LISDEXAMFETAMINE CONTAINING ORAL SOLUTION

FIELD OF THE INVENTION

The present invention relates to an oral solution of a pharmaceutically acceptable salt of lisdexamfetamine.

BACKGROUND OF THE INVENTION

Lisdexamfetamine or L-lysine-d-amfetamine (LDX), (2S)-2,6-diamino-N-[(1S)-1- methyl-2-phenylethyl] hexanamide dimethanesulfonate) was first disclosed in US7105486.

Lisdexamfetamine has the following structure.

Medications comprising lisdexamfetamine, sold under the brand names Elvanse® (DK, GB, SE), Tyvense® (IE), Venvanse® (BR), Vyvanse® (US, CA) among others, are used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as for moderate to severe binge eating disorder in adults.

Lisdexamfetamine is a pro-drug of dexamfetamine and contains D-amfetamine covalently linked to the essential amino acid L-lysine. It lacks stimulant properties but is hydrolyzed in the gut wall to release D-amfetamine. As it is an inactive material, it cannot be taken nasally, intravenously or in any other way to achieve an illicit stimulant effect. Furthermore, the metabolic hydrolysis of the pro-drug takes some time and as such the formulation has an element of in-built controlled release. The product can deliver dexamfetamine over a period of about 8 hours and so it is useful to treat ADHD in paediatric populations (aged 6 to 12), but the extent of its duration is not considered to be sufficient to treat adolescent and adult populations having much longer active days.

Lisdexamfetamine is currently commercially available only as hard capsules or chewable tablets. Each capsule or chewable tablet contains 10, 20, 30, 40, 50, 60 or 70 mg lisdexamfetamine dimesylate, equivalent to 5.8 mg, 11.6 mg, 17.3 mg, 23.1 mg, 28.9 mg, 34.7 mg or 40.6 mg of lisdexamfetamine, respectively.

Lisdexamfetamine dimesylate has the following structure.

Although oral solid dosage forms such as capsules and chewable tablets are very popular, mainly because of ease of management, for certain users (e.g. children) 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.

Although lisdexamfetamine acid addition salts, such as lisdexamfetamine dimesylate and lisdexamfetamine hydrochloride are very soluble in water, the desire for the development of an oral solution dosage form of a lisdexamfetamine salt is complicated by the fact that lisdexamfetamine degrades significantly, mainly, at basic (alkaline), oxidative, or other conditions.

According to WO 2006/121552, lisdexamfetamine can be formulated as an aqueous solution, or a sterile composition. The composition may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In use, the composition may be deployed in an aqueous solution containing salts, e.g., NaCI, detergents such as sodium dodecyl sulfate (SDS), and other components. Furthermore, according to WO 2006/121552 lisdexamfetamine may be formulated as a liquid dispersion for oral administration, for example as a syrup, emulsion, or suspension.

Patent application WO 2021/136602 describes aqueous oral solutions comprising a lisdexamfetamine salt, a buffer and one or more cosolvents selected from glycols and polyols, wherein the pH of the solution is from 5.5 to 9.0.

The present invention provides a pharmaceutical product comprising a pharmaceutically acceptable salt of lisdexamfetamine with extended shelf life.

SUMMARY OF INVENTION

The present invention is directed to an oral pharmaceutical solution comprising a pharmaceutically acceptable salt of lisdexamfetamine in association with a pharmaceutically acceptable aqueous carrier.

The oral pharmaceutical solution according to the invention comprises a pharmaceutically acceptable salt of lisdexamfetamine as active ingredient and a pharmaceutically acceptable aqueous carrier comprising a standard amino acid.

With the present invention the stability of the pharmaceutically acceptable salt of lisdexamfetamine in the oral solution is better than when the same oral solution does not comprise a standard amino acid. Thus, with the present invention the oral solution exhibits a longer shelf-life and can be stored at higher temperatures than when the same oral solution does not comprise a standard amino acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable aqueous oral solution comprising lisdexamfetamine as active ingredient and a standard amino acid. The present inventors have surprisingly found that the physicochemical stability of an oral solution comprising a pharmaceutically acceptable salt of lisdexamfetamine is enhanced when a standard amino acid is added to the solution.

