BR102012009317B1 - Process of preparation of inclusion compounds involving cyclodextrins and drugs, using a continuous flow system - Google Patents

Abstract

PROCESS OF PREPARATION OF INCLUSION COMPOUNDS INVOLVING CYCLODEXTRINS AND PHARMACEUTICALS USING A CONTINUOUS FLOW SYSTEM. The present technology describes a process for the preparation of inclusion compounds in continuous flow involving drugs and cyclodextrins coupled to a spray dryer equipment. This process allows better control of drug injection and flow, preferably sertraline hydrochloride and/or sertraline base; and a carrier, which can be natural cyclodextrins (Alpha (alpha), Beta (beta) or Gamma (gamma) cyclodextrins) or semi-synthetic cyclodextrins, alkyl derivatives, hydroxyalkyl, hydroxy-propyl, acyl, or poly-cyclodextrins, preferably Beta-cyclodextrin. In addition, the process allows for better temperature control, which is essential for inclusion, as well as an optional pre-mix control.

Description

[01] The present technology describes a process for the preparation of inclusion compounds in continuous flow involving drugs and cyclodextrins coupled to a spray dryer equipment. This process allows for better control of the injection and flow of the drug, preferably sertraline hydrochloride and/or sertraline base; and a carrier, which may be natural cyclodextrins (α (alpha), β (beta) or Y (gamma) cyclodextrins) or semi-synthetic cyclodextrins, alkyl derivatives, hydroxyalkyl, hydroxy-propyl, acyl, or poly-cyclodextrins, preferably β-cyclodextrin. In addition, the process allows for better temperature control, which is essential for inclusion, as well as an optional pre-mix control.

[02] Modern techniques for the development of new drugs, such as “High-throughput screening” associated with combinatorial chemistry and synthesis, have allowed an increase in the number of lipophilic drugs, which are difficult to release, causing low bioavailability. On the other hand, nearly a third of drugs in development and half of those in clinical trials are water-insoluble. Low solubility is associated with low absorption, leading to variable bioavailability and gastrointestinal toxicity (Patil, J. S., D. V. Kadam, et al. (2010). "Inclusion complexes system; A novel technique to improve the solubility and biovailability of poorly soluble drugs: A review." International Journal of Pharmaceutical Sciences Review and Research, 2(2): 29-34).

[03] Some studies have shown that about 40% of the failures observed in the development of new drugs are related to problems of dissolution and permeability of the active ingredient; and, among the 200 best-selling drugs in the world, about 75% had some solubility problem (Davis, M. E. and M. E. Brewster (2004). "Cyclodextrin-based pharmaceutics: Past, present and future." Nature Reviews Drug Discovery, 3(12): 1023-1035; Takagi, T., C. Ramachandran, et al. (2006). "A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. " Molecular Pharmaceutics, 3(6): 631-643 ). Therefore, there is a need to develop new pharmacological formulations, in order to improve the solubility and the physicochemical and/or biological properties of drugs.

[04] The increase in solubility and improvement in the physicochemical properties of drugs can be obtained through changes in chemical structures, for example, by the insertion of substituent groups. Another alternative is the modification of pharmaceutical formulations, which, in general, involve the use of organic solvents, surfactants, variations in the pH of the medium and/or changes in their polymorphic forms. Although these strategies increase the solubility of drugs, they still have limitations in their use, in general, due to the low biocompatibility of the excipients used, causing irritation and/or adverse effects (Giordano, F., C. Novak, et al. (2001). ). "Thermal analysis of cyclodextrins and their inclusion compounds." Thermochimica Acta 380(2): 123-151; Del Valle, E. M. M. (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39(9): 1033-1046; Brewster, M.E. and T. Loftsson (2007). "Cyclodextrins as pharmaceutical solubilizers." Advanced Drug Delivery Reviews, 59(7): 645-666 ).

[05] An alternative to these strategies has been the use of cyclodextrins (CD's), which can improve the solubility and, consequently, the bioavailability and pharmacological activity of drugs. CD's are synthesized from the degradation of starch and form macrocycles of glycopyranosidic units, containing 6 to 8 glucose units. Due to configurational restrictions, CD's form a conical structure, which has a hydrophobic cavity and a hydrophilic outer part (Del Valle, E. M. M. (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39(9) : 1033-1046; Brewster, M.E. and T. Loftsson (2007). "Cyclodextrins as pharmaceutical solubilizers." Advanced Drug Delivery Reviews, 59(7): 645-666 ). These characteristics allow DC's to form inclusion compounds, receiving, in their cavity, part or all of biologically active molecules. Considering a drug that is poorly soluble in aqueous media, when interacting with CD, it can be solvated more easily, increasing its solubility, without changes in its chemical structure.

[06] Although the CD/drug interaction can happen naturally, the preparation process of the inclusion compound influences its physicochemical characteristics, such as solubility, melting point, boiling point, polarity, among other properties. The. Several processes are used in the preparation of inclusion compounds, such as melting, extrusion, co-precipitation, paste, dry mixing, atomization or “spray drying” (SD) and lyophilization (LF) among others (Hedges, A. R. (1998) "Industrial applications of cyclodextrins." ChemicalReviews, 98(5): 2035-2044; Loftsson, T. and D. Duchene (2007). "Cyclodextrins and their pharmaceutical applications." International Journal of Pharmaceutics, 329(1-2): 111; Del Valle, E.M.M. (2004). "Cyclodextrins and their uses: a review." Process Biochemistry 39(9): 1033-1046; De Sousa, F.B., A.M.L. Denadai, et al. (2008). "Supramolecular complex of fluoxetine with beta-cyclodextrin: An experimental and theoretical study." International Journal of Pharmaceutics, 353(1-2): 160-169; Salustio, P. J., G. Feio, et al. (2009). "The influence of the preparation methods on the inclusion of model drugs in a beta-cyclodextrin cavity." European J. of Pharmaceutics and Biopharmaceutics, 71(2): 377-386).

[07] Co-precipitation, slurry and melting methods have several limitations such as the use of organic solvents, the physical state of the samples and thermodynamic limitations due to the need for heating and elevation of temperatures in the drying phase (Hedges, A. R. (1998) "Industrial applications of cyclodextrins." ChemicalReviews, 98(5): 2035-2044) Although inclusion compounds can be prepared in semi-solid and solid media, in general the solution preparation is used more because of the greater probability and speed. of interactions between molecules. The process basically consists of mixing and homogenizing, at a given molar ratio, previously prepared solutions of CD and the guest molecule, leaving the final solution under stirring at a given temperature for a period of time, until equilibrium is reached. Water is the preferred solvent, however organic solvents or organo-aqueous mixtures can be used for prior solubilization of the molecules (Hedges, A. R. (1998). "Industrial applications of cyclodextrins." ChemicalReviews, 98(5): 20352044; Del Valle, E.M.M. (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39(9): 1033-1046 ). After reaching equilibrium, the solvent present in the reaction medium, be it water, organic solvent or mixtures, needs to be removed by a drying process (Del Valle, E. M. M. (2004). "Cyclodextrins and their uses: a review." Process Biochemistry 39( 9): 1033-1046; Salustio, P. J., G. Feio, et al. (2009). "The influence of the preparation methods on the inclusion of model drugs in a beta-cyclodextrin cavity." European Journal of Pharmaceutics and Biopharmaceutics, 71(2): 377-386).

[08] Drying basically consists of converting a liquid, dissolved solute, suspension and/or semi-solid into a dry solid product of low humidity, generally involving the consumption of thermal energy for the evaporation of water (Ratti, C. (2001). " Hot air and freezedrying of high-value foods: a review." Journal of Food Engineering 49(4): 311-319; Rane, M. V., S. V. K. Reddy, et al. (2005). "Energy efficient liquid desiccant-based dryer. "Applied Thermal Engineering, 25(5-6): 769781). Drying processes also have high financial and energy costs, require specialized equipment, and their choice depends on the cost-benefit ratio, productivity and quality of the final product (Boss;, E. A. (2004). Modeling and optimization of the drying process lyophilization: Application for skim milk and soluble coffee. Faculdade de Engenharia Química. Campinas, Universidade de Campinas. PhD: 129; Misiuk, W. and M. Zalewska (2011). "Spectroscopic investigations on theinclusion interaction between hydroxypropyl-beta-cyclodextrin and bupropion." Journal of Molecular Liquids, 159(3): 220-225).

