Liquid pharmaceutical composition of tretinoin

Abstract

The present invention relates to a liquid pharmaceutical composition comprising (i) totally dissolved tretinoin or a pharmaceutically acceptable isomer thereof; (ii) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); (iii) a pH-modifying agent selected in the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, and mixtures thereof), potassium acetate (anhydrous, trihydrate, and mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof; and (iv) water. The present invention also relates to the medical uses of such a composition.

Description

[0001] LIQUID PHARMACEUTICAL COMPOSITION OF TRETINOIN

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to liquid pharmaceutical compositions for the oral or parenteral administration of tretinoin or any pharmaceutically acceptable isomer thereof, and their use in the medical field.

[0004] BACKGROUND OF THE INVENTION

[0005] Tretinoin, also named all-trans retinoic acid (ATRA), is a derivative of vitamin A widely recognized for its clinical efficacy in the treatment of acute promyelocytic leukemia (APL) by promoting the differentiation and apoptosis of promyelocytic cells. Besides its oncological applications, tretinoin is also used in dermatology for the treatment of acne and other skin conditions due to its ability to influence cell proliferation and differentiation. Tretinoin has the following formula (I):

[0006] Recent clinical trials, such as "LySATRA", highlight the evolving therapeutic applications of tretinoin beyond APL, particularly in the context of oligometastatic solid cancers. In these trials, tretinoin is investigated for its potential to support lymphocyte function when combined with advanced radiotherapy techniques such as stereotactic body radiation therapy (SBRT). This combination aims to enhance the immune-mediated effects of radiation therapy, potentially increasing the systemic antitumor response and improving overall survival outcomes.

[0007] Tretinoin is commercially available mainly in topical and oral forms:

[0008] Topical formulations include creams and gels with concentrations ranging from 0.025% to 0. 1% tretinoin. While effective for treating acne and minor skin conditions, the dosage cannot be easily adjusted for systemic diseases.

[0009] Oral capsules comprise suspended tretinoin for oral use, primarily in the treatment of acute promyelocytic leukemia (APL). The standard oral product for systemic treatment is Vesanoid®. The typical dosage is 45 mg / m2per day, administered as 10 mg capsules taken two to four times daily. This dosage may vary depending on the patient's body surface area and clinical response.

[0010] The dosages available for topical and oral tretinoin are constrained by their administration routes: Topical: limited to local application, hence not suitable for diseases requiring systemic treatment.

[0011] Oral: while effective for certain types of leukemia, oral dosage are inflexible in terms of rapid dosage adjustments and can result in systemic side effects which make them unsuitable for continuous high-dose applications, particularly in sensitive populations like children.

[0012] Isotretinoin, also named 13-cis-retinoic acid, is an isomer of tretinoin which is widely recognized for its clinical efficacy to treat severe acne. It is also used to prevent certain skin cancers (squamous-cell carcinoma), and in the treatment of other cancers. In addition, it is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Isotretinoin has the following formula (II):

[0013] Another tretinoin isomer is alitretinoin (9-cis-retinoic acid), which is a naturally-occurring endogenous retinoid indicated for topical treatment of cutaneous lesions in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Alitretinoin inhibits the growth of Kaposi's sarcoma (KS) cells in vitro. Alitretinoin has the following formula (III):

[0014] Despite their therapeutic potential, the application of tretinoin or isomers thereof in clinical settings is constrained by several pharmacological and practical challenges:

[0015] Hydrophobicity, tretinoin is highly hydrophobic, which prevents its formulation into aqueous solutions suitable for oral or intravenous administration. This characteristic renders the delivery of the drug more difficult, particularly when aqueous environments are required for safe and efficient systemic therapies.

[0016] Dosing limitations in paediatric oncology, the conventional formulation of tretinoin requires the administration of multiple capsules to achieve therapeutic doses, particularly in paediatric oncology. This poses a significant challenge for treatment adherence in young children who may struggle with swallowing multiple capsules or who require precise dosing adjustments based on body weight to avoid toxicity or subtherapeutic dosing.

[0017] Lack of intravenous formulation', currently, there is no available intravenous formulation of tretinoin, limiting its use in patients who are unable to take oral medications or in clinical situations where rapid achievement of therapeutic blood levels is necessary. Moreover, the absence of an IV formulation restricts opportunities to conduct comprehensive pharmacokinetic studies, which are essential for better understanding the dynamics of tretinoin absorption, distribution, metabolism, and excretion. Intravenous administration is crucial for such studies as it allows for precise control over the drug dosage and timing, providing clear insights into the drug's pharmacokinetic profde. This is particularly important in developing optimized dosing regimens that maximize therapeutic efficacy while minimizing side effects, thereby enhancing the overall safety and effectiveness of tretinoin therapy in diverse patient populations.

[0018] Thus, there remains a need to provide liquid formulations of tretinoin or any pharmaceutically acceptable isomer thereof, which would address these limitations.

[0019] SUMMARY OF THE INVENTION

[0020] The present invention seeks to address these limitations by introducing a novel tretinoin formulation that allows its total solubility, enhances its stability in aqueous media, allows for precise dosing, and facilitates both oral and parenteral (such as intravenous) administration. This formulation is particularly relevant considering ongoing clinical research exploring the immunomodulatory roles of tretinoin in oncology.

[0021] The proposed injectable liquid formulation of tretinoin of the invention introduces a solution that can be tailored to patient-specific needs, particularly in an acute care setting:

[0022] Higher dosages: the formulation can deliver higher doses of tretinoin effectively and safely, potentially exceeding the typical oral dosage ceiling due to better manageability of side effects and immediate bioavailability. For example, dosages tailored for intensive cancer treatment protocols could be administered efficiently in a controlled manner, allowing for dosages tailored to the metabolic and therapeutic needs of the patient.

[0023] Rapid dose adjustments: intravenous administration allows for quick adjustments in dosage (critical for pediatric oncology and acute leukemia treatment) where precise body weight adjustments are crucial.

