WO2013155586A1 - Process for preparing inclusion compounds enclosing cyclodextrins and drugs, using a continuous-flow system - Google Patents

Process for preparing inclusion compounds enclosing cyclodextrins and drugs, using a continuous-flow system Download PDF

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Publication number
WO2013155586A1
WO2013155586A1 PCT/BR2013/000135 BR2013000135W WO2013155586A1 WO 2013155586 A1 WO2013155586 A1 WO 2013155586A1 BR 2013000135 W BR2013000135 W BR 2013000135W WO 2013155586 A1 WO2013155586 A1 WO 2013155586A1
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cyclodextrins
drug
inclusion compounds
flow
cyclodextrin
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PCT/BR2013/000135
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French (fr)
Portuguese (pt)
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Robson Augusto Souza Dos Santos
Rubén DARIO SINISTERRA MILLÁN
Joel José PASSOS
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Universidade Federal De Minas Gerais - Ufmg
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present technology describes a process for the preparation of continuous flow inclusion compounds involving drugs and cyclodextrins coupled to a spray dryer equipment.
  • This process allows better control of injection and drug flow, preferably sertraline hydrochloride and / or base sertraline; and a vehicle, which may be natural cyclodextrins (a (alpha), ⁇ (beta) or ⁇ (gamma) cyclodextrins) or semi-synthetic cyclodextrins, alkyl, hydroxyalkyl, hydroxypropyl, acyl derivatives, or preferably polycyclodextrins, preferably ⁇ -cyclodextrin.
  • the process allows for better temperature control, which is critical for inclusion as well as optional premix control.
  • CD's which may improve the solubility and consequently the bioavailability and pharmacological activity of medicines.
  • CD's are synthesized from starch degradation and form macrocycles of glycopyranoside units containing from 6 to 8 glucose units. Due to the configurational constraints, the CD's form a conical structure which has a hydrophobic cavity and the hydrophilic exterior (Del Valle, EMM (2004). "Cyclodextrins and their uses: a review.” Process Biochemistry, 39 (9) : 1033-1046; Brewster, ME and T. Loftsson (2007). "Cyclodextrins as pharmaceutical solubilizers.” Advanced Drug Delivery Reviews, 59 (7): 645-666).
  • CD form inclusion compounds, receiving in its cavity, part or all of biologically active molecules.
  • CD / drug interaction can occur naturally, the preparation process of the inclusion compound influences its physicochemical characteristics, such as solubility, melting point, boiling point, polarity, among other properties.
  • Drying basically consists of converting a liquid, dissolved solute, suspension and / or semi-solid into a low moisture dry solid product, generally involving thermal energy consumption for water evaporation (Ratti, C. (2001). "Hot air and freeze-drying of high-value foods: a review. "Journal of Food Engineering 49 (4): 311-319; Rane, MV, SVK Reddy, et al. (2005).” Energy efficient liquid desiccant-based dryer. " Applied Thermal Engineering, 25 (5-6): 769-781). Drying processes also present high financial and energy costs, requiring specialized equipment, and their choice depends on the cost-benefit ratio, productivity and quality of the final product (Boss ;, EA (2004).
  • Lyophilization and spray drying are drying processes that allow the removal of the solvent used in the preparation of the inclusion compounds, the former being removed by sublimation and the second by evaporation (Schwegman, JJLM; Hardwick, et al. (2005 ) "Practical formulation and process development of freeze-dried products.”
  • the lyophilization process is one of the most used in the preparation of inclusion compounds, involving drugs and cyclodextrins.
  • This process consists of premixing two generally aqueous solutions of the drug and cyclodextrin, which, after homogenization, is frozen. Subsequent to the freezing step, the material is introduced into a lyophilizer and solid state water is removed by sublimation until dry material is obtained (Abdul-Fattah, AM, DS 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, MJ and M. van de Weert (2008).” Drying methods for protein pharmaceuticals.
  • Freezing large volumes of solutions containing inclusion compounds is technically limited and may make their preparation unfeasible and may generate thermal stress on samples. This produces different crystalline forms (depending on the cooling rate) affecting the particle size.
  • large, high-cost refrigerators are used, which may make the preparation process unfeasible continuously.
  • the spray drying process consists of spraying a solution or suspension into a cylindrical chamber in an unsaturated hot air stream, which removes the solvent, allowing the solute that was dissolved or dissolved to be powdered in one step. in suspension (Abdul-Fattah, AM, DS 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 particle shape. , a distinct feature 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).
  • the spray drying process is more economical due to the high expansion of the specific surface area which increases the evaporation rate and reduces the drying time. Reducing the drying time protects the active agent as it reduces the contact between the microtropules and the spray dryer heated air.
  • the drug (active agent) / air contact may range from a few seconds on a laboratory scale to minutes on an industrial scale.
  • the spray drying process has other advantages over freeze drying such as obtaining uniformly sized particles, increasing specific surface area, energy efficiency, use of organic solvents, industrial scaling, high productivity, continuous flow in preparation of materials, among others (Maltesen, MJ and M. van de Weert (2008).