[09] Among these preparation and drying processes available in the industrial area, lyophilization is one of the most used methods in the areas of food, biotechnology, fine chemicals and pharmaceuticals (Ratti, C. (2001). "Hot air and freeze-drying of high-value foods: a review." Journal of Food Engineering, 49(4): 311-319; Schwegman, J.J., L.M. Hardwick, et al. (2005). "Practical formulation and process development of freeze-dried products. " Pharmaceutical Development and Technology, 10(2): 151-173; Abdul-Fattah, A. M., D. S. Kalcinia, et al. (2007). "The challenge of drying method selection for protein pharmaceuticals: Product quality implications." Journal of Pharmaceutical Sciences, 96(8): 1886-1916; Chernykh, E. V. and S. B. Brichkin (2010). "Supramolecular complexes based on cyclodextrins." High Energy Chemistry, 44(2): 83-100 ). Lyophilization has also been widely used on a laboratory scale, due to the ease of execution, being very useful in the preparation of inclusion compounds of thermolabile substances.

[010] On the other hand, more complex processes, such as supercritical fluid, spray drying or that involve higher cost equipment have been little explored for the preparation of inclusion compounds between drugs and CDs.

[011] Lyophilization and spray drying are drying processes that allow the removal of the solvent used in the preparation of the inclusion compounds, the first being the solvent removed by sublimation, and the second by evaporation (Schwegman, J.J.L.M.; Hardwick, et al. . (2005). "Practical formulation and process development of freeze-dried products." Pharmaceutical Development and Technology, 10(2): 151-173; Pisano, R., D. Fissore, et al. (2010). "Freeze -Drying Cycle Optimization Using Model Predictive Control Techniques." Industrial & Engineering Chemistry Research, 50(12): 7363-7379; Sollohub, K. and K. Cal (2010). "Spray Drying Technique: II. Current Applications in Pharmaceutical Technology ." Journal of Pharmaceutical Sciences, 99(2): 587-597 ). Most of the preparation processes present some technical limitation for industrial scaling, and their choice depends on the cost/benefit ratio, the quality of the product to be obtained and productivity (Boss;, E. A. (2004). Modeling and optimization of the freeze-drying process: Application for skimmed milk and soluble coffee. Faculty of Chemical Engineering. Campinas, University of Campinas. Doctoral Thesis: 129).

[012] The lyophilization process is one of the most used in the preparation of inclusion compounds, involving drugs and cyclodextrins. This process consists of the previous mixing of two solutions, generally aqueous, of the drug and the cyclodextrin, which, after homogenization, is frozen. After the freezing step, the material is introduced into a lyophilizer, and the solid water is removed by sublimation until the dry material is obtained (Abdul-Fattah, A. M., D. S. Kalcinia, et al. (2007). "The challenge of drying method selection for protein pharmaceuticals: Product quality implications." Journal of Pharmaceutical Sciences, 96(8): 1886-1916; Maltesen, M. J. and M. van de Weert (2008). "Drying methods for protein pharmaceuticals." Drug Discovery Today : Technologies, 5(2-3): e81-e88). The main advantages of the freeze-drying process are the increase in the physical-chemical stability of the dry product, the ease of storing the powder obtained, the formation of pores and the maintenance of the organoleptic characteristics (Boss;, E. A. (2004). Modeling and optimization of the freeze-drying process: Application for skimmed milk and soluble coffee. Faculty of Chemical Engineering. Campinas, University of Campinas. Doctorate: 129).

[013] Studies show that from a total of 129 biopharmaceuticals commercialized on the market until 2002, about 41% are prepared by lyophilization, which indicates the importance of this process in the pharmaceutical and biotechnological area (Schwegman, J. J., L. M. Hardwick, et al. (2005). "Practical formulation and process development of freeze-dried products." Pharmaceutical Development and Technology, 10(2): 151-173). However, some limitations in using the lyophilization process can be observed:

[014] The freezing of large volumes of solutions containing inclusion compounds is technically limited and can make their preparation unfeasible, which can generate thermal stress in the samples. This produces different crystalline forms (depending on the cooling rate) affecting particle size. In addition, large, high-cost refrigerators are used, which can make the continuous preparation process unfeasible.

[015] The freeze-drying method, as with other methods, requires pre-mixing the solutions. Thus, it is necessary to store large volumes of the mixture until freezing;

[016] The time required for the complete drying of the material can make the process financially expensive, and may make the production cost of a particular inclusion compound unfeasible;

[017] In addition, the operating cost is about 4 to 8 times higher than the hot air drying process, mainly due to the long time of the freeze-drying cycle until obtaining the dehydrated product (Maltesen, M. J. and M. van de Weert). (2008). "Drying methods for protein pharmaceuticals." Drug Discovery Today: Technologies, 5(2-3): e81-e88; Ratti, C. (2001). "Hot air and freeze-drying of high-value foods: a review." Journal of Food Engineering, 49(4): 311-319).

[018] The use of organic solvents in the lyophilization process, often necessary for the solubilization of certain drugs, can technically make the process unfeasible. Certain organo-aqueous mixtures may not freeze at a given temperature or require special equipment; and

[019] The removal of organic solvents by sublimation can damage lyophilization equipment.

[020] Thus, an alternative process to lyophilization is the spray drying process, widely used in the food and pharmaceutical industry (Gibbs, B. F., S. Kermasha, et al. (1999). "Encapsulation in the food drying industry: a review." International Journal of Food Sciences and Nutrition, 50(3): 213-224; Abdul-Fattah, A. M., D. S. Kalcinia, et al. (2007). "The challenge of drying method selection for protein pharmaceuticals: Product quality implications." Journal of Pharmaceutical Sciences, 96(8): 1886-1916; Vehring, R. (2008). "Pharmaceutical particle engineering via spray drying." Pharmaceutical Research 25(5): 999-1022; Sollohub, K. and K. Cal (2010). "Spray Drying Technique: II. Current Applications in Pharmaceutical Technology." Journal of Pharmaceutical Sciences, 99(2): 587-597 ).

[021] The spray drying process consists of spraying a solution or suspension in a cylindrical chamber, in a current of unsaturated hot air, which removes the solvent, allowing to obtain in the form of powder, in just one step, the solute that was dissolved or in suspension (Abdul-Fattah, A. M., D. S. Kalcinia, et al. (2007). "The challenge of drying method selection for protein pharmaceuticals: Product quality implications." Journal of Pharmaceutical Sciences, 96(8): 1886- 1916; Wang, S. and T. Langrish (2009). "A review of process simulations and the use of additives in spray drying." Food Research International, 42(1): 13-25). Among the drying processes described in the literature, spray drying is the only process in which the removal of the solvent is immediately followed by the definition of the shape of the particles, which is a distinct characteristic of this process (Wang, S. and T. Langrish ( 2009). "A review of process simulations and the use of additives in spray drying." Food Research International, 42(1): 13-25).

[022] Compared to other solvent removal processes, the spray drying process is more economical, due to the high expansion of the specific surface area that increases the evaporation rate and reduces the drying time. The reduction of the drying time protects the active agent, since it reduces the contact between the microdroplets and the heated air of the spray dryer. The drug (active agent)/air contact can vary from a few seconds on a laboratory scale to minutes on an industrial scale. In addition to fast and efficient drying, the spray drying process has other advantages in relation to lyophilization, such as obtaining uniform size particles, increasing the specific surface area, energy efficiency, use of organic solvents, industrial scaling, high productivity, continuous flow in the preparation of materials, among others (Maltesen, M. J. and M. van de Weert (2008). "Drying methods for protein pharmaceuticals." Drug Discovery Today: Technologies, 5(2-3): e81-e88; Wang, S. and T. Langrish (2009). "A review of process simulations and the use of additives in spray drying." Food Research International 42(1): 13-25; Vehring, R. (2008). "Pharmaceutical particle engineering via spray drying ." Pharmaceutical Research, 25(5): 999-1022 ).

