Patent Application
20230381101
All references cited herein, are incorporated by reference herein, in their entirety.
The invention relates to the field of medicine, particularly veterinary medicine. In particular, the invention relates to novel aqueous pharmaceutical compositions comprising at least one SGLT-2 inhibitor and one or more solubilizing agents.
The treatment of diabetes and other metabolic disorders includes the inhibition of the renal sodium-dependent glucose co-transporter SGLT-2. SGLT-2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood. SGLT-2 inhibition thus induces glucosuria and may reduce blood glucose levels.
A large variety of SGLT-2 inhibitors are known. A pharmaceutical formulation of SGLT-2 inhibitors is essential in order to administer such compounds in an adequate way to the patient.
EP 1 609 785 discloses C-glycoside derivatives and salts thereof, wherein B ring is bonded to A ring via —X— and A ring is directly bonded to the glucose residue, and it is usable as a Na+-glucose cotransporter inhibitor, especially for a therapeutic and/or preventive agent for diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes related diseases such as an insulin-resistant diseases and obesity.
WO 2006/064033 discloses glucopyranosyl-substituted benzene derivatives including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof, which are suitable for the treatment of metabolic disorders.
SGLT-2 inhibitors are for instance described in WO 2007/028814 which is directed to crystalline forms of 1-chloro-4-([beta]-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, a method for the preparation thereof, as well as the use thereof for preparing medicaments. It discloses solutions of 1-chloro-4-([beta]-D-glucopyranos-1-y1)-2-(4-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.
WO 2007/080170 describes crystalline forms of 1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl) methyl]-5′-methyl-1H-pymzol-3′-O-[beta]-D-glucopyranoside, a method for the preparation thereof, as well as the use thereof for preparing medicaments. It discloses solutions of 1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl) methyl]-5′-methyl-1H-pymzol-3′-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, WO 2007/093610 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 1-cyano-2-(4-cyclopropyl-benzyl)-4-(0-D-glucopyranos-1-y1)-benzene (velagliflozin).
Further SGLT-2 inhibitors are described in WO 2007/128749 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 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (velagliflozin).
US 2011/077213 discloses methods for treating and/or preventing kidney stones, employing an SGLT-2 inhibitor alone, or in combination with a supply of carbohydrate, and/or in combination with a diuretic agent.
WO 2013/079501 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.
WO 2014/016381 (US 2014/031540) describes crystalline complexes of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene with natural amino acids, methods for the preparation thereof as well as the use thereof for preparing medicaments. It discloses solutions of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-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, WO 2014/195966 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.
WO 2015/110402 relates to SGLT-2 inhibitors for use in the treatment and/or prevention of metabolic disorders in canine animals
WO 2015/173584 discloses methods for avoiding an increase in glucagon secretion associated with the administration of a sodium glucose co-transporter 2 (SGLT-2) inhibitor via the co-administration of a dipeptidyl peptidase IV (DPP IV) inhibitor. Additionally, methods are disclosed for normalizing the glucagon secretion associated with the administration of a sodium glucose co-transporter 2 (SGLT-2) inhibitor via the co-administration of a dipeptidyl peptidase IV (DPP IV) inhibitor. The WO publication also relates to methods for treating diabetes, especially Type 2 diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis and related diseases, comprising administering an SGLT-2 inhibitor and a dipeptidyl peptidase IV (DPP IV) inhibitor.
WO 2017/032799 deals with liquid pharmaceutical compositions comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the one or more polar organic solvents preferably always comprise propane-1,2-diol (propylene glycol).
US 2017/145000 discloses canagliflozin monohydrate and its crystalline forms.
US 2020/237794 discloses one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use in the treatment and/or prevention of a metabolic disorder of an equine animal, such as laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome.
WO 2020/219645 discloses methods of reducing the weight loss and/or increasing the weight of a feline in need thereof and/or methods of managing the disease of a feline with diabetes mellitus and elevated IGF-1 concentration, said methods include administering to a feline in need thereof a total daily dosage of about 2 to 50 mg of velagliflozin or a pharmaceutically acceptable form thereof.
