Oral solutions comprising fludrocortisone acetate

Physicochemically stable oral pharmaceutical solution comprising fludrocortisone acetate and a non-aqueous liquid carrier comprising one or more medium-chain fatty acid triglycerides.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit and priority of EP20386012.7, filed Feb. 25, 2020. The entire disclosure of the above application is incorporated herein by reference.

FIELD

The present invention relates to oral pharmaceutical solutions comprising as active substance fludrocortisone acetate.

BACKGROUND

Fludrocortisone is most commonly used in its acetate form.

Fludrocortisone acetate is a corticosteroid and exhibits a powerful mineralocorticoid activity along with some additional but comparatively very weak glucocorticoid activity. Relative to cortisol, it is said to have 10 times the glucocorticoid potency but 250 to 800 times the mineralocorticoid potency and it is used to treat adrenogenital syndrome, postural hypotension, and adrenal insufficiency. In case of adrenal insufficiency, it is generally administered along with hydrocortisone.

Fludrocortisone acetate is considered a prodrug as it is hydrolyzed to its active form fludrocortisone when in human organism.

Fludrocortisone acetate is a typical example of a hydrophobic therapeutic agent. Although it is very stable as a solid, in aqueous and alcoholic solutions the a-ketol side chain, as in all such corticosteroids, is prone to oxidative rearrangement and degradation at alkaline pH. It has been reported that hydrocortisone and prednisolone, when exposed to ultraviolet light or ordinary fluorescent laboratory lighting in alcoholic solutions, undergo photolytic degradation of the A-ring. Since fludrocortisone acetate has the same A-ring as hydrocortisone it is also labile under these conditions.

Fludrocortisone acetate is currently formulated only in solid state forms and is commercially available as a 0.1 mg tablet under the brand name Florinef® among others.

Although oral solid dosage forms such as tablets are very popular for reasons that are mainly due to ease of management, for certain users (e.g. children and the elderly) these forms are not necessarily a convenient option, especially due to difficulty in swallowing these forms. This lack of convenience results in high incidence of non-compliance and ineffective therapy.

However, it is apparently extremely challenging to formulate fludrocortisone acetate in the form of a solution for oral administration, since it is an extremely hydrophobic agent.

Cisternino et. al., “Stability of fludrocortisone acetate solutions prepared from tablets and powder”, European journal of pharmaceutics and biopharmaceutics 55 (2003) 209-213, discloses that fludrocortisone acetate 40 μg/ml oral solutions prepared from tablets and powder show significant degradation of fludrocortisone acetate even when stored at 23° C.

Najim A. AL-Awwadi et. al. “Challenges in administration of corticosteroids for the treatment of Addison's disease: a case study of fludrocortisone acetate”, J Bioanal Biomed 2017, 9:3, discloses different liquid formulations of fludrocortisone by using various polymers such as poly(ε-caprolactone), Eudragit® RS and Eudragit® RL and different processes such as oil-in-water solvent evaporation methods and suspension-in-oil-in-water evaporation methods. Small poly(ε-caprolactone)-based microparticles were developed during this study, leading to good efficiency when they were prepared as oil-in-water emulsion with 7.5 mg/ml of fludrocortisone.

U.S. Pat. No. 6,294,192 also discloses that another conventional approach to formulating hydrophobic therapeutic agents takes advantage of the increased solubility of hydrophobic therapeutic agents in oils (e.g. triglycerides). Hydrophobic therapeutic agents, while poorly soluble in aqueous solution, could be sufficiently lipophilic that therapeutically effective concentrations of the therapeutic agents can be prepared in triglyceride-based solvents. Thus, one conventional approach is to solubilize a hydrophobic therapeutic agent in a bioacceptable triglyceride solvent, such as a digestible vegetable oil, and disperse this oil phase in an aqueous solution. The dispersion may be stabilized by emulsifying agents and provided in emulsion form. Alternatively, the therapeutic agent can be provided in water-free formulations.

