Oral composition of arsenic trioxide for cancer treatment

Abstract

The present invention relates to a liquid pharmaceutical composition comprising totally dissolved arsenic trioxide, at least one solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates, and a solvent system which comprises a non-ionic surfactant and propylene glycol. The invention also relates to pharmaceutical capsule comprising the liquid composition of the invention. The invention further relates to said liquid pharmaceutical composition or said pharmaceutical capsule for use in the treatment of cancer or autoimmune diseases.

Description

[0001] ORAL COMPOSITION OF ARSENIC TRIOXIDE FOR CANCER TREATMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to pharmaceutical compositions for the oral administration of arsenic trioxide and their use in the treatment of cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] Arsenic trioxide (ATO) has been established as an effective treatment for certain types of cancer, such as acute promyelocytic leukemia (APL).

[0006] Similarly, ATO is known to be an effective treatment for Acute myeloblastic leukemia (AML) and is also being investigated for efficacy in treating refractory cancer patients harboring TP53 mutations, hepatocellular carcinoma, NPM1 mutations in AML, neuroblastoma, metastatic ovarian and endometrial cancer, HIV-1, myelodysplastic syndrome (MDS), Multiple Sclerosis (MS) and more.

[0007] Currently, ATO is administered daily as a sterile injectable solution via intravenous (IV) infusion, requiring hospitalization and caregiver administration due to safety concerns, including the potential risks and side effects associated with the drug.

[0008] There is a need for an alternative mode of administration that provides the same therapeutic benefits while enabling outpatient treatment and reducing the burden on healthcare systems.

[0009] Attempts to develop an oral formulation that would avoid these drawbacks have been made. Most of these oral formulations comprise sodium hydroxide for solubilizing ATO.

[0010] For example, U.S. Pat. No. 7,521,071 B2 and European Patent EP 3106169 Bl, involve preparing an ATO oral solution using sodium hydroxide.

[0011] U.S. Pat. Nos. 10,111,836 B2 and 10,653,628 B2, disclose lyophilization method for solubilizing ATO with sodium hydroxide. However, this method requires multiple stages and poses potential difficulties at a larger scale.

[0012] The US Pat. Application No. 20220257647 discloses a formulation comprising arsenic trioxide in a dissolved state within a hard or soft capsule, utilizing a liquid fill matrix. This matrix consists of at least 80% nonaqueous components, encompassing sodium hydroxide, fill materials, and optionally a solvent or cosolvent, coupled with an antioxidant. Further, it may incorporate surfactants, absorption enhancers, and crystal growth inhibitors. While addressing solubility challenges, the reliance on sodium hydroxide and 80% nonaqueous medium presents concerns about long-term stability and capsule sheath integrity.

[0013] U.S. Pat. No. 10,493,099 B2 addresses solubility by introducing new salt forms (Arsenic carbonate / bicarbonate) to address the poor solubility and low dissolution rates of arsenic trioxide. The new salts are formulated as a solid oral dosage form wherein the arsenic salt is present in the solid state, blended with excipients and fdled into a capsule, but challenges persist in achieving a solid oral dosage form.

[0014] Consequently, despite advancements in oral ATO formulations, challenges persist in safety, exposure risks, manufacturing complexity, and scalability. Urgent development of a solid oral dosage form that ensures safety, stability, optimal bioavailability, and streamlined manufacturing processes is imperative.

[0015] SUMMARY OF THE INVENTION

[0016] The inventors have developed a liquid composition which enables the constant solubility of arsenic trioxide (ATO), which is essential for achieving a high, reliable and consistent bioavailability of the drug substance when compared to intravenous (IV) administration. The proposed composition aims to facilitate the treatment of patients without the need for hospitalization, enhancing the convenience and quality of care.

[0017] The liquid composition of the invention is suitable for fdling hard gel and soft gel capsules, providing a convenient and safe means of administering ATO to patients.

[0018] In particular, the present invention introduces liquid compositions comprising arsenic trioxide, achieving high solubility (295 mg / mU) in a water-free environment to ensure compatibility with various capsule shells (hard gel, soft gelatin, or HPMC). The liquid composition carefully avoids conditions that could lead to gelatin solubilization, such as unfavorable pH levels or reactive excipients, thus preventing softening and potential leakage of the capsule shell.

[0019] As shown by the Examples, the composition of the invention has the following advantages:

[0020] • Higher solubility: significantly improves arsenic trioxide solubility for enhanced therapeutic effects and long-term stability.

[0021] • Dose adaptation: offers flexibility in dosing for personalized treatment.

[0022] • Capsule compatibility: compatible with both hard and soft gelatin capsules, providing administration options.

[0023] • Industrial production: facilitates cost-effective large-scale manufacturing.

[0024] • Outpatient treatment: reduces the burden on healthcare facilities, enhancing patient convenience.

[0025] • Cost efficiency: potential cost savings in healthcare by minimizing hospitalization needs.

[0026] • Improved patient compliance: a patient-friendly administration mode may improve adherence.

[0027] • Comparable bioavailability: ensures effectiveness comparable to intravenous administration.

[0028] • Safer administration: eliminates intravenous complications, providing a safer and more convenient option. The inventors have surprisingly discovered that a liquid composition of the invention comprising a specific blend of propylene glycol, a non-ionic surfactant, and metal-alkali acetates or lactates allows to overcome the technical problems set forth in the present invention. In particular, the liquid composition enhances the solubility of ATO and ensures the stability of the capsule sheath. This liquid composition also overcomes the technical challenges previously encountered, such as phase separation, precipitation, and instability of the active components.

[0029] Furthermore, the remarkable solubilizing capacity of the liquid composition of the invention, allowing for the dissolution of high quantities of Arsenic Trioxide, enables the production of capsules with significantly reduced sizes, reaching as low as 0.1 mb in volume. This substantial reduction in capsule size enhances patient compliance, making them particularly suitable for both elderly and younger individuals, ensuring ease of administration.

