WO2024023367A1 - Solution à administrer par voie orale contenant de la lisdexamfétamine - Google Patents

Solution à administrer par voie orale contenant de la lisdexamfétamine Download PDF

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Publication number
WO2024023367A1
WO2024023367A1 PCT/EP2023/071211 EP2023071211W WO2024023367A1 WO 2024023367 A1 WO2024023367 A1 WO 2024023367A1 EP 2023071211 W EP2023071211 W EP 2023071211W WO 2024023367 A1 WO2024023367 A1 WO 2024023367A1
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WO
WIPO (PCT)
Prior art keywords
lisdexamfetamine
solution
oral pharmaceutical
solution according
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2023/071211
Other languages
English (en)
Inventor
Georgios Liolios
Ioannis Psarrakis
Original Assignee
Labomed Pharmaceutical Company S.A.
Adalvo Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Labomed Pharmaceutical Company S.A., Adalvo Limited filed Critical Labomed Pharmaceutical Company S.A.
Publication of WO2024023367A1 publication Critical patent/WO2024023367A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • the present invention relates to an oral solution of a pharmaceutically acceptable salt of lisdexamfetamine.
  • 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.
  • ADHD attention deficit hyperactivity disorder
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition may be deployed in an aqueous solution containing salts, e.g., NaCI, detergents such as sodium dodecyl sulfate (SDS), and other components.
  • salts e.g., NaCI
  • detergents such as sodium dodecyl sulfate (SDS)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • lisdexamfetamine such as diadipate, dioxalate, difumarate, toluene sulfonate, acetate, alginate, aspartate, benzoate, besylate, bisulfate, calcium
  • 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.
  • 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.
  • 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.
  • 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.
  • polyols such as maltitol, glycerol, mannitol, sorbitol and xylitol, or mixtures thereof
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a base and/or acid e.g. sodium hydroxide or hydrochloric acid
  • This example shows the influence of various standard amino acids, at different pH values, in the stability of lisdexamfetamine dimesylate solutions.
  • 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.
  • 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
  • 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
  • total impurities is the sum of all known (specified) and unknown (not specified) impurities of lisdexamfetamine observed in the chromatogram.
  • This example shows the effect of various standard amino acids at different concentrations in the stability of a lisdexamfetamine dimesylate solution.
  • 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.
  • 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
  • total impurities is the sum of all known (specified) and unknown (not specified) impurities of lisdexamfetamine observed in the chromatogram.
  • compositions IV & III lisdexamfetamine dimesylate solutions disclosed in WO 2021/136602
  • composition N a solution according to the present invention
  • 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:

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Abstract

L'invention concerne une solution pharmaceutique aqueuse à administrer par voie orale comprenant un sel pharmaceutiquement acceptable de lisdexamfétamine en tant que principe actif et un acide aminé standard en tant que stabilisant.
PCT/EP2023/071211 2022-07-29 2023-07-31 Solution à administrer par voie orale contenant de la lisdexamfétamine WO2024023367A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22386051.1 2022-07-29
EP22386051 2022-07-29

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WO2024023367A1 true WO2024023367A1 (fr) 2024-02-01

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105486B2 (en) 2002-02-22 2006-09-12 New River Pharmaceuticals Inc. Abuse-resistant amphetamine compounds
WO2006121552A2 (fr) 2005-04-08 2006-11-16 New River Pharmaceuticals Inc. Promedicaments a base d'amphetamine resistants a la consommation abusive
US20090137674A1 (en) * 2002-02-22 2009-05-28 Shire Llc Abuse-resistant amphetamine prodrugs
RU2445085C2 (ru) * 2005-04-08 2012-03-20 Шир Ллс Пролекарства амфетаминов с защитой от неправильного употребления
WO2021136602A1 (fr) 2019-12-30 2021-07-08 Laboserve Pharmaceutical Company S.A. Solutions orales comprenant des sels de lisdexamfétamine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105486B2 (en) 2002-02-22 2006-09-12 New River Pharmaceuticals Inc. Abuse-resistant amphetamine compounds
US20090137674A1 (en) * 2002-02-22 2009-05-28 Shire Llc Abuse-resistant amphetamine prodrugs
WO2006121552A2 (fr) 2005-04-08 2006-11-16 New River Pharmaceuticals Inc. Promedicaments a base d'amphetamine resistants a la consommation abusive
RU2445085C2 (ru) * 2005-04-08 2012-03-20 Шир Ллс Пролекарства амфетаминов с защитой от неправильного употребления
WO2021136602A1 (fr) 2019-12-30 2021-07-08 Laboserve Pharmaceutical Company S.A. Solutions orales comprenant des sels de lisdexamfétamine

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