  • thermosensitive substances such as proteins, peptides, hormones, antibiotics, among others
  • Spray Drying Technique II. Current Applications in Pharmaceutical Technology.
  • Characterization and aerodynamic evaluation of spray dried recombinant human growth hormone using protein stabilizing agents. International Journal of Pharmaceutics, 352 (1-2): 209-216; Blanco, MD, RL Sastre, et al.
  • This process has been increasingly used for pharmaceutical applications , mainly in the preparation of microspheres, involving biodegradable drugs and 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, CM, MT Vieira , et 1. (2002). "Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds.” European Journal of Pharmaceutical Sciences, 15 (1): 79-88; EsclusaDiaz, MT, M. GayoOtero, et al. (1996).
  • the spray drying process is presented as an alternative to the lyophilization process in the preparation of inclusion compounds involving laboratory scale cyclodextrins and drugs and can be an alternative for application in industrial processes, mainly being a more environmentally compatible drying process, due to energy saving.
  • Estimates indicate that about 12% of all energy consumed in the industrial sector in the world is associated with drying processes, which is a high cost, since much of it is produced from petroleum as an economically unstable energy source ( Rane, MV, SVK Reddy, et al. (2005). "Energy efficient liquid desiccant-based dryer.” Applied Thermal Engineering, 25 (5-6): 769-781).
  • the preparation of inclusion compounds involving drugs and cyclodextrins by conventional spray drying (MC) process, basically consists of preparing solutions and or suspensions, isolated from CD's and drugs, which are then mixed and left under stirring by a given time period, the resulting mixture being injected into the spray d / yer equipment (Bootsma, HPR, HW 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.
  • thermodynamics of the inclusion process may be exothermic (for the most part) and in some cases endothermic;
  • Patent application BRPI0510382A entitled "Pharmaceutical Inclusion and Inclusion Complex” refers to an inclusion complex containing a benzimidazole derivative and its preparation process using cyclodextrin and a water soluble polymer. However, sertraline is not used, but benzimidazole derivatives. In addition, the system and process of preparation of the inclusion compound differ from the treated matter.
  • US20080200533 entitled “Drug or pharmaceutical compounds and the preparation thereof”, reports processes for preparing inclusion compounds using cyclodextrin and sertraline, not limiting them.
  • US20050250738A1 entitled “Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin”
  • 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 cyclodextrin.
  • US7037928B2 entitled “Compositions of N- (methylethylaminocarbonyl) -4 - (- 3-methylphenylamino) -3-pyridylsulfonamide and cyclic oligosaccharides” describes a method of preparing torasemide and cyclodextrin-based inclusion compounds, or derivatives thereof, where some drying equipment is used; Among them, the spray dryer. In that patent, however, a temperature range comprising a range of 10 to 100 ° C is claimed. The treated material, in turn, uses lower temperatures and also uses only the spray dryer as a drying equipment.
  • 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 ⁇ -cyclodextrin at a 1: 2.5 molar ratio by spray drying applied on a scale. pilot 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 of 28-30% to solubilize piroxicam and works with a pilot scale of 12kg of drug.
  • Equipment inlet temperatures between 175 ° C and 195 ° C, outlet temperature 110 ° C, temperature of solution to be injected between 70 ° C and 80 ° C.
  • the material now treated does not use additives for solubilization of the drug, as well as as it differs from inlet, outlet and solution temperatures which are different from this patent.
  • Patent application PI06120326A2 entitled “Cyclodextrin Inclusion Complexes and Methods of Preparing Them” describes the preparation of inclusion compounds between flavorants, volatile substances and derivatives, in addition to cyclodextrins, using some drying processes, including spray or spray drying drying.
  • the application shows the preparation of complexes by dry mixing of two or more compounds, one being cyclodextrin, and further dissolving, emulsifying and or suspending by addition of solvents.
  • the active ingredient mixture and cyclodextrin may be formed in a closed or open reactor, with or without heating.
  • the process described in the patent application does not describe the use of a continuous flow and double injection system according to the subject matter herein.
  • the active compound and cyclodextrin are mixed in batches and the reactor is cooled in different temperature ranges than those shown in the process material treated in this application. Additionally, the solution temperature reduction is performed statically in the reactor, different from the continuous flow control proposed by the present application. In the subject matter 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.
  • the subject matter has modifications 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 premixing; in addition to the temperature control in smaller ranges required for inclusion.
  • Figure 1 shows (a) schematic representation of the process of preparing inclusion compounds using a continuous flow system (SD.LT), (b) schematic representation of the SD.LT process, alternatively continuous flow, with premixing of drug and CD solutions for preparation of the inclusion compounds.
  • SD.LT continuous flow system
  • Figure 2 shows the X-ray powder diffractograms, (a) SRT, (b) PCD, (c) 1: 1 physical mixture (MM) and inclusion compounds prepared at 1: 1 (d) CI molar ratio.
  • CI.SRT: CD1: 1SD.LT shows the X-ray powder diffractograms
  • Figure 3 shows TG curves: (a) SRT, (b) CD, (c) 1: 1 physical mixture (MM) and inclusion compounds prepared at 1: 1 molar ratio (d) CI.SRT:pCD1: 1 LF, (e) CI.SRT:pCD1: 1SD.LT.