[0030] A first object of the invention relates to a liquid pharmaceutical composition comprising:

[0031] • Dissolved arsenic trioxide, in a concentration range of 0. 1 % to 19.5 % by weight, in relation to the total weight of the liquid composition;

[0032] • At least one solubilizing agent selected from the metal-alkali acetates, metal-alkali lactates, and mixtures thereof, in a concentration range of 0.15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition; and

[0033] • A solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10.

[0034] A second object of the invention relates to a pharmaceutical capsule comprising the liquid pharmaceutical composition of the invention.

[0035] The invention also relates to a liquid pharmaceutical composition according to the invention, or pharmaceutical capsule according to the invention, for use as a medicament.

[0036] The invention also relates to a liquid pharmaceutical composition according to the invention, or pharmaceutical capsule according to the invention, for use in a method of treating cancer, in particular a cancer selected from Acute promyelocytic leukemia (APL), Acute myeloblastic leukemia (AML), Myelodysplastic Syndromes, and Multiple Myeloma.

[0037] The invention also relates to a liquid pharmaceutical composition according to the invention, or pharmaceutical capsule according to the invention, for use in a method of treating autoimmune diseases such as lupus, Multiple sclerosis, Rheumatoid arthritis, or Psoriasis. BRIEF SUMMARY OF THE FIGURES

[0038] Figure 1 shows the appearance of the liquid composition No 9 of Table 1. A clear and transparent solution is obtained.

[0039] Figure 2 shows the appearance of hard capsule No. 7 of Table 2, three months post-manufacture. A clear and transparent solution is observed in a capsule in perfect condition.

[0040] Figure 3 shows the dissolution rates of the compositions No 1 (5 mg ATO), No 4 (10 mg ATO), and No 7 (15 mg ATO) of Table 2, in hard-gel capsules. A quick and complete dissolution of ATO is obtained in less than five minute for each dosage form.

[0041] DETAIEED DESCRIPTION OF THE INVENTION:

[0042] Definition

[0043] “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.

[0044] 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, or 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 ATO 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. An “rectar composition is a composition that is suitable for an administration to a patient through the rectal blood vessels.

[0048] 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.

[0049] "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.

[0050] 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.

[0051] 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%.

[0052] Liquid composition

[0053] A first object of the invention is a liquid pharmaceutical composition comprising:

[0054] Dissolved arsenic trioxide, in a concentration range of 0. 1 % to 19.5 % by weight, in relation to the total weight of the liquid composition; At least one solubilizing agent selected from the metal-alkali acetates, metal-alkali lactates, and mixtures thereof, in a concentration range of 0.15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition; and

[0055] A solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10.

[0056] In the context of the invention, the liquid pharmaceutical composition is advantageously adapted for an oral, sublingual or rectal administration. Preferably, the liquid pharmaceutical composition is an oral liquid pharmaceutical composition.

[0057] Preferably, the liquid composition of the invention can be in the form of a solution or syrups. In particular, the liquid composition of the invention can be a solution fdled in a capsule such as soft-gel or hard-gel capsule. In other terms, the liquid composition of the invention can be sealed in a capsule.

[0058] The liquid pharmaceutical composition of the invention comprises from 0.1 % to 19.5 % by weight of ATO, in relation to the total weight of the liquid composition. Advantageously, the liquid pharmaceutical composition of the invention comprises from 0.1% to 10%, more advantageously 0.1% to 5%, even more advantageously from 1% to 5 %, by weight of ATO, in relation to the total weight of the liquid composition. In a preferred embodiment, the liquid pharmaceutical composition of the invention comprises from 0.2% to 4%, more advantageously 0.5% to 3%, even more advantageously from 1% to 2 %, by weight of ATO, in relation to the total weight of the liquid composition.

[0059] In the context of the invention, the ATO is in a fully dissolved state within the liquid composition of the invention. In other words, the ATO is fully in the liquid state in the liquid composition. Therefore, the liquid composition of the invention is free of ATO in solid form. Typically, optical microscopy measurements can be carried out to confirm the absence of any detectable solid particles, ensuring ATO remains solubilized / dissolved in the liquid composition.

[0060] The liquid pharmaceutical composition of the invention also comprises at least one solubilizing agent selected from the metal-alkali acetates, metal-alkali lactates, and mixtures thereof, preferably metal- alkali acetates.

[0061] Metal-alkali acetates refer herein to the salts formed by the combination of acetic acid with alkali metals, such as sodium or potassium. Some examples of metal-alkali acetates include sodium acetate, potassium acetate, and mixtures thereof. The metal-alkali acetates can be anhydrous or hydrates.

[0062] Metal-alkali lactates refer herein to the salts formed by the combination of lactic acid with alkali metals, such as sodium, potassium. Some examples of metal -alkali acetates include sodium lactate, potassium lactate, and mixtures thereof. The metal-alkali lactates can be anhydrous or hydrates. In a preferred embodiment, the solubilizing agent is selected from the group consisting of sodium acetate, potassium acetate, sodium lactate, potassium lactate, and mixtures thereof. In particular, the solubilizing agent is preferably sodium acetate.

[0063] Without wishing to be bound by a theory, the Inventors believe that the presence of at least one solubilizing agent selected from metal-alkali acetates, metal-alkali lactates and any mixtures thereof; is pivotal not only for their efficacy in dissolving ATO but also for the comparatively gentler effect on the solubility of gelatin in the capsule shell.

[0064] While metal-alkali acetates and metal-alkali lactates effectively enhance ATO solubility, their concentration must be carefully calibrated. Excessive amounts of metal-alkali acetates or metal-alkali lactates, despite their advantages, can still pose a risk to the integrity of the capsule shell, potentially leading to softening or damage.

