Patent Description:
Various formulations for parenteral administration are known from the prior art.

<CIT> discloses a therapeutic calcitriol solution which is suitable for packaging into pharmaceutical vials without producing discoloration of the antioxidant component of the solution.

<CIT> relates to a method for obtaining aqueous formulations with easily oxidizable active principles, notably phenols, stable over prolonged period, which consists of subjecting them to extreme deoxygenation by bubbling with an inert gas and/or placing under vacuum, protecting them against possible resorption of oxygen by keeping them under an inert gas atmosphere by filling, under inert gas, into bottles previously cleared of air by insufflation with inert gas, then subjecting them, whilst stoppering, to low pressure as obtained in the bottle, of <NUM>,<NUM> Pa maximum, and thus obtaining aqueous solutions having a residual oxygen concentration in the solution below <NUM> ppm, and preferably of the order of <NUM> ppm and even <NUM> ppm.

<CIT> relates to parenterally administrable, especially infusible, aqueous paracetamol solutions which are stable in storage and free of particles and discoloration. Said solutions contain a mixture of: a) between <NUM> and <NUM> grams of paracetamol per liter, and b) between <NUM> and <NUM> grams of at least one physiologically compatible antioxidant per liter, selected from the group comprising ascorbic acid, N-acetyl-L-cysteine and stabilizer compounds containing SH groups which are different from N-acetyl-L-cysteine. The aqueous solution is free of organic solvents and has a pH value of between <NUM> and <NUM> and an oxygen content of less than <NUM> milligrams per liter.

<CIT> a method for producing stabilized antioxidant-free solutions based on phenolic substances which consists in: deoxygenation of the solutions with an inert gas, and in deoxygenation of gas holdups of the vessels, of the manufacturing pipes and inerting of ampoules and flasks containing the solute with a dense inert rare gas such as argon, at low temperature and with pH adjusted above <NUM> and below <NUM> to obtain stable solutions of phenolic substances containing not more than <NUM> ppm of oxygen in the solution, which is filtered by double sterilizing filtration.

<CIT> discloses stabilized aqueous compositions of tissue factor pathway inhibitor (TFPI) or TFPI variants that comprise a solubilizing agent, an antioxidant, and a buffer system. The combination of a solubilizing agent and an antioxidant can lead to a significant improvement in the storage life of TFPI or TFPI variant compositions. The solubilizing agent and antioxidant substantially counteract the effects of TFPI or TFPI variant degradation through aggregation and oxidation.

<CIT> relates to a liquid formulation, stable to oxidation, based on a phenolic active principle susceptible to oxidation such as paracetamol in an aqueous solvent and to a method for preparing such formulation. The formulation and the method are characterized in that the active principle is admixed in the aqueous solvent having a temperature between <NUM> and <NUM>, a pH between <NUM> and <NUM> and an oxygen concentration below <NUM>%.

<CIT> concerns a stable aqueous pharmaceutical composition comprising <NUM>-[(2RS)-<NUM>-cyclopropyl-<NUM>,<NUM>-dimethoxy-<NUM>-<NUM>-benzopyran-<NUM>-ylmethyl]-pyrimidine-<NUM>,<NUM>- diamine in form of the water soluble methanesulfonic acid salt, a physiological sodium chloride solution, ethanol and Povidone <NUM> PF, the liquid having a pH of over and above <NUM>, but not higher than <NUM>, and wherein the oxygen amount is controlled to be <NUM> ppm or less; which can be sterilized by filtration and/or by heated treatment, stored for longer time periods and which can be used for bolus injection or diluted for i.

<CIT> relates to stable liquid formulations of paracetamol for pharmaceutical use and to a method of preparation of stable paracetamol solutions.

<CIT> discloses a stable ready-to-use pharmaceutical composition comprising pemetrexed or pharmaceutically acceptable salts thereof, wherein the composition is free from antioxidants, amino acids and chelating agents. Also provided is a process for preparing a stable ready-to-use pharmaceutical composition comprising the steps: i) purging inert gas into a parenterally acceptable aqueous solvent until the dissolved oxygen content of the solvent comes to less than <NUM>/L, preferably less than <NUM>/L; ii) adding pemetrexed disodium under stirring; iii) adjusting the pH of the resulting solution to between <NUM> to <NUM>; iv) optionally adding additional aqueous solvent; wherein the composition is purged with inert gas throughout the entire process.

Pharmaceutical dosage forms of Tapentadol are also known from the prior art, e.g., <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <NPL>.

<CIT> relates to an aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof and being adapted for oral administration. The composition has excellent storage stability without relying on the presence of high amounts of preservatives.

<CIT> discloses parenteral formulations for the administration of Tapentadol. The concentration of Tapentadol in these formulations is preferably below <NUM>/mL. The concentration of Tapentadol in the exemplified formulations according to <CIT> is <NUM>/mL and <NUM>/mL, respectively. According to <CIT> Tapentadol exhibits antimicrobial properties. These antimicrobial properties are more pronounced at higher pH values. In consequence, preservatives may be omitted or their content in the formulations may at least be decreased. The complete absence of preservatives is preferred when the content of Tapentadol is sufficiently high so that due to its preserving property the desired shelf life or in use stability can be achieved by the presence of Tapentadol itself. For that purpose, the concentration of Tapentadol is preferably at least <NUM>/mL, based on the total volume of the composition.

<CIT> discloses a Tapentadol hydrochloride injection, particularly a small-capacity injection and a preparation method thereof. The injection is composed of Tapentadol hydrochloride or Tapentadol alkali with active ingredients, and medicinal carriers. The Tapentadol hydrochloride injection can be suitable for small-capacity injections with various sizes. Compared with the conventional oral preparations, the tapentadol hydrochloride injection has the advantages of high bioavailability, good absorption effect of medicine, fast distribution, good treatment effect and the like. The medicinal occasion of the Tapentadol hydrochloride is enlarged, and the clinical medication level of the Tapentadol hydrochloride is improved.

It has been found, however, that in solutions the dissolved Tapentadol may tend to decomposition (chemical degradation) having a negative impact on storage stability of parenteral formulations.

It is an object of the invention to provide parenteral formulations of Tapentadol that have advantages compared to the parenteral formulations of Tapentadol of the prior art. The parenteral formulations should contain Tapentadol or physiologically acceptable salts thereof at sufficiently high concentrations but at the same time should have a good storage stability and shelf life.

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

The inventors have unexpectedly found that chemical stability of Tapentadol can be substantially improved by providing an adjusted and robustly maintained pH value. While conventional diluted solutions of Tapentadol are instable and show a successive increase of the pH value after autoclaving and long-term storage, the pH value of the composition according to the invention remains substantially unchanged.

Therefore, it has been surprisingly found that adjusting, especially lowering the pH value of the pharmaceutical composition for parenteral administration has a stabilizing effect so that decomposition (degradation) of Tapentadol can be significantly reduced or even suppressed, also under stress conditions after repeated autoclaving. It appears that under certain conditions antimicrobial effect of Tapentadol on the one hand (cf. <CIT>) and chemical stability of Tapentadol on the other hand are both function of the pH value, but in opposite directions.

Further, it has been surprisingly found that at low pH values below <NUM>, the stability of Tapentadol is a function of the buffer concentration, whereas the buffer has a relative stabilizing effect (the higher the buffer concentration, the less degradation). In contrast, however, it has been surprisingly found that at higher pH values of <NUM>, i.e. outside the pH range according to the invention, the stability of Tapentadol is also function of the buffer concentration, whereas the buffer has a relative destabilizing effect (the higher the buffer concentration, the more degradation). Unexpectedly, within the pH range according to the invention, Tapentadol is stable against chemical decomposition at various buffer concentrations.