[0024] By developing a solution-based, highly dosed formulation of tretinoin, the present invention aims to: Enhance the clinical management of cancers where modulation of the immune environment is crucial;

[0025] Improve patient compliance with high dose tretinoin therapy, especially in pediatric settings where reduced pill burden is critical;

[0026] Provide a versatile platform for tretinoin administration, potentially expanding its use in emergency settings or when oral administration is not feasible. The inventors have discovered that the combination of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and a strong base such as KOH or NaOH, enhances the solubility and stability of tretinoin in aqueous solutions.

[0027] A first object of the invention is a liquid pharmaceutical composition comprising:

[0028] (i) Tretinoin or a pharmaceutically acceptable isomer thereof;

[0029] (ii) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS);

[0030] (iii) from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition, of a pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof; and

[0031] (iv) Water.

[0032] Another object of the invention is a liquid pharmaceutical composition comprising:

[0033] (i) Tretinoin or a pharmaceutically acceptable isomer thereof;

[0034] (ii) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS);

[0035] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof; and

[0036] (iv) Water.

[0037] A second object of the invention is the liquid pharmaceutical composition of the invention for use as a medicament.

[0038] Another object of the invention is the liquid pharmaceutical composition of the invention for use in the treatment of acute promyelocytic leukaemia (APL).

[0039] Another object of the invention is the liquid pharmaceutical composition of the invention for use in the treatment of skin disorders such as acne.

[0040] Another object of the invention is the liquid pharmaceutical composition of the invention for use in the treatment of cancer.

[0041] Another object of the invention is the liquid pharmaceutical composition of the invention for use in the prevention or treatment of cancer-related or treatment-related immune disorders.

[0042] DETAILED DESCRIPTION OF THE INVENTION:

[0043] Definition

[0044] “Pharmaceutically acceptable” refers to what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use. In the context of the invention, a “liquid pharmaceutical composition” is a pharmaceutical formulation in liquid form, typically comprising one or more totally dissolved active pharmaceutical ingredients (APIs) combined with excipients to ensure its stability and solubility. Liquid pharmaceutical compositions may include solutions, suspensions, emulsions, and syrups, preferably solutions and syrups. Liquid pharmaceutical composition can also be filled within capsule such as soft-gel or hard-gel capsule.

[0045] A liquid solution or liquid composition containing an active agent is "stable" for a certain period of time if, during this period, the physico-chemical properties and microbial quality of the medicinal product remain within the limits that ensure its continued efficacy and safety. Preferably, over this period of time, the concentration of active agent in the solution (dissolved active agent) does not decrease of more than 10%, preferably no more than 5%, and / or the formation of degradation products follows the requirements of the ICH Q3 guidelines (ICH refers to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). A liquid solution or liquid composition comprising less than 0.5% of degradation products is compliant with said guidelines. In a preferred embodiment, no tretinoin (or isomer thereof) precipitation or degradation can be detected after at least 15 days, preferably after at least 30 days, more preferably after at least 3 months, more preferably after at least 6 months and even more preferably after at least 12 months of storage under ICH conditions (25°C / 60% RH) .

[0046] An “oral” composition is a composition that is suitable for an administration to a patient via the oral, buccal and / or transmucosal route.

[0047] An “sublingual” composition is a composition that is suitable for an administration to a patient via the mucous membrane.

[0048] An “injectable” composition or “parenteral” composition is a composition that is suitable for an administration to a patient by means of a syringe or a needle. There are 4 routes of injection: intradermal injection, subcutaneous injection, intramuscular injection and intravenous injection.

[0049] A “therapeutically effective amount” is the amount of a therapeutic agent necessary and sufficient for slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the disease, or condition; alleviating the symptoms of the disease or condition, and / or curing the disease or condition.

[0050] "Treating" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully "treated" for an infection if, after receiving a therapeutic amount of an antibody according to the methods of the present invention, the patient shows observable and / or measurable reduction in or absence of one or more parameters, such as the following: reduction in the number of pathogenic cells; reduction in the percent of total cells that are pathogenic; and / or relief to some extent, one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.

[0051] A “subject” is an animal, including a human. In the sense of the present invention, a subject may be a patient, i.e. a person receiving medical attention, undergoing or having underwent a medical treatment, or monitored for the development of a disease. In one embodiment, the subject is an adult (for example a subject above the age of 18). In another embodiment, the subject is a child (for example a subject below the age of 18). In one embodiment, the subject is a male. In another embodiment, the subject is a female.

[0052] The term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical value of plus and minus 15%the numerical value, preferably between plus and minus 10%, more preferably between plus and minus 5%.

[0053] “Isomers” are compounds that have the same molecular formula but differ in the arrangements of atoms in space. Two main forms of isomerism are: structural (or constitutional) isomerism, in which bonds between the atoms differ; and stereoisomerism or (spatial isomerism), in which the bonds are the same but the relative positions of the atoms differ.

[0054] “Stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers, and anomers. In a specific aspect of the disclosure, the stereoisomers include diastereoisomers and enantiomers.

[0055] “Tautomers” are isomeric compounds that differ only in the position of the protons and the electrons.

[0056] Liquid composition

[0057] A first object of the invention is a liquid pharmaceutical composition comprising:

[0058] (i) Tretinoin or a pharmaceutically acceptable isomer thereof;

[0059] (ii) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS);

[0060] (iii) from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition, of a pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof; and

[0061] (iv) Water.

[0062] Another object of the invention is a liquid pharmaceutical composition comprising:

[0063] (i) Tretinoin or a pharmaceutically acceptable isomer thereof; (ii) TPGS;

[0064] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof; and

[0065] (iv) Water.

[0066] In the context of the invention, the liquid pharmaceutical composition is advantageously adapted for injection, oral administration or sublingual administration. In one embodiment, the liquid pharmaceutical composition is an oral liquid pharmaceutical composition. In another embodiment, the liquid pharmaceutical composition is an injectable liquid pharmaceutical composition.

[0067] Preferably, the liquid composition of the invention can be in the form of a solution or syrups.