[023] The spray drying process has been widely used in the preparation and drying of thermosensitive substances, such as proteins, peptides, hormones, antibiotics, among others (Sollohub, K. and K. Cal (2010). "Spray Drying Technique: II Current Applications in Pharmaceutical Technology." Journal of Pharmaceutical Sciences, 99(2): 587-597; Jalalipour, M., K. Gilani, et al. (2008). "Characterization and aerodynamic evaluation of spray dried recombinant human growth hormone using protein stabilizing agents." International Journal of Pharmaceutics, 352(12): 209-216; Blanco, M.D., R.L. Sastre, et al. (2006). "Degradation behavior of microspheres prepared by spray-drying poly(D,L- lactide) and poly(D,L-lactide-co-glycolide) polymers." International Journal of Pharmaceutics, 326(1-2): 139-147; Silva-Júnior, A.A., M.V. Scarpa, et al. (2008). "Thermal analysis of biodegradable microparticles containing ciprofloxacin hydrochloride obtained by spray drying technique." Thermochimica Ac TA, 467(1-2): 91-98). This process has been increasingly used for applications in the pharmaceutical area, mainly in the preparation of microspheres, involving drugs and biodegradable polymers, preparation of particles (polymeric and non-polymeric) for inhalation, alteration of polymorphic forms, preparation of inclusion compounds involving drugs. /cyclodextrins, among other applications (Fernandes, C. M., M. T. Vieira, et al. (2002). "Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds." European Journal of Pharmaceutical Sciences, 15(1): 79- 88; EsclusaDiaz, M.T., M. GayoOtero, et al. (1996). "Preparation and evaluation of ketoconazole-beta-cyclodextrin multicomponent complexes." International Journal of Pharmaceutics, 142(2): 183-187; Blanco, M.D., R.L. Sastre, et al. (2006). "Degradation behavior of microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers." International Journal of Pharmaceutics 326(1-2): 139-147; Blanco, M.D., M.V. Bernardo, et al. (2003). "Preparation of bupivacaine-loaded poly([var epsilon]-caprolactone) microspheres by spray drying: drug release studies and biocompatibility." European Journal of Pharmaceutics and Biopharmaceutics, 55(2): 229-236; Vehring, R. (2008). "Pharmaceutical particle engineering via spray drying." Pharmaceutical Research, 25(5): 999-1022; Cabral-Marques, H. and R. Almeida (2009). "Optimization of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes." European Journal of Pharmaceutics and Biopharmaceutics, 73(1): 121129; Salustio, P.J., G. Feio, et al. (2009). "The influence of the preparation methods on the inclusion of model drugs in a betacyclodextrin cavity." European Journal of Pharmaceutics and Biopharmaceutics, 71(2): 377-386 ). Thus, the spray drying process presents itself as an alternative to the lyophilization process in the preparation of inclusion compounds involving cyclodextrins and drugs on a laboratory scale and can be an alternative for application in industrial processes, mainly being a more environmentally compatible drying process, due to energy savings. Estimates indicate that about 12% of all energy consumed in the industrial sector in the world is associated with drying processes, representing a high cost, given that a large part is produced from oil, an unstable energy source from an economic point of view ( Rane, M.V., S.V.K. Reddy, et al. (2005). "Energy efficient liquid desiccant-based dryer." Applied Thermal Engineering, 25(5-6): 769-781 ). However, most of the works found in the literature report the preparation of inclusion compounds only by premixing the drug and CD solutions, followed by drying, with no innovations being introduced in the preparations (EsclusaDiaz, M. T., M. GayoOtero, et al. (1996) "Preparation and evaluation of ketoconazole-beta-cyclodextrin multicomponent complexes." International Journal of Pharmaceutics, 142(2): 183-187; Vehring, R. (2008). "Pharmaceutical particle drying via spray." Research, 25(5): 999-1022; Koester, L.S., J.B. Bertuol, et al. (2004). "Bioavailability of carbamazepine:beta-cyclodextrin complex in beagle dogs from hydroxypropylmethylcellulose matrix tablets." European Journal of Pharmaceutical Sciences, 22 (2-3): 201-207; Fernandes, C. M., M. T. Vieira, et al. (2002). "Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds." European Journal of Pharmaceutical Sciences, 15( 1): 79-88; Figueiras, A., R. A. Carvalho, et al. (2007). "Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified beta-cyclodextrin." European Journal of Pharmaceutics and Biopharmaceutics, 67: 531-539; Cabral-Marques, H. and R. Almeida (2009). "Optimization of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes." European Journal of Pharmaceutics and Biopharmaceutics, 73(1): 121-129 ).

[024] In another aspect, the preparation of inclusion compounds involving drugs and cyclodextrins, by the conventional spray drying (MC) process, basically consists of preparing solutions and or suspensions, isolated from CD's and drugs, which are later mixed and left under agitation for a given period of time, and the resulting mixture was injected into a spray dryer (Bootsma, H. P. R., H. W. Frijlink, et al. (1989). "Beta-cyclodextrin an excipient in solid oral dosage forms - in vitro and in vivo evaluation of spray-dried diazepam-beta-cyclodextrin products." International Journal of Pharmaceutics, 51(3): 213-223; Koester, L.S., J.B. Bertuol, et al. (2004). "Bioavailability of carbamazepine: beta-cyclodextrin complex in beagle dogs from hydroxypropylmethylcellulose matrix tablets." European Journal of Pharmaceutical Sciences, 22(2-3): 201-207; Figueiras, A., R. A. Carvalho, et al. (2007). "Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified beta-cyclodextrin." European Journal of Pharmaceutics and Biopharmaceutics, 67: 531-539). The spray drying process as well as the other drying processes have some limitations, such as:

[025] Preparation of a premix of two solutions outside the equipment, before injection, leading to the concept of batch production;

[026] Injection of the sample containing the inclusion compound at room temperature,

[027] They do not consider the thermodynamics of the inclusion process, since the processes can be exothermic (mostly) and in certain cases endothermic;

[028] Absence of temperature control of the solution to be injected, which can reduce the inclusion process efficiency;

[029] Selective precipitation of the drug and/or CD due to differences in solubility between them, making inclusion difficult;

[030] Increase in the temperature of the sample within the microdroplets formed in the "spray" due to the current of hot air, changing the thermodynamics of the drug/CD inclusion process;

[031] Loss of biological activity of bioactive compounds, such as proteins and peptides, by thermal denaturation, among other specific problems.

[032] These limitations are better evidenced through the analysis of patent applications, CN1546145 and CN1247080, in addition to patent EA005111 report the preparation of inclusion compounds using the spray drying process. Patent US6720003B1 entitled “Serotonin reuptake inhibitor formulations” reports a process for preparing a solid dispersion comprising an active ingredient and a water-soluble polymer. The use of spray dryer for drying the drug-carrier inclusion complex is claimed. Alpha-, beta- and gamma-cyclodextrins are also claimed as a carrier vehicle, in addition to the drug to be carried, which may be sertraline. However, a modified flow system similar to that proposed in the present invention is not claimed, nor a temperature range that favors inclusion. This temperature range, in turn, comprised between 40 and 50°C; much higher than that claimed in the present application.

[033] Patent application BRPI0510382A, entitled “Inclusion complex and pharmaceutical preparation” refers to an inclusion complex containing a benzimidazole derivative and its preparation process, using cyclodextrin and a water-soluble polymer. However, the drug sertraline is not used, but benzimidazole derivatives. Furthermore, the system and process for preparing the inclusion compound differs from the subject matter.

[034] The patent application US20080200533, entitled “Drug or pharmaceutical compounds and a preparation thereof” reports processes of preparation of inclusion compounds, using cyclodextrin and sertraline, not limiting them. The patent application US20050250738A1, entitled “Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin” reports the process of preparing aqueous oral formulations containing sertraline or a pharmaceutically acceptable salt, and cyclodextrin. However, these applications do not report the use of a modified flow system coupled to a spray dryer that allows the inclusion of the drug in the cyclodextrin.

[035] Patent application US20090004262A1 entitled “Nanoparticulate formulations and methods for the making and use therof” describes the process of preparing nanoparticulate compositions, which include inclusion compounds using cyclodextrin. However, it does not refer to the process of preparing the cyclodextrin-sertraline inclusion compound, nor is the spray drying step claimed.

[036] Patent application US5376645, entitled “Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof” describes a process for preparing inclusion compounds involving cyclodextrins in an aqueous base. However, the temperature range considered appropriate by the inventor is 70 to 80°C. The treated material, in turn, comprises a temperature control in a much lower range.

[037] Patent US7037928B2, entitled "Compositions of N-(methylethylaminocarbonyl)-4-(-3-methylphenylamino)-3-pyridylsulfonamide and cyclic oligosaccharides" describes a method of preparing inclusion compounds based on torasemide and cyclodextrins, or derivatives of this, where some drying equipment is used; among them, the spray dryer. In that patent, however, a temperature range is claimed comprising a range of 10 to 100°C. The treated material, in turn, uses lower temperatures and also uses only the spray dryer as a drying equipment.

[038] Patent EP1793862B1 entitled "A process for the preparation of a piroxicam: Beta-cyclodextrin inclusion compound" describes a method of preparing the inclusion compound between the drug piroxicam and β-cyclodextrin at a molar ratio of 1:2.5 by spray drying applied. on a pilot scale to improve the physicochemical and biopharmaceutical properties of preparations for oral administration. This patent claims the use of an additive, ammonium hydroxide, at a concentration between 28 - 30% to solubilize piroxicam and works with a pilot scale of 12 kg of drug. The equipment inlet temperatures between 175°C and 195°C, outlet temperature of 110°C, temperature of the solution to be injected between 70°C and 80°C. The material treated herein does not use additives for drug solubilization, as well as differs from the inlet, outlet and solution temperatures, which are different from this patent.