However, according to U.S. Pat. No. 6,294,192, although triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some hydrophobic therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages. For example emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation.

The present invention overcomes the problems of the prior art and provides an oral pharmaceutical solution, comprising fludrocortisone acetate, which exhibits excellent stability and extended lifetime.

SUMMARY

The present invention provides a physicochemically stable oral pharmaceutical solution comprising fludrocortisone acetate.

The oral pharmaceutical solution according to the invention comprises fludrocortisone acetate and a non-aqueous liquid carrier comprising one or more medium-chain fatty acid triglycerides.

The oral pharmaceutical solution according to the invention presents excellent physicochemical stability.

The present invention has the advantage that it provides a stable oral pharmaceutical solution of fludrocortisone acetate, by inhibiting hydrolysis and oxidation that typically occur after extended storage.

Preferably, the oral pharmaceutical solution according to the invention is free from ethanol, propylene glycol, polyethylene glycol, sorbitol, glycerol, maltitol, polyvinylpyrrolidone, copolyvidone, sorbitan monolaurate, propylene glycol monolaurate (lauroglycol), carboxymethyl cellulose and microcrystalline cellulose mixtures, as well as free from lipophilic surfactants such as polysorbate 80, polyethylene glycol, castor oils and polyethylene glycol hydrogenated castor oils.

DETAILED DESCRIPTION

The present invention provides an oral pharmaceutical solution comprising fludrocortisone acetate, in association with a pharmaceutically acceptable non-aqueous liquid carrier.

The term “% w/v” refers to g of the respective substance per 100 ml of the oral solution.

As used throughout the present description and claims, the term “non-aqueous” means essentially water-free.

As used throughout the present description and claims, the term “total impurities” refers to the sum of all fludrocortisone acetate degradation impurities present in the oral solution, except for fludrocortisone.

The term “stable” as used herein, refers to both physical and chemical stability, wherein no more than 1.2% w/w of fludrocortisone and no more than 1.5% w/w of total impurities are formed on storage at 40° C. and 75% relative humidity over a period of three months.

The desire for the development of an oral solution of fludrocortisone acetate is complicated by the fact that the molecule is susceptible to hydrolysis and degrades significantly especially at alkaline and oxidative conditions. Although fludrocortisone acetate is very soluble in lipids and triglycerides, the physicochemical stability of fludrocortisone acetate oily solutions has not been addressed in the prior art.

There are numerous lipids comprising triglycerides of fatty acids commercially available to formulators as excipients for lipid-based drug delivery systems. Many synthetic lipids are also available in which the glycerol backbone has been replaced by propylene glycol and/or polyethylene glycols. Additionally, the degree of esterification of the fatty acid moiety may vary, forming mono-, di- and tri-glycerides as well as different esters of propylene glycol and polyethylene glycols. The fatty acids are not necessarily long chain (C11-C22); they can be medium-chain (C6-C10), short chain, unsaturated or branched. Due to these differences in chemical nature, there are numerous lipids or lipid-like excipients available commercially, all of which are colloquially called ‘lipids’ in the pharmaceutical field.

The term “medium-chain triglycerides” according to the present invention refers to triglycerides of saturated fatty acids having an aliphatic chain of 6 to 10 carbon atoms (C6:0to C10:0).

Unexpectedly, it has been found that the inclusion of many mixed mono-, di- and tri-glycerides, such as glycerol monocaprylocarpate (i.e. medium chain monoglyceride (60% w/w) and diglyceride (35% w/w) consisting of 83% w/w caprylic acid and 17% w/w capric acid) and glycerol dicaprylate (i.e. medium chain diglyceride (83% w/w) comprising 75%-85% w/w caprylic acid) to oral solutions comprising fludrocortisone acetate did not actually enhance the stability of fludrocortisone acetate.

It has been further found that many lipophilic surfactants, commonly used in drug carrier systems such as polysorbate 80, polyethylene glycol castor oils and polyethylene glycol hydrogenated castor oils are also ineffective to slow down the decomposition of the active agent after storage.