[0068] Preferably, the liquid pharmaceutical composition of the invention is an aqueous liquid composition, more preferably an aqueous solution or aqueous syrups. That means that the liquid pharmaceutical composition of the invention preferably comprises no oil component.

[0069] The liquid pharmaceutical composition of the invention comprises the tretinoin or the pharmaceutically acceptable isomer thereof at a concentration from about 0.1 % to about 6.5 % by weight, with respect to the total weight of the composition. Advantageously, the liquid pharmaceutical composition of the invention comprises from 0.5% to 6.5%, more advantageously from 0.8% to 6.5%, more advantageously from 1% to 6%, even more advantageously from 2% to 6 %, by weight of tretinoin or a pharmaceutically acceptable isomer thereof, in relation to the total weight of the liquid composition.

[0070] In the context of the invention, the tretinoin or the pharmaceutically acceptable isomer thereof is in a fully dissolved state within the liquid composition of the invention. In other words, the tretinoin or the pharmaceutically acceptable isomer thereof is fully in the liquid state in the liquid composition. Therefore, the liquid composition of the invention is free of tretinoin or the pharmaceutically acceptable isomer thereof in solid form. Typically, optical microscopy measurements can be carried out to confirm the absence of any detectable solid particles, ensuring tretinoin or the pharmaceutically acceptable isomer thereof remains solubilized / dissolved in the liquid composition.

[0071] In one embodiment of the invention, the pharmaceutically acceptable isomer of tretinoin is isotretinoin or alitretinoin, preferably isotretinoin.

[0072] In a specific embodiment of the invention, the liquid pharmaceutical composition comprises tretinoin or isotretinoin as compound (i).

[0073] Without wishing to be bound by any theory, the inventors believe that the tretinoin is preferably present in an anionic form due to the pH environment facilitated by the strong base, enhancing its solubility and stability in the aqueous medium.

[0074] In the context of the invention, the liquid pharmaceutical composition comprises TPGS. In a specific embodiment, the liquid pharmaceutical composition of the invention comprises TPGS at a concentration from about 0.2 % to about 8.6 % by weight, with respect to the total weight of the composition. Advantageously, the liquid pharmaceutical composition of the invention comprises from 0.3% to 8.6%, more advantageously from 0.3 % to 7%, more advantageously from 0.3% to 5%, more advantageously from 0.5% to 4%, more advantageously from 0.5% to 3%, more advantageously from 0.5% to 2%, by weight of TPGS, in relation to the total weight of the liquid composition

[0075] Without wishing to be bound by any theory, the inventors believe that TPGS plays a pivotal role by acting as a surfactant which enhances the solubility of tretinoin by stabilizing micelle formations thereby preventing the re-aggregation of tretinoin and therefore allowing tretinoin to remain in a solubilized state. This physical stabilization is crucial for the prolonged stability and effectiveness of the drug in solution.

[0076] In a specific embodiment, the liquid pharmaceutical composition of the invention can further comprise a surfactant selected from the group consisting of polysorbate such as polysorbate 20, polysorbate 40 polysorbate 80 or mixtures thereof (Tween 20, 40, 80, or mixtures thereof); polyoxyl 35 castor oil (Cremophor EL); polyoxyl 40 hydrogenated castor oil; polyoxyl 60 hydrogenated castor oil; polyethylene glycol 12-hydroxystearate (Solutol HS 15); lecithin; glycerol; monocaprylocaprate; and mixtures thereof.

[0077] In this context, the concentration of the mixture of TPGS and the further surfactant is from about 0.2 % to about 8.6 % by weight, in relation to the total weight of the liquid composition. Advantageously, the liquid pharmaceutical composition ofthe invention comprises from 0.3%to 8.6%, more advantageously from 0.3 % to 7%, more advantageously from 0.3% to 5%, more advantageously from 0.5% to 4%, more advantageously from 0.5% to 3%, more advantageously from 0.5% to 2%, by weight of TPGS and the further surfactant, in relation to the total weight of the liquid composition.

[0078] In the context of the invention, the liquid pharmaceutical composition comprises a pH-modifying agent selected from the group consisting of meglumine, sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof.

[0079] In a particular embodiment, the pH-modifying agent is selected from the group consisting of meglumine, sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof. More preferably, the pH-modifying agent is selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof. In particular, the pH-modifying agent is selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof. Advantageously, the pH-modifying agent is at a concentration from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition. Advantageously, the liquid pharmaceutical composition of the invention comprises from 0.2% to 1.5%, preferably from 0.25% to 1.3%, more preferably from 0.25 to 1.2%, more preferably from 0.25% to 1.0%, by weight of pH-modifying agent, in relation to the total weight of the liquid composition.

[0080] Without wishing to be bound by any theory, the inventors believe that the strong bases that can be used as pH-modifying agent allow to enhance the solubility of tretinoin by converting it into a more soluble anionic form. The transformation of tretinoin into its anionic form is optimally achieved in the presence of strong bases or the strongest among the weak bases, such as meglumine.

[0081] In a specific embodiment, the liquid pharmaceutical composition of the invention further comprises a co-solvent which is a pharmaceutically acceptable water-soluble solvent. The co-solvent is preferably selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol (PEG200-PEG1000), propylene glycol, glycerol, and mixtures thereof. Advantageously, the co-solvent is selected from the group consisting of PEG300, PEG400, PEG600, PEG 1000, propylene glycol, glycerol, and mixtures thereof. In particular, the co-solvent can be selected from the group consisting of PEG600, propylene glycol, glycerol, and mixtures thereof.

[0082] In a specific embodiment of the invention, the co-solvent is propylene glycol.

[0083] In another specific embodiment of the invention, the co-solvent is glycerol.

[0084] In another specific embodiment of the invention, the co-solvent is polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol (PEG200-PEG1000), preferably selected from the group consisting of PEG300, PEG400, PEG600, PEG 1000, and mixtures thereof, more preferably PEG600.

[0085] In another specific embodiment of the invention, the co-solvent is a mixture of propylene glycol and polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol. Preferably, the co-solvent is a mixture of propylene glycol and a PEG selected from the group consisting of PEG300, PEG400, PEG600, PEG 1000, and mixtures thereof. More preferably, the co-solvent is a mixture of propylene glycol and PEG600.

