ES2796370T3 - Aqueous pharmaceutical formulation of tapentadol for oral administration - Google Patents

Abstract

An aqueous pharmaceutical composition that contains tapentadol or a physiologically acceptable salt thereof and that is adapted for oral administration, where the composition additionally contains a preservative, where the preservative content is at most 90% of the content that would be necessary according to the Pharmacopoeia European in order to sufficiently preserve the pharmaceutical composition in the absence of tapentadol.

Description

DESCRIPTION

Aqueous pharmaceutical formulation of tapentadol for oral administration

The invention relates to an aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof and which is adapted for oral administration.

Tapentadol is a centrally acting analgesic with a dual mode of action as a p-opioid receptor agonist and as a norepinephrine reuptake inhibitor (cf. T.M. Tzschentke et al., Drugs of the future, 2006, 12, 1053-1061). Solid state oral dosage forms are known from the prior art, for example from WO 02/067651, WO 03/035053, WO 2006/002886, WO 2007/128412, WO 2007/128413, WO 2008/110323 , WO 2009/092601, WO 2009/067703, and US 2007-128412.

However, solid state oral dosage forms containing tapentadol are not satisfactory in all respects and there is a demand for pharmaceutical formulations which have advantages compared to known solid state oral dosage forms.

The stability of the active ingredient in the final product is a primary concern for the formulator. In general, drug substances are less stable in aqueous media than solid dosage forms, and it is important to properly stabilize and preserve aqueous liquid formulations such as solutions, suspensions, and emulsions. Acid-base reactions, acid or base catalysis, oxidation and reduction can all occur in these products. These reactions can arise from drug-ingredient, ingredient-ingredient interactions, or container-product interactions. For pH sensitive compounds, any of these interactions can alter the pH and can cause precipitation.

Oxidative labile drug substances or vitamins, essential oils, and almost all fats and oils can be oxidized by autoxidation. Such reactions can be initiated by heat, light, peroxides, or other labile compounds or heavy metals, such as copper or iron.

The effect of trace metals can be minimized by the use of chelating agents, such as EDTA. Antioxidants can slow or delay oxidation by rapidly reacting with free radicals as they form (inactivation). Common antioxidants include propyl, octyl, and dodecyl esters of gallic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, sodium ascorbate, monothioglycerol, potassium or sodium metabisulfite, propionic acid, propyl gallate, sodium bisulfite , sodium sulfite, and tocopherols or vitamin E.

In addition to stabilizing pharmaceutical preparations against chemical and physical degradation, liquid and semisolid preparations, particularly multiple-dose preparations, must generally be protected against microbial contamination. Unlike solid preparations, aqueous solutions, syrups, emulsions, and suspensions often provide excellent growth media for microorganisms, such as molds, yeasts, and bacteria (eg, Pseudomonas aeruginosa, E. Coli, Salmonella spp., Staphylococcus aureus, Candida albicans, Aspergillus niger). Contamination by these microorganisms can occur during manufacture or when a dose is taken from a multiple dosage formulation. The growth of microorganisms occurs when a sufficient amount of water is present in the formulation.

Ophthalmic and injectable preparations are usually sterilized by autoclaving or by filtration. However, many of them require the presence of an antimicrobial preservative to maintain aseptic conditions throughout their stated shelf life, specifically for multiple-dose preparations. When a preservative is required, its selection is based on several considerations, in particular, the place of use whether internal, external or ophthalmic (for more details reference can be made to, for example, Remington, The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005).

Many liquid formulations for oral administration, particularly multiple dosage formulations, contain parabens as preservatives, for example, methyl paraben (methyl-4-hydroxybenzoate) and propyl paraben (propyl-4-hydroxybenzoate). For example, in the Federal Republic of Germany, liquid oral formulations containing parabens are marketed under the trademarks: ben-u-ron®; Cetirizin-ratiopharm®; Pipamperon Hexal®; Sedotussin®; TALOXA®; Truxal®; XUSAL®; Talvosilen®; and Timonil®. Other commercially available liquid formulations contain sorbic acid or its potassium salt as a preservative, for example liquid ibuprofen formulations and liquid morphine formulations.

Due to the amount of excipients and additives in these preparations, it is recommended that all ingredients be listed on the container to reduce the risks hypersensitive patients face when these products are administered.

The preservatives benzalkonium chloride and potassium sorbate are also widely used, for example in nasal drops and sprays. Recently, side effects resulting from mucosal damage caused by benzalkonium chloride and potassium sorbate have been reported (cf. C.Y. Ho et al., Am J Rhinol. 2008, 22 (2), 125-9). With regard to hypersensitivity reactions to preservatives in topical ophthalmic therapies, quaternary ammoniums (benzalkonium chloride) are commonly associated with irritating toxic reactions, while organomercurial compounds (thimerosal) and alcohols (chlorobutanol) have high associations, respectively, with allergic responses (cf. J. Hong et al., Curr Opin Allergy Clin Immunol. 2009, 9 (5), 447-53). Parabens have been implicated in numerous cases of contact sensitivity associated with skin exposure (cf. MG Soni et al., Food Chem Toxicol. 2001, 39 (6), 513-32) and have been reported to exert estrogenic activity. weak (cf. S. Oishi, Food Chem Toxicol. 2002, 40 (12), 1807-13 and MG Soni et al., Food Chem Toxicol. 2005, 43 (7), 985-015).

Due to these unwanted side effects of known preservatives, it is desirable to provide pharmaceutical compositions for oral administration which exhibit sufficient shelf life and stability in use in the absence of preservatives or at least in the presence of comparatively low amounts thereof.

Document WO 2008/110323 describes a composition for parenteral administration of 20 g of (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol hydrochloride in 1 l of water for purposes injection that has been isotonized by adding NaCl.

An object of the invention is to provide tapentadol pharmaceutical formulations which have advantages over prior art pharmaceutical formulations. The pharmaceutical formulations should not have the side effects due to the above preservatives that are normally seen with the pharmaceutical formulations containing preservatives, such as allergic reactions.

This object has been achieved by the subject matter of the patent claims.

It has surprisingly been discovered that tapentadol, as such, exhibits preservative properties and therefore, when formulating relatively labile compositions, particularly aqueous liquid or semi-solid compositions, preservatives can be omitted entirely or at least need to be present in relatively low amounts. in order to achieve the indicated shelf life.

A first aspect of the invention relates to an aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof and which is adapted for oral administration, where the composition additionally contains a preservative, where the content of the preservative is at most 90% of the content that would be necessary according to the European Pharmacopoeia in order to sufficiently preserve the pharmaceutical composition in the absence of tapentadol.

For the purpose of the specification, the term "tapentadol" includes the free base ((1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol), as well as any physiologically acceptable salt thereof, particularly the hydrochloride, ((1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) -phenol hydrochloride) hydrochloride. Therefore, unless expressly stated otherwise, the term "tapentadol" refers not only to the free base but also to any physiologically acceptable salt. In addition, unless expressly stated otherwise, all amounts, contents, and concentrations are equivalent relative to tapentadol free base.

The composition according to the invention is aqueous. For the purpose of the specification, the term "aqueous" means that its water content is preferably higher than the typical water content of solid state pharmaceutical dosage forms that humidify from the atmosphere due to more or more hygroscopic properties. less pronounced of its constituents.

Preferably, the water content of the composition is at least 0.5% by weight, more preferably at least 1.0% by weight, even more preferably at least 2.0% by weight, even more preferably at least 3, 0% by weight, most preferably at least 4.0% by weight and in particular at least 5.0% by weight, based on the total weight of the composition.