On the other hand, it has now been found that the physicochemical stability of fludrocortisone acetate is considerably enhanced in non-aqueous liquid carriers comprising one or more medium-chain fatty acid triglycerides. This finding is unexpected since it does not apply to other triglycerides, such as long chain triglycerides. For example, the addition of corn oil, sunflower oil or castor oil does not enhance the stability of fludrocortisone acetate in a non-aqueous solution.

The oral pharmaceutical solution according to the invention comprises fludrocortisone acetate and a non-aqueous liquid carrier comprising one or more medium-chain fatty acid triglycerides.

Preferably, the oral pharmaceutical solution according to the invention comprises from 0.001% w/v to 0.01% w/v fludrocortisone acetate.

More preferably, the oral pharmaceutical solution according to the invention comprises from 0.002% w/v to 0.005% w/v fludrocortisone acetate.

The European Pharmacopoeia (Ph. Eur. 6.0) describes medium-chain triglycerides as the fixed oil extracted from the hard, dried fraction of the endosperm ofCocos nuciferaL. or from the dried endosperm ofElaeis guineenisJacq. They comprise a mixture of triglycerides of saturated fatty acids, mainly of caprylic acid (C8:0) and of capric acid (C10:0). They contain no less than 95% w/w of saturated fatty acids (expressed as percent (%) by weight of total mixture).

According to Handbook of excipients, sixth edition (2009), medium-chain triglycerides (synonyms; MCT oil, caprylic/capric triglyceride, glyceryl tricaprylate/caprate) may also be known as fractionated coconut oil, which contains three saturated lipid chains bound to a glycerin backbone, and are distinguished from other triglycerides by the length of the carbon chains, normally between 6 and 10.

Medium chain triglycerides have been used in a variety of pharmaceutical formulations including oral, parenteral and topical preparations mainly as emulsifying agents or solvents. They are usually colorless to slightly yellow liquids that are practically odorless and tasteless, while they solidify at about 0° C.

According to a preferred embodiment, the medium-chain triglyceride according to the invention is caprylic acid triglyceride.

According to another preferred embodiment, the medium-chain triglyceride according to the invention is a mixture of caprylic acid and capric acid triglycerides. Preferably the medium-chain triglyceride according to the invention is a mixture of caprylic acid and capric acid triglycerides in a weight ratio caprylic acid:capric acid from 4:6 to 99:1. More preferably the medium-chain triglyceride according to the invention is a mixture of caprylic acid and capric acid triglycerides in a weight ratio caprylic acid:capric acid from 4.5:5.5 to 95:5. Even more preferably the medium-chain triglyceride according to the invention is a mixture of caprylic acid and capric acid triglycerides in a weight ratio caprylic acid:capric acid from 5:5 to 90:10.

Preferably the medium-chain triglyceride according to the invention has a saponification value from 320 to 380 mg KOH/g. More preferably the medium-chain triglyceride according to the invention has a saponification value from 330 to 370 mg KOH/g. Even more preferably the medium-chain triglyceride according to the invention has a saponification value from 335 to 365 mg KOH/g.

Preferable examples of medium-chain triglycerides according to the invention include caprylic triglyceride with fatty-acid composition of about 99% w/w caprylic acid (C8:0) (synonyms: tricaprylin, glycerol trioctanoate), with a saponification value of 335 to 360 mg KOH/g e.g. Captex® 8000, which is a synthetic triglyceride manufactured by esterification of caprylic acid and glycerin.

The total concentration of the medium-chain triglycerides in the oral pharmaceutical solution according to the invention is at least 45% w/v. Preferably the total concentration of the medium-chain triglycerides is at least 60% w/v. Even more preferably the total concentration of the medium-chain triglycerides is at least 90% w/v. Even more preferably the total concentration of the medium-chain triglycerides is at least 95% w/v.