[0086] In another specific embodiment of the invention, the co-solvent is a mixture of glycerol and polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol. Preferably, the cosolvent is a mixture of glycerol and a PEG selected from the group consisting of PEG300, PEG400, PEG600, PEG1000, and mixtures thereof. More preferably, the co-solvent is a mixture of glycerol and PEG600.

[0087] Preferably, the co-solvent is at a concentration from about 5 % to about 90 % by weight, with respect to the total weight of the composition. Advantageously, the liquid pharmaceutical composition of the invention comprises from 10% to 80%, more advantageously from 10% to 75%, more advantageously from 15% to 70%, more advantageously from 15% to 60%, more advantageously from 20% to 50%, by weight of co-solvent, in relation to the total weight of the liquid composition In the context of the invention, the co-solvent can help dissolving tretinoin and adjusting the composition's viscosity. The co-solvent can also act as a viscosity modifying agent, facilitating the formation of a homogeneous solution.

[0088] In a specific embodiment, the liquid composition of the invention is devoid of oily or lipophilic cosolvents.

[0089] In a particular embodiment, the liquid pharmaceutical composition of the invention has a pH from 7.2 to 8.9.

[0090] In a specific embodiment, the liquid composition of the invention can further comprise one or more of the following excipients: antioxidants, preservatives, absorption enhancers, crystal growth inhibitors, colorants, taste -modifier agents, taste-masking agents, sweetening agents, flavoring agents, viscosityenhancing polymers, and texturizing agents.

[0091] All these additional excipients are pharmaceutically acceptable. One skilled in the art is able to adapt the nature and / or amount of each additional excipient depending among others on the intended administration route, the amount of tretinoin or the pharmaceutically acceptable isomer thereof, and / or the intended patient type (age or other).

[0092] The liquid pharmaceutical composition may further comprise any other suitable conventional additional constituent, especially if its addition to the composition does not substantially affect the therapeutical efficacy and / or the stability of the composition.

[0093] Examples of antioxidant can include ascorbic acid (Vitamin C), Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), alpha-tocopherol (Vitamin E), sodium ascorbate, sodium metabisulfite, propyl gallate, Ethylene Diamine Tetraacetic Acid (EDTA), citric acid, citrate salts, sodium sulfite, and combinations thereof. In a specific embodiment, the composition of the invention can comprise one or more antioxidant(s) in a concentration from about 0.05 % to about 1.95 % by weight, with respect to the total weight of the composition.

[0094] Examples of absorption enhancer and crystal growth inhibitor can include polyvinyl pyrrolidone (PVP, with average molecular weights ranging from around 2000 to 60,000 Daltons), Copovidone, Macrogol 15 Hydroxystearate (Solutol), Propylene Glycol Caprylate (Capryol), Polyoxyl 40 Hydrogenated Castor Oil, and combinations thereof.

[0095] Examples of sweetening agents can include Stevia (Steviol glycosides), acesulfame k, sucralose, saccharin, xylitol, erythritol, aspartame, and combinations thereof. In a specific embodiment, the composition of the invention can comprise one or more sweetening agent(s) in a concentration from about 0.03% to about 0.65% by weight, with respect to the total weight of the composition.

[0096] Examples of flavoring agents can include Orange extract, Peppermint oil, Lemon oil for citrus flavor, Menthol for mint flavor, Ethylvanillin for vanilla flavor, Cinnamon extract, Ethyl maltol (for a sweet, fruity flavor), Isoamyl acetate (for a banana-like flavor...), and combinations thereof. In a specific embodiment, the composition of the invention can comprise one or more flavoring agent(s) in a concentration from about 0.03% to about 0.65% by weight, with respect to the total weight of the composition.

[0097] Examples of preservative can include potassium sorbate, sodium benzoate, and combinations thereof. In a specific embodiment, the composition of the invention can comprise one or more preservative in a concentration from about 0.05% to about 0.5% by weight, with respect to the total weight of the composition.

[0098] Examples of viscosity-enhancing polymers can include xanthan gum, cellulose derivatives (such as hydroxypropyl methylcellulose or carboxymethylcellulose), and alginates. In a specific embodiment, the composition of the invention can comprise one or more viscosity-enhancing polymers in a concentration from about 0.35% to about 1.95% by weight, with respect to the total weight of the composition. Typically, the inclusion of a viscosity-enhancing polymer enables the composition of the invention of denser solutions suitable for syrups or semi-solid forms such as gels and gummies. For example, the denser or semi-solid forms are particularly formulated to facilitate ease of administration, especially in paediatric and geriatric patient populations.

[0099] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises tretinoin; TPGS; a pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; and water.

[0100] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises isotretinoin; TPGS; a pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; and water.In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises tretinoin; TPGS; A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, trisodium phosphate, tri -potassium phosphate, and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; and water.

[0101] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises isotretinoin; TPGS; A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; and water.

[0102] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises tretinoin; TPGS; A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; a sweetening agent; and water.

[0103] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises isotretinoin; TPGS; A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; a sweetening agent; and water.

[0104] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises tretinoin; TPGS; a pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; and water.

[0105] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises isotretinoin; TPGS; a pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; and water.

[0106] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises tretinoin; TPGS; A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; and water.

[0107] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises isotretinoin; TPGS; A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; and water.

[0108] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises tretinoin; TPGS; A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; a sweetening agent; and water.

[0109] In another specific embodiment of the present invention, the liquid pharmaceutical composition comprises isotretinoin; TPGS; A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, preferably at a content from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition; a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof; a sweetening agent; and water.

[0110] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0111] (i) Tretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0112] (ii) TPGS, at a concentration from about 0.2% to about 8.6 % by weight;

[0113] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, and mixtures thereof), potassium acetate (anhydrous, trihydrate, and mixtures thereof), dipotassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tripotassium phosphate, and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and (iv) Qsp 100 Water; the concentration being with respect to the total weight of the liquid composition.