[0065] Preferably, the solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates is comprised in the liquid composition in a concentration range of 0.15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition. In an embodiment, more preferably, the solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates is comprised in the liquid composition in a concentration range of 1% to 7.5%, in particular 2.5% to 5%, by weight, in relation to the total weight of the liquid pharmaceutical composition. In an embodiment, more preferably, the solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates is comprised in the liquid composition in a concentration range of 0.2% to 5%, in particular 0.4% to 1.5%, by weight, in relation to the total weight of the liquid pharmaceutical composition. In an embodiment, more preferably, the solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates is comprised in the liquid composition in a concentration range of 0.5% to 4%, in particular 1% to 2%, by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0066] In a specific embodiment of the invention, the liquid pharmaceutical composition comprises

[0067] Dissolved arsenic trioxide;

[0068] At least one solubilizing agent selected from the group consisting of sodium acetate, potassium acetate, sodium lactate, potassium lactate, and mixtures thereof; and

[0069] A solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10.

[0070] In another specific embodiment of the invention, the liquid pharmaceutical composition comprises Dissolved arsenic trioxide;

[0071] At least one solubilizing agent selected from the group consisting of sodium acetate, potassium acetate, and mixtures thereof; and A solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10.

[0072] In a specific embodiment of the invention, the liquid pharmaceutical composition comprises: Dissolved arsenic trioxide, in a concentration range of 0. 1 % to 5 % by weight, in relation to the total weight of the liquid composition;

[0073] At least one solubilizing agent selected from the group consisting of sodium acetate, potassium acetate, and mixtures thereof, in a concentration range of 0.2% to 7.5% by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0074] In a specific embodiment of the invention, the liquid pharmaceutical composition comprises: Dissolved arsenic trioxide, in a concentration range of 1 % to 5 % by weight, in relation to the total weight of the liquid composition;

[0075] At least one solubilizing agent selected from the group consisting of sodium acetate, potassium acetate, and mixtures thereof, in a concentration range of 0.2% to 5% by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0076] In a specific embodiment of the invention, the liquid pharmaceutical composition comprises: Dissolved arsenic trioxide, in a concentration range of 0. 1 % to 5 % by weight, in relation to the total weight of the liquid composition;

[0077] At least one solubilizing agent selected from the group consisting of sodium acetate, potassium acetate, and mixtures thereof, in a concentration range of 1% to 7.5% by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0078] In a specific embodiment of the invention, the liquid pharmaceutical composition comprises: Dissolved arsenic trioxide, in a concentration range of 1 % to 5 % by weight, in relation to the total weight of the liquid composition;

[0079] At least one solubilizing agent selected from the group consisting of sodium acetate, potassium acetate, and mixtures thereof, in a concentration range of 2.5% to 5% by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0080] In the context of the invention, the liquid pharmaceutical composition comprises a solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10.

[0081] In a specific embodiment, the liquid pharmaceutical composition comprises a solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 20:80 to 90: 10. For example, the weight ratio propylene glycol : non-ionic surfactant can be from 10:90 to 90: 10, or from 12:88 to 90: 10, or from 15:85 to 90: 10, or from 17:83 to 90: 10, or from 18:82 to 90: 10, or from 20:80 to 90: 10, or from 10:90 to 85: 15, or from 10:90 to 80:20, or from 10:90 to 70:30, or from 10:90 to 60:40, or from 10:90 to 50:50, or from 10:90 to 48:52 or from 20:80 to 48:52.

[0082] In a specific embodiment, the weight ratio propylene glycol : non-ionic surfactant is from 15:85 to 48:52, preferably from 17:83 to 48:52.

[0083] In a specific embodiment, the weight ratio propylene glycol : non-ionic surfactant is from 10:90 to 10:20 or from 10:90 to 10:30, or from 10:90 to 10:40

[0084] In a specific embodiment, the weight ratio propylene glycol : non-ionic surfactant is from 20:80 to 48:52.

[0085] Preferably, the weight ratio propylene glycol : non-ionic surfactant is from 10:90 to 48:52.

[0086] Without wishing to be bound by a theory, the Inventors believe that the inclusion of the non-ionic surfactant in the solvent system serves a dual purpose. It ensures high miscibility with propylene glycol while also imparting a certain degree of hydrophobicity to the mixture. This balance enables protecting the capsule shell against the effects of excessive hydrophilicity, which might be introduced by the propylene glycol and metal-alkali acetates or lactates combination. The result is a solvent system that not only optimizes the solubility of ATO but also maintains the physical integrity and compatibility of the capsule shell. It ensures that the therapeutic efficacy of ATO is maintained throughout the product's shelf life.

[0087] Preferably, the liquid composition comprises propylene glycol in a concentration range of 9.5 % to 31.5% by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0088] For example, the concentration range of propylene glycol in the composition can be from 9.5 % to 31.5%, or 10% to 31.5%, or from 12% to 31.5%, or from 15% to 31.5% or from 16% to 31.5%, or from 17% to 31.5%, or from 18% to 31.5%, or from 19% to 31.5%, or from 19.5% to 31.5% , by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0089] In a specific embodiment, the liquid composition comprises propylene glycol in a concentration range of 19.5 % to 31.5% by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0090] In a specific embodiment, the liquid composition comprises a non-ionic surfactant, in a concentration range of 48 % to 91 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0091] For example, the concentration range of the non-ionic surfactant in the composition can be from 50 % to 91 %, or from 52% to 91%, or from 54.5% to 91%, or from 60% to 91%, or from 48% to 90.25%, or from 50% to 90.25%, or from 52% to 90.25%, or from 54.5% to 90.25%, or from 60% to 90.25%, or from 48% to 90%, or from 50% to 90%, or from 52% to 90%, or from 54.5% to 90%, or from 60% to 90%, or from 48% to 80%, by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0092] In a specific embodiment,, the liquid composition comprises a non-ionic surfactant, in a concentration range of 60 % to 91 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0093] Preferably, the liquid composition comprises a non-ionic surfactant, in a concentration range of 54.5 % to 91 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0094] Preferably, the liquid composition comprises a non-ionic surfactant, in a concentration range of 54.5 % to 90.25 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0095] In a specific embodiment,, the liquid composition comprises a non-ionic surfactant, in a concentration range of 48 % to 80 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0096] In a specific embodiment, the liquid composition of the invention comprises:

[0097] • Dissolved arsenic trioxide, in a concentration range of 0.1 % to 19.5 % by weight, in relation to the total weight of the liquid composition;

[0098] • At least one solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates, in a concentration range of 0.15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition;

[0099] • Propylene glycol in a a concentration range of 19.5 % to 31.5% by weight, in relation to the total weight of the liquid pharmaceutical composition; and

[0100] • A non-ionic surfactant, in a concentration range of 48 % to 80 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0101] In a specific embodiment, the liquid composition of the invention comprises:

[0102] • Dissolved arsenic trioxide, in a concentration range of 0.1 % to 19.5 % by weight, in relation to the total weight of the liquid composition;

[0103] • At least one solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates, in a concentration range of 0. 15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition;

[0104] • Propylene glycol in a a concentration range of 9.5 % to 31.5% by weight, in relation to the total weight of the liquid pharmaceutical composition; and

[0105] • A non-ionic surfactant, in a concentration range of 60 % to 90.25 % by weight, in relation to the total weight of the liquid pharmaceutical composition.

[0106] The term "non-ionic surfactant” is used herein to mean a surfactant that has a hydrophilic (waterattracting) head group and a hydrophobic (water-repelling) tail, but the head group is not charged. This means that non-ionic surfactants do not undergo ionization when dissolved in water, resulting in high stability and less susceptibility to the effects of strong electrolytes. Non-limitative examples of nonionic surfactant can be selected in the group consisting of polysorbates, polyethylene glycol (PEG) esters, sorbitan esters, glycerol esters, PEG-40 hydrogenated castor oil (Cremophor® RH 40), PEG-35 castor oil (Cremophor® EL), poloxamers, and mixtures thereof.

[0107] Polysorbate are esters of fatty acids and polyoxyethylene sorbitan. Polysorbates are often referred to as Tweens. The polysorbates includes:

[0108] • Polysorbate 20 (E432) - Polyoxyethylene sorbitan monolaurate

[0109] • Polysorbate 40 (E434) - Polyoxyethylene sorbitan monopalmitate m

[0110] • Polysorbate 60 (E435) - Polyoxyethylene sorbitan monostearate

[0111] • Polysorbate 65 (E436) - Polyoxyethylene sorbitan tristearate

[0112] • Polysorbate 80 (E433) - Polyoxyethylene sorbitan monooleate

[0113] Polyethylene glycol (PEG) esters are manufactured by reacting polyethylene glycol with a fatty acid, where the polyethylene glycol forms the hydrophilic part of the surfactant and the fatty acid forms the hydrophobic part. Some common PEG esters include PEG 400 diolate, PEG 600 diolate, PEG 600 mono-oleate, PEG-40 Hydrogenated Castor Oil, PEG-8 mono- and diesters of caprylic (C8) and capric (CIO) acids with a small fraction of mono-, di- and triglycerides, and PEG-40 Stearate.

[0114] Sorbitan esters (also known as Spans) are nonionic surfactants derived from sorbitan by esterification of one or more of its alcohol functions. Some examples of sorbitan esters include sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 85).

[0115] Glycerol esters are chemical compounds derived from glycerol and fatty acids. Some examples of glycerol esters include glycerol monostearate and glycerol monooleate.

[0116] Poloxamers are non-ionic triblock copolymers, typically consisting of a central hydrophobic block of polypropylene glycol (PPG) and two hydrophilic blocks of polyethylene glycol (PEG). Some common types include Poloxamer 184, Poloxamer 407, and Poloxamer 188.

[0117] In a specific embodiment of the invention, the non-ionic surfactant is selected in the group consisting of polysorbates, polyethylene glycol (PEG) esters, sorbitan esters, glycerol esters, PEG-40 hydrogenated castor oil (Cremophor® RH 40), PEG-35 castor oil (Cremophor® EL), poloxamers, and mixtures thereof.

[0118] Preferably, the non-ionic surfactant is a polysorbate. More preferably, the non-ionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and mixtures thereof. Even more preferably, the non-ionic surfactant is polysorbate 80. In a particular embodiment of the invention, the liquid composition further comprises a colloidal silica. .In this embodiment, the colloidal silica can be used as texturizing agent. Preferably, the liquid composition of the invention comprises from 0 % to 5% by weight of colloidal silica, in relation to the total weight of the liquid composition.

[0119] Without wishing to be bound by a theory, the Inventors have noted that the concomitant use of metal- alkali acetates or metal-alkali lactates and a colloidal silica offers a remarkable synergy to sustain the enhanced solubility of ATO, and to efficiently preserve the integrity of the gelatin shell.

[0120] Preferably, the liquid composition further comprises a colloidal silicon dioxide such as the commercial product Aerosil®.

[0121] In a specific embodiment, the liquid composition of the invention can further comprises one or more of the following excipients: cosolvents, antioxidants, absorption enhancers, crystal growth inhibitors, colorants, taste modifiers, taste masking agents, sweetening agents, flavoring agents, and texturizing agents.

[0122] 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 ATO, and / or the intended patient type (age or other).

[0123] 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.

[0124] Examples of cosolvent can include glycerin, polyethylene glycol, water, and combinations thereof.