Further, it has been surprisingly found that even at pH values of the composition within the range of from <NUM> to <NUM>, stable pharmaceutical compositions for parenteral administration can be provided that need neither a preservative nor an antioxidant and are nevertheless storage stable for a long period of time.

Still further, it has been surprisingly found that the composition remains chemically stable under the harsh conditions of autoclaving, e.g. for at least <NUM> at <NUM> bar and <NUM>. Thus, the storage stability of the composition according to the invention does not need to rely on the antimicrobial effect of Tapentadol alone. Autoclaving achieves sufficient storage stability against antimicrobial decontamination without the need for preservatives.

Furthermore, it has been surprisingly found that Tapentadol may be sufficiently stabilized against chemical decomposition by degassing and providing the composition under an inert gas atmosphere, respectively, e.g. by means of degassing with nitrogen purge. The use of antioxidants can thus be avoided.

A first aspect of the invention relates to a stable aqueous pharmaceutical composition for parenteral administration being stable upon autoclaving and comprising Tapentadol or a physiologically acceptable salt thereof, wherein the concentration of Tapentadol is greater than <NUM>/mL, preferably at least <NUM>/mL, more preferably at least <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition; wherein the composition comprises a buffer system; the buffer system comprises at least one conjugate base and at least one conjugate acid, wherein said at least one conjugate base and said at least one conjugate acid are selected from the group consisting of citrate, hydrogencitrate, dihydrogencitrate and citric acid; the total concentration of said at least one conjugate base and said at least one conjugate acid is at least <NUM> mmol/L, based on the total content of the at least one conjugate base and the at least one conjugate acid and based on the total volume of the composition; and wherein the pH value of the composition is within the range of from <NUM> to not greater than <NUM>.

Preferably the composition according to the invention has undergone autoclaving, preferably at least for at least <NUM> minutes at least at <NUM> bar and at least at <NUM>, and the pH value before autoclaving as well as the pH value after autoclaving is independently within the range of from <NUM> to not greater than <NUM>.

The term "pharmaceutical composition" includes any pharmaceutical preparation or formulation that is customized for being administered to a human being or animal. Preferably, the composition is an aqueous solution.

Unless expressly stated otherwise, all percentages are weight percent, relative to the total weight of the pharmaceutical composition according to the invention.

Unless expressly stated otherwise, all values in mL and L refer to the total volume of the pharmaceutical composition according to the invention.

Unless expressly stated otherwise, parameters and conditions (such as temperature, pressure, relative humidity, volume, weight, concentration, pH value, titration acidity, capacity of buffer system, osmolarity, content of molecular oxygen, storage stability, color, and the like) are determined and measured in accordance with the requirements and recommendations as set forth in the European Pharmacopoeia (Ph. Unless expressly stated otherwise, all references to Ph. refer to the version that is officially valid in September <NUM>. General conditions are typically ambient conditions.

For the purpose of the specification, the term "Tapentadol" includes the free base ((1R,2R)-<NUM>-(<NUM>-dimethylamino-<NUM>-ethyl-<NUM>-methyl-propyl)-phenol) as well as any physiologically acceptable salt thereof, particularly the hydrochloride ((1R,2R)-<NUM>-(<NUM>-dimethylamino-<NUM>-ethyl-<NUM>-methyl-propyl)-phenol hydrochloride).

Thus, unless expressly stated otherwise, the term "Tapentadol" does not only refer to the free base but also to any physiologically acceptable salt. Further, unless expressly stated otherwise, all amounts, contents and concentrations are equivalents related to Tapentadol free base.

Preferably, Tapentadol is present in the composition according to the invention as Tapentadol hydrochloride. In a preferred embodiment, Tapentadol is present as solubilized Tapentadol hydrochloride salt form A. Form A of Tapentadol hydrochloride is known from the prior art. In this regard, it can be referred to e.g. <CIT>. Preferably, form A is characterized by showing at least one or more X-ray lines (<NUM>-theta values) in a powder diffraction pattern when measured using Cu Kα radiation selected from the list comprising <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM> and <NUM>±<NUM>.

The concentration of Tapentadol in the composition according to the invention is greater than <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition.

Preferably, the concentration of Tapentadol in the composition according to the invention is at least <NUM>/mL or at least <NUM>/mL, more preferably at least <NUM>/mL or at least <NUM>/mL, still more preferably at least <NUM>/mL or at least <NUM>/mL, yet more preferably at least <NUM>/mL or at least <NUM>/mL, even more preferably at least <NUM>/mL or at least <NUM>/mL, most preferably at least <NUM>/mL or at least <NUM>/mL, and in particular at least <NUM>/mL or at least <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition.

In preferred embodiments according to the invention, the concentration of Tapentadol in the composition according to the invention is at least <NUM>/mL or at least <NUM>/mL, more preferably at least <NUM>/mL or at least <NUM>/mL, still more preferably at least <NUM>/mL or at least <NUM>/mL, yet more preferably at least <NUM>/mL or at least <NUM>/mL, even more preferably at least <NUM>/mL or at least <NUM>/mL, most preferably at least <NUM>/mL or at least <NUM>/mL or at least <NUM>/mL, and in particular at least <NUM>/mL or at least <NUM>/mL or at least <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition.

Preferably, the concentration of Tapentadol in the composition according to the invention is at most <NUM>/mL or at most <NUM>/mL, more preferably at most <NUM>/mL or at most <NUM>/mL, still more preferably at most <NUM>/mL or at most <NUM>/mL, yet more preferably at most <NUM>/mL or at most <NUM>/mL, even more preferably at most <NUM>/mL or at most <NUM>/mL, most preferably at most <NUM>/mL or at most <NUM>/mL, and in particular at most <NUM>/mL or at most <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition.

In preferred embodiments according to the invention, the concentration of Tapentadol in the composition according to the invention is at most <NUM>/mL or at most <NUM>/mL, more preferably at most <NUM>/mL or at most <NUM>/mL, still more preferably at most <NUM>/mL or at most <NUM>/mL, yet more preferably at most <NUM>/mL or at most <NUM>/mL, even more preferably at most <NUM>/mL or at most <NUM>/mL, most preferably at most <NUM>/mL or at most <NUM>/mL, and in particular at most <NUM>/mL or at most <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition.

According to a preferred embodiment, the concentration of Tapentadol in the composition according to the invention is within the range of <NUM>±<NUM>/mL, more preferably <NUM>±<NUM>/mL, still more preferably <NUM>±<NUM>/mL, yet more preferably <NUM>±<NUM>/mL, even more preferably <NUM>±<NUM>/mL, most preferably <NUM>±<NUM>/mL, and in particular <NUM>±<NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition.

The composition according to the invention is aqueous, i.e. the composition comprises water which is typically water for injection purposes, i.e. highly pure and sterile water.

Preferably, the water content is at least <NUM> wt. -%, more preferably at least <NUM> wt. -%, still more preferably at least <NUM> wt. -%, yet more preferably at least <NUM> wt. -%, most preferably at least <NUM> wt. -% and in particular at least <NUM> wt. -%, based on the total weight of the composition.

Besides water, the composition according to the invention may contain further solvents.

