Process for the solubilization of olopatadine and use thereof

Abstract

The invention relates to a process, and the use thereof, for the solubilization of olopatadine in an aqueous medium to obtain stable aqueous compositions with a high content of olopatadine, either alone or in combination with other pharmaceutical agents. Specifically, the solubilization process enables the obtainment of aqueous compositions with suitable properties, such as pH, for nasal and ocular administration, useful in the treatment of allergic conditions.

Description

OLOPATADINE SOLUBILIZATION PROCESS AND ITS USE Field of Invention

[0001] The present invention relates to a process for solubilizing olopatadine in an aqueous medium, which allows obtaining stable aqueous compositions of olopatadine, alone or in combination with other drugs, with properties suitable for nasal and ocular administration. The present invention falls within the fields of pharmacotechnics and pharmaceutical technology. Background of the Invention

[0002] Inflammation of the airways, especially the nasal mucosa, can result in changes in the integrity of the nasal epithelium and in mucociliary transport and clearance, which, among other things, impair the defense and clearance mechanisms of the air breathed. Allergic inflammations, such as allergic rhinitis, are triggered by the inhalation of allergens, such as dust mites and animal hair, which trigger the formation of specific IgE antibodies that promote the release of acute (immediate) phase inflammatory mediators, responsible for the characteristic clinical picture of these conditions. Allergic rhinitis, specifically, is characterized by the presence of nasal and ocular congestion, conjunctival hyperemia, runny nose, sneezing and itching.

[0003] In addition to prevention through environmental interventions to avoid contact with allergens and adjuvant treatment, which consists of nasal lavage with saline solution, an allergic rhinitis crisis can be treated by combining antihistamines and topical nasal corticosteroids, in addition to decongestants.

[0004] The olopatadine molecule, normally available in the form of hydrochloride salt, was disclosed in 1986 and 1989 in documents US4871865 and US4923892, respectively, and acts as a selective antagonist of the histamine H1 receptor, inhibiting the release of histamine by mast cells. Olopatadine can therefore be used alone in the treatment of ocular symptoms, as described in patent document WO2012159064, which discloses ophthalmic compositions, or in combination with corticosteroids, in document WO201 5036902, which discloses compositions of olopatadine with mometasone and in WO2011 141929, which discloses aqueous compositions of olopatadine and fluticasone.

[0005] Among the most common problems in the use of the olopatadine molecule is the existence of several ionic forms depending on the pH of the solution, as demonstrated in Scheme (I). In the pH region between the pKa values ​​of the molecule (4.18 <pH<9,79), a olopatadina está, preferencialmente, na forma zwitteriônica (b). Em faixas de pH menores que 4,18, a forma catiônica é a forma predominante (a) e, em pH acima de 9,79, predomina a forma aniônica (c). Scheme (I)

[0006] The ionization profile of olopatadine, consequently, defines the solubility curve of the molecule. The reduction in the solubility of the zwitterionic form, compared with the anionic and cationic forms, is possibly explained by the occurrence of intramolecular interactions between the carboxyls and the amine, which decreases the ionic character and the dipole of the molecule.

[0007] The solubility restrictions of olopatadine make it difficult to obtain aqueous solutions of olopatadine with a pH close to neutral, which is more suitable for nasal administration. Products currently available on the market have a pH in the range of 3.7, while products available for ophthalmic administration (optimal pH in the range between 5.5 and 8.0) have a lower concentration of olopatadine.

[0008] Formulations for nasal administration with properties Unsuitable for the mucosa, for example, acidic pH, can cause irritation and lesions, which in itself reduces the patient's adherence to the proposed pharmacological treatment, and can reduce the ciliary movement of the nasal cavity, which at pH below 6.4, ceases completely. The paralysis of ciliary movement, together with the already impaired functions of an irritated mucosa, impairs the mucosa's defenses and favors the proliferation and colonization of pathogens in the upper airways.

[0009] Thus, the main challenge in obtaining formulations with a suitable pH for nasal and ocular administration, containing high concentrations of olopatadine, is the complete dissolution of this drug before the incorporation of other drugs, in the case of combinations, or other excipients, in cases of isolated administration. Document US8399508 discloses compositions of olopatadine for nasal administration containing approximately 0.6% (w / w) of olopatadine that still do not solve the technical problem of the presence of crystallization nuclei in aqueous solutions containing a high content of the drug, which implies a decrease in the stability of the final product and, consequently, its therapeutic potential.

[0010] Document WO2012159064, for example, discloses an ophthalmic composition containing olopatadine prepared by heating a solution containing NaOH and PVP for a period of 20 minutes, with HCI subsequently added. The solution obtained is then cooled to a temperature in the range of 30 to 40 °C, and only then olopatadine and other excipients, such as cyclodextrin, PEG, EDTA and boric acid, are added. Document WO093358 teaches the solubilization of olopatadine at temperatures in the range of 60 to 70 °C and the use of vitamin E derivatives, obtaining compositions with pH in the range of 3.5 and 5.0, still unsuitable for nasal administration. It is also worth highlighting that vitamin E, as well as its derivatives, are lipophilic compounds that do not contribute to the dissolution of olopatadine in the pH range proposed for the product, since the lipophilicity of the compounds is not the same.Additionally, the use of a solubility adjuvant with such distinct physicochemical properties can. cause the final product to present stability problems, for example, phase separation, which implies the loss of therapeutic properties and product quality. Finally, document CN112807275 teaches a process for preparing compositions containing olopatadine in which all active ingredients and excipients are mixed and subjected to temperatures close to 100 °C, which increases the thermal degradation of the components and reduces the therapeutic potential of the product obtained.