In a preferred embodiment, the water content of the composition is at least 5 % by weight, more preferably at least 10% by weight, even more preferably at least 20% by weight, even more preferably at least 30% by weight, most preferably at least 40% by weight and in particular at least 50% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 35 ± 30% by weight, more preferably 35 ± 25% by weight, even more preferably 35 ± 20% by weight, even still more preferably 35 ± 15 % by weight, most preferably 35 ± 10% by weight and in particular 35 ± 5% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 45 ± 30% by weight, more preferably 45 ± 25% by weight, even more preferably 45 ± 20% by weight, even more preferably 45 ± 15%. % by weight, most preferably 45 ± 10% by weight and in particular 45 ± 5% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 55 ± 30% by weight, more preferably 55 ± 25% by weight, even more preferably 55 ± 20% by weight, even more preferably 55 ± 15%. % by weight, most preferably 55 ± 10% by weight and in particular 55 ± 5% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 65 ± 30% by weight, more preferably 65 ± 25% by weight, even more preferably 65 ± 20% by weight, even still more preferably 65 ± 15 % by weight, most preferably 65 ± 10% by weight and in particular 65 ± 5% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 75 ± 24% by weight, more preferably 75 ± 22% by weight, even more preferably at least 75 ± 20% by weight, even more preferably 75 ± 15% by weight, most preferably 75 ± 10% by weight and in particular 75 ± 5% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 85 ± 14% by weight, more preferably 85 ± 12% by weight, even more preferably 85 ± 10% by weight, most preferably 85 ± 7, 5% by weight and in particular 85 ± 5% by weight, based on the total weight of the composition.

In another preferred embodiment, the water content of the composition is within the range of 95 ± 4.75% by weight, more preferably 95 ± 4.5% by weight, even more preferably 95 ± 4% by weight, even more. preferably 95 ± 3.5% by weight, most preferably 95 ± 3% by weight and in particular 95 ± 2.5% by weight, based on the total weight of the composition.

In a preferred embodiment, the water content of the composition is within the range of 75 to 99.99% by weight, more preferably 80 to 99.98% by weight, even more preferably 85 to 99.95% by weight, even even more preferably 90 to 99.9% by weight, most preferably 95 to 99.7% by weight and in particular 96.5 to 99.5% by weight, based on the total weight of the composition.

In a preferred embodiment, the composition has a viscosity within the range of 15 ± 12 mPas, more preferably 15 ± 10 mPas, even more preferably 15 ± 8 mPas, even more preferably 15 ± 6 mPas, most preferably 15 ± 4 mPas. , and in particular 15 ± 2 mPas.

In another preferred embodiment, the composition has a viscosity within the range of 30 ± 28 mPas, more preferably 30 ± 20 mPas, even more preferably 30 ± 16 mPas, even more preferably 30 ± 12 mPas, most preferably 30 ± 8 mPas. , and in particular 30 ± 4 mPas.

In another preferred embodiment, the composition has a viscosity within the range of 60 ± 56 mPas, more preferably 60 ± 40 mPas, even more preferably 60 ± 32 mPas, even more preferably 60 ± 24 mPas, most preferably 60 ± 16 mPas. , and in particular 60 ± 8 mPas.

In another preferred embodiment, the composition has a viscosity within the range of 120 ± 112 mPas, more preferably 120 ± 80 mPas, even more preferably 120 ± 64 mPas, even more preferably 120 ± 48 mPas, most preferably 120 ± 32 mPas. , and in particular 120 ± 16 mPas.

In another preferred embodiment, the composition has a viscosity within the range of 240 ± 224 mPas, more preferably 240 ± 160 mPas, even more preferably 240 ± 128 mPas, even more preferably 240 ± 96 mPas, most preferably 240 ± 64 mPas. , and in particular 240 ± 32 mPas.

In another preferred embodiment, the composition has a viscosity within the range of 500 ± 400 mPas, more preferably 500 ± 300 mPas, even more preferably 500 ± 200 mPas, even more preferably 500 ± 150 mPas, most preferably 500 ± 100 mPas. , and in particular 500 ± 50 mPas.

One skilled in the art knows how to measure the viscosity of pharmaceutical compositions. Preferably, the viscosity is measured at room temperature.

In addition to water, the composition according to the invention may contain additional solvents.

Additional suitable solvents include all physiologically acceptable substances that are normally liquid at ambient or ambient temperatures. Preferably, the additional solvent is water soluble or water miscible. Additional solvents may be selected from the group consisting of propylene glycol, ethanol, poly (ethylene glycol) or PEG, propylene carbonate, diethylene glycol monoethyl ether, poloxamer, glycofurol, glycerol, and mixtures thereof.

Other solvents include surfactants (emulsifiers) and / or fats.

In a preferred embodiment, the composition contains a surfactant. In a preferred embodiment, the composition contains a single surfactant. In another preferred embodiment, the composition contains a mixture of two or more surfactants.

Preferably, the surfactant has a hydrophilic-lipophilic balance (HLB) of at least 10. More preferably, the hydrophilic-lipophilic balance (HLB) is at least 12. Most preferably, the hydrophilic-lipophilic balance (HLB) ranges between 14 and 16.

The surfactant can be an ionic surfactant, an amphoteric surfactant, or a non-ionic surfactant.

In a preferred embodiment, the surfactant is ionic, in particular anionic. Suitable anionic ionic surfactants include, but are not limited to, sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetylstearyl sulfate, dioctylsulfosuccinate sodium (docusate sodium), and the corresponding potassium or calcium salts thereof. In another preferred embodiment, the surfactant is nonionic. Suitable nonionic surfactants include, but are not limited to, □ polyoxyethylene sorbitan fatty acid esters, for example mono- and tri-lauryl, palmitic, stearyl and oleyl esters, such as the type known by the name of "polysorbate" and commercially available under the trade name "Tween®", including the surfactants tween 20 [polyoxyethylene (20) sorbitan monolaurate], tween 40 [polyoxyethylene (20) sorbitan monopalmitate], 60 [polyoxyethylene (20) sorbitan monostearate], tween 65 [polyoxyethylene sadarate polyoxyethylene (20) sorbitan], tween 80 [polyoxyethylene (20) sorbitan monooleate], tween 85 [polyoxyethylene (20) sorbitan trioleate], tween 21 [polyoxyethylene (4) sorbitan monolaurate] and tween 81 [polyoxyethylene monooleate ( 5) sorbitan];

polyoxyethylene fatty acid esters, the fatty acid preferably has from about 8 to about 18 carbon atoms, for example polyoxyethylene esters of 12-hydroxystearic acid, such as the known type and commercially available under the trade name "Solutol® ";

- polyoxyethylene esters of alpha-tocopheryl succinate, for example, D-alpha tocopheryl succinate PEG 1000 (TPGS); - polyglycolized glycerides, such as the types known and commercially available under the trade names "Gelucire®" and "Labrasol®";

- reaction products of a natural or hydrogenated castor oil and ethylene oxide, such as the various liquid surfactants known and commercially available under the trade name "Cremophor®";

- glycerol fatty acid esters, for example mono- and tri-lauryl, palmityl, stearyl and oleyl esters, such as, for example, glyceryl monooleate 40, known and commercially available under the trade name "Peceol®".

Examples of fats include glycerol monostearate, glycerol monopalmitate, stearic acid, diglycol stearate, glycerol trioleate, carnauba wax, beeswax, cetylstearyl alcohol, and the like.

Preferably, however, water is the only liquid constituent of the composition according to the invention.

The composition according to the invention is adapted for oral administration. In this sense, oral administration includes all administration through the oral cavity, such as peroral, sublingual, buccal, and the like. Preferably, oral administration is for the purpose of administering tapentadol systemically by swallowing. The term "pharmaceutical composition" includes any pharmaceutical preparation or formulation that has been customized for administration to a human or animal. Preferably, the composition contains one or more physiologically acceptable carriers, preferably water, and / or excipients. The pharmaceutical composition can be a subunit of a pharmaceutical dosage form, for example, the liquid core of a capsule.

Preferably, the composition according to the invention is buffered, that is, it contains one or more buffers and buffer systems (that is, conjugated acid-base pairs), respectively. Preferred buffer systems are derived from the following acids: organic acids, such as acetic acid, propionic acid, maleic acid, fumaric acid, malonic acid, malic acid, mandelic acid, citric acid, tartaric acid; or inorganic acids, such as phosphoric acid. Citric acid or citric acid monohydrate are especially preferred. When the buffer systems are derived from any of the above acids, the buffer system consists of said acid and its conjugate base.