[0125] Examples of antioxidant can includes 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, Sodium Sulfite, and combinations thereof;

[0126] Examples of absorption enhancer and crystal growth inhibitor can include polyvinyl pyrrolidone (PVP), Macrogol 15 Hydroxystearate (Solutol), Propylene Glycol Caprylate (Capryol), Polyoxyl 40 Hydrogenated Castor Oil, and combinations thereof.

[0127] Examples of colorants can include Beta-Carotene (El 60a), Chlorophyll (EMO), Turmeric / Curcumin (E100), FD&C Blue No. 1 (Brilliant Blue FCF, E133), FD&C Red No. 40 (Allura Red AC, E129), and combinations thereof.

[0128] Examples of sweetening Agents can include Stevia (Steviol glycosides), Xylitol, Erythritol, Aspartame, Sucralose, Saccharin, and combinations thereof. 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.

[0129] In a specific embodiment of the invention, the liquid composition comprises at least 80 %, preferably at least 90%, more preferably 100%, by weight of nonaqueous components, in relation to the total weight of the said matrix (which is the liquid composition). The absence of an aqueous component enhances the stability and shelf-life of the capsule and eliminates the need for water-soluble ATO solubilizers like KOH or NaOH.

[0130] In a preferred embodiment, the liquid composition comprises 100% of nonaqueous components.

[0131] In a specific embodiment of the invention, the liquid composition does not comprise water.

[0132] In a specific embodiment of the invention, the liquid composition does not comprise sodium hydroxide (NaOH) or potassium hydroxide (KOH).

[0133] In a specific embodiment of the invention, the liquid composition does not comprise polyethylene glycol (PEG) as such.

[0134] In a specific embodiment of the invention, the liquid composition does not comprise any solids components or particles.

[0135] The liquid composition can be prepared by means commonly known by the one skilled in the art.

[0136] For example, the process for manufacturing a liquid pharmaceutical composition according to the invention can comprise the steps of:

[0137] (a) Dissolving ATO in a solution comprising at least one solubilizing agent selected from the metal- alkali acetates and metal-alkali lactates, and a solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 20:80 to 90: 10; and

[0138] (b) Optionally sterilizing the solution obtained in step (b).

[0139] Step (a) may be performed by any suitable technique known in the art.

[0140] Step (a) is preferably performed under stirring. The addition of the ATO 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 ATO is added. Step (a) can further comprise a step of homogenizing the solution obtained. Homogenizing may be performed under stirring, preferably until a clear and transparent solution is obtained.

[0141] Step (b) 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.

[0142] Preferably, the liquid composition of the invention is suitable for filling a hard gel capsule, soft gel capsule, derived plant-based capsule, or HPMC capsule.

[0143] A second object of the invention relates to a pharmaceutical capsule comprising a liquid pharmaceutical composition, said liquid pharmaceutical composition comprising:

[0144] Dissolved arsenic trioxide, in a concentration range of 0. 1 % to 19.5 % by weight, in relation to the total weight of the liquid composition;

[0145] At least one solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates, in a concentration range of 0. 15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition; and

[0146] A solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10, in particular 20:80 to 90: 10.

[0147] In a particular embodiment of the invention, the pharmaceutical capsule comprises the liquid pharmaceutical composition of the invention, in particular as disclosed herein, particularly as disclosed in the section “liquid composition”.

[0148] The capsule of the invention is preferably a hard gel capsule, soft gel capsule, HPMC capsule or derived plant-based capsule.

[0149] Typically, a hard gel capsule is a two-piece oral dosage form commonly used to encapsulate solid formulations such as liquid, powders, granules, or pellets. Typically, the capsule shell is rigid and designed to dissolve in the digestive system, releasing its contents for absorption. For example, it can comprise two cylindrical parts: the cap (shorter and wider) and the body (longer and narrower), which fit together to form a sealed unit. These capsules are typically made from gelatin derived from animal collagen or plant-based alternatives like hydroxypropyl methylcellulose (HPMC) for vegetarian or vegan options.

[0150] Typically, a soft gel capsule is a one-piece, hermetically sealed oral dosage form used to encapsulate liquid, semi -liquid, or suspension formulations. In particular, the shell is formed around the content in one step, providing a fully sealed unit. Typically, the capsule shell is flexible and designed to dissolve in the digestive system, releasing its contents for absorption. Typically, soft gel capsules can be made from gelatin-based materials, which are traditionally derived from animal sources such as bovine, porcine, or fish gelatin, or from non-gelatin alternatives, such as plant-based polymers like starch, carrageenan, or tapioca. Typically, the shell composition typically includes water and plasticizers (e.g., glycerin or sorbitol) to provide elasticity and durability. Advantageously, these capsules are widely used in pharmaceutical and nutritional applications due to their ability to protect sensitive ingredients and improve bioavailability.

[0151] In a specific embodiment, the capsule of the invention is a gelatin capsule. For example, the capsule of the invention can be a gelatin hard gel capsule such as Capsugel®, Licaps®, and Vcaps®; or the capsule of the invention can be a gelatin soft gel capsule.

[0152] The pharmaceutical capsule of the invention is preferably adapted for an oral, sublingual or rectal administration, preferably for oral administration.

[0153] In a specific embodiment of the invention, the capsule comprises at least 0.1 mb in volume of the liquid composition of the invention. In particular, the capsule of the invention can comprise from 0.1 mb to 1.5 mb, preferably from 0.15 mb to 1.0 mb, and more preferably from 0.2 to 0.65 mb, in volume of the liquid composition of the invention. In particular, the capsule can comprise from 0.1 mb to 0.5 mb, preferably from 0.15 mb to 0.4 mb, of the liquid composition of the invention. Typically, the capsule can comprise 0. 1 mb, 0.15 mb, 0.2 mb, 0.25 mb, 0.3 mb, 0.35 mb, 0.4 mb, 0.45 mb, 0.5 mb, 0.55 mb, 0.6 mb, 0.65 mb, 0.7 mb, 0.75 mb, 0.8 mb, 0.9 mb, 1 mb, 1.25 mb or 1.5 mb, of the liquid composition of the invention.