WO 2021/105152 discloses the use of at least one SGLT-2 inhibitor in a non-human mammal, preferably ruminant, preferably for drying-off of a non-human mammal, preferably ruminant, as well as corresponding methods, such as improving and/or facilitating the drying-off of a non-human mammal, preferably ruminant, comprising administering to such non-human mammal, preferably ruminant, at least one SGLT-2 inhibitor.
WO 2021/165177 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the prophylaxis and/or treatment of one or more cardiac diseases in feline animals
US 2022/016078 discloses a method of treating or preventing kidney stones in a patient: a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate or hydrate thereof which induces glucosuria or a pharmaceutical composition thereof is administered to the patient in need thereof.
WO 2023/006718 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the prophylaxis and/or treatment of one or more cardiac diseases in a non-human mammal/non-human mammal patient excluding a feline, in particular a canine/canine patient.
WO 2023/006745 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the prophylaxis and/or treatment of hypertension in a non-human mammal, preferably a carnivore, in particular a cat or a dog.
WO 2023/006747 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the prophylaxis and/or treatment of one or more renal diseases in a non-human mammal, such as a carnivore, in particular a cat or a dog.
Xu G et al. (Journal of Medical Chemistry 2014, 57: 1236-1251) is directed to the design, synthesis and biological evaluation of deuterated C-aryl glycosides as potent and long-acting renal SGLT-2 inhibitors for the treatment of type 2 diabetes.
Further challenges known in the prior art are the limited solubility of SGLT-2 inhibitors in water due to their positive log10P 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 a liquid formulation before administering it into the body of a patient.
The present invention concerns an aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents.
In the course of the present invention the term “aqueous” with regard to the term “pharmaceutical composition” refers to a water-containing pharmaceutical composition, wherein preferably such water is present in the form of an aqueous buffer, such as for instance citric acid buffer. However, any suitable aqueous buffer (system) can be used according to the knowledge and skills of the person skilled in the art. The water content/aqueous buffer content of such water-containing pharmaceutical composition is from 30 to 100 g/100 mL (30 to 100% w/v), preferably from 30 to 95 g/100 mL (30 to 95% w/v), more preferably from 30 to 90 g/100 mL (30 to 90% w/v), more preferably from 30 to 85 g/100 mL (30 to 85% w/v), even more preferably from 30 to 80 g/100 mL (30 to % w/v), most preferably from 50 to 80 g/100 mL (50 to 80% w/v).
The present invention also concerns an aqueous pharmaceutical composition as described and/or claimed herein, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of:
The present invention also concerns an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition comprises only one SGLT-2 inhibitor, preferably only velagliflozin as single SGLT-2 inhibitor.
The present invention also concerns an aqueous pharmaceutical composition as described and/or claimed herein, wherein the at least one SGLT-2 inhibitor is velagliflozin, which preferably is the only SGLT-2 inhibitor contained in such aqueous pharmaceutical composition, and/or wherein the aqueous pharmaceutical composition is for, preferably direct, administration to a subject, preferably without further mandatory processing and/or purification steps, more preferably an animal, even more preferably a mammal, in particular a horse, cat, dog or cow; wherein preferably the aqueous pharmaceutical composition is sterile.
The present invention also concerns an aqueous pharmaceutical composition as described and/or claimed herein for use in a method of 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, dog or cow, selected from among the medicinal indications:
The present invention further concerns a process for producing the aqueous pharmaceutical composition as described and claimed herein, comprising the steps:
In the course of the present invention, such process steps (i) to (vi) do not need to be carried out in the given order but can also be performed in any other meaningful order, e.g. (i), (v), (ii), (iii), (iv), (vi). 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 aqueous 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 at least one SGLT-2 inhibitor, preferably velagliflozin (e.g., 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 aqueous 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 1 to 5% 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 Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
The at least one SGLT-2 inhibitor according to the invention includes, but is not limited to, glucopyranosyl-substituted benzene derivatives, for example as described in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940, WO 2009/022020 or WO 2009/022008.
