbate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then glycerol, sucrose, sodium cyclamate, sodium saccharin, mint oil and flavour were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
Table 1
Figure imgf000012_0001
Figure imgf000013_0001
Interestingly, composition A1 found to be unacceptable resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
The solutions were also studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen. The flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All solutions were administered by means of a cup and they were administered directly into mouth and swallowed i.e. without first diluting them with a liquid carrier prior to their administration.
Table 2: Volume administered
Figure imgf000013_0002
Five out of five judges preferred composition A2 to composition A1 since they all noticed that the bitter aftertaste was more intense in case of A1.
Moreover, five out of five judges also preferred composition A2 to compositions A3 respectively since they all noticed that the intense bitter aftertaste last longer in case of A3 probably due to bigger volume of solution required to be administered directly to mouth. Thus, it has been surprisingly found that composition A2 provides for the administration of the same dose a higher and more consistent palatability effect than solutions comprising lower or higher concentrations of tramadol hydrochloride and acetaminophen. It is assumed that bigger volumes give rise to a bitter aftertaste since some of the bitter tasting active ingredients is retained in the mouth long enough to contact the taste buds of the tongue. A liquid carrier comprising high concentrations of taste masking agents such as sucrose, polyols, essential oils or sweeteners seems to magnify this unacceptable aftertaste effect.
EXAMPLE 2
The purpose of this experiment was to evaluate the palatability and acceptability of compositions similar to those disclosed in WO 2010/040652 (i.e. composition AT), also including tramadol hydrochloride.
The tramadol hydrochloride & acetaminophen compositions were prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 6000 and sodium sorbate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then xanthan gum, glycerol, sorbitol, xylitol and sucralose were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The flavour was then added under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
Table 3
Figure imgf000014_0001
Figure imgf000015_0001
Interestingly, composition A1’ found to be unacceptable resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
The compositions were also studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen. The flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All compositions were administered by means of a cup and they were administered directly into mouth and swallowed i.e. without first diluting them with a liquid carrier prior to their administration.
Table 4: Volume administered
Figure imgf000015_0002
Five out of five judges preferred composition A2’ to composition AT since they all noticed that the bitter aftertaste was more intense in case of AT.
Moreover, five out of five judges also preferred composition A2’ to compositions A3’ respectively since they all noticed that the intense bitter aftertaste last longer in case of A3’ probably due to bigger volume of solution required to be administered directly to mouth. Thus, it has been surprisingly found that composition A2’ provides for the administration of the same dose a higher and more consistent palatability effect than solutions comprising lower or higher concentrations of tramadol hydrochloride and acetaminophen.
EXAMPLE 3
The purpose of this experiment was to evaluate the palatability and acceptability of compositions similar to commercial“Vetopar 500 mg/5ml oral solution” product (i.e. composition A1”), also including tramadol hydrochloride. The tramadol hydrochloride & acetaminophen compositions were then prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 400 and sodium methyl parahydroxybenzoate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then propylene glycol, glycerol and sodium saccharin were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The flavour was then added under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
Table 5
Figure imgf000016_0001
Interestingly, composition A1” found to be unacceptable resulting in the formation of a suspension, with the presence of visible particles that become apparent upon production.
The compositions were studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen. The flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All compositions were administered by means of a cup and they were administered directly into mouth and swallowed i.e. without first diluting them with a liquid carrier prior to their administration.
Table 6: Volume administered
Figure imgf000017_0001
Five out of five judges preferred composition A2” to composition A1” since they all noticed that the bitter aftertaste was more intense in case of A1”.
Moreover, five out of five judges also preferred composition A2” to compositions A3” respectively since they all noticed that the intense bitter aftertaste last longer in case of A3” probably due to bigger volume of solution required to be administered directly to mouth. Thus, it has been surprisingly found that composition A2” provides for the administration of the same dose a higher and more consistent palatability effect than solutions comprising lower or higher concentrations of tramadol hydrochloride and acetaminophen.
EXAMPLE 4
The tramadol hydrochloride & acetaminophen compositions of this example were prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 400 and potassium sorbate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then propylene glycol, glycerol, sorbitol and sodium saccharin were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The flavour was then added under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water. Table 7
Figure imgf000018_0001
The compositions were studied in relation to their aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen. The flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis.
The descriptive analysis methodology adopted in this case is characterized in the following Table 8. The test results are illustrated in the following Table 9.
Table 8: Flavour scale
Figure imgf000018_0002
It is mentioned that, although a sweet aftertaste intensity lower than 12.0 is considered acceptable, when it is greater than 12.0 a rather disagreeable“syrupy” mouthfeel is revealed. Table 9
Figure imgf000019_0001
Interestingly, when the concentrations of tramadol hydrochloride and acetaminophen are as low as 3.75 mg/ml and 32.5 mg/ml and a solution volume of 20 ml is required to be administered directly to mouth, it gives rise to a bitter aftertaste since some of the bitter tasting active ingredient is retained in the mouth long enough to contact the taste buds of the tongue.
On the other hand the solutions according to the invention i.e. B1 , B2 & B3 present excellent taste masking effect while at the same time allows the optimal selection of concentration of taste masking excipients, surfactants or cosolvents at the lowest feasible level.
EXAMPLE 5
Table 10 shows preferred oral solution compositions according to the present invention.
These solutions were prepared in the following manner: Purified water was added into a vessel. Polyethylene glycol 400 and sodium methyl parahydroxybenzoate were dissolved in purified water heated to 35 - 40°C. Acetaminophen was added into the vessel under continuous stirring. The temperature of the resultant solution was lowered to 25°C, then maltitol, xylitol, sodium saccharin and sucralose (for composition I) or maltitol, sodium saccharin and sucralose (for composition II) or maltitol, sucrose, sucralose and sodium saccharin (for composition III) were added and dissolved. Tramadol hydrochloride was added to the clear solution under continuous stirring until complete dissolution. The flavour was then added under continuous stirring until complete dissolution. The pH of the solution was then adjusted to 5.5 - 7.0 with aqueous citric acid / sodium citrate solution. Finally, the volume was adjusted with purified water.
Table 10
Figure imgf000020_0001
The solutions were studied in relation to their basic taste and aftertaste after the administration of 75 mg tramadol hydrochloride and 650 mg acetaminophen. The flavor test results were based on the analysis of five trained judges who are experienced in detailed flavor analysis. All solutions were administered by means of an oral syringe and they were administered directly into mouth and swallowed, without first diluting them with a liquid carrier prior to their administration. The descriptive analysis methodology adopted is characterized in Table 8 of Example 4. The test results are illustrated in the following Table 11.
Table 11
Figure imgf000021_0001