[039] Patent application PI06120326A2 entitled "Cyclodextrin inclusion complexes and methods of preparation thereof" describes the preparation of inclusion compounds among flavorings, volatile substances and derivatives, in addition to cyclodextrins, using some drying processes, including drying by spraying or spray drying. The application shows the preparation of complexes by the dry mixture of two or more compounds, one of them being cyclodextrin, and subsequent dissolution, emulsification and/or suspension by the addition of solvents. The mixture of the active component and the cyclodextrin can be formed in a reactor, closed or open, with or without heating. The process described in the patent application does not describe the use of a continuous flow system and double injection according to the material treated herein. Furthermore, the mixing of the active compound and the cyclodextrin is done in batches and the reactor cooling is carried out in different temperature ranges from those shown in the process of the matter dealt with in this application. Additionally, the temperature reduction of the solution is carried out statically in the reactor, different from the continuous flow control proposed by the present application. In the matter discussed herein, the homogenization time is shorter than the range established by the aforementioned patent application, thus showing that the two technologies are distinct and divergent.

[040] Unlike the documents mentioned above, the subject matter shows changes in the process used to prepare the inclusion compounds. The modifications introduced allow better control of the injection and flow of drugs and cyclodextrin, as well as their pre-mixing; in addition to temperature control in smaller ranges, necessary for inclusion to occur.

DESCRIPTION OF THE FIGURES

[041] Figure 1 shows (a) schematic representation of the process of preparing the inclusion compounds, using a continuous flow system (SD.LT), (b) schematic representation of the SD.LT process, alternatively to continuous flow, with pre-mixing the drug and CD solutions to prepare the inclusion compounds.

[042] Figure 2 shows the X-ray diffractograms of powder, (a) SRT, (b) βCD, (c) physical mixture (MM) 1:1 and the inclusion compounds prepared at 1:1 molar ratio (d ) CI.SRT:βCD1:1LF, (e) CI.SRT:βCD1:1SD.MC and (f) CI.SRT:βCD1:1SD.LT.

[043] Figure 3 shows the TG curves: (a) SRT, (b) βCD, (c) physical mixture (MM) 1:1 and the inclusion compounds prepared at 1:1 molar ratio (d) CI.SRT: βCD1:1LF, (e) CI.SRT:βCD1:1SD.LT.

[044] Figure 4 shows SEM micrographs of the inclusion compound prepared at 1:1 molar ratio by the SD.LT process (a) 2000x magnification, (b) 7000x, (c) 10000x, and prepared by the lyophilization process (d ) 2000x, (e) 3000x and (f) 10000x.

[045] Figure 5 shows the particle size distribution curves of free molecules (a) SRT, (b) βCD and inclusion compounds (c) CI.SRT:βCD1:1LF, (d) CI.SRT:βCD1 :1SD.MC and (e) CI.SRT:βCD1:1SD.LT prepared by the different processes at a 1:1 molar ratio.

[046] Figure 6 shows the 2D ROESY nuclear magnetic resonance spectra of inclusion compounds formed between sertraline (SRT) and β-CD: (a) through the use of a modified flow system, using a spray dryer with temperature control of the spray drying process (SD.LT), (b) through the conventional spray drying process (SD.MC), and (c) through the lyophilization process (LF).

[047] Figure 7 shows the image of an acrylic box with 24 quadrants for performing the spontaneous locomotor activity test - "crossing" - and evaluating the influence of SRT, β-CD, and inclusion compounds on motor activity mice, using doses of 20 mg/kg.

[048] Figure 8 shows in (a) the oral administration (gavage) of aqueous solutions of free SRT, β-CD, and inclusion compounds in mice; (b) tail suspension test (TSC) for predictive evaluation of the antidepressant activity of free SRT, β-CD, and inclusion compounds, prepared by different processes, using doses of 20 mg/kg.

[049] Figure 9 shows the graph of the TSC results with the immobility measures of the groups of animals after treatment with free SRT, β-CD, and the inclusion compounds prepared by the different processes.

[050] Figure 10 shows the graph of the evaluation of locomotor activity (number of crossings) of each group of animals after treatment with free SRT, β-CD, and the inclusion compounds prepared by the different processes.

[051] Figure 11 shows the 2D ROESY nuclear magnetic resonance spectra of the inclusion compounds formed between losartan potassium and β-CD: (a) through the conventional lyophilization process (LF), (b) through the use of a modified flow system, using a spray dryer equipment with temperature control of the spray drying process (SD.LT).

DETAILED DESCRIPTION OF THE INVENTION

[052] The treated matter comprises a process of preparation of inclusion compounds that uses a continuous flow system, as outlined in Figure 1a.

[053] The Process of preparation of inclusion compounds involving cyclodextrins and drugs, using a flow system (Figure 1a), is characterized by comprising the following steps:

[054] Preparation of aqueous solutions of the soluble drug losartan, of poorly soluble drugs, preferably sertraline, and of cyclodextrin, at a concentration between 1.0 x 10-3 and 1.0 x10-2 mol/L, preferably 5, 0x10-3;

[055] Pumping the drug solution and the cyclodextrin solution, respectively, through pumps B1 and B2, in continuous, independent flow and in separate flow lines (Figure 1a);

[056] Adjustment of the pumping flow of B1 and B2;

[057] Mixture of solutions in controller C1, which can be a container or a pipe, this preferably in the form of a coil, and may also have a temperature control;

[058] Directing the resulting solution to the C2 controller, this preferably in the form of a serpentine;

[059] Control of the temperature of the mixture in C2; it can be a container or a pipe, this is preferably in the shape of a serpentine;

[060] Directing the solution to a spray dryer equipment through a B3 pump, at a given temperature;

[061] Adjustment of spray dryer equipment control parameters;

[062] Production of a dry powder.

[063] The process of preparing inclusion compounds involving cyclodextrins and poorly soluble drugs, using a continuous flow system (Figure 1a) is also characterized by using, as solvents, water, organic solvents, mixtures of co-solvents, of the drug. and CDs; characterized in that the pumping flow of B1, B2 and B3 comprises a range between 1 and 28 ml/min, preferably between 8 and 12 ml/min; characterized by the maintenance of the drug/CDs molar ratio comprising a range between 1:0.001 and 1:10, preferably between 1:0.1 and 1:5; and characterized by controlling the temperature of the mixture at C1 comprising a range between 0 and 100°C, preferably between 20 and 30°C, and at C2, comprising a range between -5.0 and 30°C, preferably between 0° and 5°C.

[064] The spray dryer equipment control parameters (SD, Figure 1a) that must be adjusted are characterized by comprising:

[065] Spray dryer air flow control; it can vary at a pressure between 5 and 8 bar and at a flow that can vary between 600 and 800 L/h;

[066] Control of the spray dryer vacuum flow, which can vary between 50 and 100%, with a flow that can vary between 30 and 40 m3/h;

[067] Control of the inlet temperature in the spray dryer, which can vary between 100 and 200 °C, preferably between 120 - 150 °C;

[068] Control of the spray dryer outlet temperature, which can vary between 40 and 65 °C, preferably between 50 and 60 °C.

[069] The cyclodextrins that can be used in the present invention (Figure 1a) comprise the natural cyclodextrins α (alpha), β (beta) or Y (gamma) cyclodextrins and or semi-synthetic cyclodextrins, alkyl, hydroxyalkyl, hydroxy-propyl derivatives (eg hydroxy-propyl-α-cyclodextrins, hydroxy-propyl-β-cyclodextrins, hydroxy-propyl-Y-cyclodextrins), acyl, or cross-linked poly-cyclodextrins or poly-cyclodextrins, preferably β-cyclodextrin and/or combinations with other cyclodextrins.

[070] The drugs that can be used in the present invention comprise an antidepressant from the selective serotonin reuptake inhibitor class such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine; or selective serotonin/noradrenaline reuptake inhibitors such as duloxetine, venlafaxine; or serotonin reuptake inhibitors and alpha-2 antagonists, nefazadone, tradazone; or serotonin reuptake stimulant, tianeptine, non-selective monoamine reuptake inhibitors (Serotonin/Noradernalin) or also known as tricyclic antidepressants), amitriptyline, nortriptyline, clomipramine, imipramine, desipramine, doxepin, maprotiline; or monoamine oxidase inhibitors, tranylcypromine, isocarboxazid, iproniazid, phenelzine, chlorgyline, moclobemide, toloxatone, brofaromine, befloxatone; or alpha-2 adrenoreceptor antagonists, mirtazapine, mianserin; or selective dopamine reuptake inhibitors, minaprine, bupropion, amineptine; or selective norepinephrine, viloxazine and reboxetine reuptake inhibitors, preferably sertraline hydrochloride.