Further suitable solvents include all types of physiologically acceptable hydrophilic solvents, preferably selected from the group consisting of ethanol, glycerol, propylene glycol, <NUM>,<NUM>-butanediol and macrogol <NUM>.

Preferably, however, the composition according to the invention does not contain further solvents besides water.

The pH value of the composition according to the invention is buffered, i.e. the composition comprises a buffer system (i.e. a pair of at least one conjugate acid and at least one conjugate base).

Preferably, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid, wherein said at least one conjugate base and said at least one conjugate acid are selected from the group consisting of citrate, hydrogencitrate, dihydrogencitrate and citric acid.

A skilled person is fully aware that multiprotonic acids can form more than a single pair of a conjugate acid and a conjugate base. For example, citric acid is a triprotonic acid so that it forms the following pairs of conjugate acid and conjugate base: (i) citric acid - dihydrogencitrate, (ii) dihydrogencitrate - hydrogencitrate, (iii) and hydrogencitrate - citrate. In other words, any of citric acid, dihydrogencitrate and hydrogencitrate can be the acid of a buffer system with the conjugate base. A skilled person is also fully aware that the conjugate acids and conjugate bases are in equilibrium with one another and that the predominant species that are present in a mixture of citrate, hydrogencitrate, dihydrogencitrate and citric acid can be determined on the basis of the pKA values and the pH value of the composition.

For the purpose of the specification, the expression "buffer system" refers to the total quantity of conjugate acids and conjugate bases. For example, when the buffer system is derived from citric acid, i.e. is a citrate buffer system, the expression "buffer system" refers to the total quantity of citrate, hydrogencitrate, dihydrogencitrate and citric acid. Further, a skilled person is fully aware that a buffer system, e.g. citric acid as conjugate acid and sodium dihydrogencitrate as conjugate base, can be established either by adding citric acid and an appropriate amount of sodium hydroxide, or sodium citrate and an appropriate amount of hydrochloric acid, or citric acid and sodium dihydrogencitrate as such. Unless expressly stated otherwise, "sodium citrate" is synonymous to "trisodium citrate". Sodium citrate dihydrate (= trisodium citrate dihydrate) thus has the linear formula HOC(COONa)(CH2EOONa)<NUM> · <NUM><NUM>O and a relative molecular weight of <NUM>/mol.

Accordingly, in case that the composition contains an appropriate amount of Tapentadol in form of its hydrochloride, a buffer system can be established by adding sodium citrate, e.g. in form of sodium citrate dihydrate. Nevertheless, Tapentadol and its physiologically acceptable salts are not to be considered as conjugate acid or conjugate base of the buffer system.

Preferably, the concentration of the buffer system, preferably sodium citrate or its dihydrate, is adjusted to provide a sufficient buffer system capacity.

The composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid selected from the group consisting of citrate, hydrogencitrate, dihydrogencitrate and citric acid.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above and having a total concentration (i.e. an overall concentration of all conjugate bases and all conjugate acids of the buffer system) of at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%; more preferably at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%; still more preferably at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%; yet more preferably at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%; even more preferably at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%; most preferably at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. - %, or at least <NUM> wt. -%; and in particular at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -%, or at least <NUM> wt. -% , or at least <NUM> wt. -% , or at least <NUM> wt. -% , or at least <NUM> wt. -% , or at least <NUM> wt. -% , or at least <NUM> wt. -% , or at least <NUM> wt. -% , or at least <NUM> wt. -%; based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

Preferably, the total concentration of said at least one conjugate base and said at least one conjugate acid is at least <NUM> wt. -%, more preferably at least <NUM> wt. -%, still more preferably at least <NUM> wt. -%, yet more preferably at least <NUM> wt. -%, and in particular at least <NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above and having a total concentration of at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%; more preferably at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%; still more preferably at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%; yet more preferably at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%; even more preferably at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%; most preferably at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%; and in particular at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. - %, or at most <NUM> wt. -%, or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -%, or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -% , or at most <NUM> wt. -%; based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

Preferably, the total concentration of said at least one conjugate base and said at least one conjugate acid is not more than <NUM> wt. -%, more preferably not more than <NUM> wt. -%, still more preferably not more than <NUM> wt. -%, yet more preferably not more than <NUM> wt. -%, and most preferably not more than <NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above and having a total concentration within the range of from <NUM> to <NUM> wt. -%, or from <NUM> to <NUM> wt. -%, or from <NUM> to <NUM> wt. -%, , or from <NUM> to <NUM> wt. -% , or from <NUM> to <NUM> wt. -%, more preferably within the range of from <NUM> to <NUM> wt. -%, still more preferably within the range of from <NUM> to <NUM> wt. -%, yet more preferably within the range of from <NUM> to <NUM> wt. -%, even more preferably within the range of from <NUM> to <NUM> wt. -%, most preferably within the range of from <NUM> to <NUM> wt. -%, and in particular within the range of from <NUM> to <NUM> wt. -% based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

Preferably, the total concentration of said at least one conjugate base and said at least one conjugate acid is within the range of from <NUM> to <NUM> wt. -%, more preferably within the range of from <NUM> to <NUM> wt. -%, still more preferably within the range of from <NUM> to <NUM> wt. -%, and most preferably within the range of from <NUM> to <NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

Preferably, the buffers system comprises sodium citrate or its dihydrate such that depending upon the adjusted pH value of the composition, citrate, hydrogencitrate, dihydrogencitrate and citric acid are in equilibrium with one another.

In a preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In another preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In still another preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In yet another preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In even another preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In a further preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

In another preferred embodiment, the content of the buffer system, preferably sodium citrate or its dihydrate, is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the at least one conjugate base and the at least one conjugate acid and based on the total weight of the composition.

The composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid and having a total concentration of at least <NUM> mmol/L; preferably at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L; yet more preferably at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L; even more preferably at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L; most preferably at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L; and in particular at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L, or at least <NUM> mmol/L; based on the total content of the at least one conjugate base and the at least one conjugate acid and based on the total volume of the composition.

Preferably, the total concentration of said at least one conjugate base and said at least one conjugate acid is at least <NUM> mmol/L, still more preferably at least <NUM> mmol/L, yet more preferably at least <NUM> mmol/L, and most preferably at least <NUM> mmol/L, based on the total content of the at least one conjugate base and the at least one conjugate acid and based on the total volume of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above wherein the total concentration of protonated or deprotonated acidic functional groups (equivalents) is at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; more preferably at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; still more preferably at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; yet more preferably at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; even more preferably at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; most preferably at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; and in particular at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L, or at least <NUM> mmol-eq/L; based on the total quantity of said protonated or deprotonated acidic functional groups and based on the total volume of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above and having a total concentration of at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; more preferably at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; still more preferably at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; yet more preferably at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; even more preferably at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; most preferably at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; and in particular at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L, or at most <NUM> mmol/L; based on the total content of the at most one conjugate base and the at most one conjugate acid and based on the total volume of the composition.