[0011] In view of the above, it is clear that the prior art fails to provide solutions that enable the total solubilization of olopatadine in water in order to eliminate the persistence of crystallization nuclei and ensure the stability of the final product, as well as failing to provide solutions that allow a product with an ideal pH for nasal and ocular administration with adequate concentrations of olopatadine. There is therefore no evidence that the prior art reveals the present invention, or that it would lead a person skilled in the art to develop it. Brief Description of Figures

[0012] Figure 1 shows the olopatadine crystals observed in the test sample 3, kept at room conditions for a period of 24 hours. In (A) a 37.4 pm crystal is observed and in (B) a 126.89 pm crystal.

[0013] Figure 2 shows, in detail, the microscopic image obtained from the crystals from the test 7 solution. In (a), it is possible to observe the X-ray diffraction (XRD) pattern of the olopatadine crystals in the trihydrated zwitterionic form, verified in the test 7 sample, kept at room conditions. In (b), it is possible to observe the diffractogram of olopatadine hydrochloride in form I, starting material, presented to demonstrate the change in the crystalline form of the drug obtained at the end of the test.

[0014] Figure 3 shows the variation in the olopatadine content (concentration of 1.787 to 1.799% m / v) observed in samples kept at room conditions for 7 days, produced with the solution at 80 °C at different heating times: 30, 45 and 60 minutes. Average standard deviation in the content values ​​of approximately ± 3%.

[0015] Figure 4 shows the olopatadine hydrochloride crystals verified by microscopy in the sample heated at 80 °C for a period of 30 minutes, after storage for 7 days at ambient conditions.

[0016] Figure 5(a) shows the chromatogram for the sample at pH 5.0, indicating the peak attributed to a degradation product (PD) with a retention time of 4.7 min. In (b), the peak attributed to the degradation product (PD) is shown in the samples produced with different heating times (30, 45 and 60 min) and olopatadine hydrochloride standard in buffered solution at pH 5.0 (without heating). In this figure, it is possible to observe the absence of the degradation product peak in the chromatogram of the olopatadine hydrochloride standard.

[0017] Figure 6 shows the peak area of ​​the degradation product (PD) in the chromatogram with retention time (RT) at 4.7 minutes for the samples kept at ambient conditions for 7 days, produced with the solution at 80 °C with different heating times (30, 45 and 60 minutes).

[0018] Figure 7 shows the crystals observed by microscopy resulting after storage of the sample obtained in the comparative test of the process of the present invention with that disclosed in the state of the art (specifically, in example 9 of document US8399508). The crystals were observed in the sample at pH 6.0, obtained without heating after preparation of the solution. In (a) it is possible to observe the Raman spectrum of the crystals verified in the sample and in (b) the Raman spectrum of the raw material of olopatadine hydrochloride used as comparator. The unequivocal assignment of the composition of the crystals of the active olopatadine hydrochloride in the sample is performed by comparing the Raman spectra using the reference material.

[0019] Figure 8 presents the qualitative evaluation of the crystallization tendency of olopatadine hydrochloride from samples prepared with different pH values ​​and heating time after storage in the refrigerator (2-8 °C) for 7 days.

[0020] Figure 9 shows the production flow of the prototype pharmaceutical composition containing solubilized olopatadine according to the process of the present invention and fluticasone propionate.

[0021] Figure 10 shows the microscopy image obtained after analyzing the sample obtained after the experiment performed under milder temperature conditions, as described in Example 1. Summary of the invention

[0022] The present invention relates to a process for solubilizing olopatadine for the production of stable aqueous pharmaceutical compositions containing olopatadine alone or in combination with other drugs generally used in the management of allergic rhinitis. Specifically, the present invention discloses a process for solubilizing olopatadine optimized with respect to temperature and heating time in order to eliminate the remaining crystalline nuclei and minimize degradation products. The solubilization process disclosed herein allows the production of aqueous pharmaceutical compositions with a higher pH than currently available products, closer to that considered suitable for nasal and ocular administration routes.

[0023] The present invention presents as inventive concepts the objects to be followed.

[0024] The first object of the present invention is the process of solubilizing olopatadine, which comprises the following steps: (a) addition of the solvent and co-solvent system; (b) addition of solubilization adjuvants; (c) heating and homogenization of the solubilizing system; (d) addition of olopatadine under stirring and heating; (e) maintaining the mixture obtained in the previous steps under agitation and heating for a determined period and, optionally, carrying out volumetric correction to maintain the volume of the mixture; (f) cooling and adding excipients under stirring; and (g) cooling to room temperature.

[0025] It is a second object of the present invention the use of the olopatadine solubilization process, described in the first object and in its embodiments, in the preparation of stable aqueous pharmaceutical compositions containing olopatadine alone or in combination with other drugs, said pharmaceutical compositions having a pH in ranges suitable for nasal and / or ocular administration, useful in the treatment of allergic rhinitis. Detailed description of the invention

[0026] The terminology used in this report is intended to better define the specific embodiments of the present invention and is therefore not limiting in nature.

[0027] As used in this report, the term “olopatadine” refers to the selective H1 receptor antagonist compound {(1 1Z)-11-[3-(dimethylamino)propylidene]-6,1 1-dihydrobenzo[b,e]oxepin-2-yl)acetic acid, for example, disclosed in documents US4871865 and US4923892, incorporated herein by reference, its salts, such as olopatadine hydrochloride, polymorphs and isomers, intended for the treatment of allergic inflammations.

[0028] The term “other drugs generally used in the management of allergic rhinitis” refers specifically to topical corticosteroids that, even when incorporated in high concentrations in pharmaceutical compositions, have a reduced systemic effect. Topical corticosteroids of the present invention are selected from the group comprising flunisolide, fluticasone furoate, mometasone furoate, fluticasone propionate, cortisol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, ciclesonide, their prodrugs, salts, polymorphs and stereoisomers. In preferred embodiments, the topical corticosteroid is fluticasone, as disclosed in document US4335121 , incorporated herein by reference.