Moreover, the at least one SGLT-2 inhibitor according to the invention may be selected from the group consisting of the following compounds or pharmaceutically acceptable (crystalline) forms thereof:
The term “velagliflozin” as employed herein refers to velagliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound, methods of its synthesis and co-crystals thereof are described in WO 2007/128749, WO 2014/016381 and WO 2019/121509 for example.
The term “dapagliflozin” as employed herein refers to dapagliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 03/099836 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/002824 for example.
The term “canagliflozin” as employed herein refers to canagliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvates and crystalline forms are described in the patent application WO 2008/069327 for example.
The term “empagliflozin” as employed herein refers to empagliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2005/092877, WO 2006/120208 and WO 2011/039108 for example. A preferred crystalline form is described in the patent applications WO 2006/117359 and WO 2011/039107 for example.
The term “atigliflozin” as employed herein refers to atigliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2004/007517 for example. The term “ipragliflozin” as employed herein refers to ipragliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.
The term “tofogliflozin” as employed herein refers to tofogliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280 for example.
The term “luseogliflozin” as employed herein refers to luseogliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof.
The term “ertugliflozin” as employed herein refers to ertugliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound is described for example in WO 2010/023594.
The term “remogliflozin” as employed herein refers to remogliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1 213 296 and EP 1 354 888 for example.
The term “sergliflozin” as employed herein refers to sergliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1 344 780 and EP 1 489 089 for example.
The compound of formula (16) above, i.e. sotagliflozin, and its manufacture are described for example in WO 2008/042688 or WO 2009/014970.
The term “bexagliflozin” as employed herein refers to bexagliflozin of the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2009/026537 for example.
The term “TFC-039” as employed herein refers to the above structure as well as pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 2012/160218 for example.
Preferred SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives. Optionally, one or more hydroxyl groups of the glucopyranosyl group in such one or more SGLT-2 inhibitors may be acylated with groups selected from (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C1-3-alkyl)-carbonyl.
More preferred are glucopyranosyl-substituted benzonitrile derivatives of formula (1) as disclosed herein above. Yet more preferred are glucopyranosyl-substituted benzonitrile derivatives of formula (18):
Preferably, such SGLT-2 inhibitor is velagliflozin as shown in formula (2). Optionally, one or more hydroxyl groups of the β-D-glucopyranosyl group of velagliflozin may be acylated with groups selected from (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C1-3-alkyl)-carbonyl.
Thus, in a preferred embodiment, the at least one SGLT-2 inhibitor according to the present invention is a glucopyranosyl-substituted benzene derivative SGLT-2 inhibitor, preferably a SGLT-2 inhibitor of formula (1), more preferably of formula (18), or yet more preferably of formula (2), i.e. velagliflozin, in each case as defined herein above. In the course of the present invention 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (velagliflozin) is also referred to as “the substance” and is herewith understood to also comprise co-crystal 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene—L-proline as well as the 1:1:1-co-crystal 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene—L-proline—water (as disclosed in WO 2014/016381). Generally, in the case of disclosed and claimed concentrations (% w/v) and amounts (g, mg) the concentration or amount always refers to 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene as such, i.e. excluding L-proline and crystal water, unless otherwise explicitly stated —even though in practice (and in the example section) 1:1:1 co-crystal 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene—L-proline—water is actually added/used.
In the course of the present invention the term “for, preferably direct, administration to a subject” in connection with “aqueous pharmaceutical composition” means that such aqueous pharmaceutical compositions can be directly administrated to a subject, preferably 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 SGLT-2 inhibitors. Preferably, such “aqueous pharmaceutical composition” that are “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 an aqueous pharmaceutical composition as described and/or claimed herein, wherein the aqueous pharmaceutical composition is for, preferably direct, administration to a subject, preferably without further mandatory processing and/or purification steps, more preferably an animal, even more preferably a mammal, in particular a horse, cat, dog or cow; wherein preferably the aqueous pharmaceutical composition is sterile.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein the at least one SGLT-2 inhibitor is velagliflozin, which preferably is the only SGLT-2 inhibitor contained in such aqueous pharmaceutical composition.
