Pharmaceutical composition of ondansetron in the form of soft gelatin capsule; and its use

Description

1 / 33 Pharmaceutical composition of ondansetron in the form of a soft gelatin capsule; and its use. FIELD OF TECHNIQUE

[001] The present invention relates to a stable pharmaceutical composition of ondansetron in the form of a soft gelatin capsule for oral administration; and its use in the prevention and / or treatment of emesis. BACKGROUND

[002] Patent GB2153821 BI describes, among others, the molecule 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-1-yl)-methyl)-4H-carbazol-4-one, currently known as ondansetron, represented by formula (I): and its physiologically acceptable salts and solvates.

[003] According to the state of the art available, ondansetron is a selective antagonist of serotonin subtype 3 (5-HT3) receptors. Although the mechanism of action has not been fully characterized, it is known that the Petition 870250017647, dated 06 / 03 / 2025, page 15 / 55 2 / 33 Ondansetron is not a dopamine receptor antagonist, and it is not yet fully understood whether the antiemetic action of ondansetron is mediated by central, peripheral, or both receptors.

[004] Several clinical studies have demonstrated the efficacy of ondansetron in the treatment and / or prevention of emesis, particularly in the treatment and / or prevention of nausea and vomiting associated with chemotherapy and radiotherapy for cancer. Usually, ondansetron has been administered in the form of a salt, in particular as ondansetron hydrochloride dihydrate, in injectable or oral pharmaceutical form.

[005] According to the state of the art, ondansetron hydrochloride is known to be moderately soluble in water, and the free base is practically insoluble in water (0.09 g / ml). The aqueous solubility of ondansetron decreases with increasing pH, being soluble at pH 1.2, moderately soluble at pH 3.5 - 5.4, and practically insoluble at pH 8.0. It has been observed that ondansetron begins to precipitate in solution with pH values ​​between 5.7 - 7.0 (RAJAWAT, GS, et al. (2019). Biowaiver monograph for immediate-release solid oral dosage forms: Ondansetron. Journal of pharmaceutical sciences, 108 (10), 3157-3168).

[006] Additionally, it is widely known that ondansetron is a drug that has an unpleasant taste, Petition 870250017647, dated 06 / 03 / 2025, page 16 / 55 3 / 33 which makes it difficult to develop orally disintegrating products for rapid absorption.

[007] Soft gelatin capsules are useful for oral administration to patients, as they are easier to swallow than hard capsules or tablets. Furthermore, they digest rapidly in the gastrointestinal tract, resulting in faster absorption compared to tablets and hard capsules. Therefore, the soft capsule pharmaceutical form becomes an option for developing an ondansetron-based composition with faster absorption than tablets.

[008] However, filling soft gelatin capsules involves the insertion of liquid or semi-solid substances. A preferred filling formulation for soft gelatin capsules is liquid filling. However, not all liquids are suitable for use as filling for soft gelatin capsules.

[009] For example, water tends to dissolve the soft gelatin capsule shell; therefore, liquids with more than 20% water by total weight of the shell are generally not suitable as filling vehicles. Other vehicles typically used as excipients in pharmaceutical formulations, such as glycerol, propylene glycol, and alcohols, tend to impair the integrity of the soft gelatin capsule shell. Petition 870250017647, dated 06 / 03 / 2025, page 17 / 55 4 / 33

[0010] Thus, in the search for a formulation with better absorption, the researchers of the present invention sought a stable liquid formulation for filling soft gelatin capsules. During development, the major challenge was to develop a soft gelatin capsule filling formulation that would guarantee the complete solubilization of the API (ondansetron) throughout the product's shelf life, preventing its recrystallization. This development required numerous studies, trials and errors, until a stable and suitable liquid formulation for filling soft gelatin capsules was achieved, containing ondansetron as the active ingredient, and / or its physiologically acceptable salts and solvates, completely solubilized in the liquid medium. SUMMARY OF THE INVENTION

[0011] The main objective of the present invention is to provide a physiologically acceptable pharmaceutical composition of ondansetron, and / or its salts and solvates, in the form of a soft gelatin capsule for oral administration, which has good absorption and excellent shelf stability. Petition 870250017647, dated 06 / 03 / 2025, page 18 / 55 5 / 33

[0012] Thus, a first embodiment of the invention relates to a pharmaceutical composition in the form of a soft gelatin capsule, comprising: a core filler mixture comprising: (i) 2.00% to 2.78% (w / w) ondansetron, or its physiologically acceptable salts and solvates, (ii) 6.30% to 8.89% (w / w) surfactant, (iii) 6.70% to 9.35% (w / w) co-surfactant, (iv) qsp 100% (w / w) lipid carrier; and a soft gelatin capsule shell.

[0013] In a second embodiment, the invention comprises the use of the composition for the treatment of vomiting. BRIEF DESCRIPTION OF THE FIGURES

[0014] Figure 1: Image in formulation II, Test 1, (100 pm).

[0015] Figure 2: Image in formulation II, Test 2, (100 pm).