[0029] In the context of the present invention, the term “solubilization” refers to the interaction between the species to be solubilized (solute) and the dissolving substance (solvent), defined as the amount of solute that dissolves in a given amount of solvent, under equilibrium conditions. Solubility, therefore, refers to the physical property of the “solute / solvent” system that depends on temperature, pressure, pH, solute particle size, polymorphism and polarity.

[0030] In Normative Instruction No. 23 of the National Health Surveillance Agency (ANVISA), published in 2008, excipients are defined as substances present in the formulation of drugs that do not exert pharmacological or toxicological action. In the context of the present invention, excipients are separated into three different groups: the first group comprises the excipients that make up the solvent / co-solvent system, added in step (a) of the process and defined below. The second group of excipients are those that act as solubilization adjuvants, added in step (b) of the process and defined below. Finally, the excipients added in step (f), as well as the excipients added after obtaining the aqueous solution that is incorporated into a pharmaceutical composition, defined below, are those that will be part of the final product, without the specific function of assisting in the solubilization process of olopatadine.

[0031] The state of the art is clear in establishing pH and ionic strength as important parameters in the solubilization of olopatadine. Surprisingly, it was observed by the inventors that from the reproduction of the conditions established in the examples and teachings of the patent literature, incorporated herein as a reference, complete solubilization may not occur, as verified in the optical microscopy analyses described in the Examples. Another fundamental parameter in the solubilization of this drug, as revealed herein, is temperature.

[0032] Solubilization and recrystallization processes induced by successive heating-cooling cycles can be used to control crystallization parameters, such as morphology, particle size distribution, and polymorphism. Smaller crystals are eliminated by heating, and the remaining crystals function as nuclei for crystal growth and optimization of the desired parameter. Complete elimination of nuclei is usually achieved at higher temperatures and longer heating times. Thus, temperature and heating time are also fundamental parameters for the solubilization of a drug.

[0033] However, a long heating time favors the formation of degradation products. The higher the temperature and heating time, the greater the kinetics of degradation product formation. This fact is one of the main reasons why accelerated drug stability studies are performed at high temperatures. For this reason, adjusting the heating time and the temperature used during heating, in addition to the pH and ionic strength of the solution, is not a trivial task for a technician in the field.

[0034] The present invention therefore discloses an olopatadine solubilization process that uses the adjustment between the pH of the solution, temperature and heating time to ensure the definitive solubilization of the drug, thus avoiding the persistence of crystallization nuclei that impair the stability of the finished product. The olopatadine solubilization process of the present invention comprises the steps of: (a) addition of the solvent and co-solvent system; (b) addition of solubilization adjuvants; (c) heating and homogenization of the solubilizing system; (d) addition of olopatadine under stirring and heating; (e) maintaining the mixture obtained in the previous steps under agitation and heating for a determined period, and, optionally, carrying out volumetric correction to maintain the volume of the mixture; (f) cooling and adding excipients under stirring; and (g) cooling to room temperature.

[0035] In a first embodiment, in step (a) a solvent and co-solvent system composed of at least two excipients is added, the solvent being water and the co-solvent selected from the group comprising glycerin, propylene glycol, polyethylene glycol, pentylene glycol, ethyl alcohol, propylene carbonate, sorbitol, maltitol or a combination thereof. In yet another embodiment of step (a) the solvent:co-solvent ratio is in the range of 1:1 to 1:30. Preferably, in step (a) a solvent / co-solvent system composed of water and glycerin in the ratio of 1:16 is added.

[0036] In a second embodiment, the solubilization adjuvants are added to the solvent / co-solvent system in the commercially available physical state, these adjuvants being selected from the group comprising chelating agents, sweeteners, co-solvents, buffers and solubilization agents.In preferred embodiments, the chelating agent is selected from the group comprising EDTA salts and pentetic acid; the sweetener is selected from the group comprising xylitol, maltitol, sorbitol, aspartame, neotame, saccharin, sucralose, acesulfame, glucose, dextrose, polydextrose or a combination thereof; the cosolvent is selected from the group comprising polyethylene glycol, sodium chloride, potassium chloride or combinations thereof; the solubilizing agent is selected from the group comprising betacyclodextrin, alphacyclodextrin, gammacyclodextrin or their derivatives or a combination thereof; and the buffer is selected from the group comprising sodium citrate / citric acid, dibasic sodium phosphate / basic sodium phosphate, sodium acetate / acetic acid.Preferably, the chelating agent is disodium EDTA, the sweetener is xylitol, the co-solvent is polyethylene glycol, the most suitable buffer is composed of sodium citrate / citric acid and the solubilizing agent is betacyclodextrin.

[0037] In yet another embodiment of step (b), the chelating agent is added in an amount ranging from 0.005% to 0.1% m / v, the sweetener is added in an amount ranging from 0.05% to 10% m / v, the co-solvent is added in an amount ranging from 0.01% to 70% m / v, the solubilizing agent is added in an amount ranging from 0.1% to 25% m / v, and the buffer is added in an amount ranging from 0.1% to 5.0% m / v. Preferably, to the solution are added 0.025% m / v chelating agent, 0.5% m / v sweetener, 5.0% m / v co-solvent, 0.6% m / v solubilizing agent, and 1.5% m / v buffer.

[0038] In one embodiment of step (c), heating occurs until a temperature above 50 °C and below 90 °C is reached, preferably above 60 °C and below 90 °C, preferably above 70 °C and below 90 °C, preferably between 80 °C and 90 °C. In embodiments preferred, heating occurs until a temperature between 80 °C and 85 °C is reached. In yet another embodiment, heating in step (c) occurs under mechanical stirring at a speed between 200 and 400 rpm.