Preferably, the oral pharmaceutical solution according to the invention is free from ethanol, propylene glycol, polyethylene glycol, sorbitol, glycerol, maltitol, polyvinylpyrrolidone, copolyvidone, sorbitan monolaurate, propylene glycol monolaurate (lauroglycol), carboxymethyl cellulose and microcrystalline cellulose mixtures, as well as free from lipophilic surfactants such as polysorbate 80, polyethylene glycol castor oils and polyethylene glycol hydrogenated castor oils.

Preferably, the oral pharmaceutical solution according to the invention is free from any stabilizing agent which is not a medium chain triglyceride.

The oral pharmaceutical solution, according to the invention may also comprise additional excipients commonly used in preparing oral liquid compositions, such as antimicrobial preservatives, antioxidants, sweeteners and flavouring agents.

Antimicrobial preservatives may include but are not limited to sodium benzoate, benzoic acid, boric acid, sorbic acid and their salts thereof, benzyl alcohol, parahydroxybenzoic acids and their alkyl esters, methyl, ethyl and propyl parahydroxybenzoates and their salts or mixtures thereof.

Antioxidants which may be used in the present invention comprise, amongst others, butylated hydroxytoluene, butylated hydroxyanisole, ethylenediamine tetraacetic acid (“EDTA”), ascorbic acid, sodium metabisulfite and propyl gallate or any combinations thereof.

Sweeteners may include but are not limited to aspartame, acesulfame potassium, thaumatin, saccharin and salts thereof, sodium cyclamate, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate or mixtures thereof.

The oral pharmaceutical solution, according to the invention may further comprise flavours and/or colours so as to enhance its palatability and/or visual appearance. Suitable flavouring agents and colouring agents are well known to those skilled in the art. The flavouring agent may be a natural or artificial flavouring agent, including an essence, an extract, a flavour oil or combinations thereof. Exemplary flavours include, but are not limited to: honey flavour, raspberry flavour, strawberry flavour, blueberry flavour, blackberry flavour, grape flavour, peach flavour, apricot flavour, watermelon flavour, melon flavour, fruit punch flavour, cranberry flavour, mango flavour, banana flavour, citrus flavour, orange flavour, lemon flavour, grapefruit flavour, cherry flavour, vanilla flavour, caramel flavour, chocolate flavour, marshmallow flavour, coffee flavour and coconut flavour.

The oral pharmaceutical solution according to the invention is preferably supplied as multidose preparation. Each dose from a multidose container may be administered by means of a device suitable for accurately measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 mL or multiples thereof, or an oral syringe for other volumes. Preferably, the device is an oral syringe.

The oral pharmaceutical solution of the present invention may be prepared using methods well known in the art and using regular manufacturing equipment.

For example, it may be prepared using the following process: The active substance and the excipients are weighed. The selected medium-chain triglyceride(s) is added into a vessel and heated to 30-35° C. Fludrocortisone acetate is added into the vessel under stirring until it totally dissolves. The remaining excipients, if present, are successively added under continuous stirring, until complete dissolution. Finally, the volume is adjusted with a quantity of the medium-chain triglyceride(s).

The final solution is optionally filtered over a 10 μm filter, and filled preferably in light-protective containers, such as amber type III glass 50 or 100 mL bottles sealed with child resistant, tamper evident screw caps.

EXAMPLES

Aqueous liquid compositions of fludrocortisone acetate.

These fludrocortisone acetate compositions were prepared in the following manner: A quantity of purified water was added into a vessel. Fludrocortisone acetate and the cosolvent were successively dissolved into purified water. A pH buffer solution, prepared in a different vessel, was added, under continuous stirring, until fludrocortisone acetate was completely dissolved. The remaining excipients, were successively added under continuous stirring, until complete dissolution. The pH of the solution was adjusted to the desired value. Finally, the volume was adjusted with purified water.