[0016] Figure 3: Image in formulation III, with 20x magnification

[0017] Figure 4: Microscope image of formulation IV, with 20x magnification optical microscope of the mixture with 10x magnification optical microscope of the mixture with 10x magnification optical microscope of the mixture (50 pm). optical mixture (50 pm). Petition 870250017647, dated 06 / 03 / 2025, p. 19 / 55 6 / 33

[0018] Figure 5: Optical microscope image of the mixture of formulation V, with 20x magnification (50 μm). DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention relates to a pharmaceutical composition in the form of a soft gelatin capsule based on ondansetron and / or its physiologically acceptable salts and solvates; and pharmaceutically acceptable excipients, for oral administration. The invention further includes the use of the composition for the treatment of emesis.

[0020] Thus, a first embodiment of the invention relates to a pharmaceutical composition in the form of a soft gelatin capsule, comprising: a core filler mixture comprising: (i) 2.00% to 2.78% (w / w) ondansetron, or its physiologically acceptable salts and solvates, (ii) 6.30% to 8.89% (w / w) surfactant, (iii) 6.70% to 9.35% (w / w) co-surfactant, (iv) qsp 100% (w / w) lipid carrier; and a soft gelatin capsule shell.

[0021] A more specific embodiment of the invention relates to a pharmaceutical composition in the form of a soft gelatin capsule, comprising: a core filler mixture comprising: Petition 870250017647, dated 06 / 03 / 2025, page 20 / 55 7 / 33 (i) 2.56% (w / w) ondansetron, or its physiologically acceptable salts and solvates, (ii) 8.21% (w / w) surfactant, (iii) 8.63% (w / w) co-surfactant, (iv) 80.47% lipid carrier, and a soft gelatin capsule shell.

[0022] In order to better define the scope of protection of the present invention, some definitions of terms used in the claims are provided below.

[0023] Ondansetron and / or its physiologically acceptable salts and solvates are antiemetic agents. Therapeutically effective doses for clinical treatment mediated by the action of 5-HT at 5HT3 receptors, for example, in emesis, are in the range of 0.1 mg to 50 mg, preferably in the range of 4.0 mg to 32 mg; more preferably at concentrations of 4.0 mg, 8 mg, 16 mg, 24 mg or 32 mg per day, administered once daily or in divided doses, such as 1 to 4 times a day. Ondansetron exhibits central and / or peripheral action by preferentially blocking serotonin 5HT3 receptors. Ondansetron has the molecular formula C1gH19N3o and a molecular weight of 298 g / mol. Ondansetron hydrochloride dihydrate has the molecular formula C18H19N30.HCl.2H2O and a molecular weight of 365.86 g / mol. Petition 870250017647, dated 06 / 03 / 2025, page 21 / 55 8 / 33

[0024] “Physiologically acceptable salts” are ionic compounds that, when administered to the human body, do not cause significant adverse effects and are compatible with biological processes. They are chosen based on their safety and efficacy, ensuring that they do not negatively interfere with bodily functions. The physiologically acceptable salts of the present invention include, but are not limited to, (i) non-toxic acid addition salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or from organocarboxylic acids, such as gluconate, or from organosulfonic acids, such as mesylate and besylate; (ii) metal salts, preferably non-toxic alkali metal salts, including sodium or potassium salts. In the present invention, the physiologically acceptable salt is preferably hydrochloride.

[0025] “Physiologically acceptable solvates” are forms of active pharmaceutical ingredients (APIs) that contain solvent molecules incorporated into their crystalline structure. These solvents can associate with the crystalline solid in various ways, such as hydrogen bonds or dipole-dipole interactions. When the solvent is water, the solvate is called a hydrate. These solvates are considered physiologically acceptable when the solvents used do not cause adverse effects on the patient. Petition 870250017647, dated 06 / 03 / 2025, page 22 / 55 9 / 33 organism and are safe for use in medicines. In the present invention, the solvate is preferably ondansetron hydrochloride dihydrate.

[0026] A 5-HT3 receptor antagonist refers to a class of drugs useful in the prevention and relief of nausea and vomiting, including those caused by chemotherapy and anesthesia. Serotonin antagonists are believed to work by blocking the effects of serotonin, which is produced in the brain and stomach. The 5-HT3 receptor antagonists of the present invention are ondansetron and / or its physiologically acceptable salts and solvates.

[0027] “Active pharmaceutical ingredients (APIs)”, also called active principle, are substances that, when introduced into the formulation of a medicine, act as active ingredients. They are responsible for the pharmacological activity of the medicine, that is, they are compounds that produce the desired effect in the diagnosis, cure, treatment or prevention of diseases.

[0028] Emesis, that is, nausea, retching, and vomiting, includes acute emesis, delayed emesis, and anticipatory emesis. Ondansetron is useful in the prevention and treatment of emesis, regardless of the cause. For example, emesis induced by: drugs / APIs (e.g., opioid analgesics and chemotherapeutic agents), radiation therapy, poisons, toxins caused by disorders Petition 870250017647, dated 06 / 03 / 2025, page 23 / 55 10 / 33 metabolic or infection-related, pregnancy, vestibular disorders (such as motion sickness, vertigo, dizziness and Menière's disease), postoperative discomfort, visceral pain, among others.

[0029] “Pharmaceutically acceptable excipients” are inactive substances added to drug formulations to aid in the manufacture, stability, and administration of APIs. Although excipients have no therapeutic activity of their own, they perform essential functions in the formulation. Examples of excipients used in the present invention include, but are not limited to, the selected group of surfactants, co-surfactants, lipid carriers, flavoring agents, preservatives, antioxidants, gelling agents, plasticizers, and coloring agents.