Surprisingly, it has been found that the antimicrobial activity of tapentadol depends on the pH value. Preferably the composition has a pH value within the range of 3.0 to 6.5, more preferably 3.0 to 6.0, still more preferably 3.0 to 5.5, even more preferably 3.0 to 5.0, most preferably 3.2 to 4.8, and in particular 3.4 to 4.6. Higher pH values are also possible, eg 3.0 to 9.0, 3.0 to 8.5, 3.0 to 8.0 or 3.0 to 7.5.

In a preferred embodiment, the composition has a pH value within the range of 3.0 ± 1.4 or 3.0 ± 1.3, more preferably 3.0 ± 1.2 or 3.0 ± 1.1, even more preferably 3.0 ± 1.0 or 3.0 ± 0.9, even more preferably 3.0 ± 0.8 or 3.0 ± 0.7, even more preferably 3.0 ± 0.6 or 3.0 ± 0.5, most preferably 3.0 ± 0.4 or 3.0 ± 0.3, and in particular 3.0 ± 0.2 or 3.0 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 3.5 ± 1.4 or 3.5 ± 1.3, more preferably 3.5 ± 1.2 or 3.5 ± 1.1, even more preferably 3.5 ± 1.0 or 3.5 ± 0.9, even more preferably 3.5 ± 0.8 or 3.5 ± 0.7, even more preferably 3.5 ± 0.6 or 3.5 ± 0.5, most preferably 3.5 ± 0.4 or 3.5 ± 0.3, and in particular 3.5 ± 0.2 or 3.5 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 4.0 ± 1.4 or 4.0 ± 1.3, more preferably 4.0 ± 1.2 or 4.0 ± 1.1, even more preferably 4.0 ± 1.0 or 4.0 ± 0.9, even more preferably 4.0 ± 0.8 or 4.0 ± 0.7, even more preferably 4.0 ± 0.6 or 4.0 ± 0.5, most preferably 4.0 ± 0.4 or 4.0 ± 0.3, and in particular 4.0 ± 0.2 or 4.0 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 4.5 ± 1.4 or 4.5 ± 1.3, more preferably 4.5 ± 1.2 or 4.5 ± 1.1, even more preferably 4.5 ± 1.0 or 4.5 ± 0.9, even more preferably 4.5 ± 0.8 or 4.5 ± 0.7, even more preferably 4.5 ± 0.6 or 4.5 ± 0.5, most preferably 4.5 ± 0.4 or 4.5 ± 0.3, and in particular 4.5 ± 0.2 or 4.5 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 5.0 ± 1.4 or 5.0 ± 1.3, more preferably 5.0 ± 1.2 or 5.0 ± 1.1, even more preferably 5.0 ± 1.0 or 5.0 ± 0.9, even more preferably 5.0 ± 0.8 or 5.0 ± 0.7, even more preferably 5.0 ± 0.6 or 5.0 ± 0.5, most preferably 5.0 ± 0.4 or 5.0 ± 0.3, and in particular 5.0 ± 0.2 or 5.0 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 5.5 ± 1.4 or 5.5 ± 1.3, more preferably 5.5 ± 1.2 or 5.5 ± 1.1, even more preferably 5.5 ± 1.0 or 5.5 ± 0.9, even more preferably 5.5 ± 0.8 or 5.5 ± 0.7, even more preferably 5.5 ± 0.6 or 5.5 ± 0.5, most preferably 5.5 ± 0.4 or 5.5 ± 0.3, and in particular 5.5 ± 0.2 or 5.5 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 6.0 ± 1.4 or 6.0 ± 1.3, plus preferably 6.0 ± 1.2 or 6.0 ± 1.1, even more preferably 6.0 ± 1.0 or 6.0 ± 0.9, even more preferably 6.0 ± 0.8 or 6, 0 ± 0.7, even more preferably 6.0 ± 0.6 or 6.0 ± 0.5, most preferably 6.0 ± 0.4 or 6.0 ± 0.3, and in particular 6.0 ± 0.2 or 6.0 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 6.5 ± 1.4 or 6.5 ± 1.3, more preferably 6.5 ± 1.2 or 6.5 ± 1.1, even more preferably 6.5 ± 1.0 or 6.5 ± 0.9, even more preferably 6.5 ± 0.8 or 6.5 ± 0.7, even more preferably 6.5 ± 0.6 or 6.5 ± 0.5, most preferably 6.5 ± 0.4 or 6.5 ± 0.3, and in particular 6.5 ± 0.2 or 6.5 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 7.0 ± 1.4 or 7.0 ± 1.3, more preferably 7.0 ± 1.2 or 7.0 ± 1.1, even more preferably 7.0 ± 1.0 or 7.0 ± 0.9, even more preferably 7.0 ± 0.8 or 7.0 ± 0.7, even more preferably 7.0 ± 0.6 or 7.0 ± 0.5, most preferably 7.0 ± 0.4 or 7.0 ± 0.3, and in particular 7.0 ± 0.2 or 7.0 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 7.5 ± 1.4 or 7.5 ± 1.3, more preferably 7.5 ± 1.2 or 7.5 ± 1.1, even more preferably 7.5 ± 1.0 or 7.5 ± 0.9, even more preferably 7.5 ± 0.8 or 7.5 ± 0.7, even more preferably 7.5 ± 0.6 or 7.5 ± 0.5, most preferably 7.5 ± 0.4 or 7.5 ± 0.3, and in particular 7.5 ± 0.2 or 7.5 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 8.0 ± 1.4 or 8.0 ± 1.3, more preferably 8.0 ± 1.2 or 8.0 ± 1.1, even more preferably 8.0 ± 1.0 or 8.0 ± 0.9, even more preferably 8.0 ± 0.8 or 8.0 ± 0.7, even more preferably 8.0 ± 0.6 u 8.0 ± 0.5, most preferably 8.0 ± 0.4 or 8.0 ± 0.3, and in particular 8.0 ± 0.2 or 8.0 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 8.5 ± 1.4 or 8.5 ± 1.3, more preferably 8.5 ± 1.2 or 8.5 ± 1.1, even more preferably 8.5 ± 1.0 or 8.5 ± 0.9, even more preferably 8.5 ± 0.8 or 8.5 ± 0.7, even more preferably 8.5 ± 0.6 u 8.5 ± 0.5, most preferably 8.5 ± 0.4 or 8.5 ± 0.3, and in particular 8.5 ± 0.2 or 8.5 ± 0.1.

In a preferred embodiment, the composition has a pH value within the range of 9.0 ± 1.4 or 9.0 ± 1.3, more preferably 9.0 ± 1.2 or 9.0 ± 1.1, even more preferably 9.0 ± 1.0 or 9.0 ± 0.9, even more preferably 9.0 ± 0.8 or 9.0 ± 0.7, even more preferably 9.0 ± 0.6 or 9.0 ± 0.5, most preferably 9.0 ± 0.4 or 9.0 ± 0.3, and in particular 9.0 ± 0.2 or 9.0 ± 0.1.

Preferably, the concentration of the buffer and the buffer system, respectively, preferably citric acid or its monohydrate, is adjusted to provide a sufficient buffer capacity.