Preferably, the total concentration of said at least one conjugate base and said at least one conjugate acid is not more than <NUM> mmol/L, more preferably not more than <NUM> mmol/L, still more preferably not more than <NUM> mmol/L, yet more preferably not more than <NUM> mmol/L, and most preferably not more than <NUM> mmol/L, based on the total content of the at least one conjugate base and the at least one conjugate acid and based on the total volume of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above; wherein the total concentration of said protonated or deprotonated acidic functional groups (equivalents) is at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; more preferably at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; still more preferably at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; yet more preferably at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; even more preferably at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; most preferably at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; and in particular at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L, or at most <NUM> mmol-eq/L; based on the total quantity of said protonated or deprotonated acidic functional groups and based on the total volume of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above and having a total concentration within the range of <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L, or <NUM>±<NUM> mmol/L; based on the total content of the at most one conjugate base and the at most one conjugate acid and based on the total volume of the composition.

Preferably, the total concentration of said at least one conjugate base and said at least one conjugate acid is within the range of from <NUM> to <NUM> mmol/L, more preferably within the range of from <NUM> to <NUM> mmol/L, still more preferably within the range of from <NUM> to <NUM> mmol/L, yet more preferably within the range of from <NUM> to <NUM> mmol/L, and most preferably within the range of from <NUM> to <NUM> mmol/L, based on the total content of the at least one conjugate base and the at least one conjugate acid and based on the total volume of the composition.

In preferred embodiments, the composition according to the invention comprises a buffer system comprising at least one conjugate base and at least one conjugate acid as described above; wherein the total concentration of protonated or deprotonated acidic functional groups (equivalents) is within the range of <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L, or <NUM>±<NUM> mmol-eq/L; based on the total quantity of said protonated or deprotonated acidic functional groups and based on the total volume of the composition.

The buffered pH value of the composition according to the invention is within the range of from <NUM> to not greater than <NUM>.

In preferred embodiments, the buffered pH value of the composition according to the invention is not greater than <NUM>.

Preferably, the buffered pH value of the composition according to the invention is within the range of from <NUM> to <NUM>.

In yet another preferred embodiment, the composition has a buffered pH value within the range of <NUM>±<NUM> or <NUM>±<NUM>, and in particular <NUM>±<NUM> or <NUM>±<NUM>.

In another preferred embodiment, the composition has a buffered pH value within the range of <NUM>±<NUM>.

Preferably, the content of molecular oxygen of the composition, i.e. the content of dissolved molecular oxygen, is not more than <NUM>/L, more preferably not more than <NUM>/L, still more preferably not more than <NUM>/L, yet more preferably not more than <NUM>/L, and most preferably not more than <NUM>/L, based on the total volume of the composition.

Preferably, the content of molecular oxygen in the composition is not more than <NUM>/L, more preferably <NUM>/L, still more preferably <NUM>/L, based on the total volume of the composition.

In preferred embodiments, the content of molecular oxygen in the composition is not more than <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L.

In preferred embodiments, the content of molecular oxygen in the composition is not more than <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L, or <NUM>/L.

The composition according to the invention is preferably packaged in containers, e.g. in glass ampoules. The inner space of the container typically comprises at least two phases, namely a liquid phase and a gaseous phase (headspace). As far as the content of molecular oxygen is concerned, the oxygen content in the liquid phase and the oxygen content in the headspace are typically equilibrated. Thus, measuring the content of molecular oxygen in the gaseous phase of the headspace allows drawing conclusions also concerning the content of dissolved molecular oxygen of the liquid phase, i.e. the aqueous composition as such.

In preferred embodiments - when filling <NUM> of the composition into a closed glass ampoule having an inner volume of <NUM> and containing pure nitrogen gas such that the filled ampoule comprises the composition as a liquid phase and a gaseous phase in a headspace above the liquid phase, and allowing the gas dissolved in the liquid phase and the gas in the gaseous phase to equilibrate - the gaseous phase has a content of molecular oxygen of not more than <NUM> %Vbar, more preferably not more than <NUM> %Vbar, still more preferably not more than <NUM> %Vbar, yet more preferably not more than <NUM> %Vbar, even more preferably not more than <NUM> %Vbar, and most preferably not more than <NUM> %Vbar. In preferred embodiments, under the given conditions, the gaseous phase has preferably a content of molecular oxygen of not more than <NUM> %Vbar, more preferably not more than <NUM> %Vbar, still more preferably not more than <NUM> %Vbar, yet more preferably not more than <NUM> %Vbar, even more preferably not more than <NUM> %Vbar, and most preferably not more than <NUM> %Vbar.

Suitable methods for adjusting and determining the oxygen content of aqueous pharmaceutical compositions are known to the skilled person and suitable measuring devices are commercially available. The oxygen content can be reduced by purging the composition with an inert gas such as nitrogen and/or by subjecting the composition to reduced pressure and/or by purging the headspace of the composition with an inert gas such as nitrogen. Preferably, the oxygen content in the headspace is determined by means of an electrochemical oxygen sensor, e.g. a Head Space Analyzer Orbisphere <NUM>, Hach Lange.

It has been surprisingly found that by reducing the oxygen content of the pharmaceutical composition, the shelf life can be substantially improved, particularly the chemical stability of Tapentadol in the composition.

The osmolarity of the composition depends on the content of its constituents and is preferably adjusted during the manufacture of the composition by the addition of an appropriate amount of an isotonizing agent, preferably sodium chloride. Other isotonizing agents such as mannitol or sorbitol can also be added alternatively or additionally. Ionic isotonizing agents are preferred.

Thus, preferably the composition according to the invention comprises an isotonizing agent, more preferably sodium chloride.

Preferably, the content of the sodium chloride is not more than <NUM> wt. -%, more preferably not more than <NUM> wt. -%, still more preferably not more than <NUM> wt. -%, yet more preferably not more than <NUM> wt. -%, most preferably not more than <NUM> wt. -%, and in particular not more than <NUM> wt. -%, based on the total weight of the composition.

In preferred embodiments, the content of the sodium chloride is within the range of from <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, or <NUM>±<NUM> wt. -%, based on the total weight of the composition.

Preferably, the composition according to the invention does not contain any preservative. For the purpose of the specification, a "preservative" preferably refers to any substance that is usually added to pharmaceutical compositions in order to preserve them against microbial degradation or microbial growth. In this regard, microbial growth typically plays an essential role, i.e. the preservative serves the main purpose of avoiding microbial contamination. As a side aspect, it may also be desirable to avoid any effect of the microbes on the active ingredients and excipients, respectively, i.e. to avoid microbial degradation. However, the composition according to the invention may contain a citrate buffer system and under these circumstances, citric acid and its salts are to be considered as a buffer system and not as a preservative, though it is known that citric acid and its salt may also have a certain degree of preserving capacity.

Representative examples of preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, 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, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, and potassium sorbate.

Preferably, the composition according to the invention does not contain any chelating agents such as EDTA or its sodium or calcium salts. However, the composition according to the invention may contain a citrate buffer system and under these circumstances, citric acid and its salts are to be considered as a buffer system and not as a chelating agent, though it is known that citric acid and its salt also have a certain degree of chelating capacity.

Preferably, the composition according to the invention does not contain any antioxidants. Examples of antioxidants that are preferably not contained in the composition according to the invention include but are not limited to.

Preferably, the composition according to the invention contains neither any preservative nor any antioxidant.

Preferably, the composition according to the invention has a titration acidity of not more than <NUM> mmol/L, more preferably not more than <NUM> mmol/L, still more preferably not more than <NUM> mmol/L, yet more preferably not more than <NUM> mmol/L, and most preferably not more than <NUM> mmol/L.

Preferably, the composition according to the invention has a titration acidity within the range of from <NUM> to <NUM> mmol/L, more preferably <NUM> to <NUM> mmol/L.