[0039] In one embodiment of the process, in step (d), olopatadine is added in the form of a salt, while the mixture is kept heated. Preferably, an amount of between 0.1 to 1.5% m / v of olopatadine in its hydrochloride form is added to a solution at a temperature above 50 °C and below 90 °C, preferably above 60 °C and below 90 °C, preferably above 70 °C and below 90 °C, preferably between 80 °C and 90 °C. In preferred embodiments, heating occurs until a temperature between 80 °C and 85 °C is reached. In yet another embodiment, heating occurs under mechanical stirring at a speed between 200 and 400 rpm. In preferred embodiments, 0.665% of olopatadine hydrochloride is added to the solubilizing system in step (d).

[0040] In another embodiment, after the addition of olopatadine, in step (e), the mixture obtained in step (d) is kept under heating and stirring for a determined period. Specifically, in this step, heating is maintained at a temperature above 50 °C and below 90 °C, preferably above 60 °C and below 90 °C, preferably above 70 °C and below 90 °C, preferably between 80 °C and 90 °C. In preferred embodiments, heating occurs until a temperature between 80 °C and 85 °C is reached, under mechanical stirring at a speed between 200 and 400 rpm, for a period of time ranging from 15 to 85 minutes, preferably 45 minutes. Additionally, in another embodiment of step (e), optionally, purified water can be added to the mixture obtained to maintain the volume of the solution. This step is optional as it will only be necessary if high water loss due to evaporation is observed during heating.

[0041] Over a wide pH range, olopatadine has a chemical structure with two polar centers with opposite charges (zwitterionic form) that, under certain conditions, interact and form an insoluble complex. This situation is also characteristic of the solubilization process, in which if If there is an adequate supply of energy to the process, in the form of heating, solubilization occurs partially, leading to subsequent precipitation of the drug. Although heating can lead to structural changes and consequent degradation of the active ingredient, what the inventors observed here is that the degradation of the olopatadine molecule in the solution also depends on the time of exposure to heating. Thus, the heating time and temperature are decisive in obtaining a stable system without degradation of the drug.

[0042] The addition of olopatadine must be carried out in a system previously prepared for stabilization and solubilization, with all additives already solubilized. In the context of the present invention, “suitable system” should be understood as one that has all additive materials solubilized, available to interact with the drug, enhancing its solubility in aqueous medium and at the target temperature, specifically, 80 - 85 °C for a period of 45 minutes.

[0043] If it is desired to obtain an association of olopatadine, the addition of other drugs can be carried out in a secondary stage, involving prior solubilization in a suitable solvent / co-solvent and incorporation into the system after incorporation of olopatadine and / or incorporation directly into the system if it is insoluble in aqueous medium, being dispersed in the final product at room temperature.

[0044] In another embodiment of the process, in step (f), the solution is cooled until it reaches a temperature below or equal to 50 °C, for example, between 50 °C and 30 °C, between 50 °C and 40 °C, preferably between 50 °C and 45 °C. In this step, cooling can be done by removing the heat source and in industrial reactors, or by circulating ice water. The impact of cooling is not significant for the process as long as it is maintained with constant agitation. In yet another embodiment of this step, viscosity agents selected from the group comprising microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polycarbophil, carboxymethyl cellulose, pectin, gum are added as excipients. guar gum, xanthan gum, carrageenan gum, agar gum, tragacanth gum or a combination thereof. Preferably, two viscosity agents are added: microcrystalline cellulose and methyl cellulose. In yet another embodiment, the viscosity agents are added in an amount ranging from 0.01 to 5.00% m / v, preferably 0.3% m / v. In the system formed by the two preferred agents, the proportion between them is 1:20, 1:15, preferably 1:10. In another embodiment of this step, the addition of the viscosity agents occurs under conventional mechanical stirring by a naval propeller with an increase in speed to improve homogenization.

[0045] In a penultimate embodiment of the process, in step (g) the mixture is left to cool under ambient conditions until it reaches room temperature, for example, a temperature of no more than 30 °C; for example, between 20 °C and 30 °C; preferably, between 25 °C and 30 °C. During cooling, the mixture is kept under constant stirring and, at the end, homogenization is carried out under high shear.

[0046] In a final embodiment, the olopatadine solubilization process of the present invention comprises the steps of: (a) addition of the solvent / cosolvent system composed of purified water and glycerin in a ratio of 1:16; (b) addition of solubilization adjuvants in the physical state available commercially, these adjuvants being selected from the group comprising chelating agents, sweeteners, co-solvents, buffers and solubilization agents, the chelating agent being disodium EDTA in an amount of 0.025% m / v, the sweetener being xylitol in an amount of 0.5% m / v, the co-solvent being polyethylene glycol in an amount of 5.0% m / v, the solubilization agent being betacyclodextrin in an amount of 0.6% m / v, and the buffer being composed of sodium citrate / citric acid in an amount of 1.5% m / v, respectively; (c) heating and homogenization of the solubilizing system at a temperature between 80 °C and 85 °C under mechanical stirring at a speed between 200 and 400 rpm; (d) addition of 0.665% m / v olopatadine hydrochloride at a temperature between 80 °C and 85 °C under mechanical stirring at a speed between 200 and 400 rpm; (e) maintain the solution obtained in (d) under heating at a temperature between 80 °C and 85 °C and mechanical stirring at a speed between 200 and 400 rpm for a period of 45 minutes, optionally adding purified water to maintain the volume of the solution; (f) cool the solution to a temperature between 45 °C and 50 °C and add 3.0% microcrystalline cellulose and 0.3% methyl cellulose, under constant stirring; (g) cool the solution until a temperature between 25 °C and 30 °C is reached.