Preferably, the content of the buffer and the buffer system, respectively, preferably citric acid or its monohydrate, is within the range of 0.0001 to 5.0% by weight, more preferably 0.0005 to 4.5% by weight, even more preferably 0.001 to 4.0% by weight, even more preferably 0.005 to 3.5% by weight, most preferably 0.01 to 3.0% by weight and in particular 0.05 to 2.5% by weight, based on the total weight of the composition. In a preferred embodiment, the buffer and the buffer system, respectively, preferably citric acid or its monohydrate, has a concentration within the range of 1.0 ± 0.6 mg / ml, more preferably 1.0 ± 0.5 mg. / ml, even more preferably 1.0 ± 0.4 mg / ml, even more preferably 1.0 ± 0.3 mg / ml, most preferably 1.0 ± 0.2 mg / ml, and in particular 1.0 ± 0.1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the buffer and the buffer system, respectively, preferably citric acid or its monohydrate, has a concentration within the range of 1.5 ± 0.6 mg / ml, more preferably 1.5 ± 0.5 mg. / ml, even more preferably 1.5 ± 0.4 mg / ml, even more preferably 1.5 ± 0.3 mg / ml, most preferably 1.5 ± 0.2 mg / ml, and in particular 1.5 ± 0.1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the buffer and the buffer system, respectively, preferably citric acid or its monohydrate, has a concentration within the range of 2.0 ± 0.6 mg / ml, more preferably 2.0 ± 0.5 mg. / ml, even more preferably 2.0 ± 0.4 mg / ml, even more preferably 2.0 ± 0.3 mg / ml, most preferably 2.0 ± 0.2 mg / ml, and in particular 2.0 ± 0.1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the buffer and the buffer system, respectively, preferably citric acid or its monohydrate, has a concentration within the range of 2.5 ± 0.6 mg / ml, more preferably 2.5 ± 0.5 mg. / ml, even more preferably 2.5 ± 0.4 mg / ml, even more preferably 2.5 ± 0.3 mg / ml, most preferably 2.5 ± 0.2 mg / ml, and in particular 2.5 ± 0.1 mg / ml, based on the total volume of the composition.

One skilled in the art is fully aware that multiprotonic acids can form more than one single buffer system. For example, citric acid is a triprotonic acid such that it forms the acid-base pairs citric acid-dihydrogen citrate, dihydrogen citrate-hydrogen citrate and hydrogen citrate citrate. In other words, any of the citric acids, dihydrogen citrates, and hydrogen citrates can be the acid of a conjugated base buffer system. For the purposes of the specification, the term "buffer and buffer system, respectively" preferably refers to the amount of both the acid and its conjugate base. Furthermore, one of skill in the art is fully aware that a buffer system, for example the conjugated citric acid / sodium dihydrogen citrate system, can be established by either adding citric acid and an appropriate amount of sodium hydroxide or citric acid. and sodium dihydrogen citrate as such.

In a preferred embodiment, the content of tapentadol is within the range of 0.01 to 50% by weight, more preferably 0.05 to 45% by weight, even more preferably 0.1 to 40% by weight, even more preferably 0.5 to 35% by weight, most preferably 1.0 to 30% by weight and in particular 5.0 to 25% by weight, based on the total weight of the composition.

In another preferred embodiment, the content of tapentadol is within the range of 0.0001 to 5.0% by weight, more preferably 0.0005 to 4.5% by weight, even more preferably 0.001 to 4.0% by weight, even more preferably 0.005 to 3.5% by weight, most preferably 0.01 to 3.0% by weight and in particular 0.05 to 2.5% by weight, based on the total weight of the composition. In a preferred embodiment, the content of tapentadol is within the range of 0.01 to 3.0% by weight, more preferably 0.05 to 2.8% by weight, even more preferably 0.1 to 2.6% by weight. weight, even more preferably 0.2 to 2.4% by weight, most preferably 0.3 to 2.2% by weight and in particular 0.4 to 2.0% by weight, based on the total weight of the composition.

Preferably, the tapentadol concentration is equal to or less than 200 mg / ml, more preferably equal to or less than 150 mg / ml, even more preferably equal to or less than 100 mg / ml, even more preferably equal to or less than 75 mg / ml. ml, and most preferably equal to or less than 50 mg / ml, and in particular equal to or less than 30 mg / ml, based on the total volume of the composition.

Preferably, the tapentadol concentration is within the range of 0.5 to 200 mg / ml, more preferably within the range of 1.0 to 150 mg / ml, even more preferably within the range of 1.5 to 100 mg / ml. , even more preferably within the range of 2.0 to 75 mg / ml, most preferably within the range of 2.5 to 50 mg / ml, and in particular within the range of 3.0 to 25 mg / ml, based on the total volume of the composition. In a preferred embodiment, the tapentadol concentration is equal to or less than 20 mg / ml, based on the total volume of the composition.

The antimicrobial effect of tapentadol, its preservative effect, has been found to be a function of the pH value. Therefore, at a given pH value, a certain minimum concentration of tapentadol is already sufficient in order to achieve the desired preservative effect, while at another pH value another minimum concentration of tapentadol is necessary in order to achieve the same. preservative effect. This minimum concentration for a given pH value can be determined by routine experimentation.

In a preferred embodiment, the tapentadol concentration is within the range of 20 ± 6 mg / ml, more preferably 20 ± 5 mg / ml, even more preferably 20 ± 4 mg / ml, even more preferably 20 ± 3 mg / ml , most preferably 20 ± 2 mg / ml, and in particular 20 ± 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the tapentadol concentration is within the range of 17.5 ± 6 mg / ml, more preferably 17.5 ± 5 mg / ml, even more preferably 17.5 ± 4 mg / ml, even more preferably 17.5 ± 3 mg / ml, most preferably 17.5 ± 2 mg / ml, and in particular 17.5 ± 1 mg / ml, based on the total volume of the composition. In another preferred embodiment, the tapentadol concentration is within the range of 15 ± 6 mg / ml, more preferably 15 ± 5 mg / ml, even more preferably 15 ± 4 mg / ml, even more preferably 15 ± 3 mg / ml , most preferably 15 ± 2 mg / ml, and in particular 15 ± 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the tapentadol concentration is within the range of 12.5 ± 6 mg / ml, more preferably 12.5 ± 5 mg / ml, even more preferably 12.5 ± 4 mg / ml, even more preferably 12.5 ± 3 mg / ml, most preferably 12.5 ± 2 mg / ml, and in particular 12.5 ± 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the tapentadol concentration is within the range of 10 ± 6 mg / ml, more preferably 10 ± 5 mg / ml, even more preferably 10 ± 4 mg / ml, even more preferably 10 ± 3 mg / ml , most preferably 10 ± 2 mg / ml, and in particular 10 ± 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the concentration of tapentadol is within the range of 7.5 ± 6 mg / ml, more preferably 7.5 ± 5 mg / ml, even more preferably 7.5 ± 4 mg / ml, even more preferably 7.5 ± 3 mg / ml, most preferably 7.5 ± 2 mg / ml, and in particular 7.5 ± 1 mg / ml, based on the total volume of the composition.

In a further preferred embodiment, the concentration of tapentadol is within the range of 4 ± 3 mg / ml, more preferably 4 ± 2.5 mg / ml, even more preferably 4 ± 2 mg / ml, even more preferably 4 ± 1 5 mg / ml, most preferably 4 ± 1 mg / ml, and in particular 4 ± 0.5 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the tapentadol concentration is equal to or less than 20 mg / ml, based on the total volume of the composition.

In a preferred embodiment, the tapentadol concentration is within the range of 22.5 ± 6 mg / ml, more preferably 22.5 ± 5 mg / ml, even more preferably 22.5 ± 4 mg / ml, even more preferably 22.5 ± 3 mg / ml, most preferably 22.5 ± 2 mg / ml, and in particular 22.5 ± 1 mg / ml, based on the total volume of the composition. In another preferred embodiment, the tapentadol concentration is within the range of 25 ± 6 mg / ml, more preferably 25 ± 5 mg / ml, even more preferably 25 ± 4 mg / ml, even more preferably 25 ± 3 mg / ml , most preferably 25 ± 2 mg / ml, and in particular 25 ± 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the tapentadol concentration is within the range of 27.5 ± 6 mg / ml, more preferably 27.5 ± 5 mg / ml, even more preferably 27.5 ± 4 mg / ml, even more preferably 27.5 ± 3 mg / ml, most preferably 27.5 ± 2 mg / ml, and in particular 27.5 ± 1 mg / ml, based on the total volume of the composition. In another preferred embodiment, the tapentadol concentration is within the range of 30 ± 6 mg / ml, more preferably 30 ± 5 mg / ml, even more preferably 30 ± 4 mg / ml, even more preferably 30 ± 3 mg / ml , most preferably 30 ± 2 mg / ml, and in particular 30 ± 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the concentration of tapentadol is within the range of 32.5 ± 6 mg / ml, more preferably 32.5 ± 5 mg / ml, even more preferably 32.5 ± 4 mg / ml, even more preferably 32.5 ± 3 mg / ml, most preferably 32.5 ± 2 mg / ml, and in particular 32.5 ± 1 mg / ml, based on the total volume of the composition. In another preferred embodiment, the tapentadol concentration is within the range of 35 ± 6 mg / ml, more preferably 35 ± 5 mg / ml, even more preferably 35 ± 4 mg / ml, even more preferably 35 ± 3 mg / ml , most preferably 35 ± 2 mg / ml, and in particular 35 ± 1 mg / ml, based on the total volume of the composition.

