Patent Description:
The treatment of diabetes and other metabolic disorders includes the inhibition of the renal sodium-dependent glucose co-transporter SGLT-<NUM>. SGLT-<NUM> in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood. SGLT-<NUM> inhibition thus induces glucosuria and may reduce blood glucose levels.

A large variety of SGLT-<NUM> inhibitors are known. A pharmaceutical formulation of SGLT-<NUM> inhibitors is essential in order to administer such compounds in an adequate way to the patient.

SGLT-<NUM> inhibitors are for instance described in <CIT> which is directed to crystalline forms of <NUM>-chloro-<NUM>-([beta]-D-glucopyranos-<NUM>-yl)-<NUM>-(<NUM>-ethynyl-benzyl)-benzene, a method for the preparation thereof, as well as the use thereof for preparing medicaments. It discloses solutions of <NUM>-chloro-<NUM>-([beta]-D-glucopyranos-<NUM>-yl)-<NUM>-(<NUM>-ethynyl-benzyl)-benzene in a solvent or a mixture of solvents and further specifies exemplarily suitable organic solvents such as ethanol or ethanol/water mixtures.

<CIT> describes crystalline forms of <NUM>'-(<NUM>-methylethyl)-<NUM>'-[(<NUM>-fluoro-<NUM>-methoxyphenyl) methyl]-<NUM>'-methyl-<NUM>-pyrazol-<NUM>'-O-[beta]-D-glucopyranoside, a method for the preparation thereof, as well as the use thereof for preparing medicaments. It discloses solutions of <NUM>'-(<NUM>-methylethyl)-<NUM>'-[(<NUM>-fluoro-<NUM>-methoxyphenyl) methyl]-<NUM>'-methyl-<NUM>-pyrazol-<NUM>'-O-[beta]-D-glucopyranoside in a solvent or a mixture of solvents and further specifies exemplarily suitable organic solvents such as ethanol or ethanol/water mixtures.

In addition, <CIT> describes glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses as well as processes for their manufacture. It mentions that such glucopyranosyl-substituted benzonitrile derivatives can be formulated among other with one or more inert carriers and/or diluents, such as water/ethanol, water/glycerol, propylene glycol and the like. It further discloses among many other compounds also <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-((<NUM>-D-glucopyranos-<NUM>-yl)-benzene.

Further SGLT-<NUM> inhibitors are described in <CIT> which relates to glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses as well as processes for their manufacture. It mentions that such glucopyranosyl-substituted benzonitrile derivatives can be formulated among other with one or more inert carriers and/or diluents, such as water/ethanol, water/glycerol, propylene glycol and the like. It further discloses among many other compounds also <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-((<NUM>-D-glucopyranos-<NUM>-yl)-benzene.

<CIT> describes crystal structures of a specific glucopyranosyl-substituted benzene derivative being an H-<NUM> form, H-<NUM> form or the (S)-propylene glycol form. It discloses solutions of such specific glucopyranosyl-substituted benzene derivative in water-miscible organic solvents.

Another prior art document <CIT> is directed to crystalline dapagliflozin hydrate and a method for the preparation thereof. It discloses solutions of dapagliflozin in a solvent or a mixture of solvents and further specifies exemplarily suitable solvents such as water and C1-C4 alcohols or mixtures thereof.

<CIT> (<CIT>) describes crystalline complexes of <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene with natural amino acids, methods for the preparation thereof as well as the use thereof for preparing medicaments. It discloses solutions of <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene in a solvent or a mixture of solvents and further specifies exemplarily suitable organic solvents such as C1-C4 alkanols, ethanol and mixtures thereof, in particular with water.

Furthermore, <CIT> describes amorphous forms of canagliflozin and processes of manufacturing thereof as well as corresponding pharmaceutical compositions and their medicinal uses. It discloses solutions of canagliflozin in one or more organic solvents and further specifies exemplarily suitable organic solvents such as ethanol.

Further challenges known in the prior art are the limited solubility of SGLT-<NUM> inhibitors in water due to their positive log<NUM>P values, which typically influences the bioavailability in the body of a patient or makes it difficult to find adequate solvents to get the substance dissolved in an liquid formulation before administering it into the body of a patient.

<CIT> relates to SGLT-<NUM> inhibitors for use in the treatment and/or prevention of metabolic disorders in canine animals.

There is an urgent need for a directly administrable pharmaceutical composition comprising at least one SGLT-<NUM> inhibitor which overcomes the problems of the prior art as described above.

