Oral pharmaceutical solutions of lisdexamfetamine
A stable oral liquid solution of lisdexamfetamine, using a polysaccharide and buffer at pH 5.0 to 8.5, addresses swallowing difficulties and hemolysis issues, offering a stable and effective treatment for ADHD and binge eating disorder.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- NEURAXPHARM PHARM SL
- Filing Date
- 2025-12-18
- Publication Date
- 2026-06-25
AI Technical Summary
Current oral solid dosage forms of lisdexamfetamine, such as capsules and tablets, are difficult to swallow and lack a suitable titration scheme, and existing aqueous solutions contain cosolvents that can cause hemolysis, necessitating a stable and cosolvent-free oral pharmaceutical composition with extended shelf life.
An oral liquid pharmaceutical solution comprising a pharmaceutically acceptable salt of lisdexamfetamine, a polysaccharide, and a buffer at a pH of 5.0 to 8.5, without cosolvents, which is stable and minimizes impurities.
The solution provides a stable, easy-to-take formulation with reduced impurities and avoids cosolvent-related hemolysis, suitable for treating ADHD and binge eating disorder.
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Abstract
Description
[0001] Oral pharmaceutical solutions of lisdexamfetamine.
[0002] This application claims the benefit of European Patent Application 24383407.4 filed on December 19th, 2024.
[0003] Field of the invention
[0004] The present invention relates to an oral pharmaceutical solution of lisdexamfetamine.
[0005] Background art
[0006] Lisdexamfetamine is a pro-drug of dexamfetamine and contains D-amfetamine covalently linked to the essential amino acid L-lysine.
[0007] Lisdexamfetamine, sold under the brand names Elvanse®, Tyvense®, Vyvanse® (US, CA) among others, is a medication that is used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of six as well as for moderate to severe binge eating disorder in adults.
[0008] Lisdexamfetamine is currently commercially available only as 10, 20, 30, 40, 50, 60 and 70 mg hard capsules or chewable tablets.
[0009] Although oral solid dosage forms such as capsules are very popular because of ease of management, there is a need for formulations that are easier to take, especially due to difficulty in swallowing these forms and the possibility of having a titration scheme with this dosage form.
[0010] WO 2021 / 136602 discloses an aqueous solution comprising a pharmaceutically acceptable salt of lisdexamfetamine, 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. However, excessive quantities of these cosolvents can cause hemolysis in humans, a condition that leads to the destruction of red blood cells.
[0011] Therefore, there is still the need of providing an oral pharmaceutical composition comprising a pharmaceutically acceptable salt of lisdexamfetamine with extended shelf life.
[0012] Summary of the invention The inventors have found that an oral liquid stable oral pharmaceutical solution comprising a pharmaceutically acceptable salt of lisdexamfetamine can be obtained in an aqueous medium in the presence of a polysaccharide, a buffer, and at a specific pH.
[0013] Accordingly, a first aspect of the present invention is directed to an oral pharmaceutical solution comprising from 1 mg / ml to 40 mg / ml of a pharmaceutical acceptable salt of lisdexamfetamine, water, a buffer, and a polysaccharide, wherein the pH of the solution is from 5.0 to 8.5. This solution is surprisingly stable, showing a fewer quantity of impurities and less different impurities.
[0014] A second aspect of the present invention is directed to the oral pharmaceutical solution as described above for use in treating attention-deficit and hyperactivity disorder.
[0015] A third aspect of the present invention is directed to a method of manufacturing the oral solution as described above, comprising the steps of adding the polysaccharide into water and then dissolving lisdexamfetamine and the buffer in the solution. This procedure is easy to reproduce.
[0016] Detailed description of the invention
[0017] As used herein, the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
[0018] Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, formic, acetic, propionic, glycolic, lactic, pyruvic, oxalic, salicylic, trichloroacetic, picric, trifluoroacetic, cinnamic, pamoic, malonic, mandelic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, paminobenzoic or glutamic acid, sulfates, nitrates, phosphates, perchlorates, borates, acetates, mesylates, dimesylate, benzoates, hydroxynaphthoates, glycerophosphates or ketoglutarates. Further examples of pharmaceutically acceptable inorganic or organic acid salts include the pharmaceutically acceptable salts listed in “Pharmaceutical Salts”, Stephen M. Berge, Journal of Pharmaceutical Science, Volume 66, Issue 1 , pages 1-19, January 1977 which are known to the skilled artisan. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines, lysine, guanidine, diethanolamine and choline.