For purposes of the specification, a "preservative" preferably refers to any substance that is routinely added to pharmaceutical compositions in order to preserve them against microbial degradation or microbial growth. In this regard, microbial growth normally plays an essential role, that is, the preservative serves the primary purpose of preventing microbial contamination. As a secondary aspect, it may also be desirable to avoid any effect of microbes on the active ingredients and excipients, respectively, that is, to avoid microbial degradation.

Representative examples of preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexidurea. , phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate. Sodium benzoate is particularly preferred.

For the purpose of the specification, a distinction is preferably made between shelf life and in-use stability. Shelf life preferably refers to the storage stability of a closed container of the pharmaceutical composition. In-use stability preferably refers to the storage container containing a multiple dose preparation that has been used for the first time. Typically, the shelf life of a multiple dose preparation is much greater than its in-use stability. The composition additionally contains a preservative, which is preferably selected from the group that consists of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenoxyethanol, phenoxyethanol , phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate.

Surprisingly, it has been found that aqueous tapentadol compositions containing sodium benzoate show less decrease in preservative at 50 ° C and less degradation products compared to aqueous tapentadol compositions containing parabens.

Therefore, sodium benzoate is a particularly preferred preservative according to the invention.

Preferably, the content of the preservative is at most 5.0% by weight, more preferably at most 4.0% by weight, even more preferably at most 3.0% by weight, even more preferably at most 2.0% by weight, most preferably not more than 1.0% by weight and in particular not more than 0.5% by weight, based on the total weight of the composition.

In a preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 1.0 ± 0.6 mg / ml, more preferably 1.0 ± 0.5 mg / ml, even more preferably 1.0 ± 0.4 mg / ml, even more preferably 1.0 ± 0.3 mg / ml, most preferably 1.0 ± 0.2 mg / ml, and in particular 1.0 ± 0, 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 1.5 ± 0.6 mg / ml, more preferably 1.5 ± 0.5 mg / ml, even more preferably 1.5 ± 0.4 mg / ml, even more preferably 1.5 ± 0.3 mg / ml, most preferably 1.5 ± 0.2 mg / ml, and in particular 1.5 ± 0, 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 2.0 ± 0.6 mg / ml, more preferably 2.0 ± 0.5 mg / ml, even more preferably 2.0 ± 0.4 mg / ml, even more preferably 2.0 ± 0.3 mg / ml, most preferably 2.0 ± 0.2 mg / ml, and in particular 2.0 ± 0, 1 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the preservative, preferably benzoic acid or its sodium salt, has a concentration within the range of 2.5 ± 0.6 mg / ml, more preferably 2.5 ± 0.5 mg / ml, even more preferably 2.5 ± 0.4 mg / ml, even more preferably 2.5 ± 0.3 mg / ml, most preferably 2.5 ± 0.2 mg / ml, and in particular 2.5 ± 0, 1 mg / ml, based on the total volume of the composition.

In a preferred embodiment, the relative weight ratio of tapentadol to the preservative is within the range of 10: 1 to 0.25: 1, more preferably 9: 1 to 0.33: 1, even more preferably 8: 1 to 0.5: 1, even more preferably 7: 1 to 0.66: 1, most preferably 6: 1 to 0.75: 1 and in particular 5: 1 to 1: 1. Preferably, the relative weight ratio of tapentadol to the preservative is within the range of 5: 1 to 1: 1, more preferably 4.5: 1 to 1: 1, even more preferably 4: 1 to 1: 1, even more. preferably 3.5: 1 to 1: 1, most preferably 3: 1 to 1: 1 and in particular 2.5: 1 to 1: 1.

Preferably, the sum of the tapentadol concentration and the preservative concentration is equal to or less than 50 mg / ml, preferably equal to or less than 20 mg / ml, based on the total volume of the composition.

In a preferred embodiment, the sum of the tapentadol concentration and the preservative concentration is within the range of 4.0 ± 3.5 mg / ml, more preferably 4.0 ± 3.0 mg / ml, even more preferably 4 , 0 ± 2.5 mg / ml, even more preferably 4.0 ± 2.0 mg / ml, most preferably 4.0 ± 1.5 mg / ml, and in particular 4.0 ± 1.0 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the sum of the tapentadol concentration and the preservative concentration is within the range of 6.0 ± 3.5 mg / ml, more preferably 6.0 ± 3.0 mg / ml, even more preferably 6 , 0 ± 2.5 mg / ml, even more preferably 6.0 ± 2.0 mg / ml, most preferably 6.0 ± 1.5 mg / ml, and in particular 6.0 ± 1.0 mg / ml, based on the total volume of the composition.

In another preferred embodiment, the sum of the tapentadol concentration and the preservative concentration is within the range of 8.0 ± 3.5 mg / ml, more preferably 8.0 ± 3.0 mg / ml, even more preferably 8 , 0 ± 2.5 mg / ml, even more preferably 8.0 ± 2.0 mg / ml, most preferably 8.0 ± 1.5 mg / ml, and in particular 8.0 ± 1.0 mg / ml, based in the total volume of the composition.

The content of the preservative is at most 90%, more preferably at most 80%, even more preferably at most 70%, even more preferably at most 60%, most preferably at most 50% and in particular at most 40% of the content which would be necessary according to the European Pharmacopoeia in order to sufficiently preserve the pharmaceutical composition in the absence of tapentadol.

Preferably, the composition according to the invention exhibits an antimicrobial robustness that meets the requirements of the European Pharmacopoeia, preferably in its version for 2010. Preferably, the antimicrobial robustness is achieved against E. coli, S. aureus, Ps. Aeruginosa, S. spp., C. albicans, and / or A. niger, preferably satisfying the requirement of 1 log reduction after 14 and no increase after 28 days. In a particularly preferred embodiment, antimicrobial robustness is achieved against bacteria by satisfying the 3 log reduction requirement after 14 days and against 1 log reduction mold and yeast after 14 days.

Preferably, the composition according to the invention has a shelf life under accelerated storage conditions of at least 1 month, more preferably of at least 2 months, even more preferably of at least 3 months, even more preferably of at least 4 months , most preferably at least 5 months and in particular at least 6 months. Preferably the shelf life is determined according to the European Pharmacopoeia, particularly as described in the experimental section. Accelerated storage conditions preferably mean 40 ° C / 75% RH.

Preferably, the composition according to the invention has a shelf life under ambient conditions of at least 6 months, more preferably of at least 12 months, even more preferably of at least 15 months, even more preferably of at least 18 months, which more preferably at least 21 months and in particular at least 24 months.

Preferably, the composition according to the invention is a multiple dosage preparation exhibiting a stability in use under ambient conditions of at least 1 week, more preferably of at least 2 weeks, even more preferably of at least 3 weeks, even more preferably of at least 4 weeks, most preferably at least 5 weeks and in particular at least 6 weeks.

Preferably, the composition according to the invention is liquid or semi-solid.

Preferably, the composition according to the invention is selected from the group consisting of syrups, drops, solutions, dispersions, suspensions and emulsions. Emulsions can be of the ac / a type (oil in water) or of the a / ac type (water in oil).