The present invention concerns a liquid pharmaceutical composition comprising at least one SGLT-<NUM> inhibitor and one or more polar organic solvents, wherein the at least one SGLT-<NUM> inhibitor is <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-((<NUM>-D-glucopyranos-<NUM>-yl)-benzene according to formula (I):
<CHM>
wherein <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene is the only SGLT-<NUM> inhibitor contained in such liquid pharmaceutical composition.

Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

The present invention also concerns a liquid pharmaceutical composition as described and claimed herein for use in a method for treating and/or preventing one or more medicinal indications in a subject in need of such treatment and/or prevention, preferably an animal, more preferably a mammal, in particular a horse, cat or dog, selected from among the medicinal indications:.

The present invention further concerns a process for producing the liquid pharmaceutical composition as described and claimed herein, comprising the steps:.

whereby, optionally, independently from each other after any of the individual process steps - be they mandatory or optional - an additional mixing step is performed.

In the course of the present invention, such process steps (i) to (v) do not need to be carried out in the given order, but can also be performed in any other meaningful order, e.g. (ii)+(i)+(iv)+(iii)+(v). It is within the knowledge of the skilled person to vary the order of process steps in order to obtain the desired process result, i.e. the liquid pharmaceutical composition according to the present invention. For instance, if one or more viscosity-enhancing agents are added, it is preferred to heat the mixture up for complete dissolution of the one or more viscosity-enhancing agents. In turn such resulting mixture needs to be cooled down before the API <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-((<NUM>-D-glucopyranos-<NUM>-yl)-benzene (in the form of its L-proline-water cocrystal) is added in order to avoid unnecessary and unwanted degradation of the substance through such heating steps.

The present invention further concerns a kit-of-parts comprising:.

The advantages of the liquid pharmaceutical compositions according to the present invention are as follows:.

Before the embodiments of the present invention are described in further details it shall be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by <NUM> to <NUM> % unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term "about" was usually omitted from the description and claims.

In the course of the present invention <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(P-D-glucopyranos-<NUM>-yl)-benzene is also referred to as "the substance" and is herewith understood to also comprise co-crystal <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene - L-proline as well as the co-crystal monohydrate <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene - L-proline - water (as disclosed in <CIT>). Generally, in the case of disclosed and claimed mass concentrations (% w/w) and amounts (g, mg) the mass concentration or amount always refers to the "free base" <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene - L-proline, i.e. excluding L-proline and crystal water, unless otherwise explicitly stated -even though in practice (and in the example section) co-crystal <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene - L-proline - water is actually added/used.

In the course of the present invention the term "suitable for direct administration to a subject" in connection with "liquid pharmaceutical composition" means that such liquid pharmaceutical compositions can be directly administration to a subject without further mandatory processing and/or purification steps and explicitly excludes (mixtures of) organic solvents that are solely mentioned in the context of producing crystalline complexes of SGLT2 inhibitors. Preferably, such "liquid pharmaceutical composition" that are "suitable for direct administration to a subject" are therefore sterile and/or comply with GMP manufacturing conditions as well as GCP compliant clinical protocols.

In one aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein the liquid pharmaceutical composition is suitable for direct administration to a subject, preferably an animal, more preferably a mammal, in particular a horse, cat or dog; wherein preferably the liquid pharmaceutical composition is sterile.

In another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein the liquid pharmaceutical composition is a solution, an emulsion or a suspension, preferably a solution, an emulsion or a suspension with an NTU value of equal to or less than <NUM>, more preferably equal to or less than <NUM>, even more preferably equal to or less than <NUM>, and most preferably a solution, in particular a solution with an NTU value of equal to or less than <NUM>.

In the course of the present invention the term "NTU" refers to Nephelometric Turbidity Units and to an opalescent value as defined and described in <NPL>").

In another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein the one or more polar organic solvents are independently from each other characterized by a negative log<NUM>P value, preferably a negative decadic logarithmic partition coefficient (P) in an n-octanol/water system according to formula (II): <MAT>.

The present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition as a whole is characterized by a negative LogP-Parameter, preferably a negative LogP-Parameter of equal to or less than -<NUM> (i.e.-<NUM> ≤ LogP-Parameter < <NUM>). For the avoidance of doubt, the LogP-Parameter is defined as in Eq. <NUM> of Example <NUM> and is not identical with and should not be mistaken for the (negative) log<NUM>P value as given for the one or more polar organic solvent(s).