Preferably, titration acidity is determined at a CO<NUM> partial pressure of <NUM> Hg under Argon at <NUM>. When titrating the composition according to the invention under these conditions with <NUM> NaOH up to an endpoint of pH <NUM>.

In a preferred embodiment, the titration acidity is preferably within the range of <NUM>±<NUM> mmol/L, more preferably <NUM>±<NUM> mmol/L.

In another preferred embodiment, the titration acidity is preferably within the range of <NUM>±<NUM> mmol/L, more preferably <NUM>±<NUM> mmol/L.

In order to satisfy high quality requirements for infusion and injection solutions, respectively, the composition has to exhibit a physiologically acceptable osmolarity and a physiologically acceptable pH.

Isotonic sodium chloride solution (saline), for instance, contains <NUM> wt. -% of sodium chloride and exhibits an osmolarity of <NUM> osmol/L, which is close to the osmolarity of blood.

Preferably, the composition has an osmolarity of at least <NUM> or at least <NUM> osmol/L, more preferably of at least <NUM> osmol/L, still more preferably of at least <NUM> osmol/L, yet more preferably of at least <NUM> osmol/L, most preferably of at least <NUM> osmol/L, and in particular of at least <NUM> osmol/L.

Preferably, the composition has an osmolarity of not more than <NUM> osmol/L, more preferably of not more than <NUM> osmol/L, still more preferably of not more than <NUM> osmol/L, yet more preferably of not more than <NUM> osmol/L, most preferably of not more than <NUM> osmol/L and in particular of not more than <NUM> osmol/L.

In preferred embodiments, the composition has an osmolarity of <NUM>±<NUM> osmol/L, more preferably of <NUM>±<NUM> osmol/L, still more preferably of <NUM>±<NUM> osmol/L, yet more preferably of <NUM>±<NUM> osmol/L, most preferably of <NUM>±<NUM> osmol/L, and in particular of <NUM>±<NUM> osmol/L.

Another aspect of the invention relates to a container comprising the pharmaceutical composition according to the invention, wherein the container is preferably a closed and airtight container. All preferred embodiments that have been defined above in connection with the composition according to the invention analogously also apply to the container according to the invention.

The container according to the invention comprises a distinct volume of the composition according to the invention that is adapted for parenteral administration to the patient. As the aqueous composition according to the invention is typically liquid, it is preferably provided in a container. Prior to parenteral administration, the composition according to the invention is then removed, completely (single dosage) or partially (multiple dosage) from the container.

Preferably, the container is a glass ampoule. Preferably, the container is made from glass of quality type I that satisfies the requirements of Ph. for parenteral formulations.

Preferably, the container comprises the composition as a liquid phase and a gaseous phase in a headspace above the liquid phase, wherein the gaseous phase has a content of molecular oxygen of not more than <NUM> %Vbar, more preferably not more than <NUM> %Vbar, still more preferably not more than <NUM> %Vbar, yet more preferably not more than <NUM> %Vbar, even more preferably not more than <NUM> %Vbar, and most preferably not more than <NUM> %Vbar. In preferred embodiments, under the given conditions, the gaseous phase has preferably a content of molecular oxygen of not more than <NUM> %Vbar, more preferably not more than <NUM> %Vbar, still more preferably not more than <NUM> %Vbar, yet more preferably not more than <NUM> %Vbar, even more preferably not more than <NUM> %Vbar, and most preferably not more than <NUM> %Vbar.

The container according to the invention may comprise a single dose of Tapentadol or may be multiple dosed. For the purpose of the specification "multiple dosed" preferably means that the container encompasses more than a single dosage unit.

In a preferred embodiment, the container contains the composition according to the invention in a quantity exceeding a single administration dose (dosage unit). Under these circumstances, the container comprises multiple dosage units, i.e. is customized for more than a single administration, preferably by injection.

For example, when the container comprises a multiple dosed injection solution, its overall volume is more than the volume that is to be typically administered at once. Instead, the multiple dosed injection solution is customized for being divided into a multitude of dosage units that are to be administered over a treatment interval typically encompassing several days. The individual dosage units may preferably be separated from the multiple dosage unit by means of a syringe. A typical example for a container according to the invention that comprises multiple dosage units is a preferably sterilized glass container sealed with a septum. Said glass container contains a volume of the pharmaceutical composition well exceeding the individual volume of an individual dosage unit that is intended for at once administration to the patient. For example, when the container has a total volume of <NUM> and the prescribed dosage unit is <NUM> once daily, at day <NUM> of the treatment interval the patient takes <NUM> so that <NUM> remain in the container; at day <NUM> of the treatment interval the patient takes another <NUM> so that <NUM> remain in the container; and so on, until at day <NUM> the entire amount is administered to the patient.

Preferably, the container contains at least <NUM>, more preferably at least <NUM>, even more preferably at least <NUM>, yet more preferably at least <NUM>, most preferably at least <NUM>, and in particular at least <NUM> individual dosage units.

In another preferred embodiment, the container comprises a single dosage unit, i.e. only one individual dosage unit. Under these circumstances, according to a preferred embodiment, the container preferably comprises from <NUM> to <NUM> of the composition. According to another preferred embodiment, the container preferably comprises from <NUM> to <NUM>, preferably <NUM> to <NUM> of the composition, e.g. <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>.

Preferably, the individual dosage units have a volume of <NUM> to <NUM>, more preferably of <NUM> to <NUM>, still more preferably of <NUM> to <NUM>, and most preferably of <NUM> to <NUM>.

In a preferred embodiment, the individual dosage units have a volume of <NUM>±<NUM>, more preferably of <NUM>±<NUM>, still more preferably <NUM>±<NUM>, yet more preferably of <NUM>±<NUM>, even more preferably of <NUM>±<NUM>, most preferably of <NUM>±<NUM>, and in particular of <NUM>±<NUM>.

In another preferred embodiment, the individual dosage units have a volume of <NUM>±<NUM>, more preferably of <NUM>±<NUM>, still more preferably <NUM>±<NUM>, yet more preferably of <NUM>±<NUM>, even more preferably of <NUM>±<NUM>, most preferably of <NUM>±<NUM>, and in particular of <NUM>±<NUM>.

In still another preferred embodiment, the individual dosage units have a volume of <NUM>±<NUM>, more preferably of <NUM>±<NUM>, still more preferably <NUM>±<NUM>, yet more preferably of <NUM>±<NUM>, even more preferably of <NUM>±<NUM>, most preferably of <NUM>±<NUM>, and in particular of <NUM>±<NUM>.

According to another preferred embodiment, the individual dosage units preferably comprise from <NUM> to <NUM> of the composition, e.g. <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>.

The one or more individual dosage units that are contained in the container may be customized for administration once, twice, thrice, four times, five times, six times or even more frequently, optionally in regular time intervals.

The composition that is contained in the container may also be customized for a continual administration, preferably by infusion. Preferably, the composition that is contained in the container is adapted for a continual administration for at least <NUM> minutes or <NUM> minutes, more preferably for at least <NUM> or <NUM>, still more preferably for at least <NUM> or <NUM>, yet more preferably for at least <NUM> or <NUM>, most preferably for at least <NUM>, and in particular for at least <NUM>.

Tapentadol is administered in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the condition being treated, the severity of said condition and the patient being treated.

Preferably, the amount of Tapentadol that is contained in the individual dosage unit is preferably within the range of from <NUM> to <NUM>/kg body weight. Typically, the daily dosage of Tapentadol is within the range of from <NUM> to <NUM>, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>. Bioavailability upon parenteral administration can be higher than bioavailability upon oral administration.