When the pharmaceutical composition is a solution, it can be selected from the group consisting of aromatic waters, aqueous acids, dilute acids, vaginal washes, enemas, gargles, mouthwashes, juices, and irrigation solutions.

Preferably, the composition belongs to the group of sweet aqueous solutions and other viscous aqueous solutions that include syrups, honeys, mucilages, and jellies.

Other examples of compositions according to the invention include collodions, elixirs, glycerines, liniments, and liqueurs. In a preferred embodiment, the composition according to the invention is an emulsion, preferably selected from the group consisting of conventional emulsions, multiple emulsions, microemulsions and liposomes. In another preferred embodiment, the composition according to the invention is a suspension, preferably selected from the group consisting of sustained release suspensions, gels and magmas, and lotions.

Preferably, the composition is a multiple dosage form, that is, adapted for more than a single administration.

For the purpose of specification, "multiple dosage" preferably means that the composition encompasses more than a single dosage unit.

For example, when the composition is a multiple-dose oral solution, its total volume is greater than the volume that should normally be administered orally at one time. Instead, the multiple-dose oral solution is adapted to be divided into a multitude of dosage units to be administered over a treatment interval typically spanning several days. For example, when the oral multiple dosage form that is contained in a storage container has a total volume of 250 ml and the prescribed dosage unit is 25 ml once a day, on day 1 of the treatment interval, the patient takes 25 ml so that 225 ml remains in the storage container; on day 2 of the treatment interval, the patient takes another 25 ml so that 200 ml remains in the storage container; and so on, until on day 10 the patient takes the entire amount.

In a preferred embodiment, the composition according to the invention is ready for use, that is, it does not require particular treatment steps, such as dissolution in a solvent before it can be administered orally to the patient.

One skilled in the art recognizes that the aqueous composition according to the invention, alternatively, can be marketed as a precursor in the form of a dry powder to be dissolved or dispersed in an appropriate amount of water before the first use.

Preferably, the composition according to the invention additionally comprises a flavor enhancing component. In a preferred embodiment, the flavor enhancer component comprises at least one sweetener, preferably selected from the group comprising cyclamate (E 952), saccharin (E 954) or sodium saccharin, aspartame (E 951), sucralose (E 955 ), neotame, thaumatin (E 957), neohesperidine (E 959), acesulfame potassium (acesulfame K, E 950) and acesulfame-aspartame salt (E 962), and sorbitol (E 420). Sucralose is particularly preferred.

Preferably, the content of the sweetener is preferably <20% by weight, more preferably <15% by weight, still more preferably <10% by weight, most preferably <5.0% by weight, and in particular <1.0 %, based on the total weight of the composition.

In a preferred embodiment, the concentration of the sweetener, preferably sucralose, is within the range of 2.0 ± 1.5 mg / ml, more preferably 2.0 ± 1.25 mg / ml, even more preferably 2.0 ± 1 , 0 mg / ml, even more preferably 2.0 ± 0.75 mg / ml, most preferably 2.0 ± 0.5 mg / ml, and in particular 2.0 ± 0.25 mg / ml, based in the total volume of the composition.

In a preferred embodiment, the concentration of the sweetener, preferably sucralose, is within the range of 2.5 ± 1.5 mg / ml, more preferably 2.5 ± 1.25 mg / ml, even more preferably 2.5 ± 1 , 0 mg / ml, even more preferably 2.5 ± 0.75 mg / ml, most preferably 2.5 ± 0.5 mg / ml, and in particular 2.5 ± 0.25 mg / ml, based in the total volume of the composition.

In a preferred embodiment, the flavor enhancing component comprises at least one flavoring agent. Flavoring agents are known to those skilled in the art. In this context, reference can be made, for example, to the European Commission: Commission Decision on a registration of flavoring agents used in or on food products, dated February 23, 1999; latest consolidated version dated 03.29.06. Natural or nature-identical fruit flavors are particularly preferred. Examples of suitable flavoring agents are orange flavor, blood orange flavor, lemon flavor, lime flavor, grapefruit flavor, strawberry flavor, raspberry flavor, blackcurrant flavor, red currant flavor, pineapple flavor, blueberry flavor, cherry flavor, woodruff flavor, vanilla flavor, and mixtures thereof, such as wild berry flavor or strawberry-vanilla flavor. The raspberry flavor is particularly preferred.

In a preferred embodiment, the concentration of the flavoring agent, preferably raspberry flavor, is within the range of 2.0 ± 1.5 mg / ml, more preferably 2.0 ± 1.25 mg / ml, even more preferably 2, 0 ± 1.0 mg / ml, even more preferably 2.0 ± 0.75 mg / ml, most preferably 2.0 ± 0.5 mg / ml, and in particular 2.0 ± 0.25 mg / ml, based on the total volume of the composition.

The compositions may include one or more additional excipients selected from the group consisting of wetting agents, emulsifying agents, isotonizing agents, surfactant components, solubilizing agents, thickening agents, coloring agents, and antioxidant components.

A wetting agent or surfactant component can be included in the liquid compositions of the present invention which, when used, include one or more quaternary ammonium compounds, such as sodium chloride. benzalkonium, benzethonium chloride, and cetylpyridinium chloride; TPGS, dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, such as nonoxynol 9, nonoxynol 10, and octoxynol 9; poloxamers (block copolymers of polyoxyethylene and polyoxypropylene); polyoxyethylene fatty acid glycerides and oils, such as polyoxyethylene caprylic / capric mono- and diglycerides of polyoxyethylene (8), polyoxyethylene castor oil (35), and hydrogenated polyoxyethylene castor oil (40); polyoxyethylene alkyl ethers, such as polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid esters, such as polyoxyethylene (40) stearate; polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate 80; propylene glycol fatty acid esters, such as propylene glycol laureate; sodium lauryl sulfate; fatty acids and salts thereof, such as oleic acid, sodium oleate, and triethanolamine oleate; glyceryl fatty acid esters, for example glyceryl monostearate; sorbitan esters, such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, and sorbitan monostearate; tyloxapol; lecithin; stearyl triethanolamine; laurylaminopropionic acid; and mixtures thereof. Said surfactant component or wetting agent, if present, normally form about 0.25% by weight to about 15% by weight, preferably from about 0.4% by weight to about 10% by weight, and more preferably from about 0.5% by weight to about 5% by weight, of the total weight of the composition.

A thickening agent or viscosity enhancing agent may be included to generally thicken the liquid composition, which normally improves the mouthfeel of the composition, and / or to help coat the lining of the gastrointestinal tract. While any suitable thickening agent may be included in the compositions of the present invention, a preferred thickening agent, when used, includes one or more of acacia, alginic acid bentonite, carbomer, sodium or calcium carboxymethyl cellulose, cetostearyl alcohol, methyl cellulose , ethylcellulose, glycerin, guar gum for gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, starch glycolate and sodium xanthan gum, sodium starch glycolate, and any sodium xcanthus combination thereof. The most preferred thickening agents are glycerin, hydroxypropylmethylcellulose, and xanthan gum, and any combination thereof. Such a thickening agent, if present, will normally form from about 0.1% by weight to 20% by weight, preferably from about 0.3% by weight to about 15% by weight, and more preferably from about 0.5% by weight. weight to 4% by weight, of the total weight of the composition.

A coloring agent, when included, can provide the compositions with a more aesthetic and / or distinctive appearance. Preferable coloring agents for inclusion in the present invention include one or more water-soluble synthetic organic food additives (for example, food colors, such as red food colors # 2 and 3, yellow food colors # 4 and 5 and blue food dyes # 1 and 2), water-insoluble lacquer dyes (for example, aluminum salts of the above water-soluble synthetic organic food additives, etc.), and natural pigments (for example, beta-carotene , chlorophyll, red iron oxide, etc.). Such a coloring agent, if present, will normally form from about 0.001% by weight to about 1% by weight, preferably from about 0.001% by weight to about 0.5% by weight, and more preferably from about 0.0075% by weight. to 0.25% by weight, of the total weight of the composition.