The present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein the one or more polar organic solvents are selected from ethanol (log<NUM>P: -<NUM>), propane-<NUM>,<NUM>-diol (propylene glycol; log<NUM>P: -<NUM>), propane-<NUM>,<NUM>,<NUM>-triol (glycerol; log<NUM>P: -<NUM>). The log<NUM>P values were taken from http://www. chemicalize.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition comprises at least two different polar organic solvents, preferably two or three different polar organic solvents, more preferably propane-<NUM>,<NUM>-diol (propylene glycol) and propane-<NUM>,<NUM>,<NUM>-triol (glycerol) or ethanol and propane-<NUM>,<NUM>-diol (propylene glycol) or ethanol and propane-<NUM>,<NUM>-diol (propylene glycol) and propane-<NUM>,<NUM>,<NUM>-triol (glycerol). Preferably, if ethanol is present in the liquid pharmaceutical composition as described and claimed herein, it is present at no more than <NUM>/<NUM> (<NUM> % w/w), preferably it is present at no more than <NUM>/<NUM> (<NUM> % w/w), more preferably it is present at no more than <NUM>/<NUM> (<NUM> % w/w), most preferably it is present at <NUM>/<NUM> (<NUM> % w/w).

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition does not comprise ethanol as the one or more polar organic solvents.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition does not comprise only propane-<NUM>,<NUM>-diol (propylene glycol) as single polar organic solvent.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition additionally comprises water, preferably aqueous buffer, such as citric acid buffer (preferably with pH <NUM>) or phosphate buffer (preferably with pH <NUM>).

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition has a measured pH value of from <NUM> to <NUM>, preferably from <NUM> to <NUM>, more preferably from <NUM> to <NUM>, even more preferably from <NUM> to <NUM> and most preferably from <NUM> to <NUM>. For the avoidance of doubt, the term "measured pH value" refers to the pH value actually measured for the whole liquid pharmaceutical composition according to the present invention, although puristically only pH values of pure aqueous systems can be measured by means of standard pH determination methods.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition additionally comprises one or more solubilizing agents, preferably selected from the group consisting of: "surfactants, anionic surfactants, non-ionic surfactants, hydrogenated castor oils, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylenglycol derivatives", more preferably selected from the group consisting of: "Sodium dodecyl sulphate (SDS), Cremophor RH <NUM> (PEG-<NUM> Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate <NUM>), polysorbate <NUM>, Lutrol F <NUM> (Poloxamer <NUM>), PEG <NUM>, propylenglycol monolaurate" and/or additionally comprises one or more viscosity-enhancing agents, preferably selected from the group consisting of: "inorganic gel forming agents, organic gel forming agents, cellulose derivatives", more preferably selected from the group consisting of: "hydroxyl ethyl cellulose, hydroxyl propyl methyl cellulose, silicon dioxide" and/or additionally comprises one or more flavours and/or sweeteners, preferably selected from the group consisting of: "honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor, peppermint flavor, raspberry flavor, lemon flavor, herbs flavor, saccharine, aspartame".

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition does not comprise any apolar organic solvents, which are preferably and independently from each other characterized by a log<NUM>P value of equal to or higher than <NUM>.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, wherein such liquid pharmaceutical composition is for oral and/or parenteral administration, preferably oral administration.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, comprising.

In yet another aspect, the present invention relates to a liquid pharmaceutical composition as described and claimed herein, selected from:.

The testing criteria applied are those for evaluation of the clarity of a liquid (formulation) comprising <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene according to Pharm. Concerning the Ph. <NUM>, Chapter <NUM>. "Clarity and degree of opalescence of liquids", a liquid is considered clear if its opalescence is not more pronounced than that of reference suspension I having an opalescent value of <NUM> NTU (Table <NUM>).

In the following Table <NUM> exemplary pharmaceutical compositions of solvents which were mixed with <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene (the substance) according to the present invention are given in detail (Gly: glycerol; PG: propylene glycol, EtOH: ethanol). The turbidity was measured by using a Hach Lange <NUM> N IS apparatus.

The following procedure was used to prepare the samples:.

The mixtures of solvents applied for experiments V8 to V12 and V14 showed instability phenomena like visible sediments in the solution or on the bottom of the vessel within <NUM> weeks short term storage at room temperature. In order to quantify the solvent characteristics of these mixtures regarding their suitability to form a physical stable solution with the substance, a LogP-Parameter was introduced (Eq. <NUM>). The LogP-Parameter describes the hydrophilic/hydrophobic nature of solvent mixture containing organic and aqueous solvents and is calculated as follows: <MAT> <MAT> <MAT> <MAT>.