In another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein the aqueous 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 10.0, more preferably equal to or less than 7.0, even more preferably equal to or less than 3.0, and most preferably a solution, in particular a solution with an NTU value of equal to or less than 3.0.
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 European Pharmacopoeia 8th edition (Ph. Eur. 8, Chapter 2.2.1. “Clarity and degree of opalescence of liquids”).
In another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, which contains one or more organic solvents that are independently from each other characterized by a negative log10P value, preferably a negative decadic logarithmic partition coefficient (P) in an n-octanol/water system according to formula (II):
loh10n-octanol/water=concentration of unionized compound in n-octanol/concentration of unionized compound in water (II)
In a further aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition as a whole is characterized by a negative LogP-Parameter, preferably a negative LogP-Parameter of equal to or higher than −2.0 (i.e. −2.0≤LogP-Parameter<0). For the avoidance of doubt, the LogP-Parameter is defined as in Eq. 4 of Example 1 and is not identical with and should not be mistaken for the (negative) log10P value as given for a(n) organic solvent(s).
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein the one or more organic solvents are selected from the group consisting of: ethanol (log10P: −0.16), propane-1,2,3-triol (glycerol; log10P: −1.84), pyrrolidone (log10P:−-0.58), methylpyrrolidone (log10P: −0.356), N,N-dimethylacetamide (log10P: −0.583) and/or N,N-dimethylformamide (log10P: −0.632). The log10P values were taken from http://www.chemicalize.org/.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition comprises at least two different organic solvents, preferably propane-1,2,3-triol (glycerol) and ethanol.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such composition contains no more than 20 g/100 mL (20% w/v) of organic solvents, preferably no more than 15 g/100 mL (15% w/v) of organic solvents, more preferably no more than 10 g/100 mL (10% w/v) of organic solvents.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such composition does not contain propane-1,2-diol (propylene glycol).
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition comprises ethanol as the only organic solvent contained in such aqueous pharmaceutical composition. Preferably, the ethanol is present in such aqueous pharmaceutical composition at no more than 20 g/100 mL (20% w/v), more preferably at no more than 15 g/100 mL (15% w/v), even more preferably at no more than 10 g/100 mL (10% w/v), most preferably it is present at 8 g/100 mL (8% w/v).
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such composition is substantially free of organic solvents, preferably does not contain any organic solvents. In case no organic solvent is present, the solvent of the aqueous pharmaceutical composition is 100% water, preferably in the form of aqueous buffer.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition comprises water in the form of aqueous buffer, such as citric acid buffer, phosphate buffer, ammonium sulphate buffer, ammonium acetate buffer, sodium acetate buffer and the like, preferably aqueous buffer with pH 4.5, more preferably citric acid buffer with pH 4.5.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition contains from 30 to 100 g/100 mL (30 to 100% w/v), preferably from 30 to 95 g/100 mL (30 to 95% w/v), more preferably from 30 to 90 g/100 mL (30 to 90% w/v), more preferably from 30 to 85 g/100 mL (30 to 85% w/v), even more preferably from 30 to 80 g/100 mL (30 to 80% w/v), most preferably from 50 to 80 g/100 mL (50 to 80% w/v) water, more preferably in the form of aqueous buffer, such as citric acid buffer, even more preferably aqueous buffer with pH 4.5, most preferably citric acid buffer with pH 4.5.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition has a (measured) pH value from 2 to 7, preferably from 3 to 7, more preferably from 3.0 to 6.5, even more preferably from 4.0 to 6.5, even more preferably from 4.0 to 5.0, and most preferably of 4.5. For the avoidance of doubt, the term “measured pH value” refers to the pH value actually measured for the whole aqueous pharmaceutical composition according to the present invention, i.e. comprising both organic solvent(s) phase, if any, and aqueous phase.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition additionally comprises one or more preservatives, preferably selected from the group consisting of: sorbic acid or salts thereof, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or salts thereof, preferably sodium benzoate;
benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and salts thereof, preferably methylparaben, ethylparaben, propylparaben, butylparaben, butylparaben sodium; most preferably benzoic acid and/or salts thereof, such as sodium benzoate.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition additionally comprises one or more antioxidation agents, preferably selected from the group consisting of: ascorbic acid or pharmaceutically acceptable salts thereof, particularly sodium ascorbate; citric acid (anhydrous and/or monohydrate) or pharmaceutically acceptable salts thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisol; butylhydroxytoluene; gallate derivatives, particularly propylgallate, octylgallate; Vitamin E or pharmaceutically acceptable salts thereof; ascorbyl palmitate; edetic acid or pharmaceutically acceptable salts thereof; most preferably sodium metabisulfite.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein the one or more solubilizing agents are selected from the group consisting of: surfactants, anionic surfactants, non-ionic surfactants, hydrogenated castor oils, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, polyvinylpyrrolidones, more preferably selected from the group consisting of: sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68
(Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone), wherein preferably the total amount of the one or more solubilizing agents is from 1 to 50 g/100 mL (1-50% w/v), more preferably from 1 to 45 g/100 mL (1-45% w/v), even more preferably from 1 to 40 g/100 mL (1-40% w/v), even more preferably from 1 to 35 g/100 mL (1-35% w/v), even more preferably from 1 to 30 g/100 mL (1-30% w/v), even more preferably from 1 to 25 g/100 mL (1-25% w/v), most preferably from 5 to 25 g/100 mL (5-25% w/v).
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein two or more solubilizing agents are contained in the aqueous pharmaceutical composition.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein two solubilizing agents are contained in such aqueous pharmaceutical composition, wherein preferably the amount of the first solubilizing agent and the amount of second solubilizing agent are independently from each other selected from 1 to 50 g/100 mL (1-50% w/v), more preferably from 1 to 45 g/100 mL (1-45% w/v), even more preferably from 1 to 40 g/100 mL (1-40% w/v), even more preferably from 1 to 35 g/100 mL (1-35% w/v), even more preferably from 1 to 30 g/100 mL (1-30% w/v), even more preferably from 1 to 25 g/100 mL (1-25% w/v), most preferably from 5 to 25 g/100 mL (5-25% w/v), wherein more preferably these two solubilizing agents are independently from each other selected from the group consisting of: sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone), wherein even more preferably, such two solubilizing agents are Kollidon 12 (povidone) as well as PEG 200, PEG 300, or PEG 400, most preferably Kollidon 12 (povidone) and PEG 300.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition 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.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition 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, meat flavor, vanillin/vanilla flavor, saccharine, aspartame, sorbitol, xylitol.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition does not comprise any apolar organic solvents, which are preferably and independently from each other characterized by a log10P value of equal to or higher than 0.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, wherein such aqueous pharmaceutical composition is for oral and/or parenteral administration, preferably oral administration.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, comprising, preferably consisting of:
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, comprising, preferably consisting of:
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, comprising, preferably consisting of: velagliflozin; sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and/or Kollidon 12 (povidone);
sodium benzoate; optionally, Na-metabisulfite; optionally, ethanol; water.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, comprising, preferably consisting of: velagliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and/or Kollidon 12 (povidone); sodium benzoate; optionally, Na-metabisulfite; optionally, ethanol; water.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, comprising, preferably consisting of: velagliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and/or Kollidon 12 (povidone); sodium benzoate; optionally, Na-metabisulfite; optionally, ethanol; sorbitol and/or xylitol; honey flavor and/or vanillin and/or meat flavor; water.
In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and/or claimed herein, selected from:
The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.