Preferably, the daily dose of Tapentadol is not more than <NUM>, more preferably not more than <NUM>, yet more preferably not more than <NUM>, still more preferably not more than <NUM>, and in particular not more than <NUM>.

Preferably, the daily dose of Tapentadol is at least <NUM>, more preferably at least <NUM>, yet more preferably at least <NUM>, still more preferably at least <NUM>, most preferably at least <NUM>, and in particular at least <NUM>.

In a preferred embodiment, the amount of Tapentadol that is contained in the individual dosage unit is preferably within the range of from <NUM> to <NUM>, more preferably within the range of from <NUM> to <NUM>, still more preferably within the range of from <NUM> to <NUM>, yet more preferably within the range of from <NUM> to <NUM>, and most preferably within the range of from <NUM> to <NUM>, and in particular within the range of from <NUM> to <NUM>.

In another preferred embodiment, the amount of Tapentadol that is contained in the individual dosage unit is preferably within the range of from <NUM> to <NUM>, more preferably within the range of from <NUM> to <NUM>, still more preferably within the range of from <NUM> to <NUM>.

Preferably, the container according to the invention comprises Tapentadol in an amount within the range of from <NUM> to <NUM>, preferably from <NUM> to <NUM>, more preferably from <NUM> to <NUM> or of from <NUM> to <NUM>, based on the weight of Tapentadol free base.

In preferred embodiments, the container according to the invention comprises Tapentadol in an amount of at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, or at least <NUM>, based on the weight of Tapentadol free base.

In preferred embodiments, the container according to the invention comprises Tapentadol in an amount of at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, or at most <NUM>, based on the weight of Tapentadol free base.

In preferred embodiments, the container according to the invention comprises Tapentadol in an amount of <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or <NUM>±<NUM>, or based on the weight of Tapentadol free base.

The composition according to the invention, particularly when it is contained in the container according to the invention, has an excellent shelf life and storage stability. Thus, preferably, the composition according to the invention is stable upon storage.

Preferably, the composition according to the invention is stable upon storage under accelerated storage conditions at <NUM> and <NUM>% relative humidity for at least <NUM> months, more preferably at least <NUM> months. Preferably, stability criteria are in accordance with Ph. and EMA guidelines, respectively, preferably according to the edition that is valid in September <NUM>.

In preferred embodiments, the pH value of the composition after storage under accelerated storage conditions at <NUM> and <NUM>% relative humidity for at least <NUM> months, more preferably at least <NUM> months, does not relatively differ by more than ±<NUM> pH units, more preferably by not more than ±<NUM> pH units, more preferably by not more than ±<NUM> pH units, from the initial pH value of the composition prior to storage.

Preferably, the composition is colorless before storage and after storage under accelerated storage conditions at <NUM> and <NUM>% relative humidity for at least <NUM> months, more preferably at least <NUM> months. Preferably, the composition is colorless before storage and during/after storage, in particular during/after a storage time of more than three months, preferably of more than <NUM> months, more preferably of more than <NUM> months, most preferably of at least for twenty-four months.

In preferred embodiments, the composition has a content of decomposition products of Tapentadol after storage under accelerated storage conditions at <NUM> and <NUM>% relative humidity for at least <NUM> months, more preferably at least <NUM> months, of not more than <NUM> wt. -%, more preferably not more than <NUM> wt. -%, still more preferably not more than <NUM> wt. -%, yet more preferably not more than <NUM> wt. -%, even more preferably not more than <NUM> wt. -%, and most preferably not more than <NUM> wt. -%, relative to the total content of Tapentadol that was originally contained in the composition prior to storage and based on the weight of Tapentadol free base. Decomposition products of Tapentadol are preferably analyzed by HPLC.

For the purpose of the specification, it may additionally be distinguished between shelf life and in-use stability. Shelf life preferably refers to the storage stability of a closed container. In-use stability preferably refers to the storage container that contains a multiple dosage unit preparation which has been utilized for the first time. Typically, the shelf life of a multiple dosage unit preparation is much longer than its in-use stability. Preferably, stability criteria are in accordance with Ph. and EMA guidelines, respectively, preferably according to the edition that is valid in September <NUM>.

Preferably, the composition according to the invention, particularly when it is contained in the container according to the invention, exhibits a shelf life under ambient conditions of at least <NUM> month, more preferably at least <NUM> months, still more preferably at least <NUM> months, yet more preferably at least <NUM> months, most preferably at least <NUM> months and in particular at least <NUM> months.

Preferably, the composition according to the invention, particularly when it is contained in the container according to the invention, is provided as a multiple dosage unit preparation that exhibits an in-use stability under ambient conditions of at least <NUM> week, more preferably at least <NUM> weeks, still more preferably at least <NUM> weeks, yet more preferably at least <NUM> weeks, most preferably at least <NUM> weeks and in particular at least <NUM> weeks.

It has been surprisingly found that pH value and content of molecular oxygen can be controlled such that undesired decomposition reactions of Tapentadol can be reduced. No additional excipients are needed for stabilization.

Preferably, the composition according to the invention exhibits an antimicrobial robustness that complies with the requirements of the Ph. , preferably in its version for <NUM>. Preferably, antimicrobial robustness is achieved against S. aureus, Ps. Aeruginosa, S. albicans, and/or A. niger, preferably satisfying the requirement of log reduction of <NUM>, preferably <NUM> after <NUM> and no increase after <NUM> days. In a particularly preferred embodiment, antimicrobial robustness is achieved against bacteria satisfying the requirement of log reduction of <NUM> after <NUM> days and against molds and yeast of log reduction of <NUM> after <NUM> days.

The composition according to the invention, particularly when it is contained in the container according to the invention, exhibits an excellent autoclavability, i.e. it can be subjected to autoclaving under suitable conditions for a suitable period of time without causing significant degradation of Tapentadol under the typically drastic conditions of autoclaving. Preferably, the composition is stable upon autoclaving and preferably exhibits an unaltered pH value upon autoclaving.

Preferably, the composition is stable upon autoclaving for <NUM> minutes at <NUM> and <NUM> bar. Preferably, the composition is stable upon autoclaving for <NUM> minutes at <NUM> and <NUM> bar and preferably exhibits an unaltered pH value upon autoclaving under these conditions.

Preferably, stability criteria are in accordance with Ph. and EMA guidelines, respectively, preferably according to the edition that is valid in September <NUM>.

In preferred embodiments, the composition according to the invention, particularly when it is contained in the container according to the invention, has a content of decomposition products of Tapentadol after autoclaving of not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, more preferably not more than <NUM> wt. -%, and most preferably not more than <NUM> wt. -%, relative to the total content of Tapentadol that was originally contained in the composition prior to autoclaving and based on the weight of Tapentadol free base.

In preferred embodiments, the composition according to the invention, particularly when it is contained in the container according to the invention, has a content of decomposition products of Tapentadol after <NUM> times autoclaving, preferably in each case for <NUM> minutes at <NUM> and <NUM> bar, of not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%; more preferably not more than <NUM> wt. - %, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. - %, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. - %, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%; still more preferably not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%; most preferably not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%, or not more than <NUM> wt. -%; relative to the total content of Tapentadol that was originally contained in the composition prior to first autoclaving and based on the weight of Tapentadol free base.