[0154] Such volume allows the administration of high ATO dose while maintaining the patient compliance. For example, the capsule of the invention can enable the administration of between about 0.5 mg and about 45 mg of ATO in a single dosage form. Also for example, the capsule of the invention can enable the administration of between about 1 mg and about 45 mg of ATO in a single dosage form, preferentially between 1 and 20 mg. Examples of single dosage forms comprise about 0.5 mg, 1 mg, 3 mg, 5 mg, 8 mg, 10 mg, 15 mg or 20 mg ATO.

[0155] In a specific embodiment of the invention, the capsule may be of size 000 to size 5 (according to the A pence nationale de securite du mediament et des produits de sante (ANSM)). In particular, the caspule of the invention may have a length size of at least 11 mm.

[0156] In a specific embodiment of the invention, the capsule releases at least 90% of the ATO content within 10 minutes when tested in a simulated gastric fluid (pH 1.2). In particular, the capsule releases at least 92%, preferably at least 95 %, more preferably at least 97%, of the ATO content within 10 minutes when tested in a simulated gastric fluid (pH 1.2).

[0157] In a specific embodiment of the invention, when the capsule is totally or partially filled with the liquid composition of the invention, the capsule shell remains stable for at least 15 days, preferably at least 30 days, more preferably at least 3 months, more preferably at least 6 months and even more preferably at least 12 months under ICH conditions (25°C / 60% RH). Advantageously, a capsule remains stable when the integrity of the capsule shell is maintained (no friability or softening) and / or no leakage of the liquid composition occurs from the capsule.

[0158] The pharmaceutical caspule of the invention can be prepared by means commonly known by the one skilled in the art. In particular, the capsule of the invention can be obtained by preparing a liquid composition according to the invention and as disclosed above, and filling said liquid composition within hard gel capsules, soft gel capsules, derived plant-based capsule, or HPMC capsules.

[0159] For example, a method for preparing the capsule of the invention can comprise the following steps of: a) Dissolving ATO in a solution comprising at least one solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates, and a solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10, in particular 20:80 to 90: 10; and b) Optionally sterilizing the solution obtained in step (b). c) Filling the obtained liquid composition within hard gel capsules, soft gel capsules, derived plant-based capsule, or HPMC capsules.

[0160] Therapeutic uses

[0161] Another object of the invention is a liquid pharmaceutical composition according to the invention for use as a medicament.

[0162] Another object of the invention is a pharmaceutical capsule according to the invention for use as a medicament.

[0163] Another object of the invention is a liquid pharmaceutical composition according to the invention or a pharmaceutical capsule according to the invention, for use in the treatment of cancer in a subject.

[0164] Another object of the invention is a liquid pharmaceutical composition according to the invention or a pharmaceutical capsule according to the invention, for use in the treatment of autoimmune diseases in a subject.

[0165] 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 ATO, or a pharmaceutical capsule of the invention comprising a therapeutically effective amount of dissolved ATO, to said subject.

[0166] The disease or disorder is preferably a cancer. The disease or disorder is preferably an autoimmune disease.

[0167] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention or a pharmaceutical capsule according to the invention, in the manufacture of a medicament.

[0168] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention or a pharmaceutical capsule according to the invention, in the manufacture of a medicament, for use in the treatment of a cancer.

[0169] Another object of the invention is the use of a liquid pharmaceutical composition according to the invention or a pharmaceutical capsule according to the invention, in the manufacture of a medicament, for use in the treatment of an autoimmune disease.

[0170] In particular, the cancer to be treated according to the invention may be selected from the group consisting of Acute promyelocytic leukemia (APL), Acute myeloblastic leukemia (AML), Myelodysplastic Syndromes, and Multiple Myeloma.

[0171] In particular, the autoimmune disease to be treated according to the invention may be selected from the group consisting of lupus, Multiple sclerosis, Rheumatoid arthritis, and Psoriasis.

[0172] The form of the pharmaceutical compositions, the route of administration and the dose of administration of the dissolved ATO, or the 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.

[0173] Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting.

[0174] EXAMPLES

[0175] Example 1: Preparation of liquid compositions according to the invention

[0176] The liquid compositions as disclosed in Table 1 have been prepared as follows: dissolving ATO in a solution comprising at least one solubilizing agent selected from the metal-alkali acetates and metal- alkali lactates, and a solvent system comprising propylene glycol and Tween 80, in the concentration disclosed in Table 1. The arsenic trioxide concentration was then measured using HPLC with a validated protocol as defined in Example 5 and Table 5. The appearance of the liquid composition, in particular the absence of precipitation, was observed by optical microscopy (2 Ox magnification).

[0177] Table 1 : Liquid compositions of the invention

[0178] Figure 1 shows the appearance of the liquid composition No 9 of Table 1. A clear and transparent solution is obtained. In the examples, “WAV” refers to the weight of the considered ingredient in relation to the total weight of the liquid composition. Example 2: Preparation of hard-gel or soft-gel compositions according to the invention

[0179] The hard-gel or soft-gel compositions as disclosed in Table 2 have been prepared as follows: dissolving ATO in a solution comprising at least one solubilizing agent selected from the metal-alkali acetates and metal-alkali lactates, and a solvent system comprising propylene glycol and Tween 80, in the concentration disclosed in Table 2. After achieving complete homogenization and clarification, the liquid mixture is distributed into capsules according to the volumes specified in Table 2.

[0180] The arsenic trioxide concentration was then measured using HPLC with a validated protocol as defined in Example 5 and Table 5. The appearance of the liquid composition, in particular the absence of precipitation, was observed by optical microscopy (2 Ox magnification).