[0114] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0115] (i) Tretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0116] (ii) TPGS, at a concentration from about 0.2% to about 8.6 % by weight;

[0117] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0118] (iv) Qsp 100 Water; the concentration being with respect to the total weight of the liquid composition.

[0119] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0120] (i) Tretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0121] (ii) TPGS, at a concentration from about 0.2% to about 8.6 % by weight;

[0122] (iii) A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0123] (iv) Qsp 100 Water; the concentration being with respect to the total weight of the liquid composition.

[0124] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0125] (i) Tretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0126] (ii) TPGS, at a concentration from about 0.2% to about 8.6 % by weight;

[0127] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, and mixtures thereof), potassium acetate (anhydrous, trihydrate, and mixtures thereof), dipotassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tripotassium phosphate, and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0128] (iv) Water;

[0129] (v) A co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof, at a concentration from about 0% to about 90 % by weight; and

[0130] (vi) Optionally a sweetening agent, the concentration being with respect to the total weight of the liquid composition.

[0131] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0132] (i) Tretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0133] (ii) TPGS, at a concentration from about 0.2% to about 8.6 % by weight;

[0134] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0135] (iv) Water;

[0136] (v) A co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof, at a concentration from about 0% to about 90 % by weight; and

[0137] (vi) Optionally a sweetening agent, the concentration being with respect to the total weight of the liquid composition.

[0138] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0139] (i) Isotretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0140] (ii) TPGS, at a concentration from about 0.2 % to about 8.6 % by weight;

[0141] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, and mixtures thereof), potassium acetate (anhydrous, trihydrate, and mixtures thereof), dipotassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tripotassium phosphate, and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0142] (iv) Water; the concentration being with respect to the total weight of the liquid composition.

[0143] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0144] (i) Isotretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0145] (ii) TPGS, at a concentration from about 0.2 % to about 8.6 % by weight;

[0146] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0147] (iv) Water; the concentration being with respect to the total weight of the liquid composition. In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0148] (i) Isotretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0149] (ii) TPGS, at a concentration from about 0.2 % to about 8.6 % by weight;

[0150] (iii) A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0151] (iv) Water; the concentration being with respect to the total weight of the liquid composition.

[0152] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0153] (i) Isotretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0154] (ii) TPGS, at a concentration from about 0.2 % to about 8.6 % by weight;

[0155] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, and mixtures thereof), potassium acetate (anhydrous, trihydrate, and mixtures thereof), dipotassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tripotassium phosphate, and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0156] (iv) Water;

[0157] (v) A co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof, at a concentration from about 0% to about 90 % by weight; and

[0158] (vi) Optionally a sweetening agent, the concentration being with respect to the total weight of the liquid composition.

[0159] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0160] (i) Isotretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0161] (ii) TPGS, at a concentration from about 0.2 % to about 8.6 % by weight;

[0162] (iii) A pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0163] (iv) Water; (v) A co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof, at a concentration from about 0% to about 90 % by weight; and

[0164] (vi) Optionally a sweetening agent, the concentration being with respect to the total weight of the liquid composition.

[0165] In a specific embodiment of the present invention, the liquid pharmaceutical composition comprises:

[0166] (i) Isotretinoin, at a concentration from about 0.1 % to about 6.5 % by weight;

[0167] (ii) TPGS, at a concentration from about 0.2 % to about 8.6 % by weight;

[0168] (iii) A pH-modifying agent selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof, at a concentration from about 0.2 % to about 1.7 % by weight; and

[0169] (iv) Water;

[0170] (v) A co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof, at a concentration from about 0% to about 90 % by weight; and

[0171] (vi) Optionally a sweetening agent, the concentration being with respect to the total weight of the liquid composition.

[0172] In a specific embodiment of the invention, the liquid composition does not comprise any solids components or particles. The liquid pharmaceutical composition of the invention can be prepared as an oral dosage form (solution, or fill for hard-gel or soft-gel capsules, fill for HPMC capsule, fill for derived plant-based capsule, base for gummies...), or as a sterile solution for administration by injection. The sterile solution that can further be lyophilized.

[0173] Process for manufacturing the liquid pharmaceutical composition of the invention

[0174] The liquid pharmaceutical composition of the invention can be prepared by means commonly known by the one skilled in the art.

[0175] For example, the process for manufacturing a liquid pharmaceutical composition according to the invention can comprise the steps of:

[0176] (a) Dissolving tretinoin or a pharmaceutically acceptable isomer thereof in a solution comprising TPGS, water, and optionally: the co-solvent, and / or the surfactant and / or the sweetener; and

[0177] (b) Adjusting the pH by incorporating the pH-modifying agent; (c) Optionally sterilizing the solution obtained in step (b).

[0178] As another example, the process for manufacturing a liquid pharmaceutical composition according to the invention can comprise the steps of:

[0179] (a’) Mixing TPGS; the pH-modifying agent; water; and optionally: the co-solvent and / or the surfactant and / or the sweetener; and

[0180] (b’) Dissolving tretinoin or a pharmaceutically acceptable isomer thereof in the solution obtained in step (a’);

[0181] (c’) Optionally sterilizing the solution obtained in step (b).

[0182] Step (a) or (a’) may be performed by any suitable technique known in the art.

[0183] Step (a) or (a’) is preferably performed under stirring. The addition of the tretinoin or a pharmaceutically acceptable isomer thereof is preferably performed at a temperature comprised between 25 and 100°C, more preferably between 40 and 65°C. Alternatively, the obtained solution may be stirred at a temperature comprised between 25 and 100°C, more preferably between 40 and 65°C after the tretinoin or a pharmaceutically acceptable isomer thereof is added.

[0184] Step (b) or (b’) is preferably performed under stirring. The addition of the pH-modifying agent is preferably performed at a temperature comprised between 25 and 100°C, more preferably between 40 and 65°C. In a particular embodiment, in step (b), the pH is adjusted to obtained a pH from 7.2 to 8.9.