Preferably, the pharmaceutical composition according to the invention is for use in the treatment of pain.

Accordingly, a further aspect of the invention relates to the pharmaceutical composition according to the invention as described above for use in the treatment of pain comprising the parenteral administration of a therapeutically effective amount of the pharmaceutical composition, that may be provided in the container according to the invention as described above, to a subject in need thereof.

Furthermore, the invention also relates to the use of Tapentadol or a physiologically acceptable salt thereof for the manufacture of the pharmaceutical composition according to the invention as described above or of the container containing the pharmaceutical composition according to the invention as described above, for the treatment of pain. Preferably, Tapentadol is employed as Tapentadol hydrochloride polymorph form A. Form A of Tapentadol hydrochloride is known from the prior art. In this regard, it can be referred to e.g. <CIT>. Form A is preferably characterized by showing at least one or more X-ray lines (<NUM>-theta values) in a powder diffraction pattern when measured using Cu Kα radiation selected from the list comprising <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM> and <NUM>±<NUM>.

The pain may either be chronic pain or acute pain. Acute pain is preferred.

Preferably, the pain is selected from the group consisting of inflammatory pain, neuropathic pain, visceral pain, labor pain, cancer pain, perioperative and post-operative pain.

In a preferred embodiment, the pain is cancer pain, preferably neuropathic pain being induced by the cancer, including neuropathic pain as a direct result of the cancer on peripheral nerves, or as a side effect of chemotherapy, surgery or radiation injury.

In another preferred embodiment, the pain is perioperative or post-operative (post-surgical) pain.

In still another preferred embodiment, the pharmaceutical composition according to the invention is for use in emergency pain management.

Preferably, the composition according to the invention is for use in the treatment of pain in mammals. Preferably, the mammals are humans. Preferably, the humans are adults.

Preferably, composition according to the invention, particularly when it is contained in the container according to the invention, is a parenteral formulation selected from the group consisting of injection solutions, injection suspensions, infusion solutions, infusion suspensions, and depot formulations, such as depot injection solutions, depot injection suspensions, implants and infusion pumps.

Compared to oral formulations, parenteral formulations have several advantages, especially when the patient is young or has problems to swallow. They can be exactly dosed, e.g. according to the body weight of the patients. Further, they can be administered by infusion continually over an extended period of time (e. by means of an infusion pump.

In a preferred embodiment, the parenteral formulation according to the invention is an infusion solution or infusion suspension.

In another preferred embodiment, the parenteral formulation is an injection solution or injection suspension, which preferably is a single dosage unit form or multiple dosage unit form. Multiple dosage unit injection solutions are preferably contained in an injection vial, whereas single dosage unit forms are preferably contained in a single-use syringe.

In still another preferred embodiment, the parenteral formulation is an implantable device, such as an implantable infusion pump.

In a preferred embodiment, the parenteral formulation according to the invention is a depot formulation (retard formulation).

Preferably, the depot formulation is an infusion solution or infusion suspension, preferably customized for an intramuscular or subcutaneous administration.

Preferably, the depot formulation further contains viscosity-enhancing excipients, such as methylcellulose, gelatine, and polyvidon (polyvinylpyrrolidon) preferably having a molecular weight of not more than <NUM>,<NUM>/mol. By choosing the appropriate type and the appropriate amount of the viscosity-enhancing excipient, the depot effect of the depot formulation may be influenced.

Preferably, the depot formulation is capable of releasing the drug over time period of at least <NUM> or <NUM>, more preferably at least <NUM> or <NUM>, still more preferably at least <NUM>, yet more preferably at least <NUM>, most preferably at least <NUM>, and in particular at least <NUM>.

The depot formulation is preferably administered for use in the treatment of acute pain and/or post-surgical pain.

In a preferred embodiment, the composition according to the invention, particularly when it is contained in the container according to the invention, is adapted for local administration. In this regard, local administration includes every administration of the composition to a site which is identical to the site of disorder and/or at least is located nearby. In particular, the local administration has the purpose of delivering Tapentadol directly to the desired site of action, thereby avoiding systemic side-effects. Under these circumstances, the systemic concentration of Tapentadol is preferably kept at a sub-therapeutic concentration; i.e. during the treatment, the systemic concentration of Tapentadol never reaches the level that is required for exhibiting a therapeutic effect when the drug is only administered systemically.

In another preferred embodiment, the composition according to the invention, particularly when it is contained in the container according to the invention, is adapted for systemic administration. In this embodiment the administration of the composition preferably has the purpose of inducing a systemic action of Tapentadol.

The composition according to the invention is adapted for parenteral administration, preferably by injection or infusion.

The composition according to the invention is adapted for parenteral administration of Tapentadol. The parenteral administration may proceed by infusion or injection.

Infusion solutions or suspensions may be administered continuously, intermittently or patient-controlled. For the administration, infusion devices such as implantable infusion pumps, non-implantable infusion pumps and spinal pumps may be used.

The administration of the composition may proceed intramuscularly, intravenously, subcutaneously, epidurally, intrathecally, intraspinally and/or intracerebroventricularly. Intraveneous administration is particularly preferred.

In a preferred embodiment, the administration proceeds intraspinally, either intrathecally or epidurally, preferably by infusion. The intraspinal administration is especially suitable for treating pain selected from perioperative pain, post-operative pain, labor pain and cancer pain. The dosage of the intraspinal administration may be controlled by means of an infusion pump, either by the patient or by the selection of an appropriate steady or intermittent infusion rate.

In another preferred embodiment, the administration proceeds intramuscularly, intravenously or subcutaneously. This type of administration is especially preferred for the local or regional treatment of pain in distal extremities.

Depot formulations are preferably administered intramuscularly or subcutaneously.

Another aspect of the invention relates to a process for the preparation of the pharmaceutical composition according to the invention or of the container according to the invention, respectively, which process comprises the step of.

In a preferred embodiment, Tapentadol is employed as Tapentadol hydrochloride polymorph form A, which is preferably characterized by showing at least one or more X-ray lines (<NUM>-theta values) in a powder diffraction pattern when measured using Cu Kα radiation selected from the list comprising <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM> and <NUM>±<NUM>.

Preferably, in the course of manufacturing the composition according to the invention and the container according to the invention, respectively, the intermediate mixtures that are obtained after the process steps are purged with inert gas, preferably nitrogen, in order to discharge dissolved oxygen and to avoid entrainment of oxygen from the gas atmosphere above the composition.

Preferably, step (a) of the process according to the invention comprises a substep relating to the addition of every constituent to the composition, which substep comprises adding, dissolving/mixing and purging with inert gas, preferably nitrogen.

Thus, step (a) of the process according to the invention preferably comprises.

Substeps (a<NUM>) to (a<NUM>) may be performed in numerical order or in any other order.

Preferably, the process according to the invention comprises one or more additional steps selected from the group consisting of.

Preferably, steps (b), (c), (d) and/or (e) are performed in alphabetical order.

The invention also relates to a composition or a container that is obtainable by the process according to the invention as described above.

Another aspect of the invention relates to a kit comprising the container according to the invention as described above and a packaging, wherein the container is packaged by the packaging. The container may be regarded as a primary packaging of the composition, whereas the packaging may be regarded as a secondary packaging of said primary packaging.

Thus, when the composition according to the invention is contained in a container such as a glass ampoule, said container is preferably further packaged by a packaging. Preferably, the packaging contains printed information and/or provides a barrier to light.