Claims

1. Oral pharmaceutical solution comprising from 5 mg/ml to 20 mg/ml tramadol or a pharmaceutically acceptable salt thereof, from 50 mg/ml to 100 mg/ml acetaminophen and a pharmaceutically acceptable liquid carrier.
2. Oral pharmaceutical solution according to claim 1 , further comprising a solubilizing agent and one or more polyols, wherein the total concentration of polyols is from 50 mg/ml to 175 mg/ml.
3. Oral pharmaceutical solution according to claim 2, wherein the total concentration of polyols is from 100 mg/ml to 150 mg/ml.
4. Oral pharmaceutical solution according to claim 2 or 3, wherein the one or more polyols are selected from sugar alcohols, propylene glycol and polyvinyl alcohol.
5. Oral pharmaceutical solution according to any one of claims 2 to 4, wherein the one or more polyols are selected from glycerol, maltitol, sorbitol, xylitol, erythritol, isomalt and lactitol.
6. Oral pharmaceutical solution according to any one of claims 2 or 5, wherein the one or more polyols are selected from glycerol, maltitol, sorbitol and xylitol.
7. Oral pharmaceutical solution according to any one of claims 2 to 6, wherein the one or more polyols are selected from maltitol and xylitol.
8. Oral pharmaceutical solution according to any one of claims 1 to 7, wherein the concentration of tramadol or the pharmaceutically acceptable salt thereof is from 6 mg/ml to 10 mg/ml and the concentration of acetaminophen is from 60 mg/ml to 85 mg/ml.
9. Oral pharmaceutical solution according to any one of claims 1 to 8, wherein the concentration of tramadol or the pharmaceutically acceptable salt thereof is 7.5 mg/ml and the concentration of acetaminophen is from 65 mg/ml.
10. Oral pharmaceutical solution according to any one of claims 1 to 9, wherein the pharmaceutically acceptable salt of tramadol is tramadol hydrochloride.
1 1. Oral pharmaceutical solution according to any one of claims 2 to 10, wherein the solubilizing agent comprises a polyethylene glycol with average molecular weight lower than 600.
12. Oral pharmaceutical solution according to any one of claims 2 to 1 1 , wherein the solubilizing agent is polyethylene glycol 400.
13. Oral pharmaceutical solution according to any one of claims 1 to 12, comprising 50 mg/ml to 100 mg/ml polyethylene glycol 400.
14. Oral pharmaceutical solution according to any of claims 1 to 13, wherein the solution comprises one or more sugars in a total concentration which is lower than 100 mg/ml, or wherein the solution is free of sugars.
15. Oral pharmaceutical solution according to claim 14, wherein the solution is free of sugars.
16. Oral pharmaceutical solution according to claim 14 or 15, wherein the one or more sugars are selected from sucrose, glucose, dextrose, fructose and galactose.
17. Oral pharmaceutical solution according to any one of claims 1 to 16, wherein the solution is free of essential oils, polyvinylpyrrolidone, copolyvidone, polyethylene glycols with molecular weight of at least 900 and xanthan gum.
18. Oral pharmaceutical solution according to any one of claims 1 to 17, wherein the pharmaceutically acceptable liquid carrier comprises water.
19. Oral pharmaceutical solution according to any of claims 1 to 18, for use in a method of treatment wherein the solution is orally administered without first diluting it with a liquid carrier.
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WO2021092406A1 (en) * 2019-11-08 2021-05-14 Athena Bioscience, Llc Tramadol hydrochloride solution
US11103452B2 (en) * 2019-11-08 2021-08-31 Athena Bioscience, Llc Tramadol hydrochloride solution
US11752103B2 (en) 2019-11-08 2023-09-12 Athena Bioscience, Llc Tramadol hydrochloride solution
CN111840227A (en) * 2020-08-31 2020-10-30 陕西九州制药有限责任公司 Oral emulsion of tromethamine and its preparation method
CN111840227B (en) * 2020-08-31 2022-02-22 陕西九州制药有限责任公司 Oral emulsion of tromethamine and its preparation method

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