[0047] The olopatadine solubilization process of the present invention allows, in a second aspect, the development of a stable aqueous pharmaceutical composition, free of olopatadine crystallization nuclei, which may contain this drug alone or in association with other adjuvant drugs in the treatment of allergic rhinitis, for example, corticosteroids, specifically, fluticasone propionate, which presents suitable properties, specifically pH within the physiological range of 5.0 to 7.0, for nasal administration.

[0048] If the objective is to obtain a drug in aqueous form, containing an association of olopatadine, the addition of other drugs can be carried out in a secondary stage, involving prior solubilization in a suitable solvent / co-solvent and incorporation into the system after the addition of olopatadine and / or incorporation directly into the system if it is insoluble in an aqueous medium, being dispersed in the final product at room temperature.

[0049] Suitable compositions that use the solubilization process of the present invention, for example, use the rheological system described in document BR 10 2022 006855-0, from this same Owner, incorporated herein in its entirety, without limiting the invention.

[0050] In exemplary compositions of the present invention, obtained after solubilization of olopatadine, a sweetening system is added for isotonicity adjustment and flavor masking. Although the compositions are not intended for oral administration, taste masking is interesting since, while maintaining mucociliary clearance of the nasal mucosa, possible due to the pH of the composition within physiological ranges, there will be inevitable swallowing of part of the administered dose. Preferred sweeteners of the present invention are selected from the group comprising xylitol, sorbitol, isomaltose, maltose, maltodextrins, polydextrose or mixtures thereof.

[0051] Polymers that reduce the gelation temperature of compositions can also be used in the exemplary compositions of the present invention. Such components accelerate the formation of physical crosslinking of microcrystalline cellulose molecules, inducing microphase separation. The variation in ion concentration, also a parameter observed during the solubilization of olopatadine of the present invention, decreases the gelation temperature of microcrystalline cellulose from 60 °C to 38 °C. When ions are added to the formulation, water molecules solvate the ions and reduce the formation of intermolecular hydrogen bonding between water and the hydroxyl group of methyl cellulose. The depletion of the water layer leads to an increase in the level of hydrophobic interaction, which reduces the gelation temperature. Such an effect can be observed when materials such as polyethylene glycol, sodium chloride, potassium chloride or their combinations are added.Therefore, in the embodiments of the present invention, polyethylene glycol is used at two different times and with different functions: in the solubilization of olopatadine, it acts as a co-solvent; on the other hand, in obtaining the aqueous composition, it acts as an agent that reduces the gelation temperature of the composition.

[0052] Preservatives generally used in pharmaceutical compositions for nasal administration are responsible for several adverse effects, for example, nasal congestion, hypersensitivity reactions, itching and reduction of the mucociliary beat of the nasal mucosa, and may even harm the integrity of the mucosa. This fact explains the interest in developing nasal compositions without preservatives, containing alternative components, or packaged in single-dose containers. Benzalkonium chloride is the preferred preservative for the exemplary compositions of the present invention due to the final pH obtained using the solubilization process of the present invention.

[0053] Studies available in the state of the art show that the chronic use of solutions containing benzalkonium chloride causes functional damage to the nasal mucosa, specifically, it compromises the mucociliary beat and reduces the barrier properties of the mucosa. However, the use of low concentrations of benzalkonium chloride, less than 0.2%, does not cause damage to the mucosa, which was proven by performing different tests with different drugs and excipients and the effect on the mucociliary beat. The presence of preservatives, including benzalkonium chloride, has a ciliostatic effect that is reversible at lower concentrations of the preservative. Thus, the combination of benzalkonium chloride in low concentrations and the pH of the pharmaceutical composition, possible due to the olopatadine solubilization process of the present invention, favors mucociliary movement and recovery, maintaining the homeostatic functions of the nasal mucosa.

[0054] It is clear, therefore, that the proposed process solves the problems of the state of the art with regard to the solubilization of olopatadine in high concentrations, taking into account the adjustment between pH, heating time and heating temperature. Above all, it is clear that the present invention solves the problems of the state of the art with regard to the adjustment of pH in pharmaceutical compositions intended for nasal and ocular administration, since it keeps olopatadine fully dissolved even in higher pH ranges, reducing the incidence of irritation in the target organ, responsible for low adherence to therapy. Examples

[0055] The following examples serve to illustrate aspects of the present invention without, however, having any limiting character. Example 1 - Dissolution tests of olopatadine hydrochloride in aqueous solution at a concentration of 0.665% (m / v).

[0056] The main challenge in developing stable compositions is the complete solubilization of olopatadine. For this reason, the inventors performed a series of experiments using the teachings of documents related to the products Patanase® (US8399508) and Ryaltris® (WO2015036902) to demonstrate that such documents fail to provide methods that lead to the complete dissolution of olopatadine, as well as to prove the improvements in the process proposed here. Table 1 summarizes the various tests performed.

[0057] In the tests, the solubilization of olopatadine was performed in different ways. Tests 1 to 4 were performed in deionized water, while tests 5 to 10 were performed using a solution containing dibasic sodium phosphate at a concentration of 0.5% (m / v) and NaCl at a concentration of 0.41% (m / v). In the tests, the pH was optionally corrected with the addition of 1 M HCl or 1 M NaOH solutions, before and after the addition of olopatadine, under different temperature conditions, as described in detail below. Table 1. Tests for dissolution of olopatadine hydrochloride in aqueous solution at a concentration of 0.665% (m / v):

[0058] Tests 1 to 4 were performed in aqueous solution with the pH value adjusted by adding a few drops of 1 M HCl solution until reaching pH 2.8. The temperature was maintained at 25 °C in test 1, 40 °C in test 2 and 80 °C in tests 3 and 4 for subsequent addition of olopatadine hydrochloride. It was found that the higher the temperature of the solution before the addition of olopatadine, the better the dissolution of the drug. However, even under heating to 80 °C and the apparently immediate dissolution of olopatadine, when the sample was kept at room conditions for a period of 24 hours, the inventors were able to observe the presence of crystals of the drug by optical microscopy, as shown in Figure 1. It was demonstrated, in test 4, that increasing the pH to 3.7 with the addition of a few drops of 1 M NaOH solution also had no advantageous effects on the solubilization of olopatadine, which would be expected based on the drug's solubility curve.