[0030] “Surfactants” are substances that reduce the surface tension between two liquids, between a gas and a liquid, or between a liquid and a solid. They have a molecular structure with a hydrophilic part (affinity for water) and a hydrophobic part (affinity for oils and fats), allowing them to interact with both polar and nonpolar substances. Examples of surfactants include, but are not limited to, the selected group of caprylocaproyl macrogol-8 glycerides (Labrasol®), lecithin, sorbitan monooleate (Span®80), and monolaurate of Petition 870250017647, dated 06 / 03 / 2025, page 24 / 55 11 / 33 sorbitan (Span® 20). In the present invention, the preferred surfactant is caprylocaproyl macrogol glyceride (Labrasol®).

[0031] Co-surfactants are substances that, when added to a formulation containing primary surfactants, help to improve or modify the properties of those surfactants. Examples of co-surfactants include, but are not limited to, the selected group of polysorbate 20 (Tween® 20), polysorbate 40 (Tween® 40), polysorbate 60 (Tween® 60), and polysorbate 80 (Tween® 80). In the present invention, the co-surfactant is preferably polysorbate 80 (Tween® 80).

[0032] Lipid carriers are organic molecules composed mainly of carbon, hydrogen, and oxygen; known to be insoluble in water but soluble in organic solvents such as alcohol, ether, and acetone. Examples of lipid carriers include, but are not limited to, the selected group of glycerol monocaprylocaprate type I (Capmul® MCM), caprylic / capric triglycerides (Crodamol® GTCC), castor oil, coconut oil, palm oil, and / or mixtures thereof. In the present invention, the lipid carrier is preferably glycerol monocaprylocaprate type I (Capmul® MCM).

[0033] Flavoring agents are also known as flavor enhancers, added to the product to impart Petition 870250017647, dated 06 / 03 / 2025, page 25 / 55 12 / 33 flavor or aroma, and improve palatability. Examples of flavorings include, but are not limited to, the selected group of peppermint oil, vanilla, lemon oil, spearmint oil, artificial strawberry flavor, artificial red fruit flavor, among others. In the present invention, the flavoring is preferably peppermint oil.

[0034] “Preservatives are substances added to the formulation to prevent microbial decomposition and extend the shelf life of the product. Soft gelatin capsules, which have a liquid or semi-solid matrix within a gelatin shell, contain more moisture than hard gelatin capsules, making them more susceptible to microbial contamination. Examples of preservatives include, but are not limited to, the selected group of methylparaben, propylparaben, and / or mixtures thereof.

[0035] Antioxidants are substances that help prevent or delay the oxidation of other components of the formulation. Oxidation can lead to the degradation of active ingredients, reducing the effectiveness of the medication and, in some cases, potentially generating harmful compounds. Examples of antioxidants include, but are not limited to, the selected group of butylated hydroxytoluene (BHT), tocopherol (Vitamin E), butylated hydroxyanisole (BHA), Petition 870250017647, dated 06 / 03 / 2025, page 26 / 55 13 / 33 ethylenediaminetetraacetic acid (EDTA), and / or mixtures thereof.

[0036] According to the present invention, the formulation of the soft gelatin capsule of ondansetron and / or its physiologically acceptable salts and solvates can be manufactured in a conventional manner using the described liquid filling mixture and a shell mixture composed mainly of gelling agent and plasticizing agents, and may also contain coloring agents.

[0037] “Geling agents” are substances that promote gelation, transforming liquids into gels. In the case of soft gelatin capsules, these agents are used to create the gelatinous shell that surrounds the capsule contents. In the present invention, the gelling agent is gelatin.

[0038] “Plasticizing agents” are substances that are used to increase the flexibility and malleability of materials. In the case of soft gelatin capsules, plasticizing agents are added to the gelatin to make the shell more flexible and less brittle. This allows soft gelatin capsules to be easier to swallow and more resistant to cracking. Examples of plasticizing agents include, but are not limited to, the selected group of glycerol (glycerin), sorbitol, sorbitan, propylene glycol, Petition 870250017647, dated 06 / 03 / 2025, page 27 / 55 14 / 33 maltitol, triacetin, and / or mixtures thereof, among others. In the present invention, the plasticizing agents are preferably glycerol, sorbitol, sorbitan, and / or mixtures thereof.

[0039] “Coloring agents” are used to color and improve the appearance of soft gelatin capsules, as well as to aid in product identification. Coloring agents can be of natural or synthetic origin. Examples of coloring agents include, but are not limited to, the selected group of candurin silver, yellow iron oxide, titanium dioxide, red iron oxide, black iron oxide, among others. EXAMPLES

[0040] Examples of embodiments of the present invention are provided below. However, it should be understood that such examples are provided for illustrative purposes only and that various modifications or changes, in light of the embodiments disclosed herein, will be suggestive to those skilled in the art and should be included within the spirit and scope of this description and the scope of the claims accompanying it. And thus, they should not be understood to limit the scope or underlying principles of the invention in any way. Petition 870250017647, dated 06 / 03 / 2025, page 28 / 55 15 / 33 EXAMPLE 1 Table 1: Formulation I Soft gelatin capsule filling Components Function Qty mg / cap % Ondansetron hydrochloride dihydrate Active ingredient (API) 10.00(1) 6.45 Glycerol monocaprylocaprate (Type I) qsp 100% Lipid vehicle 145.00 93.55 TOTAL 155.00 100.00 (1)Equivalent to 8.00 mg / cap of ondansetron base