[0019] As mentioned above, an oral pharmaceutical solution comprising from 1 mg / ml to 40 mg / ml of a pharmaceutical acceptable salt of lisdexamfetamine, water, a buffer and a polysaccharide, wherein the pH of the solution is from 5.0 to 8.5 is part of the present invention. All concentrations are related to the total volume of the composition.
[0020] In an embodiment of the first aspect of the invention, the lisdexamfetamine salt is dimesylate.
[0021] In a preferred embodiment of the first aspect of the invention, the concentration of lisdexamfetamine with respect to the total volume of the oral pharmaceutical solution is between a range from 2 and 20 mg / ml, preferably 10 mg / ml.
[0022] In another embodiment of the first aspect of the present invention the polysaccharide comprises hydroxypropyl methylcellulose, xanthan gum, glucose, sucrose, starch, pectin or guar gum. In a preferred embodiment, the concentration of the polysaccharide with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 50 mg / ml, more preferably between 0.4 and 40 mg / mL.
[0023] Polysaccharides are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. Depending on the structure, these macromolecules can have distinct properties from their monosaccharide building blocks. Polysaccharides contain more than ten monosaccharide units where the most important ones can be cellulose, pectin, starch, among others.
[0024] In a preferred embodiment of the first aspect of the present invention, the polysaccharide is selected from hydroxypropyl methylcellulose and xanthan gum, preferably xanthan gum. Excellent results have been obtained when xanthan gum is used in a concentration with respect to the total volume of the oral pharmaceutical solution between 0.2 and 5 mg / mL, preferably between 0.4 and 2 mg / mL and more preferably 1 mg / mL.
[0025] In another preferred embodiment of the first aspect of the present invention, the polysaccharide is hydroxypropyl methylcellulose (HPMC). Excellent results have also been obtained with this excipient when HPMC is used in a concentration with respect to the total volume of the oral pharmaceutical solution between 10 and 45 mg / mL, preferably between 20 and 45 mg / mL and more preferably 35 mg / mL.
[0026] In another embodiment of the oral pharmaceutical solution according to the invention, the buffer can be any pharmaceutically acceptable system which acts as a buffer in the pH region of the invention can be used in the oral pharmaceutical solution. Buffer comprises dipotassium hydrogen phosphate and potassium dihydrogen phosphate or the buffer comprises disodium hydrogen phosphate and sodium dihydrogen phosphate, more preferably dipotassium hydrogen phosphate and potassium dihydrogen phosphate.
[0027] The concentration of dipotassium hydrogen phosphate or potassium dihydrogen phosphate with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 10 mg / mL, preferably between 0.1 and 5 mg / mL and more preferably 0.5 mg / mL. The pH is adjusted with this buffer to obtain the desired value, wherein the pH of the solution is from 5.0 to 7.5 and more preferably between 5.5 to 7.0.
[0028] In another embodiment, the oral pharmaceutical solution according to the invention is that where the solution does not comprise a cosolvent. In another particular embodiment, the oral pharmaceutical solution according to the invention is absence of a cosolvent selected from the group consisting of a glycol, a polyol and a mixture thereof. In another particular embodiment, the oral pharmaceutical solution according to the invention is absence of a cosolvent selected from polyethylene glycol, maltitol, glycerol, mannitol, sorbitol and xylitol. In another particular embodiment, the oral pharmaceutical solution according to the invention is absence of a cosolvent which is polyethylene glycol.
[0029] In another embodiment of the invention, the oral pharmaceutical solution further comprises a sweetener. They substantially mask the bitter taste of pharmaceutically acceptable formulations as a result of its sweet taste. Said sweetener is preferably saccharin. The concentration of the sweetener with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 10 mg / mL, preferably between 0.1 and 5 mg / mL and more preferably between 0.75 and 2 mg / mL.
[0030] In another embodiment of the invention, the oral pharmaceutical solution further comprises a preservative selected from methyl parahydroxybenzoate, propyl parahydroxybenzoate, and combinations thereof.
[0031] These preservatives have been used in a weight ratio of methyl parahydroxybenzoate and propyl parahydroxybenzoate between 0.95 / 0.05 and 0.85 / 0.15, wherein the concentration of the preservatives with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 10 mg / mL, preferably between 0.1 and 5 mg / mL and more preferably between 0.2 and 2.5 mg / mL.
[0032] The oral pharmaceutical solution of the present invention may be prepared using methods well known in the art and using regular manufacturing equipment.
[0033] Thus, the oral pharmaceutical solution according to the invention may be prepared by a process, comprising the steps of: i) adding the polysaccharide into water, ii) dissolving the lisdexamfetamine salt and the buffer into the solution, and iii) adjusting the pH.