[0185] Following step (b) or (b’), the process can comprise a further step (b”) of homogenizing the solution obtained. Homogenizing may be performed under stirring, preferably until a clear and transparent solution is obtained.

[0186] Step (c) or (c’) may be performed by any suitable technique known in the art. The suitable technique may be selected depending of the route of administration intended for the pharmaceutical composition. For instance, step (c) or (c’) may be performed by autoclaving, by aseptic distribution or by filtration, for instance by filtration on a 0.22 pm filter.

[0187] In a particular embodiment, the liquid pharmaceutical composition prepared by the process of the invention has a pH from 7.2 to 8.9.

[0188] Therapeutic uses

[0189] Another object of the invention is a liquid pharmaceutical composition according to the invention for use as a medicament.

[0190] In one embodiment, the invention relates to an oral liquid pharmaceutical composition according to the invention for use as a medicament. In another embodiment, the invention relates to an injectable liquid pharmaceutical composition according to the invention for use as a medicament.

[0191] Another object of the invention is a liquid pharmaceutical composition according to the invention, for use in the treatment of acute promyelocytic leukemia (APL) in a subject in need thereof.

[0192] Another object of the invention is a liquid pharmaceutical composition according to the invention, for use in the treatment of skin disorders such as acne in a subject in need thereof.

[0193] Another object of the invention is a liquid pharmaceutical composition according to the invention, for use in the treatment of cancer in a subject in need thereof.

[0194] Another object of the invention is a liquid pharmaceutical composition according to the invention, for use in the prevention or treatment of cancer-related or treatment-related immune disorders.

[0195] In particular, the tretinoin or pharmaceutically acceptable isomer thereof can be used as an immunomodulatory agent.

[0196] Another object of the invention is a method for treating a disease or disorder in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to the invention comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.

[0197] Another object of the invention is a method for treating acute promyelocytic leukaemia (APL) in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to the invention comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.

[0198] Another object of the invention is a method for treating skin disorder such as acne in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to the invention comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.

[0199] Another object of the invention is a method for treating a cancer in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to the invention comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.

[0200] Another object of the invention is a method for preventing or treating cancer-related or treatment-related immune disorders in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to the invention comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.

[0201] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention, in the manufacture of a medicament. Another object of the invention is the use of a liquid pharmaceutical composition according to the invention, in the manufacture of a medicament, for use in the treatment of acute promyelocytic leukaemia (APL).

[0202] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention, in the manufacture of a medicament, for use in the treatment of skin disorder such as acne.

[0203] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention, in the manufacture of a medicament, for use in the treatment of a cancer.

[0204] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention, in the manufacture of a medicament, for use in the prevention or treatment of cancer-related or treatment-related immune disorders.

[0205] In these embodiments, the pharmaceutically acceptable isomer of tretinoin is preferably isotretinoin or alitretinoin. In one preferred embodiment, the pharmaceutically acceptable isomer of tretinoin is isotretinoin.

[0206] In these embodiments, the cancer to be treated according to the invention may be selected from the group consisting of solid tumours, in particular solid tumours at an advanced stage (locally-advanced, metastatic).

[0207] In these embodiments, the treatment-related immune disorders are immune disorders related to chemotherapy or radiation therapy. For example, treatment-related immune disorders can be treatment- induced lymphopenia or treatment-induced increase of immuno-suppressive cells including subtypes of pro-tumorigenic neutrophiles, inflammatory monocytes / macrophages, immature myeloid-derived suppressive cells (MDSC) and regulatory T cells.

[0208] In these embodiments, the cancer-related immune disorders can be any condition promoting tumour immune-evasion and lymphocyte exhaustion including high circulating levels of immunosuppressive cells (such as regulatory T cells, MDSCs etc) or immunosuppressive cytokines (such as IL- 10, TGFb etc).

[0209] The form of the pharmaceutical compositions, the route of administration and the dose of administration of the dissolved tretinoin or pharmaceutically acceptable isomer thereof, or the liquid pharmaceutical compositions according to the invention can be adjusted by the one skilled in the art according to the type and severity of the disease, and to the patient, in particular its age, weight, sex, and general physical condition.

[0210] The dose of the tretinoin or the pharmaceutically acceptable isomer thereof in the composition for use according to the invention may be any dose suitable for treating the pathology and / or condition. For instance, the daily dose of the tretinoin may range between 20 and 200 mg / m2, preferably between 45 and 150 mg / m2. Typically, the concentration of tretinoin or the pharmaceutically acceptable isomer thereof in the liquid composition may range from 0.5 % to about 6.5 % by weight, with respect to the total weight of the composition. In particular, the volume of liquid composition to be administered according to the invention is preferably not higher than 5 mL, especially when the patient is a child.

[0211] The liquid pharmaceutical composition for use according to the invention may be co-administered with any other suitable treatment, in particular with any other suitable anti-cancer treatment. The coadministration may be simultaneous, sequential or separate.

[0212] Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting.

[0213] EXAMPLES

[0214] Example 1: Preparation of liquid compositions according to the invention

[0215] The liquid compositions as disclosed in Table 1 have been prepared as follows:

[0216] Tretinoin Dissolution:

[0217] Tretinoin or a pharmaceutically acceptable isomer thereof is dissolved in a solution comprising TPGS, water, and optionally the co-solvent(s) and / or the sweetening agent.

[0218] The dissolution is preferably performed under stirring at a temperature between 40°C and 50°C, to ensure complete solubility and stability of the tretinoin in the solution. pH Adjustment:

[0219] The pH of the solution is adjusted by incorporating a pH-modifying agent.

[0220] The pH adjustment is also performed under stirring and at a temperature between 40°C and 50°C to ensure that the tretinoin is converted into its anionic form for enhanced solubility.

[0221] Homogenization:

[0222] Following the pH adjustment, the solution is homogenized under stirring until a clear and transparent solution is obtained, indicating that the tretinoin is fully dissolved and stable within the solution.

[0223] Table 1 : Liquid compositions of the invention

[0224] Example 2: Comparative tests on solubility, physical stability and chemical stability a) Solubility tests

[0225] Preparation of control solutions: Prepare control solutions by dissolving tretinoin in pure water, pure ethanol, pure PEG 300, pure DMSO, and pure propylene glycol.