[0059] Tests 5 to 10 were performed in accordance with the teachings of documents US8399508 and WO2015036902, with the addition of Na2HPO4 and NaCl salts at concentrations of 0.5% m / v and 0.41% m / v, respectively. In test 5, olopatadine was added to a solution with pH adjusted to 2.8 and, at the end of dissolution, the pH was corrected to 3.7. A sample of the solution was evaluated by optical microscopy, and it was possible to note the presence of remaining crystals, as occurred in test 3. Test 6, in turn, consisted of repeating test 5, employing heating during the solubilization procedure (which occurred at 40 °C). Even with the increase in temperature, it was possible to observe the presence of remaining crystals.

[0060] Test 7 was performed under the same conditions as tests 5 and 6, with the difference that there was no pH adjustment. Before the addition of olopatadine, the pH of the solution was adjusted to 9.0 with the addition of Na2PC and NaCl and, after the addition, it equilibrated at around 6.6. It was therefore observed that the pH itself The addition of olopatadine promoted a reduction in pH. A sample of the solution was evaluated by microscopy, and a high degree of crystallization was observed, as shown in Figure 2. Still referring to Figure 2, the crystals precipitated in test 7 were characterized by X-ray diffraction (XRD), which allowed the characterization of the trihydrate zwitterionic form of olopatadine, different from the form A of olopatadine hydrochloride used as the starting material. For better comparison, the list of the most intense and characteristic peaks of the diffractograms of the A and zwitterionic forms, as well as of the crystals precipitated in test 7, is presented in Table 2. Table 2. List of the main diffraction peaks of the diffractograms of the A and zwitterionic forms and of the crystals precipitated in test 7:

[0061] Tests 8 and 9 were performed in the same way as tests 5 and 6, but with pH corrected to 2.0 and 1.2, respectively, after addition of the drug. The adjustment was performed with 1 M hydrochloric acid. Reducing the pH would initially increase the solubility of olopatadine. However, even after reducing the pH, it is still possible to verify the presence of crystals under a microscope.

[0062] Finally, test 10 consists of reproducing test 5 as taught in the prior art, using heating of the solution to 80 °C for subsequent addition of olopatadine. Even after seven days, the presence of crystals was not verified in the sample kept at room conditions, a fact that contradicts what is expected during processes that employ high temperatures for a long time.

[0063] An experiment with milder temperature conditions, specifically at 40 °C, was performed. In this experiment, olopatadine was not completely solubilized and it was possible to observe traces of crystals. Although higher temperatures usually improve the solubilization of olopatadine, this strategy has the disadvantage of, for example, evaporation of the solubilizing system, which contributes to precipitation, and thermal degradation, especially using the heating times employed here. It is clear, therefore, that the solution proposed here is not trivial and commonplace for a pharmaceutical technician, especially considering what is revealed in the prior art, which in no way suggests the use of high temperatures for a prolonged period of time to obtain a solution of olopatadine without the presence of trace crystals.

[0064] Other tests were performed with the addition of different components to the solution to verify whether or not the solubilization of olopatadine improved. The components added were, for example, disodium EDTA (0.5% m / v), PVP polymers (5% m / v) and PEG 400 (5% m / v), glycerin (10% m / v) and hydroxypropyl-β-cyclodextrin (0.6% m / v). In all experiments performed with these components, separately or combined, without heating, the presence of crystals or crystalline nuclei remaining in the samples analyzed by microscopy was verified. These tests were performed for investigative purposes and will therefore not be detailed here. Example 2. Evaluation of the impact of temperature and heating time on the solubilization process of olopatadine.

[0065] Considering the solubilization of olopatadine in aqueous solution, Further tests were performed to verify the effect of the heating time of the olopatadine solution in preventing the persistence of crystallization nuclei, as well as the crystallization of the sample, while preventing the formation of degradation products.

[0066] Tests 11 to 15, shown in Table 3, were performed with optimized formulations containing other commonly used solubilizing agents, such as hydroxypropyl-β-cyclodextrin (1.613 to 1.623% m / v), with higher concentrations of olopatadine (1.787 to 1.799% m / v) at different pH values ​​(3.5, 4.5, 5.0, 5.5 and 6.0), under heating at 80 °C and heating times of 30, 40 and 60 minutes. The steps of the processes employed in these tests are revealed here and include the steps of: (a) addition of solvents and co-solvents; (b) addition of solubilization adjuvants; (c) heating and homogenization of the solubilizing system; (d) addition of olopatadine under stirring and heating; (e) keep the mixture obtained in the previous steps under stirring and heating for a determined period, making volumetric correction to maintain the volume of the mixture, if necessary; and (f) cooling to room temperature. Table 3. Description of the compositions used in tests 11 to 15 to evaluate the impact of temperature and heating time on the solubilization of olopatadine:

[0067] Referring to Figure 3, the olopatadine content was evaluated by high-performance liquid chromatography (HPLC), using a method developed by Titular, after the samples had been stored for 7 days at ambient conditions. The method involves filtering the samples and diluting the supernatant in a pH 3 buffer solution. The buffer was prepared with 1 g of sodium lauryl sulfate for 1 L of ultrapure water and addition of phosphoric acid until the pH was corrected to 3. Standard and confirmation solutions were prepared at the same concentration of olopatadine hydrochloride, also using the buffer as a diluent. A Symmetry C18 column (4.6 μm x 150 μm x 5 μm) was used, with an injection volume of 10 μL, a flow rate of 1.2 mL / min, detection at 237 nm, and a 20-min run with detection of the olopatadine peak in approximately 7 min. The column temperature was 25 °C and the sampler temperature was 20 °C.A gradient mobile phase was used, with phase A being acetonitrile and phase B being a mixture in the proportion 90:10 of pH 3.0 buffer and acetonitrile. The gradient is described in Table 4. Table 4. Mobile phase gradient used in the olopatadine quantification method:

[0068] Despite the variations in content observed at the different pH values ​​tested, the same trend is verified in all cases: the best condition for olopatadine solubilization was obtained with heating around of 45 minutes. In this case, different causes imply the reduction of content in the samples produced with 30 and 60 minutes of heating, for example, insufficient heating for the complete reduction of the crystalline nuclei and subsequent crystallization of the active, as shown in Figure 4, in the condition of 30 minutes of heating.

[0069] The drop in content observed in samples heated for 60 minutes can be attributed to the increase in the content of degradation products resulting from the longer heating time. This can be verified by monitoring the area of ​​one of the peaks in the chromatogram (retention time of 4.5 minutes) in Figure 5A, attributed to a degradation product derived from the heating process. As can be seen in Figure 5B, the olopatadine hydrochloride standard sample produced in a buffered solution at pH 5.0 with the addition of acetonitrile (a drug solubilization aid) does not present this peak generated during the sample heating process. Referring to Figure 6, the longer heating time of the solution implies a greater amount of sample degradation and, consequently, a reduction in content. In other words, monitoring the area of ​​the sample peak at pH 5.0 in different samples illustrates the relationship between heating time and degradation.

[0070] In this way, the inventors were able to verify that the most suitable temperature and heating time for the complete removal of crystalline nuclei, while maintaining the chemical properties of the molecule, must be evaluated for each pharmaceutical composition and for the intended route of administration, at a given pH and ionic strength, but in all cases there will be an ideal condition. Example 3. Comparison of the solubilization efficiency of the process of the present invention and the process disclosed in example 9 of document US8399508.

[0071] This test was performed with the aim of verifying the effect of pH and heating time on the solubilization of olopatadine, in accordance with the teachings of document US8399508. The test was performed in an aqueous medium of dibasic sodium phosphate (0.5% m / v), EDTA (0.01% m / v) and NaCI (0.8% m / v) at 70 °C. The stock solution containing the mentioned components was prepared and fractionated into four parts, with pH adjusted with hydrochloric acid or 1 M sodium hydroxide to the following pH values: 3.7 (A), 4.0 (B), 5.0 (C) and 6.0 (D), with an acceptable variation of up to 0.1. The buffer solutions were heated in closed bottles for 4 hours in an oven at 70 °C, and the temperature was checked using a thermometer.

[0072] An amount of 66.5 mg of olopatadine hydrochloride was weighed into 20 ml glass vials, and subsequently 10 ml of each buffer solution, previously heated to 70 °C, was added to the respective vials containing olopatadine, producing solutions with a concentration of 0.665% (m / v). For each pH value, 4 solutions were prepared, totaling 16 vials. The 4 solutions prepared for each pH were subjected to different heating protocols: the first solution was kept at room temperature (close to 20 °C) until cooling (1). The others were placed in an oven at 70 °C and removed at 15 (2), 30 (3) and 60 (4) minutes, and subsequently kept at room temperature until cooling. Then, all samples were analyzed by optical microscopy, dispersing a drop of the solution on a glass slide.After the first analysis, the solutions were stored in a refrigerator (2-8 °C) for a period of 7 days, and evaluated again by optical microscopy after 3 weeks of removal from the refrigerator.

[0073] When analyzed immediately after cooling, the samples did not show olopatadine hydrochloride crystals visible under the optical microscope. When evaluated again, 3 weeks after the period of storage in the refrigerator, it was possible to observe olopatadine crystals in some of the conditions evaluated, as illustrated in Figure 7. Table 5 presents the qualitative evaluation of the presence of crystals in the different samples. In all samples heated for 30 minutes or less, olopatadine recrystallized. Only with heating for 60 minutes was it possible to eliminate all nucleation sites and avoid olopatadine recrystallization, regardless of the pH of the solution. The results are in line with what was observed in the tests previously described, confirming that the Heating time is also a determining factor for the complete solubilization of olopatadine and that by following only the teachings of the patent literature incorporated herein as a reference, the complete solubilization of the active ingredient may not occur. This result demonstrates that the state of the art fails to teach an efficient process for solubilizing olopatadine that maintains the solubilization of the drug when incorporated into a pharmaceutical form or under storage conditions, which is detrimental to pharmacotherapy using olopatadine alone or in combination with other drugs. Table 5. Evaluation after 3 weeks of olopatadine solutions at a concentration of 0.665% in dibasic sodium phosphate buffer (0.5% m / v), EDTA (0.01% m / v) and NaCI (0.8% m / v) prepared at 70 °C after 7 days in the refrigerator (2 -8 °C): Example 4. Obtaining a composition of olopatadine in association with fluticasone.