[0041] In a stainless steel container, the API ondansetron hydrochloride dihydrate was added to the lipid carrier glycerol monocaprylocaprate. The API was solubilized by mechanical stirring at a temperature of 60°C ± 2°C for 3 (three) hours. A slightly opaque solution was formed, and as it cooled, the API began to precipitate at the bottom of the container. EXAMPLE 2 Table 2: Formulation II Soft gelatin capsule filling Components Function Qty mg / cap % Ondansetron hydrochloride dihydrate Active ingredient (API) 10.00(1) 6.45 Caprylocaproyl glycerides Macrogol-8 Surfactant 17.00 10.97 Polysorbate 80 Co-surfactant 14.00 9.03 Glycerol monocaprylocaprate (Type I) qsp 100% Lipid vehicle 114.00 73.55 TOTAL 155.00 100.00 Petition 870250017647, dated 06 / 03 / 2025, page 29 / 55 16 / 33(1)Equivalent to 8.00 mg / cap of ondansetron base

[0042] Test 1: In a stainless steel container, the API ondansetron hydrochloride dihydrate was added to the lipid carrier glycerol monocaprylocaprate. The API was solubilized by mechanical stirring at a temperature of 40°C ± 2°C for 2 (two) hours. Complete solubilization of the API was visually assessed, showing a clear solution. After the solubilization step, the mixture of caprylocaproyl macrogol-8 glycerides and polysorbate 80 was added to the solution containing the API, under mechanical stirring and without heating, until complete homogenization.

[0043] The mixture of the Formulation II capsule filling prepared according to Test 1, after resting, was evaluated by optical microscopy at 10x magnification (100 pm). According to the images obtained (Figure 1), it is possible to observe the presence of crystal-like structures. This event was related to the recrystallization of the API, ondansetron hydrochloride dihydrate, after cooling of Formulation II.

[0044] Test 2: In a stainless steel container, the API ondansetron hydrochloride dihydrate was added to the lipid carrier glycerol monocaprylocaprate. The API was solubilized by mechanical stirring at a temperature of 60°C ± 2°C for 3 (three) hours. Complete solubilization of the API was visually assessed, where it presented a clear solution. Petition 870250017647, dated 06 / 03 / 2025, page 30 / 55 17 / 33 After the solubilization step, the mixture of caprylocaproyl glycerides Macrogol-8 and polysorbate 80 was added to the solution containing the active pharmaceutical ingredient (API), under mechanical stirring and without heating, until complete homogenization.

[0045] The mixture of the Formulation II capsule filling prepared according to Test 2, after resting, was evaluated by optical microscopy at 10x magnification (100 pm). According to the images obtained (Figure 2), it is possible to observe the presence of crystal-like structures. This event was related to the recrystallization of the API, ondansetron hydrochloride dihydrate, after cooling of Formulation II. Indicating that increasing the temperature to 60°C ± 2°C was not sufficient for the solubilization of the API. EXAMPLE 3 Table 3: Formulation III Soft gelatin capsule filling Components Function Qty mg / cap % Ondansetron hydrochloride dihydrate Active ingredient (API) 10.00(1) 2.78 Caprylocaproyl glycerides Macrogol-8 Surfactant 32.00 8.89 Polysorbate 80 Co-surfactant 33.66 9.35 Glycerol monocaprylocaprate (Type I) qsp 100% Lipid vehicle 284.34 78.98 TOTAL 360.00 100.00 (1)Equivalent to 8.00 mg / cap of ondansetron base Petition 870250017647, dated 06 / 03 / 2025, page 31 / 55 18 / 33

[0046] In a stainless steel container, the API ondansetron hydrochloride dihydrate was added to the lipid carrier glycerol monocaprylocaprate. The API was solubilized by mechanical stirring at a temperature of 55°C ± 2°C for 3 (three) hours. Complete solubilization of the API was visually assessed, showing a clear solution. After the solubilization step, the mixture of caprylocaproyl macrogol-8 glycerides and polysorbate 80 was added to the solution containing the API, under mechanical stirring and without heating, until complete homogenization.

[0047] The mixture of the capsule filling prepared from Formulation III, after resting, was evaluated by optical microscopy at 20x magnification (50 pm). According to the images obtained (Figure 3), it is possible to observe the presence of crystal-like structures. This event was related to the recrystallization of the API, ondansetron hydrochloride dihydrate, after cooling of Formulation III. EXAMPLE 4 Table 4: Formulation IV Soft gelatin capsule filling Components Function Qt mg / cap % Ondansetron hydrochloride dihydrate Active ingredient (API) 10.00(1) 2.56 Caprylocaproyl glycerides Macrogol-8 Surfactant 32.00 8.21 Petition 870250017647, dated 06 / 03 / 2025, page 32 / 55 19 / 33 Polysorbate 80 Co-surfactant 33.67 8.63 Glycerol monocaprylocaprate (Type I) qsp 100% Lipid vehicle 314.33 80.60 TOTAL 390.00 100.00 (1)Equivalent to 8.00 mg / cap of ondansetron base

[0048] In a stainless steel container, the API ondansetron hydrochloride dihydrate was added to the lipid carrier glycerol monocaprylocaprate. The API was solubilized by mechanical stirring at a temperature of 55°C ± 2°C for 3 (three) hours. Complete solubilization of the API was visually assessed, showing a clear solution. After the solubilization step, the mixture of caprylocaproyl macrogol-8 glycerides and polysorbate 80 was added to the solution containing the API, under mechanical stirring and without heating, until complete homogenization.