[0181] Table 2: Hard-gel or soft-gel compositions according to the invention

[0182] Figure 2 shows the appearance of hard capsule No. 7 of Table 2, three months post-manufacture. A clear and transparent solution is observed in a capsule in perfect condition.

[0183] Example 3: Dissolutions tests (of the capsule) and release of ATO

[0184] The release rates of the compositions No 1 (5 mg ATO), No 4 (10 mg ATO), and No 7 (15 mg ATO) of Table 2, in hard-gel capsules have been measured using the conditions listed below:

[0185] Apparatus 2 (paddle method Eur. Pharm.): the paddles rotate at a speed of 75 rpm.

[0186] Medium: in our analysis, we specifically focused on testing ATO dissolution under acidic conditions, as this represents the most challenging scenario. To simulate these conditions, we employed a pH 1.2 medium, which is indicative of stomach acidity. This approach was chosen over a neutral or alkaline environment, such as a pH 6.8 medium, to exclusively examine ATO's behavior in its least favorable solubility context. The volume of the acidic medium used for the test ranged from 500 to 1000 ml.

[0187] Temperature: The dissolution test was carried out at 37 ± 0.5 °C, which simulates human body temperature.

[0188] Sampling: samples were withdrawn at specified time intervals (e.g., 1, 3, 5, 10, 30 and 45 minutes) and the amount of ATO determined using HPLC technique. Results:

[0189] The results are presented in Figure 3 , and show that a quick and complete release of dissolved ATO is obtained in less than five minute for each dosage form. Example 4: Comparative tests on solubility and capsule appearance

[0190] Table 3 below summarizes all the compositions that have been prepared for these tests. The compositions according to the invention appear in bold.

[0191] All the compositions have been prepared according to the method disclosed in Example 2.

[0192] Solubility tests have been performed by the following protocols: The mixtures were visually inspected and analyzed for arsenic concentration using High-Performance Liquid Chromatography (HPLC) (see Example 5 and Table 5).

[0193] The appearance of the liquid composition, in particular the absence of precipitation, was observed by optical microscopy (2 Ox magnification).

[0194] Appearance of the capsules has been characterized by the following protocols: The flexibility and strength of the capsules were manually tested by applying pressure between the thumb and forefinger on the central part of the capsule across its width. After applying maximum pressure until the thumb and forefinger meet, if no leakage or breakage is observed, the capsule is considered to have maintained its integrity.

[0195] Table 3

[0196] Results:

[0197] Table 4 Example 5: Stability tests

[0198] Pharmacopoeia standards and defined margins:

[0199] To ensure compliance with pharmacopoeia standards, the composition of the invention was evaluated using usual accepted margins:

[0200] ATO Assay: acceptance criteria mandate that the ATO content should remain between 95.0% and 105.0% of the labeled amount throughout the product's shelf life.

[0201] Dissolution rate: capsules must release >90% of their ATO content within 10 minutes when tested in a simulated gastric fluid (pH 1.2), reflecting fast and efficient release.

[0202] Impurity levels: impurities, including Arsenate (As(V)), must not exceed:

[0203] ■ 0.2% w / w for any individual impurity;

[0204] ■ 0.5% w / w for total impuritie s ; and

[0205] ■ 0.05% w / w as the reporting limit.

[0206] These thresholds ensure both safety and therapeutic efficacy over the product's lifecycle.

[0207] Challenges in stability and monitoring:

[0208] Stability challenges include potential recrystallization, degradation, and loss of dissolution efficiency. To address these, critical quality attributes (CQAs) include:

[0209] Physical stability: optical microscopy confirms the absence of crystalline particles, ensuring ATO remains solubilized.

[0210] Chemical stability: HPLC analysis verifies that impurity levels comply with pharmacopoeia limits.

[0211] Dissolution Kinetics: in vitro dissolution testing confirms rapid and complete drug release, monitored against the specified threshold of >90% release within 10 minutes.

[0212] Materiel and methods

[0213] Samples preparation:

[0214] Liquid compositions according to the invention comprising 300pg / ml of arsenic trioxyde have been prepared according to Example 1 and filled into capsule (1 mg and 5 mg doses). These dosage forms are dose-proportional, using the same liquid fill composition with proportionate capsule volumes to achieve different dosages. Gelatin capsules of size No. 1 have been used. AS2O3 at 99.995% is used as standard.

[0215] ATO Assay: for a 1 or 5 mg capsule: Inserting the capsule into a 50 mL volumetric flask

[0216] Adding approximately 30 mL of LC-MS water previously heated to 40°C

[0217] Shaking vigorously for 30 seconds

[0218] Leaving the flask to stand for about 30 minutes, until the foam has disappeared - Making up to 50 mL with LC-MS water

[0219] Shaking and homogenizing again

[0220] Taking 500 pL for assay from the 2 mL N9 vials

[0221] Carrying out LC-MS analysis (Liquid chromatography-mass spectrometry) in the conditions of Table 5. Table 5

[0222] Impurities assay

[0223] HPLC analysis were carried out using the same isocratic elution method with a UV detector as employed in the ATO Assay, ensuring validated sensitivity (detection limit: 0.05% w / w) and reproducibility. Tests results:

[0224] Initial stability:

[0225] Tables 6 and 7 below show that the manufacturing process consistently achieved complete dissolution of ATO in the solvent system, forming a clear and homogeneous liquid matrix. Initial quality assessments are verified:

[0226] Solubility: ATO concentrations reached 300 pg / mL, exceeding the required pharmacopoeia standards ICH QI A.

[0227] Physical appearance: capsules exhibited no deformation, leakage, or particulate formation upon visual and microscopic inspection with optical microscopy (2 Ox magnification).

[0228] Stability studies:

[0229] Stability studies were conducted on the capsules (1 mg and 5 mg doses) stored under ICH conditions (storage in multi-dose smoked high-density polyethylene bottle with polyethylene cap at 25°C / 60% RH).