Thus, the present invention provides an oral solution comprising a pharmaceutically acceptable salt of lisdexamfetamine as active ingredient and a pharmaceutically acceptable aqueous carrier comprising a standard amino acid.

In a preferred embodiment, the present invention provides an oral solution comprising a pharmaceutically acceptable salt of lisdexamfetamine as active ingredient and a pharmaceutically acceptable aqueous carrier comprising a standard amino acid, wherein the pH of the solution is from 4.0 to 8.0.

As used throughout this description and claims, the term “standard amino acid” refers to twenty naturally occurring compounds that contain amino (-NH ⁺ 3, or -NH ⁺ 2- in the case of proline) and carboxylate (-CO-2) functional groups, attached to the same C atom (they are thus a-amino acids) and they are incorporated into peptides and encoded by the universal genetic code. With the exception of achiral glycine, standard amino acids have the L configuration.

The standard amino acids can be classified according to the side chain that they contain, as follows:

Aliphatic side-chain amino acids include leucine, glycine, alanine, valine, isoleucine and proline.

Sulfur-containing side-chain amino acids include methionine and cysteine.

Cationic side-chain amino acids include histidine, arginine and lysine.

Aromatic side-chain amino acids include phenylalanine, tyrosine and tryptophan.

Anionic side-chains amino acids include aspartate and glutamate.

Polar neutral side-chain amino acids include serine and threonine.

Amide side-chain amino acids include asparagine and glutamine. Preferably, the amino acid is selected from the group consisting of leucine, glycine, alanine, valine, isoleucine, proline, methionine, cysteine, histidine, arginine, and lysine. More preferably, the amino acid is selected from the group consisting of I- methionine, leucine, histidine, glycine, and arginine.

The oral solution according to the invention may comprise any pharmaceutically acceptable salt of lisdexamfetamine such as diadipate, dioxalate, difumarate, toluene sulfonate, acetate, alginate, aspartate, benzoate, besylate, bisulfate, calcium edetate, carbonate, citrate, edetate, glutamate, hydrobromide, hydrochloride, hydroiodide, lactate, laurate, malate, maleate, mesylate, oleate, pamoate, phosphate, saccharate, salicylate, stearate, succinate, sulfate, tartrate and tosylate salt, and the like. Preferably, the oral solution according to the invention comprises lisdexamfetamine dimesylate, or lisdexamfetamine hydrochloride. More preferably, the oral solution according to the invention comprises lisdexamfetamine dimesylate.

Preferably, the oral solution comprises from 4 mg/ml to 32 mg/ml of a pharmaceutically acceptable salt of lisdexamfetamine. More preferably, the oral solution comprises from 6 mg/ml to 24 mg/ml of a pharmaceutically acceptable salt of lisdexamfetamine. Even more preferably, the oral solution comprises from 8 mg/ml to 16 mg/ml of a pharmaceutically acceptable salt of lisdexamfetamine.

Preferably, the pH of the solution is from 4.0 to 8.0. More preferably, the pH of the solution is from 4.5 to 7.5. Even more preferably, the pH of the solution is from 5.0 to 7.0. The pH of the solution can be adjusted by the use of an acid and/or base, or by the use of a buffer, following methods well known in the art.

Preferably, the concentration of the standard amino acid in the oral solution is from 0.1 mg/ml to 20 mg/ml, more preferably, from 0.2 mg/ml to 15 mg/ml and even more preferably, from 1.0 mg/ml to 5.0 mg/ml.

The term “mg/ml” used throughout the present application refers to mg of an ingredient per 1 ml of the oral solution. The oral solution according to the invention may also optionally contain additional excipients commonly used in preparing oral liquid compositions, such as cosolvents, buffering agents, antimicrobial preservatives, viscosity-adjusting agents, sweeteners and flavouring agents.

Cosolvents include but are not limited to polyols, such as maltitol, glycerol, mannitol, sorbitol and xylitol, or mixtures thereof, and glycols, such as propylene glycol, polyethylene glycol or any other pharmaceutically acceptable polyalkylene glycol product such as those known in the art as the "PEG" series, or mixtures thereof.

Buffering agents include but are not limited to ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, sodium citrate, potassium citrate, acetic acid, sodium acetate, sodium hydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate or mixtures thereof.