[071] In addition to antidepressants, drugs that can also be used in the present invention include AT1 receptor antagonists, namely: telmisartan, valsartan, candersartan, azilsartan, eprosartan, ibersartan, olmesartan, or tasosartan; preferably, losartan potassium, non-limiting.

[072] Depending on the physicochemical aspects, the drugs that can be used in the present invention comprise a compound of high solubility and high permeability (Class I), according to the biopharmaceutical classification (CBS) (Amidon, G. L., H. Lennernas, et al. (1995) "A theoretical basis for abipharmaceutic drug classification - The correlation of in vitro drug product dissolution and in vivo bioavailability", Pharmaceutical Research, 12(3): 413-420) such as; amiloride, chloroquine, cyclophosphamide, diazepam, digoxin, doxycycline, fluconazole, levodopa+carbidopa, levonorgestrel, metronidazole, phenobarbital, phenoxymethylpenicillin, prednisolone, primaquine, propranolol, pyrazinamide, riboflavin, salbutamol, stavudine, theophylline, zidovudine, amoxicillin, benzinidazole, diethyl carbamazine, DL-methionine, ethosuximide, isoniazid, lithium carbonate, nicotinamide, norethisterone, pyridoxime, proguanil hydrochloride, chlorpheniramine, atropine sulfate, dexamethasone, ethinylestradiol, glyceryl trinitrate, isosorbide dinitrate, lamivudine, levamisole, sulfate morphine, metoclopramide, quinine, sodium iodide, verapamil, warfarin; or low solubility and high permeability compounds (Class II) of BCS such as amiodarone, atorvastatin, folic acid, albendazole, azithromycin, nalidixic acid, nevirapine, carbamazepine, chlorpromazine, cisaprides, ciprofloxacin, clofazimine, diloxanide, cyclosporine, diclofenac, diflunisal, digoxin, erythromycin, efavirenz, flurbiprofen, danazol, dapsone, glipazide, glibenclamide, griseofulvin, haloperidol, ivermectin, lopinavir ibuprofen, indanavir, indomethacin, itraconazole, ketoconazole, lansoprazole, lovastatin, mefloquine, mebendazole, naproxen, niclosamide, nitrofuradiantoin, ofloxafenadiantoin , phenytoin, pyrantel, pyrimethamine, piroxicam, raloxifene, rifamycin, retinol, ritonavir, saquinavir, spironolactone, sulfamethoxazole, sulfadizaine, sulfasalazine, tracrolimus, tamoxifen, terfenadine, trimethropine, valproic acid, phenazopyridine, nelfinavir, glipizide, glibenclamide, oxyprozine, raloxiprozine sirolimus, talinolol; or BCS high solubility and low permeability (Class III) compounds such as abacavir, acyclovir, acetyl salicylic acid, allupurinol, ascorbic acid, atenolol, biperiden, captopril, chlorphenicol, cimetidine, cloxacillin sodium, didanosine, ergocalciferol, ergometrine, erythromycin , ethambutol, codeine phosphate, colchicine, ergotamine, hydralazine, hydrochlorothiazide, levothyroxine sodium, methotrexate, metformin, methyldopa, neostigmine, nystatin, nifurtimox, paracetamol (acetaminophen), promethazine, propylthiouracil, pyridostigmine, reserpine, thiamine; or low solubility and low permeability (Class IV) BCS compounds such as acetazolamide, azathioprine, amphotericin, chlorthalidone, chlorthiazide, ciprofloxacin, furosemide, aluminum hydroxide, hydrochlorothiazide, indanavir, mebendazole, methotexate, neomycin, nelfinavir, ritonavir, or saquinavir, non-limiting.

[073] Alternatively, the process of preparing inclusion compounds involving cyclodextrins and drugs, also using a flow system and pre-mixing the solutions (Figure 1b), is characterized by comprising:

[074] Step C3 represents a container for pre-mixing and homogenization of drug solutions (S1) and cyclodextrin (S2), preferably in the form of a tank;

[075] The agitation of the tank in "ii" by pumping system, rotating blade, rotation of the container, agitation by rocking, preferably mechanical agitation by propeller;

[076] The stirring speed in "iii" varies between 100 and 2000rpm, preferably between 300 and 500rpm, for a period of time between 1 and 60 minutes, preferably between 5 and 20 minutes;

[077] The drug/CD molar ratio of the premix in “ii” varies between 1:0.001 and 1:5, preferably between 1:0.01 and 1:5;

[078] Pumping the premix from container C3 to C2 by B1 with flow ranging between 1.0 and 28.0 ml/min, preferably between 4 and 8.0 ml/min;

[079] The temperature control of the pre-mix in C2 by a piping system, preferably in the form of a coil;

[080] The control of the temperature of the premix in C2 by a continuous flow system in the range between -5.0 and 5.0°C, preferably between 0 and 2°C;

[081] The spray dryer gas flow (spray flow) varies between 100 and 800 L/h, preferably between 300 and 400 L/h;

[082] The flow of the spray dryer aspirator varies between 20 and 40 m3/h, preferably between 30 and 40 m3/h;

[083] The inlet temperature of the carrier gas in the spray dryer varies in the range between 30 and 200 °C, preferably between 120 and 150 °C;

[084] The outlet temperature (outlet temperature) of the dry material in the system varies between 40 and 65°C; and,

[085] Obtaining the product in the form of a dry powder.

[086] The process (Figure 1) can still be applied to the preparation of complexes between cyclodextrins and bioactive agents. The term “bioactive agent” must be understood in the broadest sense, not limited to compounds of biological origin; being considered any substance that has pharmacological activity with therapeutic, prophylactic or curative function in humans (Code of Federal Regulations 21, FDA, part 330.05 (drug categories), part 331 through 361; 440-460, revised in April 2011, “titled” drugs for human use”). These bioactive agents can be proteins and peptides, the first being defined as macromolecules formed by the chaining of 100 or more amino acid residues, while the second represented by structures with less than 100 amino acid residues. In addition to peptides and proteins, bioactive macromolecules with different chemical compositions such as polysaccharides, sugars, DNA, RNA, genes, part of nucleic acid gene sequences, lipids, enzymes, antigens, natural compounds (extracted from living systems), semi-synthetic (modified after extraction) or synthetic (artificially prepared) can be conjugated with cyclodextrins using the proposed process (Figure 1).

[087] The preparation of a solution of a vehicle; this being cyclodextrins and/or derivatives, at a given temperature, concentration and in different molar proportions of this drug and the cyclodextrin; for example 1:1 to 1:10, 2:1 to 2:10 or 3:1, preferably 1:1 to 1:5, non-limiting.

[088] The cyclodextrin solution (S1) in a concentration between 1.0 x 10-3 to 1.0 mol/L is inserted through a pump (B1), according to the molar proportion, while the drug solution to be complexed (S2) at a non-limiting concentration between 1.0 x 10-3 and 1.0 mol/L is pumped simultaneously by the pump (B2) (Figure 1a). The two pumping lines, coming from (B1) and (B2) converge through tubes to a controller (C1), where the solutions are previously mixed in a spiral system; under a temperature range of at least 0°C and at most 100°C, with a pumping flow of at least 1.0 and at most 28.0 mL/min, non-limiting. The mixture of the two solutions leaves the controller (C1) and moves, under pressure, to another spiral system or controller (C2), in which the temperature of the drug/cyclodextrin mixture can be controlled. At C2 the temperature of the mixture can be raised from 0°C to 100°C if the process of interaction between the chemical species is endothermic and or it can be reduced by at least -5°C and at most +5°C in the case of exothermic systems, according to the drug system/CDs involved. Temperature control is a critical step for the preparation of the inclusion compound by the continuous flow system, since it alters the thermodynamics of the inclusion process, favoring the interaction between two chemical species, preferably the drug sertraline hydrochloride and cyclodextrins and or potassium losartan and cyclodextrins. Then, the solution containing the inclusion compound leaves the controller (C2), in continuous flow, at a given temperature and pressure and is injected into the spray dryer equipment (SD) by the pump (B3) with a flow rate varying between 1.0 and 28.0 ml/min according to the drug/CD molar ratio used. Pumping pressure, equipment inlet temperature and vacuum pressure were controlled to obtain the product in the form of dry powder.