[0226] Target concentrations to be prepared are:

[0227] Water: up to 1 mg / mL

[0228] Ethanol: up to 5 mg / mL - PEG 300: up to 2 mg / mL

[0229] Propylene glycol: up to 5 mg / mL

[0230] DMSO: up to 50 mg / mL

[0231] Baseline solubility determination:

[0232] Measure the solubility of tretinoin in each pure solvent at 25°C by visual inspection. Record the maximum solubility values as follows:

[0233] Water: insoluble (<1 mg / mL)

[0234] Ethanol: up to 5 mg / mL (0.5%)

[0235] PEG 300: up to 2 mg / mL (0.2%)

[0236] Propylene glycol: up to 5 mg / mL (0.5%) DMSO: up to 50 mg / mL (5%)

[0237] Preparation of test solutions:

[0238] Measure and weigh the specified amounts of each tretinoin composition from Table 1 (Tests 1 to 4 and Comparative Tests 1 to 3) into separate volumetric flasks.

[0239] Add the appropriate solvent (water) to each flask and adjust to the final volume to achieve the target concentration.

[0240] Mix the solutions thoroughly using a stirring apparatus to ensure complete dissolution.

[0241] Observe the solutions visually for any undissolved particles or cloudiness to determine solubility.

[0242] Data collection and comparison:

[0243] Visually inspect and record the clarity and presence of any undissolved particles in each sample.

[0244] Compare the visual solubility of tretinoin in the tested compositions with the baseline solubility values from the control solutions.

[0245] Results:

[0246] The novel liquid compositions of the invention demonstrated significantly higher solubility of tretinoin compared to the baseline solubility in pure solvents (see table 2).

[0247] Visual inspection confirmed that Tests 1 to 4 resulted in clear solutions with no visible undissolved particles, indicating successful solubility of tretinoin at much higher concentrations.

[0248] For example, Test 1 achieved a clear solution at 22 mg / mL, Test 2 at 22 mg / mL, Test 3 at 59 mg / mL, and Test 4 at 34 mg / mL.

[0249] Comparative tests 1 to 3 showed partial solubility or the presence of undissolved particles, highlighting the effectiveness of the novel formulations.

[0250] Table 2

[0251] Conclusion:

[0252] The solubility tests, assessed by visual inspection, confirm that the novel liquid pharmaceutical compositions significantly enhance the solubility of tretinoin compared to its solubility in pure solvents. Tests 1 to 4 demonstrated clear solutions with significantly higher solubility of tretinoin at concentrations such as 22 mg / mL, 22 mg / mL, 59 mg / mL, and 34 mg / mL, respectively. This demonstrates the superior formulation approach of the invention, enabling higher drug loading and potentially improved therapeutic efficacy. While DMSO affords high solubility (up to 50 mg / mL), it is not user friendly, making the novel compositions a more viable option for therapeutic use. b) Physical stability:

[0253] Objective:

[0254] To assess whether the solubility of tretinoin in the novel liquid compositions remains stable over a 1- month storage period at 25°C.

[0255] Protocol:

[0256] Sample preparation:

[0257] Prepare samples of each tretinoin composition from Table 1 (Tests 1 to 4 and Comparative Tests 1, 2 and 3).

[0258] Storage conditions:

[0259] Store the prepared samples at 25°C for a period of 1 month.

[0260] Visual inspection:

[0261] After the 2-week storage period, visually inspect each sample to assess the presence of any aggregates or crystals.

[0262] Compare the appearance of the samples to their initial state immediately after preparation.

[0263] Results:

[0264] The solubility of tretinoin in all novel liquid compositions (Tests 1 to 4) remained stable over the 1- month storage period at 25°C.

[0265] No appearance of aggregates or crystals was observed in any of the samples.

[0266] The solutions remained clear, indicating that the solubility of tretinoin was maintained.

[0267] Conclusion: The physical stability tests confirm that the novel liquid compositions of tretinoin maintain their solubility and do not form aggregates or crystals over a 2-week storage period at 25°C. This demonstrates the effectiveness and reliability of the formulations in preserving the solubility of tretinoin under standard storage conditions. c) Chemical stability

[0268] Objective:

[0269] To evaluate the chemical stability of tretinoin in the novel liquid compositions over a 1 -month storage period at 25°C.

[0270] Protocol:

[0271] Sample preparation:

[0272] Prepare samples of each tretinoin composition from Table 1 (Tests 1 to 4).

[0273] Storage conditions:

[0274] Store the prepared samples at 25°C for a period of 1 month.

[0275] Visual inspection:

[0276] Periodically inspect each sample for any color changes during the storage period.

[0277] HPLC analysis:

[0278] Use the HPLC method described in the EP monograph for tretinoin to analyze the samples.

[0279] At the end of the 1 -month storage period, measure the tretinoin content in each sample using HPLC. Compare the tretinoin content to the initial concentration at the time of preparation.

[0280] Results:

[0281] No color change was observed in any of the samples from Tests 1 to 4 over the 1-month storage period at 25 °C.

[0282] HPLC analysis confirmed that the tretinoin content remained above 95% of the initial concentration in all samples.

[0283] Conclusion:

[0284] The chemical stability tests confirm that the novel liquid compositions of tretinoin maintain their chemical integrity over a 1-month storage period at 25°C. No color change was observed, and the tretinoin content remained above 95% of the initial concentration, demonstrating the effectiveness of the formulations in preserving the chemical stability of tretinoin under standard storage conditions. While DMSO affords high solubility, it is not pharmaceutically friendly, making the novel compositions a more viable option for therapeutic use. Example 3: Comparative test between the composition of the invention and prior art compositions.

[0285] Objective:

[0286] Demonstrate the technical benefit of the invention versus the composition disclosed in US application No 2013 / 108674, through solubility improvements and compositional design.