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

Sweeteners include but are not limited to sucralose, aspartame, acesulfame-K, thaumatin, mogroside, saccharin and salts thereof, sodium cyclamate, glucose, sucrose, lactose, fructose, erythritol, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, dextrose or mixtures thereof.

Flavouring agents include but are not limited to fruit flavours such as orange, banana, strawberry, cherry, wild cherry, lemon and the like and other flavourings, such as cardamom, anise, mint, menthol, vanillin, bubble gum or mixtures thereof.

In every pharmaceutical preparation it is desirable to keep the number and concentration of excipients at the lowest possible level, to avoid undesirable effects. Thus, preferably, the oral solution of the invention is essentially free of further stabilizers, i.e. free of an agent which is not a standard amino acid and which stabilizes the pharmaceutically acceptable salt of lisdexamfetamine in the solution.

Accordingly, in a preferred embodiment, the oral solution comprises a pharmaceutically acceptable salt of lisdexamfetamine and a pharmaceutically acceptable aqueous carrier comprising a standard amino acid, wherein the solution is essentially free of cosolvents such as glycols and polyols and further stabilizers such as a-cyclodextrins, b-cyclodextrins and y-cyclodextrins, sorbitan oleate ester and polyoxyethylene sorbitan monooleate.

The lisdexamfetamine-containing oral solution according to the invention exhibits excellent physicochemical stability at accelerated conditions of temperature (40°C) and relative humidity (75%).

The oral solution of a pharmaceutically acceptable salt of lisdexamfetamine according to the invention may be supplied as monodose or multidose preparation. Preferably, the oral solution according to the invention is supplied as a multidose preparation.

Each dose from a multidose sealed vial, can be administered by means of a device suitable for measuring the prescribed volume. The device is typically a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes.

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:

Purified water is added to a vessel. The pharmaceutically acceptable salt of lisdexamfetamine and the amino acid are successively dissolved into purified water under stirring. A pH buffer solution, if present, is prepared in a different vessel, and is added under continuous stirring until the pharmaceutically acceptable salt of lisdexamfetamine is completely dissolved. Cosolvent, if present, is added under continuous stirring until complete dissolution. Preservative, if present, is also added under continuous stirring until complete dissolution. Flavour and the remaining excipients, if present, are successively added under continuous stirring, until complete dissolution. The pH of the solution is adjusted to the desired value with a quantity of the buffer solution, if present, or with a quantity of a base and/or acid (e.g. sodium hydroxide or hydrochloric acid). Finally, the volume is adjusted with purified water.

EXAMPLES

EXAMPLE 1

This example shows the influence of various standard amino acids, at different pH values, in the stability of lisdexamfetamine dimesylate solutions.

The lisdexamfetamine dimesylate solutions shown in Table 1 were prepared in the following manner:

Purified water was added into a vessel. Lisdexamfetamine dimesylate and the amino acid were dissolved into purified water under stirring. A buffer solution, prepared in a different vessel, was added under continuous stirring until lisdexamfetamine dimesylate was completely dissolved. The pH of the solution was adjusted with a quantity of the buffer solution to the desired value. Finally, the volume was adjusted with purified water. The final solution was filled in 50 mL amber type class III glass bottles.

The compositions were stored at a temperature of 40°C and a relative humidity of 75% for a total period of six months. Quantification of lisdexamfetamine dimesylate and its impurities in the compositions was performed by HPLC. Table 1

Table 2: Initial impurity results, T=0

N.D.: Not Detected

As seen by the impurity results presented in Table 2, none of the known, specified impurities of lisdexamfetamine, i.e. dextroamphetamine, Z-Lys-(Z)- dextroamphetamine, D-lisdexamphetamine, was detected at T=0. Furthermore, no other peak that can be attributed to any unknown, unspecified impurity of lisdexamfetamine was observed in the chromatogram.

In Tables 2 and 3, the term “maximum unknown impurity” refers to an unknown (not specified) impurity of lisdexamfetamine, which in the chromatogram gives the greater peak and thus corresponds to the greater impurity concentration in the solution, while “total impurities” is the sum of all known (specified) and unknown (not specified) impurities of lisdexamfetamine observed in the chromatogram.