[0034] In an embodiment, the oral pharmaceutical solution as defined above is prepared by a process comprising: i) weighing the active substance and the excipients; ii) adding purified water into a vessel; iii) optionally, adding a preservative, under continuous stirring until complete dissolution iv) adding the polysaccharide under continuous stirring until complete dissolution; v) adding a pH buffer solution, under continuous stirring until the solution is homogenised; vi) optionally, adding the remaining excipients, if present, successively under continuous stirring, until complete dissolution; vii) dissolving the pharmaceutically acceptable salt of lisdexamfetamine into the previous solution under stirring; viii) optionally, adjusting the pH of the solution with a quantity of the corresponding salt from the buffer solution to the desired value; and ix) adjusting the volume with purified water.
[0035] In a preferred embodiment, the oral pharmaceutical solution as defined above can be prepared by a process comprising: i) weighing Lisdexamfetamine dimesylate and the excipients; ii) adding purified water into a vessel; iii) optionally, adding a preservative, under continuous stirring until complete dissolution iv) adding the polysaccharide under continuous stirring until complete dissolution; v) adding a pH buffer solution, under continuous stirring until the solution is homogenised; vi) optionally, adding the remaining excipients, if present, successively under continuous stirring, until complete dissolution; vii) dissolving the pharmaceutically acceptable salt of lisdexamfetamine into the previous solution under stirring; viii) optionally, adjusting the pH of the solution with a quantity of the corresponding salt from the buffer solution to the desired value; and ix) adjusting the volume with purified water.
[0036] In a more preferred embodiment, the oral pharmaceutical solution as defined above can be prepared by a process comprising: i) weighing Lisdexamfetamine dimesylate and the excipients; ii) adding purified water into a vessel; iii) optionally, adding a preservative, under continuous stirring until complete dissolution iv) adding the polysaccharide under continuous stirring until complete dissolution; v) adding potassium dihydrogen phosphate and dipotassium hydrogen phosphate under continuous stirring until the solution is homogenised; vi) optionally, adding the remaining excipients, if present, successively under continuous stirring, until complete dissolution; vii) dissolving Lisdexamfetamine dimesylate into the previous solution under stirring; viii) adjusting the pH of the solution with a quantity of the corresponding salt from the buffer solution to the desired value ; and ix) adjusting the volume with purified water.
[0037] More preferably, the process for preparing the oral pharmaceutical solution as defined above is prepared by a process comprising: i) weighing Lisdexamfetamine dimesylate and the excipients; ii) adding purified water into a vessel; iii) optionally, adding methylparaben and propylparaben under continuous stirring until complete dissolution; iv) adding the polysaccharide under continuous stirring until complete dissolution; dissolving Lisdexamfetamine dimesylate successively into purified water under stirring; v) adding potassium dihydrogen phosphate and dipotassium hydrogen phosphate under continuous stirring until the solution is homogenised; vi) optionally, adding the remaining excipients successively under continuous stirring, until complete dissolution; vii) dissolving Lisdexamfetamine dimesylate into the previous solution under stirring; viii) adjusting the pH of the solution with a quantity of the corresponding salt from the buffer solution to the desired value ; and ix) adjusting the volume with purified water.
[0038] In a more preferred embodiment, the process for preparing the oral pharmaceutical solution as defined above is prepared by a process comprising: i) weighing Lisdexamfetamine dimesylate and the excipients; ii) adding purified water into a vessel; iii) optionally, adding methylparaben and propylparaben under continuous stirring until complete dissolution; iv) adding xanthan gum under continuous stirring until complete dissolution; dissolving Lisdexamfetamine dimesylate successively into purified water under stirring; v) adding potassium dihydrogen phosphate and dipotassium hydrogen phosphate under continuous stirring until the solution is homogenised; vi) optionally, adding the remaining excipients successively under continuous stirring, until complete dissolution; vii) dissolving Lisdexamfetamine dimesylate into the previous solution under stirring; viii) adjusting the pH of the solution with a quantity of the corresponding salt from the buffer solution to the desired value; and ix) adjusting the volume with purified water.