TABLE 1Trial 1Trial 2Trial 3(pH~3.5)(pH~4.0)(pH~3.0)ComponentFunctionmg/mlFludrocortisoneAPI0.020.020.02acetateCitric acidBuffering agent3.03.0monohydrateBuffering agent1.01.5Sodium CitratedihydrateHydrochloricAcidifying agent——q.s. toacidpH = 3Propylene glycolCo-solvent150150150Sorbitol 70%Sweetener300300300DiluentPurified waterQs to 1 mL
Storage conditions of temperature (40° C.) and relative humidity (75%) applied for a period of three months. Quantification of fludrocortisone acetate and its degradation impurities was performed by HPLC.

According to the above results, fludrocortisone acetate is unstable and easily hydrolyzed to its active form (fludrocortisone) as the assay value decreases as time passes by and the levels of fludrocortisone increase.

The fludrocortisone acetate aqueous suspension was prepared in the following manner:

A quantity of purified water was added into a vessel. The suspending agent, the cosolvent(s) and fludrocortisone acetate were successively added into the vessel under stirring. A pH buffer solution, prepared in a different vessel, was added, under continuous stirring, into the vessel. The remaining excipients were successively added, into the vessel. The pH of the solution was adjusted to the desired value. Finally, the volume was adjusted with purified water.

The fludrocortisone acetate aqueous solution were prepared in the following manner:

A quantity of purified water was added into a vessel. Fludrocortisone acetate and the cosolvent(s), were successively dissolved into purified water under stirring. A pH buffer solution, prepared in a different vessel, was added, under continuous stirring, until fludrocortisone acetate was completely dissolved. The remaining excipients, were successively added under continuous stirring, until complete dissolution. The pH of the solution was adjusted to the desired value. Finally, the volume was adjusted with purified water.

Storage conditions of temperature (40° C.) and relative humidity (75%) applied for a period of three months. Quantification of fludrocortisone acetate and its degradation impurities was performed by HPLC.

According to the above results, the fludrocortisone suspension presents a similar degradation profile as the clear solutions.

These fludrocortisone acetate solutions were prepared in the following manner:

Approximately 80% of the total quantity of the selected medium-chain triglyceride was added into a vessel and heated to 30-35° C. Fludrocortisone acetate was added into the vessel under stirring until totally dissolving. The selected oils or glyceride mixtures were then added under continuous stirring. Finally, the volume was adjusted with the required quantity of the above medium-chain triglyceride and/or the oils or glyceride mixtures.

TABLE 3aComposition% w/vIaIIaIIIaIVaVaVIaActive substanceFludrocortisone0.0040.0040.0040.0040.0040.004acetateExcipientsMiglyol 812 ®99.99649.99889.9964———(50 to 65% (C8:0)/30% to 45%(C10:0)triglyceride)Corn oil—49.998————Sunflower oil——9.9996———Castor oil———99.996——Glycerol————99.996—dicaprylateGlycerol mono-—————99.996caprylocarpate(CapmulMCM ®)
Storage conditions of temperature (40° C.) and relative humidity (75%) applied for a period of two months. Quantification of fludrocortisone acetate and its degradation impurities was performed by HPLC.

Table IV shows preferred oral solution compositions according to the present invention.

These fludrocortisone acetate solutions were prepared in the following manner:

The active substance and the excipients were weighed. Approximately 80% of the total quantity of the selected medium-chain triglyceride(s) was added into a vessel and heated to 30-35° C. Fludrocortisone acetate was added into the vessel under stirring until totally dissolving. The flavour was then added under continuous stirring, until complete dissolution. Finally, the volume was adjusted with the required quantity of the above medium-chain triglyceride(s).

Storage conditions of temperature (40° C.) and relative humidity (75%) applied for a period of three months. Quantification of fludrocortisone acetate and its degradation impurities was performed by HPLC.

Table V shows preferred oral solution compositions according to the present invention. These fludrocortisone acetate solutions were prepared as described in previous Example 4.

Storage conditions of temperature (40° C.) and relative humidity (75%) applied for a period of three months. Quantification of fludrocortisone acetate and its degradation impurities, in the compositions prepared, was performed by HPLC.