[089] The pumping flow of B1, B2 or B3 comprises a range between 1 and 28 mL/min; the spray pressure (spray flow) varied between 5 and 8 bar, with a gas flow between 100 and 800 L/h, preferably between 300 and 400 L/h and the spray dryer vacuum flow varied between 0 and 40 m3/h , preferably, a flow between 30 and 40 m3/h. The formation of the spray jet can be performed by rotating, kinetic, ultrasound, electrostatic, preferably pneumatic atomizers.

[090] The temperature of the temperature of the mixture at C2 comprises a range between -5 and 30°C, preferably between 0° and 5°C. The injection temperature can be reduced for drug/CD systems if the process is exothermic and or high when the system is endothermic, in both cases favoring the interaction according to the thermodynamics of the inclusion process. The. In order to demonstrate the process of preparation of the inclusion compound, by the spray drying process in continuous flow (SD.LT) the drug sertraline hydrochloride (SRT) was used as an example of low solubility drug (4.0 mg/ mL), a serotonin reuptake inhibitor (SSRI) antidepressant (Johnson, B. M. (1996). "Sertraline Hydrochloride." Analytical Profiles of Drug Substances and Excipients, 24: 443-486) and as a model of high solubility drug Losartan potassium (LS) and β-cyclodextrin (β-CD) with a solubility of 18.5 mg/mL (Brewster, 2006; Salustio, 2009). In vivo biological tests were performed to evaluate the pharmacological activity of free SRT, βCD, and of inclusion compounds prepared by the process in which the treated matter consists.

[091] The solutions of drugs or cyclodextrins used in the present invention can be prepared, having as solvents, water, buffered aqueous solutions, organic solvents and co-solvents (organic/aqueous mixtures). Organic solvents can be alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, hexanol; or dichloromethane, dimethyl sulfoxide, chloroform, ether, ethyl acetate, methyl tert-butyl ether; not limiting. The. The subject matter can be better understood from the following non-limiting examples: Example 1 - Preparation of the inclusion complex between the drug sertraline hydrochloride (SRT) and β-cyclodextrin (βCD), via lyophilization (LF) and spray conventional drying process (SD.MC). B. Initially, two solutions were prepared separately, one of SRT and the other of βCD, at a concentration ranging from 1.0 x 10-3 to 1.0 x 10-2 mol/L. An aliquot of at least 100 mL of each solution was previously mixed, maintaining a molar ratio of at least 1:1 of SRT:βCD, and the final solution resulting from the mixture was kept under agitation (2000 rpm) for a period of at least 6 hours. The final solution was then divided into two aliquots. ç. The first aliquot was frozen in liquid nitrogen, and subsequently subjected to lyophilization. d. The second aliquot was injected into the spray dryer according to the conventional methodology (SD.MC) reported in the literature (Lin;, S. Y. and Y. H. Kao; (1989). "Solid particulates of drug-b-cyclodextrin inclusion complexes directly prepared by a spray-dryer technique", International Journal of Pharmaceutics, 56: 249-259). maintaining the operating parameters of the device. and. The dry powder obtained was then characterized by Nuclear Magnetic Resonance (Figures 2(b) and 2(c)).

Example 2 - Preparation of the inclusion complex between the drug sertraline hydrochloride (SRT) and β-cyclodextrin (βCD) by the spray drying-SD.LT process, by double injection and in continuous flow.

[092] Basically, the preparation of the inclusion complex consists of the following steps:

[093] Aqueous solutions of the drug between 1.0 x 10-3 and 1.0 x 10-2 mol/L, or non-aqueous solutions when the drug is poorly soluble, preferably sertraline hydrochloride, between 1 .0 x 10 -3 to 1.0 x 10 -2 mol/L, and cyclodextrin, at a concentration between 1.0 x 10 -3 to 1.0 mol/L;

[094] The drug solution, preferably sertraline hydrochloride and cyclodextrin were pumped, respectively, through pump B1 and B2, independently and in separate flow lines (Figure 1a). The pumping pressure of B1 and B2 was adjusted to a flow between 1.0 to 28.0 mL/min. for each pumping line, so that the molar ratio of SRT/cyclodextrin was maintained, preferably 1:1;

[095] The solutions in the two lines were found in the C1 controller, preferably in the form of a serpentine, at a temperature between 0 to 100°C, preferably 20 and 30°C, in order to allow homogenization between the solutions coming from B1 and B2;

[096] After mixing the solutions in C1, the resulting solution was directed to the controller C2, preferably in the form of a serpentine, where the temperature of the mixture was controlled in a range of -5.0 to 5.0°C, preferably, between 0 and 5.0°C;

[097] The solution was then directed to the spray dryer equipment, through a B3 pump in a flow range that varied between 1.0 and 28.0 mL/min preferably between 4.0 and 8.0 mL/min .;

[098] The spray dryer air flow pressure (spray flow) varied between 5 to 8 bar with a gas flow between 100 and 800 L/h, preferably between 300 and 400 L/h;

[099] The flow of the spray dryer aspirator varied between 50 and 100%, corresponding preferably to a flow between 30 and 40 m3/h;

[0100] The inlet temperature of the gas in the spray dryer ranged between 30 and 220 °C, preferably between 100 and 150 °C;

[0101] The outlet temperature (outlet temperature) of the dry material of the system varied between 40 and 65°C, preferably between 50 and 60°;

[0102] Finally, a dry powder was produced, which was characterized through physical-chemical analysis techniques.

Example 3 - Preparation of the inclusion complex between the drug Losartan potassium (LS) and β-cyclodextrin (βCD) by spray drying .LT process, by double injection and in continuous flow.

[0103] Basically, the preparation of the inclusion compound in the following steps:

[0104] Aqueous solutions of the drug Losartan potassium and cyclodextrin were previously prepared at a concentration of 1.6 x 10-3 mol/L;

[0105] The drug and cyclodextrin solution were pumped, respectively, through pump B1 and B2, independently and in separate flow lines (Figure 1a). The pumping pressure of B1 and B2 was adjusted to a flow that varied between 1.0 to 28.0 mL/min., for each pumping line, maintaining the molar ratio of LS/cyclodextrin, preferably 1:1;

[0106] The solutions in the two lines were found in the C1 controller, preferably in the form of a coil, at a temperature between 40 - 65°C, in order to allow homogenization;

[0107] After mixing the solutions in C1, the resulting solution was directed to the controller C2, where the temperature of the mixture was controlled in a range between 0 and 4°C;

[0108] The solution was then directed to the spray dryer equipment, through a B3 pump in a flow range that varied between 8.5 and 11.5 mL/min.;

[0109] The spray dryer air flow pressure (spray flow) varied between 5 to 8 bar with a gas flow between 100 and 800 L/h;

[0110] The spray dryer vacuum flow varied between 50 and 100%, corresponding to a flow between 20 and 40 m3/h;

[0111] The inlet temperature of the carrier gas in the spray dryer varied in the range between 120 and 150°C;

[0112] The outlet temperature of the dry material in the system ranged between 40 - 50°C;

[0113] Finally, a dry powder was produced, which was characterized by 2D-ROESY NMR.

Example 4 - Preparation of the inclusion complex between the drug Sertraline Hydrochloride and β-cyclodextrin (βCD) by the SD.LT process, alternatively with pre-mixing the solutions.

[0114] Aqueous solutions of the drug (S1) and cyclodextrin (S2) were prepared (Figure 1b), preferably sertraline hydrochloride and β-cyclodextrin, in a concentration between 5.0 x 10-3 and 1.0 x 10- 2 mol/L, preferably 5.0 x 10-3 mol/L;

[0115] The two solutions of item “i” were previously mixed and stirred in a container (Figure 1b - (C3)), for a period of time that varied between 1 minute and 60 minutes, preferably between 10 and 30 minutes;

[0116] The pre-mix container (C3 - Figure 1b) described in item "ii" alternatively replaces the controller (C1) in the scheme of Figure 1a, preferably in the form of a cylindrical tank, with a conical bottom;

[0117] The temperature of C3 varies between 0 and 100°C, preferably between 30 - 60°C;

[0118] The agitation of the container described in "ii" varies between 100 and 2000rpm, preferably between 300 and 500rpm;

[0119] The drug/CD molar ratio of the premix described in item “ii” varied between 1:0.1 and 1:5, preferably 1:1;

[0120] The mixture of solutions prepared according to item "i" to "v" was directed to controller C2, preferably in the form of a coil, through pump B1, as shown in Figure 1b, with a flow that varied between 1, 0 and 28.0 mL/min;

[0121] The temperature of the mixture was controlled at C2 and varied in the range between -5.0 and 5.0°C, preferably between 0 and 2°C;

[0122] The solution leaves the C2 controller and is directed to the spray dryer equipment, through a B3 pump in a flow range that varied between 1.0 and 28.0 mL/min, preferably between 4.0 and 8.0 mL/min.;

[0123] The spray dryer air flow pressure (spray flow) varied between 5 to 8 bar with a gas flow between 100 and 800 L/h, preferably between 300 and 400 L/h;

[0124] The flow of the spray dryer aspirator varied between 20 and 40 m3/h, preferably between 30 and 40 m3/h;

[0125] The inlet temperature of the carrier gas in the spray dryer ranged between 30 and 200 °C, preferably between 120 and 150 °C;

[0126] The outlet temperature (outlet temperature) of the dry material of the system varied between 40 and 65°C;

[0127] The product obtained was in the form of a dry powder, which was characterized through physical-chemical analyses.