[0287] Experimental design overview

[0288] The formulations A to E according to the invention were prepared using:

[0289] Tretinoin (solubility limit determination);

[0290] 2 % w / v of TPGS (solubilizer); pH modifiers : NaOH, KOH, or meglumine (see table 3 for nature and content);

[0291] QS 100 water

[0292] The formulation of US application No 2013 / 108674 (ref.) was prepared as in Example 5 of this U.S. application:

[0293] Tretinoin,

[0294] - 2% de TGPS,

[0295] 0.02% disodium phosphate,

[0296] 2% glycerol,

[0297] - 0.6% de MCT, et

[0298] QSlOO Eau

[0299] Tretinoin solubility is measured in simulated intestinal fluid at 25 °C, protected from light, by visual inspection.

[0300] The tested compositions and results are summarized in Table 3 below.

[0301] Table 3: Aqueous solubility of tretinoin in inventive formulations vs. prior art (ref.)

[0302] Discussion

[0303] A direct correlation is seen between alkali concentration, pH increase, and ATRA solubility.

[0304] Samples D (1.7% NaOH) and E (1.7% KOH) reach at least 30 mg / mL, i.e. a more than 15-fold increase over prior art reference US application No 2013 / 108674.

[0305] Although meglumine leads to lower solubility than strong bases, it can be used as a milder alternative when needed for tolerability reasons.

[0306] Stability and clarity were maintained at pH up to 8.9, supporting potential for parenteral use.

Claims

CLAIMS1- A liquid pharmaceutical composition comprising:(i) Tretinoin or a pharmaceutically acceptable isomer thereof;(ii) d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS);(iii) from about 0.2 % to about 1.7 % by weight, with respect to the total weight of the composition, of a pH-modifying agent selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate (anhydrous, trihydrate, or mixtures thereof), potassium acetate (anhydrous, trihydrate, or mixtures thereof), di-potassium hydrogenophosphate, di-sodium hydrogenophosphate, tri-sodium phosphate, tri-potassium phosphate, and mixtures thereof; and(iv) Water.2- The liquid pharmaceutical composition according to claim 1, wherein the tretinoin, or the pharmaceutically acceptable isomer thereof, is at a concentration from about 0.1 % to about 6.5 % by weight, with respect to the total weight of the composition.3- The liquid pharmaceutical composition according to claim 1 or 2, wherein component (i) of the composition is tretinoin, isotretinoin or alitretinoin.4- The liquid pharmaceutical composition according to any one of claims 1 to 3, wherein TPGS is at a concentration from about 0.2 % to about 8.6 % by weight, with respect to the total weight of the composition.5- The liquid pharmaceutical composition according to any one of claims 1 to 4, further comprising a surfactant selected from the group consisting of polysorbate (Tween), polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyethylene glycol 12-hydroxystearate (Solutol HS 15), lecithin, glycerol monocaprylocaprate, and mixtures thereof.6- The liquid pharmaceutical composition according to claim 5, wherein the mixture of TPGS and the surfactant is at a concentration from about 0.2 % to about 8.6 % by weight, with respect to the total weight of the composition.7- The liquid pharmaceutical composition according to any one of claims 1 to 6, further comprising a co-solvent selected from the group consisting of polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, propylene glycol, glycerol, and mixtures thereof, preferably the co-solvent is at a concentration from about5 % to about 90 % by weight, with respect to the total weight of the composition.8- The liquid pharmaceutical composition according to claim 7, wherein the co-solvent is selected from the group consisting of propylene glycol, glycerol, mixtures of propylene glycol and polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, mixtures of glycerol and polyethylene glycol with average molecular weights ranging from around 200 to 1000 g / mol, and mixtures thereof.9- The liquid pharmaceutical composition according to any one of claims 1 to 8, wherein the pH- modifying agent is at a concentration from 0.2% to 1.5%, preferably from 0.25% to 1.3%, more preferably from 0.25 to 1.2%, more preferably from 0.25% to 1.0% by weight, with respect to the total weight of the composition, and / or wherein the pH-modifying agent is selected from the group consisting of meglumine, potassium hydroxide (KOH), sodium hydroxide (NaOH), and mixtures thereof.10- The liquid pharmaceutical composition according to any one of claims 1 to 9, wherein said composition is suitable for oral or parenteral administration.11- The liquid pharmaceutical composition according to any one of claims 1 to 10, for use as a medicament.12- The liquid pharmaceutical composition according to any one of claims 1 to 10, for use in the treatment of acute promyelocytic leukemia (APL).13- The liquid pharmaceutical composition according to any one of claims 1 to 10, for use in the treatment of skin disorders such as acne.The liquid pharmaceutical composition according to any one of claims 1 to 10, for use in the treatment of cancer.The liquid pharmaceutical composition according to any one of claims 1 to 10, for use in the treatment or the prevention of cancer-related or treatment-related immune disorders.16- A method for treating acute promyelocytic leukaemia (APL) in a subject in need thereof, comprising administering a liquid pharmaceutical composition according any one of claims 1 to 10 comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.17- A method for treating skin disorder such as acne in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to any one of claims 1 to 10 comprising atherapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.18- A method for treating a cancer in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to any one of claims 1 to 10 comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.19- A method for preventing or treating cancer-related or treatment-related immune disorders in a subject in need thereof, comprising administering a liquid pharmaceutical composition according to any one of claims 1 to 10 comprising a therapeutically effective amount of dissolved tretinoin or any pharmaceutically acceptable isomer thereof, to said subject.20- Use of a liquid pharmaceutical composition according to any one of claims 1 to 10, in the manufacture of a medicament, for use in the treatment of acute promyelocytic leukaemia (APL).21- Use of a liquid pharmaceutical composition according to any one of claims 1 to 10, in the manufacture of a medicament, for use in the treatment of skin disorder such as acne.22- Use of a liquid pharmaceutical composition according to any one of claims 1 to 10, in the manufacture of a medicament, for use in the treatment of a cancer.23- Use of a liquid pharmaceutical composition according to any one of claims 1 to 10, in the manufacture of a medicament, for use in the prevention or treatment of cancer-related or treatment- related immune disorders.

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