[0049] The mixture of the capsule filling prepared from Formulation IV, after resting, was evaluated by optical microscopy at 20x magnification (50 pm). According to the images obtained (Figure 4), a translucent solution without the formation of crystals can be observed. This demonstrates the complete solubilization of the API, even after cooling and resting of the prepared mixture. EXAMPLE 5 Table 5: Formulation V Soft gelatin capsule filling Petition 870250017647, dated 06 / 03 / 2025, page 33 / 55 20 / 33 Components Function Qty mg / cap % Ondansetron hydrochloride dihydrate Active ingredient (API) 10.00(1) 2.38 Glycerol monocaprylocaprate (Type I) qsp 100% Surfactant 32.00 7.62 Polysorbate 80 Co-surfactant 33.67 8.02 Glycerol monocaprylocaprate (Type I) qsp 100% Lipid vehicle 344.33 81.98 TOTAL 420.00 100.00 (1)Equivalent to 8.00 mg / cap of ondansetron base

[0050] In a stainless steel container, the API ondansetron hydrochloride dihydrate was added to the lipid carrier glycerol monocaprylocaprate. The API was solubilized by mechanical stirring at a temperature of 55°C ± 2°C for 3 (three) hours. Complete solubilization of the API was visually assessed, showing a clear solution. After the solubilization step, the mixture of caprylocaproyl macrogol-8 glycerides and polysorbate 80 was added to the solution containing the API, under mechanical stirring and without heating, until complete homogenization.

[0051] The mixture of the capsule filling prepared from Formulation V, after resting, was evaluated by optical microscopy at 20x magnification (50 pm). According to the images obtained (Figure 5), a translucent solution without the formation of crystals can be observed. This demonstrates the complete solubilization of the API, even after cooling and resting of the prepared mixture. Petition 870250017647, dated 06 / 03 / 2025, page 34 / 55 21 / 33

[0052] After evaluating the optical microscopy analyses, it can be concluded that Formulation I, Formulation II, and Formulation III were not the most suitable due to crystallization (precipitation) of the active ingredient (ondansetron hydrochloride dihydrate). Therefore, these formulations were not considered as filler mixtures for the soft gelatin capsules.

[0053] Formulations IV and V demonstrated complete solubilization of the active ingredient (ondansetron hydrochloride dihydrate), as they did not present crystal or needle structures in the microscopic evaluation and remained as clear solutions, even after cooling and resting.

[0054] No significant differences were observed between formulation IV and formulation V for composing the soft gelatin capsule filling mixture. Therefore, formulation IV was considered to proceed with development, as it results in a smaller soft gelatin capsule size than formulation V. EXAMPLE 6 Table 6: Formulation VI gelatinous base of the casing Components Function % Gelatin Gelling agent 44.00 Petition 870250017647, dated 06 / 03 / 2025, page 35 / 55 22 / 33 Sorbitol Solution Sorbitan Plasticizing agent 11.50 Glycerol Plasticizing agent 11.50 Titanium dioxide Dye 1.00 Pearlescent dye Dye 0.50 Water (q.s.p. 100%) Vehicle 31.50 TOTAL 100.00

[0055] In a container, prepare a premix by dissolving the dyes in a portion of the water, stirring until completely homogenized, and set this premix aside. In a stainless steel container, stirring at 20 rpm at a temperature of 75°C ± 2°C, prepare mixture 1 by adding the glycerol, the sorbitol sorbitan solution, and a portion of the water for 15 minutes. Then, add the gelatin to mixture 1 while stirring at 20 rpm at a temperature of 70°C ± 2°C for 45 minutes, forming mixture 2. Next, while stirring at 20 rpm, incorporate the previously prepared dye premix into mixture 2, forming mixture 3. Using the remaining water, rinse the container containing the premix and add it to mixture 3 while stirring at 20 rpm. Thus forming the mixture of formulation VI, the gelatinous base of the soft gelatin capsule shell. EXAMPLE 7 Table 7: Formulation VII Petition 870250017647, dated 06 / 03 / 2025, page 36 / 55 23 / 33 gelatinous base of the casing Components Function % Gelatin Gelling agent 44.00 Sorbitol Solution Sorbitan Plasticizing agent 16.10 Glycerol Plasticizing agent 6.90 Titanium dioxide Colorant 1.00 Pearlescent colorant Colorant 0.50 Water (qsp 100%) Vehicle 31.50 TOTAL 100.00