Example 5 - Characterization of products and comparison of the data obtained.

[0128] The characterization of the inclusion compound formed between the SRT and the β-CD, in the molar ratio 1:1 was carried out by different physicochemical techniques; both solid-state and powder X-ray diffraction spectroscopy (XRD), infrared spectroscopy (FTIR), thermal analysis (TG/DTA), scanning electron microscopy (SEM), scattering particle size measurement light, as well as in solution by nuclear magnetic resonance (NMR) techniques.

[0129] Figure 2 shows the XRD analysis of the inclusion compound prepared between SRT and β-CD, which showed that the process claimed led to the formation of a compound with an amorphous profile (Figure 2f), similar to that observed for the same system prepared by the lyophilization processes (Figure 2d) and SD.MC (Figure 2.e), but different from the sample containing only the physical mixture of SRT and β-CD, which presented a sum profile of the isolated diffractograms.

[0130] Figure 3 shows the TG curves of the inclusion compound prepared by the claimed process (Figure 3e); which showed a different profile than that observed for the free SRT molecules (Figure 3a), β-CD (Figure 3b) and the physical mixture (Figure 3c), suggesting the formation of the inclusion compound. Complex formation by the claimed process is enhanced by the similar profile compared to the lyophilized complex curve (Figure 3d). The residual moisture of the prepared complex was 6.1% between 30 and 100°C, a value close to the 6.0% observed in the TG curve of the complex prepared by lyophilization (Figure 3d).

[0131] In Figure 4 can be seen the micrographs obtained by SEM of the particles, which presented spherical shapes, with invaginations, suggesting formation of microcapsules (Figures 4a to 4c); differently from what was observed for the particles obtained by the lyophilization process that presented laminar shapes (Figures 4d and 4e).

[0132] Figure 5 shows the particle size distribution curves, which showed that the complexes prepared by spray drying showed unimodal distribution, with particle size around 5.0 μm, by the claimed process (Figure 5e), a value significantly lower than the 265μm observed for the complexes prepared by lyophilization (Figure 5c). Controlling the particle size by the claimed process can facilitate the homogenization of the drug with excipients during the preparation of pharmaceutical formulations for oral use, as well as facilitate the dissolution process.

[0133] The effective interaction between the drug SRT and β-cyclodextrin can be observed by NMR techniques (Figure 6); thus confirming the formation of the inclusion compounds. The. Figure 6(a) shows the 2D ROESY contour map of the inclusion compound prepared by the process claimed in the present invention, involving SRT and β-cyclodextrin where a large number of spatial correlations between the hydrogens of the SRT and the CD. Comparing the expansions of the 2D ROESY contour maps shown in Figures 6(a), (b) and (c) it is observed that the contour map of the inclusion compound prepared by the spray drying process in the present invention (Figure 6a) shows a number of correlation signals between SRT and βCD similar to those observed in the contour map of the same compound prepared by the lyophilization process (Figure 6c). On the other hand, the contour map of the inclusion compound prepared by the conventional spray drying process (SD.MC) (Figure 6b) is different from the two contour maps presented in Figures 6a and 6c. This result shows the effectiveness of the present process for the preparation of inclusion compounds involving drugs of low solubility and which can be used in the preparation of inclusion compounds involving drugs and cyclodextrins to replace the lyophilization process (LF) and the conventional spray dryer process. (SD.MC), with the advantage of being a fast and continuous production process.

Example 7 - Characterization of the complex formed between Losartan and cyclodextrin by the SD.LT process.

[0134] The interaction between Losartan potassium and β-cyclodextrin can be observed by NMR techniques (Figure 1a1); thus confirming the formation of the inclusion compounds.

[0135] Figure 1a1a shows the 2D-ROESY contour maps of the LS:βCD complex in a 1:1 molar ratio prepared by the conventional lyophilization process, which shows spots indicative of scalar coupling between the hydrogens of Losartan and CD. Figure 1a1b shows the contour map of the LS:βCD complex in the 1:1 molar ratio prepared by the SD.LT process, which presents numerous stains of correlations indicative of scalar couplings, with a profile similar to that observed in Figure 1a1a (process of lyophilization). Thus, as shown in Figures 11a and 11b, the claimed preparation process can also be applied to the preparation of complexes involving also soluble drugs.

Example 7 - In vivo biological tests.

[0136] In order to verify the influence of the preparation processes on the antidepressant pharmacological profile of the inclusion compounds formed between SRT and βCD, in vivo tests were performed.

[0137] The in vivo tests were carried out in male, adult, CF1 type mice, weighing between 20 and 30 g. Before the experiments, the animals were adapted for at least 05 days in a transit vivarium. The animals were kept in plastic boxes measuring 17x28x13 cm with a maximum of eight mice. The animals were kept under a 12-hour light/dark cycle (lights on from 7 am to 7 pm), with constant temperature (23±2°C), under an exhaust system (ventilated shelves) and monitored humidity, with free access to water. and food. The experiments were carried out from 10 am to 4 pm, with an adaptation of the animals for 1 hour to the experimentation room.

[0138] Prior to drug administration, the animals underwent a 3-hour fasting period. A transparent acrylic box measuring 40x30x30cm was used for the experiments, with the bottom divided into 24 equal quadrants (Figure 7).

treatments

[0139] The mice received orally (Figure 8(a)), a dose of 20 mg/Kg from aqueous solutions of free sertraline and or respective inclusion compounds (concentration of 2.0 mg/mL), prepared by the different processes described. As a control group, only water (vehicle) was administered, without the drug. Tail suspension test (moderate severity)

[0140] The tail suspension test (TSC) was performed according to Steru et al., through adaptations (Steru, L., R. Chermat, et al. (1985). "The Tail Suspension Test - A new method for screening antidepressant in mice", Psychopharmacology, 85(3): 367 370 ). Like the forced swim test (TNF), the TSC is based on the fact that rodents (most often mice) develop an immobile posture when placed in a stressful and inescapable situation. This immobility is significantly reduced with the previous administration of antidepressants, especially those that act on the serotonergic system. The protocol consisted of pre-treating the mice orally with the appropriate doses of drugs 1 hour before suspending them by the tail end with the aid of adhesive tape 60 cm from the ground (Figure 8(b)) for a period of 6 minutes, in which the total immobility time for each animal was recorded (Duarte, F. S., G. Lach, et al. (2008). "Evidence for the involvement of the monoaminergic system in the antidepressant-like action of two 4- amine derivatives of 10,11-dihydro-5H-dibenzo[a,d]cycloheptane in mice evaluated in the tail suspension test", Progress in Neuro Psychopharmacology & Biological Psychiatry, 32(2): 368-374 ). The animals treated only with water, without the active ingredient, were used as a negative control to be compared with the treated animals. This procedure is considered moderately stressful for the animals, as it causes a transient increase in serum corticosterone levels. However, it is an intrinsic feature of the model that makes it valid as an animal model of depression, where stress is known as a triggering factor (Barbier, E. and J. B. Wang (2009). "Anti-depressant and anxiolytic like behaviors in PKCI/HINT1 knockout mice associated with elevated plasma corticosterone level" Bmc Neuroscience, 10; Wang, S. and T. Langrish (2009)", A review of process simulations and the use of additives in spray drying." Food Research International, 42 (1): 13-25). Most animal models for assessing depression, accepted in the literature, involve some degree of stress being. So, this stress is fundamental for the proposed study (Willner, P. (1990). "Animal - Models of depression - An overview", Pharmacology & Therapeutics, 45(3): 425-455) The test was performed in a controlled environment. of light and noise. Assessment of spontaneous locomotor activity: open field exposure test