[0039] Even more preferably, the process for the preparation of an oral pharmaceutical solution as defined previously comprises: i) weighing Lisdexamfetamine dimesylate and the excipients; ii) adding purified water into a vessel; iii) optionally, adding methylparaben and propylparaben added under continuous stirring until complete dissolution; iv) adding 1 mg / mL of xanthan gum under continuous stirring until complete dissolution; v) adding 0.5 mg / mL of dipotassium hydrogen phosphate and 0.5 mg / mL of potassium dihydrogen phosphate under continuous stirring until solution is homogenised; vi) optionally, adding the remaining excipients successively under continuous stirring, until complete dissolution; vii) dissolving 10 mg / mL of lisdexamfetamine dimesylate into the purified water under stirring; viii) adjusting the pH of the solution with a quantity of the corresponding salt from the buffer solution to a value between 5.5 and 7.0; and viii) adjusting the volume with purified water.
[0040] The oral pharmaceutical solution as described above for use in treating attention-deficit and hyperactivity disorder is part of the invention. This aspect can also be formulated as the use of the oral pharmaceutical solution as described above for the preparation of a medicament for treating attention-deficit and hyperactivity disorder in a human. The invention also relates to a method of treatment of a human, suffering from attention-deficit and hyperactivity disorder, said method comprising the administration to said human a therapeutically effective amount of the oral pharmaceutical solution as described above Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
[0041] Examples
[0042] Example 1: Stability assay of a formulation according to the present invention
[0043] The purpose of this experiment was to evaluate the influence of xanthan gum on the stability of lisdexamfetamine dimesylate oral solutions.
[0044] These lisdexamfetamine dimesylate compositions were prepared in the following manner: In the main vessel, purified water was transferred under magnetic stirring. The amount of lisdexamfetamine dimesylate was slowly added in the main vessel under stirring until complete dissolution. The amounts of xanthan gum, parabens and saccharin were slowly added until complete dissolution. The pH value of the solution was measured and adjusted, if needed, at the optimum value. Purified water was added to the final batch size.
[0045] Storage conditions of temperature (40°C) and relative humidity (75%) applied for a period of time sufficient to compare results with the prior art. Quantification of lisdexamfetamine dimesylate and its impurities, in the compositions prepared, was performed by HPLC. HPLC method is herein described:
[0046] Equipment: High Performance Liquid Chromatograph (HPLC) equipped with degasser, quaternary pump, autosampler, column oven, diode array detector and Chromatographic Data Management System (CDS) Column: C18; 5 pm particle size, 250 x 4.6 mm
[0047] Mobile phase A: 1 -Octanesulfonic acid sodium salt 0.0054M I Potassium dihydrogenphoshate-buffer 0.05M pH 2.6 Mobile phase B: Acetonitrile / Methanol (80 / 20) (v / v) Gradient (table 1):
[0048] Table 2: Comparative results from stability studies extracted from patent WO 2021 / 136602 are shown below.
[0049] Tables 3.1 and 3.2 show the formulations described in this document, (tables 4c and 4d) Table 3.1 :
[0050] Table 3.2:
[0051] As it can be seen in tables 3.3 and 3.4, compared with the values obtained following the described invention, the final dosage forms obtained have better stability results regarding less percentage of total impurities.
[0052] Table 3.3:
[0053] Table 3.4:
[0054] Citation List
[0055] Patent Literature
[0056] - WO 2021 / 136602
[0057] Non-Patent Literature - “Pharmaceutical Salts”, Stephen M. Berge, Journal of Pharmaceutical Science, Volume
[0058] 66, Issue 1 , pages 1-19, January 1977
Claims
CLAIMS1. Oral pharmaceutical solution comprising from 1 mg / ml to 40 mg / ml of a pharmaceutical acceptable salt of lisdexamfetamine, water, a buffer and a polysaccharide wherein the pH of the solution is from 5.0 to 8.5.
2. Oral pharmaceutical solution according to claim 1, wherein the lisdexamfetamine salt is dimesylate.
3. Oral pharmaceutical solution according to any of the preceding claims, wherein the concentration of lisdexamfetamine with respect to the total volume of the oral pharmaceutical solution is between 2 and 20 mg / mL, preferably 10mg / mL.
4. Oral pharmaceutical solution according to any of the preceding claims, wherein the concentration of polysaccharide with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 50 mg / mL, preferably between 0.4 and 40 mg / mL.
5. Oral pharmaceutical solution according to any of the preceding claims, wherein the polysaccharide is selected from the group consisting of hydroxypropyl methylcellulose, xanthan gum, glucose, sucrose, starch, pectin, guar gum, and mixtures thereof, preferably HPMC and xanthan gum, even more preferably xanthan gum.
6. Oral pharmaceutical solution according claim 5, wherein the polysaccharide is selected from hydroxypropyl methylcellulose and xanthan gum.