[0056] In a container, prepare a premix by dissolving the dyes in a portion of the water, stirring until completely homogenized, and set this premix aside. In a stainless steel container, stirring at 20 rpm at a temperature of 75°C ± 2°C, prepare mixture 1 by adding the glycerol, the sorbitol sorbitan solution, and a portion of the water for 15 minutes. Then, add the gelatin to mixture 1 while stirring at 20 rpm at a temperature of 70°C ± 2°C for 45 minutes, forming mixture 2. Next, while stirring at 20 rpm, incorporate the previously prepared dye premix into mixture 2, forming mixture 3. Using the remaining water, rinse the container containing the premix and add it to mixture 3 while stirring at 20 rpm. Thus forming the mixture of formulation VII, the gelatinous base of the soft gelatin capsule shell. Petition 870250017647, dated 06 / 03 / 2025, page 37 / 55 24 / 33 EXAMPLE 8 Encapsulation process

[0057] In the encapsulation process, that is, the formation of the soft gelatin capsule, formulation IV (as the filling mixture) and formulations VI and VII (as the gelatinous base mixture of the shell) were used. The capsules obtained using formulation VI as the shell base were designated as Batch 1 and those with formulation VII as Batch 2. The process for obtaining the soft gelatin capsules followed the same procedure, as described below.

[0058] In a soft gelatin capsule encapsulator, the IV formulation (as a filling mixture) was encapsulated. For capsules containing the equivalent of 8 mg of ondansetron (base), the weight of the soft gelatin capsule filling is 390 mg / capsule ± 19.5 mg / capsule.

[0059] After encapsulation, pre-drying occurs, followed by passage through the capsule drying tunnel and finally classification of the resulting capsules. Through this process, batches 1 and 2 were obtained (formulations VI and VII, respectively). Table 8: Dissolution test results Lot 1 (Formulation VI) Cubas Lot 1 Collection Times Petition 870250017647, dated 06 / 03 / 2025, page 38 / 55 25 / 33 8 min 11 min 15 min Cuba 01 90.4 100.4 101.0 Cuba 02 79.4 99.1 100.3 Cuba 03 95.8 100.7 101.1 Cuba 04 85.8 98.3 99.5 Cuba 05 92.4 100.6 101.3 Cuba 06 88.2 99.8 101.3 Dissolution in % 88.7 99.8 100.8 DPR (%) 6.4 1.0 0.7 Table 9: Dissolution test results Lot 2 (Formulation VII) Batch 2 Collection Times 8 min 11 min 15 min Batch 01 88.6 99.3 100.9 Batch 02 89.5 99.7 101.1 Batch 03 95.3 103.4 103.7 Batch 04 81.3 97.9 100.9 Batch 05 89.1 100.5 100.9 Batch 06 91.1 99.5 100.9 Dissolution in % 89.2 100.1 101.4 DPR (%) 5.1 1.8 1.1

[0060] According to the results obtained in batches 01 and 02, it is concluded that the content formulation (filling mixture) and the determined process are effective. For the formulation of the gelatinous base of the casing, no significant difference was observed between the formulations of batches 1 and 2 tested, therefore the product development continued considering formulation VI (batch 1).

[0061] For the 4 mg concentration, the same proportion of formulation IV established for the 8 mg concentration was considered, and formulation VI as the gelatinous base of the shell. Petition 870250017647, dated 06 / 03 / 2025, page 39 / 55 26 / 33 EXAMPLE 9: ANALYSIS METHODS A.) Optical microscopy analysis method

[0062] The samples were observed under a phase contrast optical microscope and dispersed in sunflower oil on a microscope slide measuring 1.2 mm thick, 26 mm wide, and 76 mm long. B.) Ondansetron content

[0063] High-Performance Liquid Chromatography (HPLC) Analytical Method - according to the general method<USP / NF 2024> . Parameters: Flow rate: 1.2 mL / minute Mobile phase: Isocratic Detector: UV Wavelength: 248 nm Injection volume: 10 pmL Chromatographic column: Luna omega 3 pm - polar - C18 100Â (150 mm x 4.6 mm) PN:00f-4760-E0 Sampler temperature: 10 °C Column temperature: 30 °C Running time: 15 minutes Approximate retention time: Ondansetron 6.5 minutes Petition 870250017647, dated 06 / 03 / 2025, pages 40 / 55 27 / 33 C.) Dissolution test

[0064] The dissolution test was performed in a calibrated dissolution apparatus, adding 900 mL of the dissolution medium to the chambers at 37°C and 125 rpm. The collection volume used was 5 mL, and the sample was filtered with a 33 mm syringe filter in 0.2 µm nylon directly into an HPLC vial, according to the general method.<USP / NF 2024> . D.) Microbial count: Total aerobic bacteria

[0065] Weigh 10 g of the sample into 90 mL of TA broth base diluent supplemented with 4% polysorbate 20 (dilution 1:10). Transfer 10 mL of the 1:10 dilution to 90 mL of TA broth base supplemented with 4% polysorbate 20 (dilution 1:100). Pipette 2 mL of the 1:100 dilution into 5 Petri dishes. Express the result in CFU / g. As described in the general method of the Brazilian Pharmacopoeia 6th ed. E.) Microbial count: Fungi and Yeasts

[0066] Weigh 10 g of the sample into 90 mL of TA broth base diluent supplemented with 4% polysorbate 20 (dilution 1:10). Transfer 10 mL of the 1:10 dilution to 90 mL of TA broth base supplemented with 4% polysorbate 20 (dilution 1:100). Pipette 2 mL of the 1:100 dilution into 5 Petri dishes. Express the result in CFU / g. As described in the general method of the Brazilian Pharmacopoeia 6th ed. Petition 870250017647, dated 06 / 03 / 2025, page 41 / 55 28 / 33 EXAMPLE 11: Stability study

[0067] During development, the major challenge was to develop a soft gelatin capsule filling formulation that would ensure complete solubilization of the API throughout the shelf life of the final product, thus preventing its recrystallization.