Preferably, the packaging is made of a material that is intransparent to visual light.

Preferably, the packaging is disposable. Suitable packaging materials are known to the skilled person and include but are not limited to paper, cardboard, plastics, and metal foil. Preferably, the packaging comprises or essentially consists of cardboard.

Preferably, the composition which is contained in the container and packaged by the packaging is photostable.

In preferred embodiments, the content of decomposition products of Tapentadol in the composition after subjecting the kit for <NUM> hours to UV radiation at <NUM> Wh/m<NUM> and an illumination of <NUM> kLxh is not more than <NUM> wt. -%, more preferably not more than <NUM> wt. -%, and most preferably not more than <NUM> wt. -%, relative to the total content of Tapentadol that was originally contained in the composition prior to subjecting the composition to UV radiation and based on the weight of Tapentadol free base.

Another aspect of the invention relates to the use of Tapentadol or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition according to the invention as described above or of a container according to the invention as described above.

Preferably, Tapentadol is employed as Tapentadol hydrochloride polymorph form A, which is preferably characterized by showing at least one or more X-ray lines (<NUM>-theta values) in a powder diffraction pattern when measured using Cu Kα radiation selected from the list comprising <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM>, <NUM>±<NUM> and <NUM>±<NUM>.

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

A reference solution containing <NUM>/mL tapentadol was formulated according to the following table:.

The pH value of this solutions was measured to be <NUM>. Thus, this solution is not in accordance with the present invention, as its pH value is too high.

Different injection solutions for intravenous administration were prepared having a concentration of Tapentadol amounting to <NUM>/mL. In each case, hydrochloric acid <NUM> mol q. was added in the amount needed in order to adjust a pH value of <NUM> (comparative), <NUM> (comparative), <NUM> (inventive), <NUM> (comparative) and <NUM> (comparative), respectively. For adjusting a pH value at buffer concentrations of <NUM> wt. -% and <NUM> wt. -%, sodium hydroxide <NUM> mol q.

Batch sizes were <NUM>, <NUM>, <NUM> and <NUM>. Volumes of <NUM> were filled into glass ampoules.

The comparative compositions at pH <NUM> (i.e. compositions 1A, 2A, 3A, 4A and 5A), the comparative compositions at pH <NUM> (i.e. compositions 1B, 2B, 3B, 4B and 5B), the inventive compositions at pH <NUM> (i.e. compositions 1C, 2C, 3C, 4C and 5C), the comparative compositions at pH <NUM> (i.e. compositions 1D, 2D, 3D, 4D and 5D), and the comparative compositions at pH <NUM> (i.e. compositions 1E, 2E, 3E, 4E and 5E) were each autoclaved <NUM> time for <NUM> at <NUM> bar and <NUM> ("1x auto") and <NUM> times for <NUM> at <NUM> bar and <NUM> ("10x auto").

The pH values of the compositions at pH <NUM>, <NUM> and <NUM>, in each case before autoclaving ("IPC pH"), after <NUM> time autoclaving ("1x auto") and after <NUM> times autoclaving ("10x auto") were measured. The experimental results are compiled in the tables here below. "Δ pH 1x-10x" indicates the relative change of the pH value after <NUM> times autoclaving compared to <NUM> time autoclaving. "Δ pH IPC-10x" indicates the relative change of the pH value after <NUM> times autoclaving compared to the initial pH value before (any) autoclaving:.

It can be concluded from the above experimental data that at a pH value of <NUM>, at all buffer concentrations ranging from <NUM> to <NUM> wt. -%, the pH values of all compositions decreased upon autoclaving. Furthermore, it appears that at a pH value of <NUM>, minor increases of the pH values were observed, whereas at a pH value of <NUM>, the pH value of all compositions was robust against autoclaving.

Summing up, at all buffer concentrations, the compositions having a pH value of <NUM> showed the best stability of pH under harsh storage conditions.

The appearance of the compositions at pH <NUM>, <NUM> and <NUM>, in each case after <NUM> time autoclaving ("1x auto") and after <NUM> times autoclaving ("10x auto") was visually assessed. The experimental results are compiled in the tables here below:.

It can be concluded from the above experimental data that at pH <NUM> at all buffer concentrations ranging from <NUM> to <NUM> wt. -%, a yellowish impurity was formed after <NUM> times autoclaving. Such formation could not be visually observed at pH <NUM> and pH <NUM>.

Summing up, at all buffer concentrations, the compositions having a pH value of <NUM> and <NUM> showed a better stability under harsh storage conditions than the compositions at pH <NUM>.

For the compositions at pH <NUM>, <NUM>, and <NUM>, in each case the residual concentration of Tapentadol was determined by an assay. The measured residual concentration of Tapentadol after <NUM> time autoclaving ("<NUM>× auto") and after <NUM> times autoclaving ("<NUM>× auto") was determined relative to the initially adjusted concentration of <NUM>/mL. The experimental results are compiled in the tables here below. "Δ assay" indicates the relative change after <NUM> times autoclaving compared to <NUM> time autoclaving:.

It can be concluded from the above experimental data that at pH <NUM>, at all buffer concentrations ranging from <NUM> to <NUM> wt. -%, the residual concentration of Tapentadol decreased upon autoclaving. Furthermore, it appears that at pH values below <NUM> the stability of Tapentadol can be improved by increasing the buffer concentration. This is particularly pronounced at pH <NUM>, where at a buffer concentration of <NUM> wt. -%, the residual concentration of Tapentadol relatively decreased by <NUM>%, whereas at higher buffer concentrations of <NUM> wt. -% and above, the relative decrease was merely <NUM>% and <NUM>%, respectively.

Summing up, at all buffer concentrations, the compositions having a pH value of <NUM> and <NUM> showed a better stability under harsh storage conditions than the compositions at pH <NUM>. Furthermore, increasing the buffer concentration has a stabilizing effect.

For all compositions, i.e. at pH <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, in each case the degradation products of Tapentadol were analyzed by HPLC. The total amount of various known or unknown decomposition products of Tapentadol after <NUM> time autoclaving ("<NUM>× auto") and after <NUM> times autoclaving ("<NUM>× auto") was measured. The experimental results are compiled in the tables here below.

Degradation at pH <NUM> (sum of all impurities):.

The results after <NUM> times autoclaving for the sum of all degradation products at all tested pH values and all tested buffer concentrations are summarized in the table here below:.

The results are also visualized in <FIG> (◆ <NUM> wt. -% buffer, ▪ <NUM> wt. -% buffer, ▲ <NUM> wt. -% buffer, Δ <NUM> wt. -% buffer, ∘ <NUM> wt. -% buffer).

Claim 1:
An aqueous pharmaceutical composition for parenteral administration being stable upon autoclaving and comprising Tapentadol or a physiologically acceptable salt thereof;
wherein
- the concentration of Tapentadol is greater than <NUM>/mL, based on the weight of Tapentadol free base and based on the total volume of the composition;
- the composition comprises a buffer system;
- the buffer system comprises at least one conjugate base and at least one conjugate acid, wherein said at least one conjugate base and said at least one conjugate acid are selected from the group consisting of citrate, hydrogencitrate, dihydrogencitrate and citric acid;
- the total concentration of said at least one conjugate base and said at least one conjugate acid is at least <NUM> mmol/L, based on the total content of the at least one conjugate base and the at least one conjugate acid and based on the total volume of the composition; and
- the pH value of the composition is within the range of from <NUM> to not greater than <NUM>.