Table 3: Stability results after 6 months at 40°C/75%

RRT: Relative retention time

From this study, it is concluded that the physicochemical stability of lisdexamfetamine dimesylate is surprisingly enhanced, when a standard amino acid is added to the solution. Hence, lisdexamfetamine remains stable in the solution and there is no need to add a further stabilizer, e.g. a non-aqueous cosolvent.

It has also been found that the stabilizing effect of the amino acids is exhibited at a wide pH range.

EXAMPLE 2

This example shows the effect of various standard amino acids at different concentrations in the stability of a lisdexamfetamine dimesylate solution.

The lisdexamfetamine dimesylate solutions shown in Table 4 were prepared in the following manner:

Purified water was added into a vessel. Lisdexamfetamine dimesylate and the amino acid were dissolved into purified water under stirring. A buffer solution, prepared in a different vessel, was added under continuous stirring until lisdexamfetamine dimesylate was completely dissolved. The pH of the solution was adjusted with a quantity of the buffer solution to the desired value. Finally, the volume was adjusted with purified water. The final solution was filled in 50 mL amber type class III glass bottles.

The compositions were stored at a temperature of 40°C and a relative humidity of 75% for a total period of six months. Quantification of lisdexamfetamine dimesylate and its impurities in the compositions was performed by HPLC. Table 4 Table 5: Initial impurity results, T=0

N.D.: Not Detected

As seen by the impurity results presented in Table 5, none of the known, specified impurities of lisdexamfetamine i.e. dextroamphetamine, Z-Lys-(Z)- dextroamphetamine, D-lisdexamphetamine, was detected at T=0. Furthermore, no other peak that can be attributed to any unknown, unspecified impurity of lisdexamfetamine was observed in the chromatogram. In Tables 5 and 6, the term “maximum unknown impurity” refers to an unknown (not specified) impurity of lisdexamfetamine, which in the chromatogram gives the greater peak and thus corresponds to the greater impurity concentration in the solution, while “total impurities” is the sum of all known (specified) and unknown (not specified) impurities of lisdexamfetamine observed in the chromatogram.

Table 6: Stability results after 6 months at 40°C/75%

RRT: Relative retention time The above results show that the stabilizing effect of the standard amino acids is exhibited in a wide concentration range.

EXAMPLE 3

The purpose of this experiment was to compare the stability of two lisdexamfetamine dimesylate solutions disclosed in WO 2021/136602 (compositions IV & III) with the stability of a solution (composition N) according to the present invention and shown in Table 7.

Lisdexamfetamine dimesylate solutions disclosed in WO 2021/136602 were prepared in the following manner:

Purified water was added into a vessel. Lisdexamfetamine dimesylate and the cosolvent, were dissolved into purified water under stirring. A buffer solution, prepared in a different vessel, was added under continuous stirring until lisdexamfetamine dimesylate was completely dissolved. Preservative was also added under continuous stirring until complete dissolution. The flavour was then added under continuous stirring, until complete dissolution. The pH of the solution was adjusted with a quantity of the buffer solution to the desired value. Finally, the volume was adjusted with purified water.

The lisdexamfetamine dimesylate solution according to the invention was prepared in the following manner:

Purified water was added into a vessel. Lisdexamfetamine dimesylate and L-leucine were dissolved into purified water under stirring. A buffer solution, prepared in a different vessel, was added under continuous stirring until lisdexamfetamine dimesylate was completely dissolved. Preservative was also added under continuous stirring until complete dissolution. The flavour was then added under continuous stirring, until complete dissolution. The pH of the solution was adjusted with a quantity of the buffer solution to the desired value. Finally, the volume was adjusted with purified water. The compositions were stored at a temperature of 25°C and at a relative humidity of 60% for a total period of twelve months. Quantification of lisdexamfetamine dimesylate and its impurities in the compositions was performed by HPLC. Table 7: Oral solutions

Table 8: Stability results

^RT: Relative retention time, D-Ldxamfet: D-lisdexamfetamine From this study, it is also concluded that the physicochemical stability of lisdexamfetamine dimesylate is surprisingly enhanced, when a standard amino acid is added to the solution. Hence, lisdexamfetamine remains stable in the solution and there is no need to add a further stabilizer, e.g. a non-aqueous cosolvent.