[0074] Based on the results described in the previous examples for optimizing the olopatadine solubilization process, a pharmaceutical form for nasal administration containing olopatadine in combination with fluticasone propionate was developed. For this purpose, the olopatadine solutions produced in tests 11 to 15, at different pH values, were used to obtain a suspension of fluticasone propionate at a concentration of 0.025% w / v and other excipients. Table 6 shows the different compositions reported for different pH values. Table 6. Pharmaceutical compositions containing the combination of olopatadine hydrochloride and fluticasone propionate:

[0075] The composition prototype has the following aspects: (a), olopatadine concentration between 5.12 and 6.65 mg / mL; (b). pH between 5.0 and 7.0; (c). pseudoplastic behavior (allows atomization into droplets) small and rapid increase in viscosity in contact with the mucosa).

[0076] The rheological system is the same as that reported in document BR 10 20220068550, of the same title as the present invention, the teachings of which are incorporated herein in their entirety. The drug delivery platform via the nasal route has pseudoplastic behavior, obtained by combining several excipients. Methylcellulose was initially chosen, since it has the greatest hydrophobicity and the ability to exhibit thermogelling behavior with increasing temperature (25 to 35 °C), even at low concentrations. Figure 8 presents a proposed flow for the production of the prototype pharmaceutical composition comprising olopatadine hydrochloride and fluticasone propionate.

Claims

Claims 1. OLOPATADINE SOLUBILIZATION PROCESS characterized by the fact that it comprises the following steps: (a) addition of the solvent and co-solvent system; (b) addition of solubilization adjuvants; (c) heating and homogenization of the solubilizing system; (d) addition of olopatadine under stirring and heating; (e) maintaining the mixture obtained in the previous steps under stirring and heating for a determined period and, optionally, carrying out volumetric correction to maintain the volume of the mixture; (f) cooling and adding excipients under stirring; and (g) cooling to room temperature.

2. PROCESS, according to claim 1, characterized by the fact that, in step (a) a solvent and co-solvent system composed of at least two excipients is added, the solvent being water and the co-solvent being selected from the group comprising glycerin, propylene glycol, polyethylene glycol, pentylene glycol, ethyl alcohol, propylene carbonate, sorbitol, maltitol or a combination thereof.

3. PROCESS, according to claim 2, characterized by the fact that the proportion between the solvent and the co-solvent added in step (a) is in the range of 1:1 to 1:

30.

4. PROCESS, according to any one of the previous claims, characterized by the fact that the solubilization adjuvants added in step (b) are selected from the group comprising chelating agents, sweeteners, co-solvents, buffers and solubilization agents.

5. PROCESS, according to claim 4, characterized by the fact that the chelating agent is selected from the group comprising EDTA salts and pentetic acid; the sweetener is selected from the group comprising xylitol, maltitol, sorbitol, aspartame, neotame, saccharin, sucralose, acesulfame, glucose, dextrose, polydextrose or a combination thereof; the cosolvent is selected from the group comprising polyethylene glycol, sodium chloride, potassium chloride or combinations thereof; the solubilizing agent is selected from the group comprising betacyclodextrin, alphacyclodextrin and gammacyclodextrin or its derivatives or a combination thereof; and the buffer is selected from the group comprising sodium citrate / citric acid, dibasic sodium phosphate / basic sodium phosphate and sodium acetate / acetic acid.

6. PROCESS, according to claims 4 and 5, characterized by the fact that, in step (b), 0.005% to 0.1% m / v of chelating agent, 0.005% to 10% m / v of sweetener, 0.01 to 70% m / v of co-solvent, 0.1% to 25% m / v of solubilizing agent and 0.1% to 5.0% m / v of buffer are added.

7. PROCESS, according to any one of the previous claims, characterized by the fact that, in step (c), the mixture is heated to a temperature in the range of 50 °C to 90 °C, under mechanical stirring at a speed between 200 and 400 rpm.

8. PROCESS, according to any one of the previous claims, characterized by the fact that, in step (d), 0.1% to 1.5% m / v of olopatadine salt are added.

9. PROCESS, according to any one of the previous claims, characterized by the fact that, in step (e), the temperature is maintained in the range of 50 °C to 90 °C, under mechanical stirring at a speed between 200 and 400 rpm, for a period ranging from 15 to 85 minutes.

10. PROCESS, according to claim 9, characterized by the fact that, optionally, in step (e), purified water is added in quantities sufficient to maintain the volume of the solution.

11. PROCESS, according to any one of the preceding claims, characterized in that, in step (f) the mixture is cooled to a temperature below or equal to 50 °C.

12. PROCESS, according to claim 11, characterized by the fact that, in step (f), the cooling is done by removing the heat source or by circulating chilled water.

13. PROCESS, according to claims 11 and 12, characterized by the fact that, in step (f), the added excipients are viscosity agents selected from the group comprising microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polycarbophil, carboxymethyl cellulose, pectin, guar gum, xanthan gum, carrageenan gum, agar gum, tragacanth gum or a combination thereof.

14. PROCESS according to any one of claims 11 to 13, characterized in that, in step (f), at least two viscosity agents are added, in a proportion ranging from 1:20 to 1:

15.

15. PROCESS according to any one of claims 11 to 14, characterized by the fact that, in step (f), the viscosity agents are added to the mixture in an amount ranging from 0.01% to 5.00% m / v.

16. PROCESS, according to any one of the previous claims, characterized by the fact that, in step (g), the mixture cools under ambient conditions until it reaches a temperature of a maximum of 30 °C, under stirring.

17. PROCESS, according to any one of the preceding claims, characterized in that it additionally comprises a high shear homogenization step.

18. USE OF THE PROCESS as defined in any of the preceding claims, characterized in that it is in the preparation of stable aqueous pharmaceutical compositions comprising olopatadine alone or in combination.

19. USE, according to claim 18, characterized in that the stable aqueous pharmaceutical compositions are for ocular or nasal administration.

Images