[0068] To perform the stability study of the final product, formulation IV was used for capsule filling and formulation VI as the gelatinous base of the shell.

[0069] However, in preparing the product for the stability study, mint flavoring was added to formulation IV to reduce the unpleasant aftertaste of ondansetron. Table 10: Formulation of the filling mixture for the 4 mg and 8 mg capsules Components Function 4 mg 8 mg % Qty mg / cap Qty mg / cap Ondansetron hydrochloride dihydrate Active ingredient (API) 5.00(1) 10.00(2) 2.56 Caprylocaproyl glycerides Macrogol-8 Surfactant 16.000 32.000 8.21 Polysorbate 80 Co-surfactant 16.835 33.670 8.63 Mint flavor Flavor 0.250 0.500 0.13 Petition 870250017647, dated 06 / 03 / 2025, page 42 / 55 29 / 33 Glycerol monocaprylocaprate (Type I) qsp 100% Lipid vehicle 156.915 313.830 80.47 TOTAL 195.000 390.00 100.00 (1) Equivalent to 4.00 mg / cap of ondansetron base (2) Equivalent to 8.00 mg / cap of ondansetron base

[0070] In the preparation of the base of the soft gelatin capsule shell, at a concentration of 8 mg, the dye yellow iron oxide was added.

[0071] To evaluate the stability of the formulations at concentrations of 4 mg and 8 mg, described in Table 10, the capsules were packaged in PVC / PVDC / PVC blisters. The samples were placed under accelerated stability conditions of 40°C ± 2°C / 75% RH ± 5% RH and long-term stability conditions of 30°C ± 2°C / 75% RH ± 5% RH for 6 months.

[0072] The tests performed to verify the product's stability were visual assessment within the stability specification, verification of capsule integrity, optical microscopy analysis of the filling mixture, ondansetron content assay, dissolution test, microbial count of total bacteria and fungi and yeasts. The results obtained at the initial, 3-month, and 6-month times are described in Tables 11 and 12.

[0073] Based on the results obtained in the stability study, we found that the formulation remained Petition 870250017647, dated 06 / 03 / 2025, page 43 / 55 30 / 33 stable throughout the mixing of the filler, in ondansetron in the mixture at the time of the study. Including the one in which there was no crystallization of the filler. Petition 870250017647, dated 06 / 03 / 2025, pages 44 / 55 31 / 33 Table 11: Stability study Product: Ondansetron 4 MG Soft Gelatin Capsules Pharmaceutical form: Soft gelatin capsule Lot number: 21100473 Primary packaging: PVC / PVDC / PVC TESTS Release Specification Initial Stability Specification ACCELERATED 40°C ± 2°C / 75% RH ± 5% RH LONG DURATION 30°C ± 2°C / 75% RH ± 5% RH 3 months 6 months 3 months 6 months Description Soft gelatin capsule, pearly white in color, oval in shape, with translucent yellowish to whitish contents with a characteristic mint odor Soft gelatin capsule, pearly white in color, oval in shape, with translucent yellowish to whitish contents with a characteristic mint odor According to According to According According to According Capsule Integrity In the visual assessment of the capsules, no deformations or any other significant alteration in relation to their appearance should be observed In the visual assessment of the capsules, no deformations or any other significant alteration in relation to their appearance should be observed According to According According According According Optical microscopy: Evaluation of capsule filling.No crystal formation. Capsule filling evaluation, no crystal formation. According to: Ondansetron content: 4.00 mg 95.0-105.0% 4.00 mg 90.0-110.0% 98.6% 98.0% 93.1% 99.9% 96.3% Dissolution test: Q at 80% in 30 minutes Q at 80% in 30 minutes 100% 99% 96% 101% 100% Microbial content: Bacteria Maximum 1000 CFU / g Maximum 1000 CFU / g < 10 CFU / g NA < 10 CFU / g NA < 10 CFU / g Microbial content: Fungi / Yeast Maximum 100 UFC / g Maximum 100 UFC / g < 10 UFC / g NA < 10 UFC / g NA < 10 UFC / g, Petition 870250017647, dated 06 / 03 / 2025, pages 45 / 55 32 / 33 Table 12: Stability study Product: Ondansetron 8 mg Soft Gelatin Capsules Pharmaceutical form: Soft gelatin capsule Lot number: 20904183 Primary packaging: PVC / PVDC / PVC TESTS Release Specification Initial Stability Specification ACCELERATED 40°C ± 2°C / 75% RH ± 5% RH LONG DURATION 30°C ± 2°C / 75% RH ± 5% RH 3 months 6 months 3 months 6 months Description Soft gelatin capsule, pearly yellow in color, oval in shape, with translucent yellowish to whitish contents with a characteristic mint odor Soft gelatin capsule, pearly yellow in color, oval in shape, with translucent yellowish to whitish contents with a characteristic mint odor According to According to According According to According Capsule Integrity In the visual assessment of the capsules, no deformations or any other significant alteration in relation to their appearance should be observed In the visual assessment of the capsules, no deformations or any other significant alteration in relation to their appearance should be observed According to According According According According Optical microscopy: Evaluation of capsule filling.No crystal formation. Capsule filling evaluation, no crystal formation. According to: According to: According to: According to: Ondansetron content: 8.00 mg 95.0-105.0% 8.00 mg 90.0-110.0% 101.5% 99.9% 97.2% 100.9% 100.7% Dissolution test: Q to 80% in 30 minutes Q to 80% in 30 minutes 104% 101% 99% 102% 102% Microbial content: Bacteria Maximum Total 1000 CFU / g Maximum 1000 CFU / g < 10 CFU / g NA < 10 CFU / g NA < 10 CFU / g Microbial content: Fungi / Yeast Maximum 100 UFC / g Maximum 100 UFC / g < 10 UFC / g NA < 10 UFC / g NA < 10 UFC / g, Petition 870250017647, dated 06 / 03 / 2025, pp. 46 / 55 33 / 33