[0141] Motor parameters are commonly evaluated in rodents in the early stages of investigation of a likely central effect of compounds, mainly due to their simplicity (Steru, L., R. Chermat, et al. (1985). "The Tail Suspension" Test - A new method for screening antidepressants in mice", Psychopharmacology, 85(3): 367370). Changes in locomotor activity can lead to misinterpretations of the results obtained in the TSC test, since the reduction or increase in locomotion may be caused by CNS stimulatory effects and not by the predictive antidepressant effect of the tested compounds (Porsolt, R. D., G Anton, et al. (1978). "Behavioral despair in rats - New model sensitive to antidepressant treatments." European Journal of Pharmacology, 47(4): 379-391; Crowley, J.J., J.A. Blendy, et al. (2005) ). "Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test." Psychopharmacology 183(2): 257-264). Thus, it is necessary to evaluate locomotor activity, which can be performed by the open field exposure test (ACT), one of the most used models due to its simplicity (Porsolt, R. D., G. Anton, et al. (1978) "Behavioral despair in rats - New model sensitive to antidepressant treatments." European Journal of Pharmacology, 47(4): 379-391; Crowley, J.J., J.A. Blendy, et al. (2005). "Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test" Psychopharmacology, 183(2): 257-264; Porsolt, R.D., A. Bertin, et al. (1977), "Behavioral despair in mice - Primary screening-test for antidepressants." Archives Internationales De Pharmacodynamie Et De Therapie, 229(2): 327-336).

[0142] After the TSC test, the mice were immediately transferred to the acrylic box (Figure 7) to perform the open field test (TCA Test), and they were observed for a period of 6 minutes and the number of crossings between the quadrants (“crossings”) recorded. The procedure was performed in an environment with reduced light and noise.

[0143] Subsequently, the observed results were compiled and analyzed by one-way ANOVA (analysis of variance) with “post-hoc” Newman-Keuls Multiple Comparison Test and/or Dunnett's Multiple Comparison Test to determine the observations, shown in Figures 5 and 6.

[0144] Thus, in Figures 9 and 10 are presented, respectively, the results of the TSC tests and TCA tests in mice for antidepressant activity; using the vehicle, SRT, β-CD, inclusion compounds prepared by the lyophilization process (LF), by the conventional spray drying process (SD.MC) and by the claimed spray drying process (SD.LT).

[0145] The results of the TSC test (Figure 9) showed that the inclusion compounds prepared by lyophilization (LF) and by spray drying-LT showed statistically significant pharmacological activity in relation to the vehicle, (p < 0.001). In this case, the compounds obtained showed pharmacological activity, although the inclusion compound prepared by the conventional spray dryer method (SD.MC) showed no statistically significant difference (p > 0.05) in relation to animals treated only with the vehicle (water) (Figure 9a). Furthermore, the antidepressant activity of inclusion compounds prepared by lyophilization and by the innovative method (SD.LT) was not statistically significant (p > 0.05), indicating that similar inclusion compounds were obtained.

[0146] Comparing the pharmacological activity of animals treated with vehicle and free SRT, with those treated with the inclusion compound prepared by the conventional spray dryer process (SD.MC), no significant differences were observed between them (Figure 9a), indicating that the Inclusion compound prepared by the conventional process must not have formed between the SRT and CD. This result is in agreement with the 2D ROESY analyzes of these inclusion compounds (Figure 7c) which did not indicate the presence of significant spatial correlations between the SRT hydrogens and the βCD cavity hydrogens, which was observed both in the compounds prepared by lyophilization and by the spray dryer process claimed SD.LT (Figure 7a and c).

[0147] In Figure 10 are presented the results of tests of spontaneous locomotor activity by exposure to the open field (TCA Test) for the vehicle, free SRT, β-CD, and for the inclusion compounds prepared by the different processes previously described . Through the one-way ANOVA statistical analysis with the “post-hoc” Newman-Keuls Multiple Comparison Test, no significant differences were observed between the number of crossings of the groups of animals that received only the vehicle and those treated with free SRT, β-CD, and the inclusion compounds prepared by the different processes reported above. This result shows that the anti-immobility effect observed in the TSC test comes from the pharmacological activity of SRT and its complexes and not from a central nervous system (CNS) stimulant action, thus showing that the administration of the inclusion compound did not affect the animal motor.

Claims (4)

1. Process of preparation of inclusion compounds involving cyclodextrins and drugs, using a flow system, characterized in that it comprises the following steps: a. Separately prepare an aqueous solution (S1) of the soluble drug losartan or the sparingly soluble drug sertraline, and an aqueous solution (S2) of beta-cyclodextrin (βCD), both at a concentration between 1.0 x 10-3 and 1 .0 x 10 -2 mol/L, preferably 5.0 x 10 -3 mol/L; B. Pump the drug solution (S1) and the βCD solution (S2) prepared in “a”, through two separate pumps (B1 and B2, respectively), in continuous, independent flow and in separate flow lines, with a flow of pumping from 1 to 28 ml/min, preferably from 8 to 12 ml/min; ç. Mix the solutions obtained in “b” in a controller (C1), which can be a container or a pipe, this preferably in the form of a coil, and can also have a temperature control in the range between 0 and 100°C, preferably between 20 and 30°C; d. Direct the resulting solution in “c” to a second controller (C2), this preferably in the form of a coil; and. Control the temperature of the mixture obtained in “d”, in a range between -5.0 and 30°C, preferably between 0° and 5°C, which can be in a container or a pipe, this preferably in the form of a serpentine; f. Direct the solution obtained in “e” to a spray dryer (SD) through a third pump (B3), the pumping flow being from 1 to 28 mL/min, preferably from 8 to 12 mL/min; g. Adjust the equipment control parameters (SD), where the spray dryer air flow can vary at a pressure between 5 and 8 bar and at a flow between 600 and 800 L/h, the spray aspirator flow control dryer can vary between 50 and 100%, with a flow that can vary between 30 and 40 m3/h, the inlet temperature to the spray dryer can vary between 100 and 200 °C, preferably between 120 and 150 °C and the temperature of output may vary between 40 and 65°C, preferably between 50 and 60°C; H. Produce a dry powder. 2. Process of preparation of inclusion compounds involving cyclodextrins and drugs, using a continuous flow system, according to claim 1, characterized in that, in step "a", the aqueous solutions are prepared with the solvents selected from the group comprising water , organic solvents, co-solvent mixtures or organo-aqueous mixtures, or buffered aqueous solutions, the organic solvents being alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, hexanol, or the organic solvents being dichloromethane, dimethyl sulfoxide, chloroform, ether, ethyl acetate, methyl tert-butyl ether. 3. Process for the preparation of inclusion compounds involving cyclodextrins and drugs, using a continuous flow system, according to claim 1, characterized in that, in step "c", the drug/eCD molar ratio is 1:0.001 to 1 :10, or from 2:0.001 and 2:10, or from 3:0.001 and 3:10, being preferably from 1:0.1 to 1:5. 4. Process for the preparation of inclusion compounds involving cyclodextrins and drugs, using a flow system, according to claim 1, characterized in that it alternatively comprises pre-mixing the solutions, according to the following steps: i. The change from continuous flow to batch process (C3), replacing (C1) in step "c" of claim 1, where (C3) is a container for pre-mixing and homogenization of drug (S1) and cyclodextrin (S2) solutions ), preferably in the form of a tank, wherein the molar ratio S1/S2 of the premix may vary between 1:0.001 and 1:5, preferably between 1:0.01 and 1:5; ii. The agitation of the tank in "i" by pumping system, rotating paddle, rotation of the container, agitation by rocking, preferably mechanical agitation by propeller, and the agitation speed can vary between 100 and 2000 rpm, preferably between 300 and 500 rpm , for a period of time between 1 and 60 minutes, preferably between 5 and 20 minutes; iii. Pumping the premix from container C3 to C2 through B1 with flow ranging between 1.0 and 28.0 ml/min, preferably between 4 and 8.0 ml/min; iv. Control the temperature of the premix in C2 by a piping system, preferably in the form of a coil, or by a continuous flow system, in the range between -5.0 and 5.0°C, preferably between 0 and 2° Ç; v. Direct the solution obtained in “iv” to a spray dryer (SD) equipment, and the spray dryer gas flow (SD) must be between 100 and 800 L/h, preferably between 300 and 400 L/h, the spray dryer (SD) aspirator flow must be between 20 and 40 m3/h, preferably between 30 and 40 m3/h, the inlet temperature of the carrier gas in the spray dryer (SD) must be between 30 and 200°C , preferably between 120 and 150°C, and the outlet temperature of the dry material from the system (SD) can vary between 40 and 65°C; saw. Obtain the product in the form of a dry powder.

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