The testing criteria applied are those for evaluation of the clarity of a liquid (formulation) comprising 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (velagliflozin) according to Pharm. Eur. 8. Concerning the Ph. Eur. 8, Chapter 2.2.1. “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 3 NTU (Table 1).
In the following, exemplary pharmaceutical compositions of solvents which were mixed with 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (velagliflozin; the substance) according to the present invention are given in detail. The turbidity was measured by using a Hach Lange 2100 N IS apparatus.
20 In order to quantify the solvent characteristics regarding their suitability to form a physical stable solution with the substance, a LogP-Parameter was introduced (Eq. 4). The LogP-Parameter describes the hydrophilic/hydrophobic nature of solvent mixture containing organic and aqueous solvents and is calculated as follows:
As described in WO 2017/032799 instability phenomena are expected for LogP-Parameters <−2.0.
For ethanol the log10P value (=LogPi) is given as −0.16 and the molecular weight as 46.07 g/mol. The solvent mixture of Composition 1 consists of 80.0 mg/mL ethanol and 644.3 mg/mL H2O (sum of water purified and aqueous buffer), which corresponds to an organic phase of 11.0% (m/m).
Because ethanol is the only organic solvent, the amount of ethanol in the organic phase is 100% (m/m) or 100 g/100g which corresponds to 0.0217 mol/g (=moehtanol). Therefore, Moethanol is 1 (Eq. 1) and LogPo is calculated as −0.16 (Eq. 2). The mass fraction of the organic phase is 11.0% (m/m) or according to Eq. 3 X0=0.11. Following Eq. 4 a LogP Parameter of −1.45 is calculated for the solvent mixture of Composition 1.
In the following Table 2, 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 (1000 mL) in form of a general instruction is as follows:
Formulation samples were produced with compositions listed in the following Table 3 (API: active pharmaceutical ingredient).
The following procedure was used to prepare the samples:
Formulation samples were produced with compositions listed in the following Table 4.
The following procedure was used to prepare the samples:
Furthermore, the efficacy of antimicrobial preservation of Compositions 1 to 4 was investigated. The testing criteria applied are those for evaluation of antimicrobial activity for oral preparations according to Pharm. Eur. 7 (tests at 14 days and 28 days). The acceptance criteria of the Ph. Eur. 7, Method 5.1.3 “Efficacy of Antimicrobial Preservation”, and USP 34, Method <51>“Antimicrobial Effectiveness Testing” are listed in the following Table 6.
1) for Ph. Eur: No increase = no increase in number
2) for USP: No increase = not more than 0.5 log10 units higher than reference value
The following microorganisms were tested: Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus brasiliensis, Burkholderia cepacia.
In the performed tests the USP 34 Method <51> Criteria as listed in Table 6 were found to be fulfilled for all solutions for all microorganisms
After sample preparation the solution was filled in polyethylene bottles and closed with polypropylene caps for chemical stability investigations.
20 For the Compositions 1, 2, 3 and 4 the API content stays constant as 15.0±0.1 mg/mL and no additional degradation ≥1.0% was measured by HPLC analytics after 6 months at 25° C/60% r.h and 40° C/75% r.h. (table 7).
Formulation samples were produced with compositions listed in the following Tables 8 and 9.
The following procedure was used to prepare the samples:
A temperature test (alternating storage between 4° C. and 23° C., over 3 weeks) showed no visual changes for all samples (Table 10).
The following clauses are also part of the disclosure and are comprised by the spirit and scope of the present invention:
SGLT-2 inhibitor is velagliflozin, which preferably is the only SGLT-2 inhibitor contained in such aqueous pharmaceutical composition, and/or wherein the aqueous pharmaceutical composition is for administration to a subject, preferably an animal, more preferably a mammal, in particular a horse, cat, dog or cow; wherein preferably the aqueous pharmaceutical composition is sterile.
| Number | Date | Country | Kind |
|---|---|---|---|
| 22175413.8 | May 2022 | EP | regional |