For glycerol the log<NUM>P value (= LogPi) is given as -<NUM> and the molecular weight as <NUM>/mol. <NUM> of solvent mixture of V1 contains <NUM>% glycerol which corresponds to <NUM> glycerol or <NUM> mol (=mo glycerol). The other organic solvent is propylene glycol (PG) having a log<NUM>P value (= LogPi) of -<NUM> and a molecular weight of <NUM>/mol. <NUM> of the solvent mixture of V1 contains <NUM>% PG which corresponds to <NUM> PG or <NUM> mol (=mo PG). Concerning Eq. <NUM> Mo glycerol is <NUM> and Mo PG is <NUM>. LogPo is calculated as -<NUM> (Eq. <NUM>). <NUM> of solvent mixture of V1 contains <NUM>% aqueous buffer which results in a mass fraction of organic phase of Xo = <NUM> (Eq. <NUM>). Following Eq. <NUM> a LogP Parameter of -<NUM> is calculated for the solvent mixture of experiment V1. For mixtures containing ethanol, a log<NUM>P value (= LogPi) for ethanol of -<NUM> and a molecular weight of <NUM>/mol was used.

By correlating the measured Turbidity over the values for the LogP-Parameter between -<NUM> and -<NUM>, an exponential function is observed (<FIG>). Furthermore it was found, that solvent mixtures prepared with the phosphate buffer pH <NUM> or the citric acid buffer pH <NUM> having a LogP-Parameter ≥<NUM> are physically instable after preparing a solution with the substance.

In the following Table <NUM> exemplary pharmaceutical compositions according to the present invention are given in detail (API: active pharmaceutical ingredient).

The production procedure of an exemplary pharmaceutical composition according to the present invention for a single small scale batch (<NUM>) in form of a general instruction is as follows:.

Formulation samples were produced with compositions listed in the following Table <NUM>.

The solutions were found to have the following densities and appearances (Table <NUM>).

The testing criteria applied are those for evaluation of antimicrobial activity for oral preparations according to Pharm. <NUM> (tests at <NUM> days and <NUM> days). The acceptance criteria of the Ph. <NUM>, Method <NUM>. <NUM> "Efficacy of Antimicrobial Preservation", and USP <NUM>, Method <<NUM>> "Antimicrobial Effectiveness Testing" are listed in the following Table <NUM>.

The formulations tested in the trial are shown in the following Table <NUM>.

After preparation of the samples, the solutions were filtrated via a <NUM> filter.

The following microorganisms were tested: Pseudomonas aeruginosa, Straphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus brasiliensis, Zygosaccharomyces rouxi.

In the performed tests the USP <NUM> Method <<NUM>> Criteria as listed in Table <NUM> were found to be fulfilled for all solutions for all microorganisms. It was also found, that an additional preservative like propyl-hydroxy-benzoate is not needed to get antimicrobial effectiveness.

Formulation samples were produced as follows:.

The following solubilizing agents were used:.

For the experiments <NUM>, <NUM>, <NUM> and <NUM> no additional significant degradation are measured by HPLC analytics (table <NUM>).

Trials with different flavors:
<NUM> stock-solution was filled in a separate beaker and <NUM> of flavor was added (see table <NUM>, experiments <NUM> to <NUM>, experiment <NUM> is the stock solution).

Trials with different sweeteners:
<NUM> stock solution was filled in a separate beaker and <NUM> of sweetener was added (see Table <NUM>, experiments <NUM> and <NUM>).

Claim 1:
A liquid pharmaceutical composition comprising at least one SGLT-<NUM> inhibitor and one or more polar organic solvents, wherein the at least one SGLT-<NUM> inhibitor is <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene according to formula (I):
<CHM>
wherein the one or more polar organic solvents are selected from the group consisting of: ethanol, propane-<NUM>,<NUM>-diol (propylene glycol) and/or propane-<NUM>,<NUM>,<NUM>-triol (glycerol),
wherein <NUM>-cyano-<NUM>-(<NUM>-cyclopropyl-benzyl)-<NUM>-(β-D-glucopyranos-<NUM>-yl)-benzene is the only SGLT-<NUM> inhibitor contained in such liquid pharmaceutical composition, and
wherein such liquid pharmaceutical composition as a whole is characterized by a negative LogP-Parameter of equal to or more than -<NUM> (i.e.-<NUM> ≤ LogP-Parameter ≤ <NUM>), wherein the LogP-Parameter is defined as follows: <MAT> <MAT> <MAT> <MAT>
moi [mol/g]: molecular amount of an organic solvent in the organic phase of a solvent mixture
Moi [-]: molecular fraction of organic solvent moi in the organic phase of a solvent mixture
LogP; [-]: log<NUM> Pn-octanol/water = concentration of unionized compound in n-octanol / concentration of unionized compound in water of an organic solvent
LogPo [-]: auxiliary parameter of the organic phase of a solvent mixture
aw [g]: mass of water or aqueous buffer in a solvent mixture
asol [g]: mass of solvent mixture
Xo [-]: mass fraction of organic phase in a solvent mixture.