7. Oral pharmaceutical solution according to claim 6, wherein the polysaccharide is xanthan gum.
8. Oral pharmaceutical solution according to claim 7, wherein the concentration of xanthan gum with respect to the total volume of the oral pharmaceutical solution is between 0.2 and 5mg / mL.
9. Oral pharmaceutical solution according to claim 8, wherein the concentration of xanthan gum is between 0.4 and 2mg / mL.
10. Oral pharmaceutical solution according to claim 9, wherein the concentration of xanthan gum is 1mg / mL.
11. Oral pharmaceutical solution according to any of the claims 1-6, wherein the polysaccharide is hydroxypropyl methylcellulose.
12. Oral pharmaceutical solution according to claim 11 , wherein the concentration of hydroxypropyl methylcellulose with respect to the total volume of the oral pharmaceutical solution is between 10 and 45 mg / mL and more preferably between 20 and 40 mg / mL.
13. Oral pharmaceutical solution according to claim 12, wherein the concentration of hydroxypropyl methylcellulose is 35 mg / mL.
14. Oral pharmaceutical solution according to any of the preceding claims, wherein the buffer comprises dipotassium hydrogen phosphate and potassium dihydrogen phosphate or the buffer comprises disodium hydrogen phosphate and sodium dihydrogen phosphate.
15. Oral pharmaceutical solution according to claim 14, wherein the buffer consists of dipotassium hydrogen phosphate and potassium dihydrogen phosphate.
16. Oral pharmaceutical solution according to any of the claims 14-15, wherein the concentration of dipotassium hydrogen phosphate and potassium dihydrogen phosphate with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 10 mg / mL.
17. Oral pharmaceutical solution according to claim 16, wherein the concentration of dipotassium hydrogen phosphate or potassium dihydrogen phosphate is between 0.1 and 5 mg / mL.
18. Oral pharmaceutical solution according to claim 17, wherein the concentration of dipotassium hydrogen phosphate and potassium dihydrogen phosphate is 0.5 mg / mL.
19. Oral pharmaceutical solution according to any of the preceding claims, wherein the solution does not comprise a cosolvent.
20. Oral pharmaceutical solution according to claim 19, wherein said cosolvent is selected from the group consisting of a glycol, a polyol and a mixture thereof.
21. Oral pharmaceutical solution according to claim 20, wherein said cosolvent is selected from polyethylene glycol, maltitol, glycerol, mannitol, sorbitol and xylitol.
22. Oral pharmaceutical solution according to claim 21 , wherein said cosolvent is polyethylene glycol.
23. Oral pharmaceutical solution according to any of the preceding claims, wherein the pH of the solution is from 5.0 to 7.5.
24. Oral pharmaceutical solution according to claim 23, wherein the pH of the solution is from 5.5 to 7.0.
25. Oral pharmaceutical solution according to any of the preceding claims, wherein the solution further comprises a sweetener, preferably saccharin.
26. Oral pharmaceutical solution according to claim 25, wherein the concentration of the sweetener with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 10 mg / mL.
27. Oral pharmaceutical solution according to claim 26, wherein the concentration of the sweetener is between 0.5 and 5 mg / mL.
28. Oral pharmaceutical solution according to claim 27, wherein the concentration of the sweetener is between 0.75 and 2 mg / mL.
29. Oral pharmaceutical solution according to any of the preceding claims, wherein the solution further comprises one or more preservatives30. Oral pharmaceutical solution according claim 29, wherein the preservative comprises methyl parahydroxybenzoate, propyl parahydroxybenzoate, or mixtures thereof.
31. Oral pharmaceutical solution according to claim 30, wherein the preservative ratio of methyl parahydroxybenzoate and propyl parahydroxybenzoate is between 0.95 / 0.05 and 0.85 / 0.15.
32. Oral pharmaceutical solution according to claim 26, wherein the concentration of the preservatives with respect to the total volume of the oral pharmaceutical solution is between 0.1 and 10 mg / mL.
33. Oral pharmaceutical solution according to claim 27, wherein the concentration of the preservatives is between 0.1 and 5 mg / mL.
34. Oral pharmaceutical solution according to claim 28, wherein the concentration of the preservatives is between 0.2 and 2.5 mg / mL.
35. Oral pharmaceutical solution according to any of the preceding claims for use in treating attention-deficit and hyperactivity disorder.
36. A method of manufacturing an oral pharmaceutical solution according to any of the claims 1-34, comprising the steps of: i) adding the polysaccharide into water, ii) dissolving the lisdexamfetamine salt and the buffer into the solution, and iii) adjusting the pH.