[0074] All publications and patent applications mentioned in the description are indicative of the level of expertise of those skilled in the art to which the invention relates. All publications and patent applications are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated for incorporation by reference.

[0075] Although the present invention is described in some detail by means of illustrations and examples, it is for the sake of clarity and understanding, and it is obvious that certain changes and modifications may be made within the scope of the claims accompanying this description. Petition 870250017647, dated 06 / 03 / 2025, pages 47 / 55

Claims

1 / 4 CLAIMS 1. PHARMACEUTICAL COMPOSITION of ondansetron in the form of a soft gelatin capsule, characterized in that it comprises: (a) a core filling mixture comprising: (i) 2.00% to 2.78% (w / w) of ondansetron, or its physiologically acceptable salts and solvates, (ii) 6.30% to 8.89% (w / w) of surfactant, (iii) 6.70% to 9.35% (w / w) of co-surfactant, (iv) qsp 100% (w / w) of lipid carrier; and (b) a soft gelatin capsule shell.

2. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized by comprising: (a) a core filler mixture comprising: (i) 2.56% (w / w) ondansetron, or its physiologically acceptable salts and solvates, (ii) 8.21% (w / w) surfactant, (iii) 8.63% (w / w) co-surfactant, (iv) q.s.p. 100% (w / w) lipid carrier; and (b) a soft gelatin capsule shell. Petition 870250017647, dated 06 / 03 / 2025, p. 48 / 55 2 / 4 3. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized in that ondansetron is in the form of its hydrochloride salt.

4. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized in that ondansetron is in the form of its solvate, ondansetron hydrochloride dihydrate.

5. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized in that the core filling mixture may contain flavoring agents, preservatives and / or antioxidants.

6. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized in that the surfactant is selected from the group consisting of caprylocaproyl macrogol-8 glycerides (Labrasol®), lecithin, sorbitan monooleate (Span® 80) and sorbitan monolaurate (Span® 20).

7. PHARMACEUTICAL COMPOSITION, according to claim 6, characterized in that the surfactant is caprylocaproyl macrogol-8 glycerides (Labrasol®). Petition 870250017647, dated 06 / 03 / 2025, page 49 / 55 3 / 4 8. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized in that the co-surfactant is selected from the group consisting of polysorbate 20 (Tween® 20), polysorbate 40 (Tween® 40), polysorbate 60 (Tween® 60) and polysorbate 80 (Tween® 80).

9. PHARMACEUTICAL COMPOSITION, according to claim 8, characterized in that the co-surfactant is polysorbate 80 (Tween® 80).

10. PHARMACEUTICAL COMPOSITION, according to claim 1, characterized in that the lipid carrier is selected from the group consisting of type I glycerol monocaprylocaprate (Capmul® MCM), caprylic / capric triglycerides (Crodamol® GTCC), castor oil, coconut oil, palm oil, and / or mixtures thereof.

11. PHARMACEUTICAL COMPOSITION, according to claim 10, characterized in that the lipid carrier is glycerol monocaprylocaprate type I (Capmul® MCM).

12. PHARMACEUTICAL COMPOSITION, according to claim 2, characterized by comprising: a) a core filler mixture comprising: Petition 870250017647, dated 06 / 03 / 2025, page. 50 / 55 4 / 4 (i) 2.56% (w / w) ondansetron, in the form of its solvate ondansetron hydrochloride dihydrate, (ii) 8.21% (w / w) surfactant, consisting of caprylocaproyl macrogol-8 glycerides (Labrasol®), (iii) 8.63% (w / w) co-surfactant, consisting of polysorbate 80 (Tween® 80), (v) qsp 100% (w / w) lipid carrier, consisting of glycerol monocaprylocaprate type I (Capmul® MCM); and (b) a soft gelatin capsule shell.

13. USE of the pharmaceutical composition as described in claim 1, characterized by being for the treatment of emesis. Petition 870250017647, dated 06 / 03 / 2025, pp. 51 / 55

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