Examples of a suitable antioxidant component, if used, include one or more of the following: sulfites; ascorbic acid; ascorbates, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; Ascorbyl Palmitate; fumaric acid; ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallates, such as propyl gallate, octyl gallate, or dodecyl gallate; Vitamin E; and mixtures thereof. The antioxidant component provides long-term stability for liquid compositions. The addition of the antioxidant component can help to improve and ensure the stability of the compositions and makes the compositions stable even after six months at 40 ° C. A suitable amount of the antioxidant component, if present, is from about 0.01% by weight to about 3% by weight, preferably from about 0.05% by weight to about 2% by weight, of the total weight of the composition.

Solubilizing and emulsifying agents can be included to facilitate more uniform dispersion of the active ingredient or other excipient that is not generally soluble in the liquid carrier. Examples of a suitable emulsifying agent, if used, include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, ketostearyl alcohol, cetyl alcohol, and mixtures of the themselves. Examples of a suitable solubilizing agent include glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures of the themselves. Preferably, the solubilizing agent includes glycerin. The solubilizing or emulsifying agent is / are generally present in an amount sufficient to dissolve or disperse the active ingredient, ie tapentadol, in the vehicle. Typical amounts when a solubilizer or emulsifier is included are from about 1% by weight to about 80% by weight, preferably from about 20% by weight to about 65% by weight, and more preferably from about 25% by weight to about 55 % by weight, of the total weight of the composition.

A suitable isotonizing agent, if used, includes sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof. A suitable amount of the isotonizing agent, when included, is usually from about 0.01% by weight to about 15% by weight, more preferably from about 0.3% by weight to about 4% by weight, and more preferably from about 0.5% by weight to 3% by weight, of the total weight of the composition.

Compositions E1 to E8 are summarized in the table below. Only compositions containing additionally a preservative form part of the claimed invention.

Compositions F1 to F8 are summarized in the table below. Only compositions containing additionally a preservative form part of the claimed invention.

A further aspect of the invention relates to a pharmaceutical dosage form comprising the pharmaceutical composition according to the invention. All the preferred embodiments described above in relation to the composition according to the invention also apply to the dosage form according to the invention. Preferably, the dosage form is selected from the group consisting of oral solutions, oral gels, suspensions, emulsions, liquid or gel filled capsules, liquid filled tablets, metered liquid dispensing devices, atomizers, nebulizers, aerosols, and edible liquid-releasing capsules. Compared to solid dosage forms, liquid dosage forms have several advantages. They can be exact doses, for example according to the body weight of the patients, which can be particularly important in pediatric patients. In addition, they can be administered by means of tubes, for example, when the patient is young or has problems swallowing.

Furthermore, liquid dosage forms tend to have a more rapid release, that is, the concentration of the active ingredient in serum or plasma increases faster than after administration of a solid dosage form (rapid start), even if the Solid dosage form is qualified as immediate release (IR) dosage form. Such a rapid onset is particularly desirable in pain management, since pain relief is to be achieved as quickly as possible.

Preferably, the dosage form according to the invention is adapted for administration once a day, twice a day, three times a day, four times a day, five times a day, six times a day or even more frequently. In a preferred embodiment, the dosage form according to the invention is adapted for administration to pediatric patients. For purposes of specification, pediatric patients preferably encompass infants, children, and adolescents. Preferably, the upper age limit for these patients is 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

In this regard, the surprising preservative properties of tapentadol are even more beneficial, as the drug approval authorities have established stricter regulations regarding the presence of preservative in medicines for pediatric patients. Furthermore, since tapentadol is suitable for pain treatment in patients suffering from serious diseases, for example, for the treatment of cancer pain, such patients, including pediatric patients, are generally treated simultaneously with other drugs, for example, chemotherapeutic agents that have serious side effects. Under these circumstances, it is even more desirable not to expose these pediatric patients to preservatives, if avoidable. A further aspect of the invention relates to the pharmaceutical composition according to the invention, as described above, or the pharmaceutical dosage form according to the invention, as described above for use in the treatment of pain.

A further aspect of the invention relates to the use of tapentadol for the manufacture of the pharmaceutical composition according to the invention, as described above, or the pharmaceutical dosage form according to the invention, as described above for the treatment of pain.

Preferably, the pain is selected from the group consisting of inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain, and cancer pain.

Furthermore, the use of tapentadol or a physiologically acceptable salt thereof as a preservative is described.

The following examples further illustrate the invention, but should not be construed as limiting its scope.

Example 1:

Determination of the effective antimicrobial concentration of tapentadol hydrochloride

Tapentadol hydrochloride in a concentration of 10 mg / ml free base has been revealed in initial studies to have high antimicrobial activity and high activity against yeast. The activity against mold ( Aspergillus niger) is lower but still within the limits of the requirements of the European Pharmacopoeia. The activity of tapentadol hydrochloride against Aspergillus niger has been evaluated at lower pharmacological concentrations and at pH 4.0 and 5.0 in formulations containing citric acid as a buffer system and hydrochloric acid and sodium hydroxide to adjust the pH.

Results:

At pH 5 there is better antimicrobial activity of tapentadol hydrochloride than at pH 4 after 14 and 28 days (see Table 1).

Table 1 arithmic reduction of As er illus ni er 14 28 days after inoculation

European Pharmacopoeia requirements for oral solutions (1 log reduction after 14 and no increase after 28 days relative to A. niger mold) are met at pH 4 for tapentadol concentrations equal to or greater than 8 mg / ml and at pH 5 for concentrations equal to or greater than 4 mg / ml.

Conclusion:

At pH 4, the minimum concentration of 8 mg / ml of tapentadol is necessary to meet the requirements of the European Pharmacopoeia regarding Aspergillus niger. There is a concentration limit of 4-8 mg / ml for the antimicrobial efficacy of tapentadol as a function of pH.

Example 2:

Antimicrobial robustness test of 20 mg / ml tapentadol oral solution

The 20 mg / ml tapentadol solution has been tested for antimicrobial robustness. As the drug substance tapentadol hydrochloride acts as the preservative, the antimicrobial activity of the formulation was determined at 100% and 90% of the drug substance at three different pH levels (target, upper and lower limit - 3.5 - 4-4.5). The following formulation compositions were used for the antimicrobial robustness test (Table 2):

Table 2 Com osition of formulations concentrations in m / ml

The test results revealed that 20 mg / ml of tapentadol oral solution has a high antibacterial effect and a high effect on inhibiting the growth of C. albicans at the three pH levels tested, even at a concentration below 90%. . The effect on A. niger is minor, but the requirements of the European Pharmacopoeia and USP, which show the global spectrum of tapentadol hydrochloride as a preservative, are met for both concentrations.

Example 3:

Tapentadol Oral Solution 4mg / ml Antimicrobial Robustness Test ( Lower Sodium Benzoate Concentration )

The 4 mg / ml tapentadol solution has also been tested for antimicrobial robustness. At this concentration, the antimicrobial effect of the drug substance tapentadol hydrochloride is not sufficiently pronounced. Therefore, sodium benzoate has been used as a preservative in the formulation. The antimicrobial activity of the formulation was determined with 100% at the target pH of 4 and with 80% sodium benzoate at the pH limits of 3.5 and 4.5.

The following formulation compositions were used for the antimicrobial robustness test (Table 3).

Table 3 Com osition of formulations concentrations in m / ml

The test results revealed that the 4 mg / ml tapentadol oral solution including 1.77 mg / ml sodium benzoate at target pH did not meet the requirements of the USP and the European Pharmacopoeia after an increase in Ps . Aeruginosa from day 14 to day 28.

Both formulations containing 80% preservative at the pH limits were met, however, the obtained log reduction of 3.3 for E. coli is borderline.

Example 4:

Tapentadol Oral Solution 4 mg / ml Antimicrobial Robustness Test ( Higher Sodium Benzoate Concentration)

Based on the results obtained, the test was repeated using a formulation containing a higher concentration of 2.36 mg / ml of preservative instead of 1.77 mg / ml of sodium benzoate.