[0230] Physical stability:

[0231] Liquid samples were prepared on sealed glass slides for high-resolution analysis, ensuring no interference from evaporation or contamination.

[0232] High-resolution microscopy (20x magnification) revealed no crystalline particles or recrystallization at any time points (0, 3, 6, and 12 months) (see Tables 6 and 7).

[0233] Capsule integrity:

[0234] A visual inspection and manual integrity test were carried out to assess the physical appearance and robustness of the capsule. The capsule was subjected to light finger pressure to check for structural integrity, ensuring no leakage, softening, or breakage.

[0235] Capsules retained their shape without leakage or softening (see Tables 6 and 7).

[0236] Chemical stability:

[0237] ■ ATO Assay: the ATO content remained within the pharmacopoeia margin of 95.0%- 105.0% of the labeled amount, with measured values consistently between 98.2% and 101.4% (see Tables 6 and 7).

[0238] ■ Impurities: no individual impurity, including As(V), exceeded 0.2% w / w, and total impurities remained below 0.5% w / w, aligning with pharmacopoeia specifications (see Tables 6 and 7). ■ Dissolution kinetics: in Vitro Dissolution Testing: Capsules consistently released >97% of ATO within 10 minutes in a pH 1.2 medium, exceeding the pharmacopoeia requirement of >90%. This result was maintained across all storage conditions and time points (see Tables 6 and 7).

[0239] Table 6: Stability data for ARSENIC TRIOXIDE 1 mg batch 23248 capsule, stored in multi-dose smoked high-density polyethylene bottle with polyethylene cap at 25°C / 60% HR

[0240] ND: non detected / NA: non applicable / NMT: no more than Table 7: Stability data for ARSENIC TRIOXIDE 5 mg batch 23247 capsule, stored in multi -dose smoked high-density polyethylene bottle with polyethylene cap at 25°C / 60% HR:

[0241] ND: non detected / NA: non applicable / NMT: no more than Conclusion

[0242] The liquid pharmaceutical composition of the invention comprising ATO meets or exceeds pharmacopoeia standards for solubility, stability, and in vitro dissolution performance. Stability studies confirmed the product’s robustness, with no evidence of recrystallization, degradation, or impaired dissolution kinetics over 12 months of storage. These results demonstrate that the composition provides a reliable, effective, and patient-friendly alternative to intravenous administration, ensuring therapeutic equivalency and regulatory compliance.

Claims

CLAIMS1- A liquid pharmaceutical composition comprising:• Dissolved arsenic trioxide, in a concentration range of 0. 1 % to 19.5 % by weight, in relation to the total weight of the liquid composition;• At least one solubilizing agent selected from the metal-alkali acetates, metal-alkali lactates, and mixtures thereof, in a concentration range of 0.15% to 9% by weight, in relation to the total weight of the liquid pharmaceutical composition; and• A solvent system comprising propylene glycol and a non-ionic surfactant, in a weight ratio propylene glycol : non-ionic surfactant from 10:90 to 90: 10.2- The liquid pharmaceutical composition according to claim 1, being adapted for an oral, sublingual or rectal administration, preferably for an oral administration.3- The liquid pharmaceutical composition according to claim 1 or 2, wherein the non-ionic surfactant is selected in the group consisting of polysorbates, polyethylene glycol (PEG) esters, sorbitan esters, glycerol esters, PEG-40 hydrogenated castor oil (Cremophor® RH 40), PEG-35 castor oil (Cremophor® EL), poloxamers, and mixtures thereof, preferably the non-ionic surfactant is a polysorbate.4- The liquid pharmaceutical composition according to any one of claims 1 to 3, comprising propylene glycol in a concentration range of 9.5 % to 31.5% by weight, in relation to the total weight of the liquid pharmaceutical composition.5- The liquid pharmaceutical composition according to any one of claims 1 to 4, comprising the non- ionic surfactant, in a concentration range of 60 % to 90.25 % by weight, in relation to the total weight of the liquid pharmaceutical composition.6- The liquid pharmaceutical composition according to any one of claims 1 to 5, further comprising a colloidal silica.7- The liquid pharmaceutical composition according to any one of claims 1 to 6, comprising at least 80 %, preferably at least 90%, more preferably 100%, by weight of nonaqueous components, in relation to the total weight of the said composition.8- The liquid pharmaceutical composition according to any one of claims 1 to 7, wherein said composition does not comprise sodium hydroxide or potassium hydroxide.9- The liquid pharmaceutical composition according to any one of claims 1 to 8, being adapted for fdling a hard gel capsule, soft gel capsule, derived plant-based capsule, or HPMC capsule.10- A pharmaceutical capsule comprising the liquid pharmaceutical composition as defined in any one of claims 1 to 9.11- The pharmaceutical capsule according to claim 10, comprising at least 0.1 mL in volume of said liquid composition. 12- The pharmaceutical capsule according to claim 10 or 11, being a hard gel capsule, soft gel capsule, derived plant-based capsule, or HPMC capsule.13- The pharmaceutical capsule according to any one of claims 10 to 12, being adapted for an oral, sublingual or rectal administration, preferably for oral administration.14- A liquid pharmaceutical composition according to any one of claims 1 to 9 or a pharmaceutical capsule as defined in any one of claims 10 to 13, for use as a medicament.15- A liquid pharmaceutical composition according to any one of claims 1 to 9 or a pharmaceutical capsule as defined in any one of claims 10 to 13, for use in the treatment of cancer, in particular a cancer selected from Acute promyelocytic leukemia (APL), Acute myeloblastic leukemia (AML), Myelodysplastic Syndromes, and Multiple Myeloma; or for use in the treatment of an autoimmune diseases such as lupus, Multiple sclerosis, Rheumatoid arthritis, or Psoriasis.

Images