The above study of Example 3 was repeated using a formulation of 4 mg / ml of tapentadol and 2.36 mg / ml of sodium benzoate (corresponding to 2 mg / ml of benzoic acid). The antimicrobial activity of the formulation was determined with 100% at the target pH of 4 and with 80% sodium benzoate at the pH limits of 3.5 and 4.5.

The following formulation compositions were used for the antimicrobial robustness test (Table 4).

Table 4 Com osition of formulations concentrations in m / ml

The test results revealed that all USP and European Pharmacopoeia requirements are met at the target pH 4 and 100% sodium benzoate, as well as for the other two formulations (pH limits at 80% sodium benzoate) . Therefore, it can be concluded that 2.36 mg / ml of sodium benzoate (corresponding to 2 mg / ml of benzoic acid) is sufficient to provide antimicrobial efficacy for a 4 mg / ml tapentadol oral solution.

Example 5:

In-use stability study with 20 mg / ml tapentadol oral solution

For tapentadol oral solution intended to be used as a multiple dosage form, an in-use stability study was conducted with the focus on microbial stability. Therefore, over a period of 4 weeks, approx. 1 ml of product was extracted 2 times in each working day in an environment not controlled by simulating the domestic conditions for the patients. The test was carried out on a total quantity of 10 bottles. The solution was representatively removed (by dosing pipet) and the bottles were stored at room temperature after each extraction. After the 4 week period, a microbial count was performed on the residual solution from all tested bottles.

No microbial growth was observed in any of the bottles showing the overall good antimicrobial properties of tapentadol in a 20 mg / ml oral solution. It could be shown that the formulation shows a sufficient antimicrobial effect from the incorporated drug substance.

Example 6:

Determination of Chemical Stability of Tapentadol Oral Solution 10 mg / ml

The chemical properties of a preliminary formulation containing tapentadol in the concentration of 10 mg / ml have been evaluated at different temperatures during a storage period of 6 months. As preservatives, sodium benzoate was used in the formulation strategy, while methyl- and propyl parabens were used in a separate formulation strategy.

Results:

After 1, 3 and 6 months at room temperature (25 ° C) and high temperature (50 ° C) the 10 mg / ml solution was evaluated with respect to IFA tapentadol test parameters, degradation products, as well as the preservative test. The IFA test remains stable within 6 months of storage life. For the paraben formulation, a degradation product was observed after 3 months with higher level at higher temperature.

Conclusion:

The formulation containing sodium benzoate showed less degradation products compared to the paraben formulation. Therefore, sodium benzoate is used as a selected preservative for further development.

Example 7:

Chemical Stability of 4 and 20 mg / mL Tapentadol Oral Solution

To investigate the chemical stability of oral tapentadol solutions at different concentrations (4 and 20 mg / ml), stability studies were performed for 3 months evaluating the following parameter aspects, tapentadol test, degradation, test preservative (only for the 4 mg / ml formulation) and pH at 25 ° C / 60% RH, 40 ° C / 75% RH and 50 ° C. In addition, for the 4 mg / ml solution, 2-week cyclical studies (-15 ° C to 30 ° C as well as 5 ° C to 40 ° C) were performed.

Results:

Stability trends for both formulations (4 and 20 mg / ml) of tapentadol oral solution independent on the flavor used (raspberry flavor or flavor masker) are not evident after a storage time of 3 months showing good stability of IFA tapentadol hydrochloride in solution. Example 8:

Antimicrobial effect of tapentadol at pH 3 and pH 8

A tapentadol solution was prepared with a concentration of 15 mg / ml tapentadol (free base). The pH value was adjusted to the target value of 3 or 8 using citric acid and 1N NaOH solution, respectively. No additional buffer system was added. To ensure that the placebo solution does not show an antimicrobial effect by itself, a placebo solution with pH 8 was prepared, with the focus on the same pH value, even though a different amount of NaOH 1 solution was used. N to adjust the pH.

The formulations were prepared, filled into glass bottles and sterilized in an autoclave for 30 min at 121 ° C and 2 bar. The sterilized glass bottles were enriched with Staphylococcus aureus ( Staph. Aureus), Pseudomonas aeruginosa ( Ps. Aerouginosa), Aspergillus niger ( Asp. Niger) and Candida albicans for the "Efficacy of antimicrobial preservation" test based on the Pharmacopoeia European 6.6 monograph 5.1.3.

The European Pharmacopoeia test acceptance criteria for parenteral preparations are given in the Table (SA = no increase, SR = no recovery). Criterion A expresses the recommended efficacy to be achieved, in justified cases where criterion A cannot be achieved, for example, for reasons of an increased risk of adverse reaction, criterion B must be satisfied. To reduce the number of experiments for this first start-up In the course of pH value experiments, the test points at 6 and 24 hours were replaced with a test point at 30 min (Table 5).

Table 5 Acceptance criteria for parenteral preparations for "Efficacy of antimicrobial preservation" (European Pharmacopoeia)

The results for the microbial test of the solutions for each bacteria / fungus are given in Tables 6 to 9.

Table 6 Microbial growth of Sta h. aureus

Table 7 Microbial growth of Ps. aeru inosa

Table 8 Microbial growth of As. nor er

Table 9 Microbial growth of Candida albicans

In the absence of additional preservatives, the tapentadol solution with pH 3 is not sufficiently preserved according to the European Pharmacopoeia (crit. A and B) for Asp. niger and Cand. albicans, while the tapentadol solution with pH 8 passed the crit. A and B for all bacteria and fungi tested. The pH 8 placebo solution does not show any preservative effect of the solution itself, so the antimicrobial effect of the formulation containing tapentadol HCl is a consequence of the added amount of tapentadol HCl. Taking these results into account, a clear dependence of the pH value on the preservative effect of the tapentadol HCl solution could be demonstrated.

The tapentadol HCl solution with a pH value greater than 8 has an improved antimicrobial effect over the pH 3 solution, thus a clear dependence of the pH value of the solution on the preservative effect of tapentadol was found.

Claims (13)

1. An aqueous pharmaceutical composition that contains tapentadol or a physiologically acceptable salt thereof and that is adapted for oral administration, where the composition additionally contains a preservative, where the preservative content is at most 90% of the content that would be necessary according to the European Pharmacopoeia in order to sufficiently preserve the pharmaceutical composition in the absence of tapentadol. 2. The composition according to claim 1, which (i) additionally contains a buffer; me (ii) has a pH value within the range of 3.0 to 6.5. The composition according to claim 1 or 2, wherein the concentration of tapentadol is equal to or less than 50 mg / ml, based on the total volume of the composition. 4. The composition according to any of the preceding claims, wherein the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine , chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, isobyl paraben, isobyl paraben, isobyl paraben , benzyl paraben, sorbic acid, and potassium sorbate. The composition according to any of the preceding claims, wherein the content of the preservative is at most 5.0% by weight, based on the total weight of the composition. The composition according to any of the preceding claims, wherein the sum of the tapentadol concentration and the preservative concentration is equal to or less than 50 mg / ml, based on the total volume of the composition. The composition according to any of the preceding claims, which has a shelf life under accelerated storage conditions of at least 3 months. 8. The composition according to any of the preceding claims, which is selected from the group consisting of syrups, drops, solutions, dispersions, suspensions and emulsions. 9. A pharmaceutical dosage form comprising the pharmaceutical composition according to any one of claims 1 to 8. The dosage form according to claim 9, which is selected from the group consisting of oral solutions, oral gels, suspensions, emulsions, and liquid or gel filled capsules. The dosage form according to claim 9 or 10, which is adapted for administration to pediatric patients. 12. The pharmaceutical composition according to any one of claims 1 to 8 or the pharmaceutical dosage form according to any one of claims 9 to 11 for use in the treatment of pain. The pharmaceutical composition or pharmaceutical dosage form according to claim 12, wherein the pain is selected from the group consisting of acute pain and chronic pain.