  • Figure 4 shows SEM by micrographs of the inclusion compound prepared at 1: 1 molar ratio by SD.LT process (a) 2000x magnification, (b) 7000x, (c) 10000X, and prepared by lyophilization process (d) 2000x, (e) 3000x and (f) 10000X.
  • Figure 5 shows the particle size distribution curves of the free molecules (a) SRT, (b) CD and the inclusion compounds (c) CI.SRT: CD1: 1 LF, (d) CI.SRT :pCD1: 1 SD.MC and (e) CI.SRT:pCD1: 1SD.LT prepared by different processes at 1: 1 molar ratio.
  • Figure 6 shows the 2D ROESY nuclear magnetic resonance spectra of the inclusion compounds formed between sertraline (SRT) and ⁇ -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 freeze drying process (LF).
  • SD.LT spray dryer with temperature control of the spray drying process
  • SD.MC spray drying process
  • LF freeze drying process
  • Figure 7 shows the image of a 24-quadrant acrylic box for the spontaneous locomotor activity test - "crossing" - and evaluation of the influence of SRT, ⁇ -CD, and inclusion compounds on the motor activity of mice, using doses of 20 mg / kg.
  • Figure 8 shows in (a) oral administration (gavage) of free SRT, ⁇ -CD aqueous solutions, and inclusion compounds in mice; (b) tail suspension test (TSC) for evaluation predictive of antidepressant activity of free SRT, ⁇ -CD, and inclusion compounds prepared by different processes using doses of 20 mg / kg.
  • TSC tail suspension test
  • Figure 9 shows the graph of TSC results with the immobility measures of the animal groups following treatment with free SRT, ⁇ -CD, and the inclusion compounds prepared by the different processes.
  • Figure 10 shows the graph of the assessment of locomotor activity (number of crossings) of each animal group after treatment with free SRT, ⁇ -CD, and the inclusion compounds prepared by the different processes.
  • Figure 11 shows the 2D ROESY nuclear magnetic resonance spectra of the inclusion compounds formed between Losartan potassium and ⁇ -CD: (a) through the conventional freeze drying (LF) process, (b) using a system flow modified using a spray drying equipment with temperature control of the spray drying process (SD.LT).
  • LF freeze drying
  • SD.LT spray drying equipment with temperature control of the spray drying process
  • the subject matter comprises a process of preparing inclusion compounds using a continuous flow system as outlined in Figure 1a.
  • controller C1 which may be a container or a pipe, preferably in the form of a coil, may also have a temperature control;
  • Control of mixture temperature in C2 it may be a container or a pipe, it is preferably in the shape of a coil;
  • the process of preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system is also characterized by using as solvents water, organic solvents, co-solvent mixtures, drug and CD. ; 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 in that the maintenance of the drug / CD molar ratio comprises a range between 1: 0.001 and 1: 10, preferably between 1: 0.1 and 1: 5; and characterized in that the temperature control of the mixture in C1 comprises the range between 0 and 100 ° C, preferably between 20 and 30 ° C, and in C2, comprises a range between -5.0 and 30 ° C, preferably between 0 and 5 ° C.
  • Control parameters of spray dryer equipment (SD, Figure 1a) to be adjusted are characterized by:
  • Control of spray dryer air flow ranging from 5 to 8 bar pressure and from 600 to 800 L / h;
  • Control of spray dryer vacuum flow which can vary between 50 and 100%, with a flow that can vary between 0 and 40 m 3 / h, preferably 30 and 40 m 3 / h; iii. Control of the inlet temperature in the spray dryer, ranging from 100 to 200 ° C, preferably between 120 - 150 ° C;
  • natural ⁇ (alpha), ⁇ (beta) or Y (gamma) cyclodextrins and / or semi-synthetic cyclodextrins alkyl, hydroxyalkyl, hydroxypropyl derivatives (eg hydroxypropyl acyclodextrins, hydroxypropy
  • Drugs which may be used in the present invention comprise an antidepressant of the class of selective serotonin reuptake inhibitors 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, thianeptin, non-selective monoamine reuptake inhibitors (Serotonin / Noradernaline) or otherwise known as tricyclic antidepressants), amitriptyline, nortriptyline, clomipramine, imipramine, desipramine, doxepine, maprotiline; or monoaminoxidase, tranylcypromine, isocarboxazide, iproniazide, phene
  • AT1 receptor antagonists namely: telmisartan, valsartan, candersartan, azilsartan, eprosartan, ibersartan, olmesartan, or tasosartan; preferably non-limiting losartan potassium.
  • the drugs which may 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.
  • CBS biopharmaceutical classification
  • Step C3 represents a container for premixing and homogenizing drug (S1) and cyclodextrin (S2) solutions, preferably in the form of a tank;
  • the stirring rate at "iii” will range from 100 to 2000rpm, preferably from 300 to 500rpm, for a period of time from 1 to 60 minutes, preferably from 5 to 20 minutes;
  • the drug / CD molar ratio of premix in "ii" will range from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 5;
  • the spray dryer gas flow varies between 100 and 800 L / hr, preferably between 300 and 400 L / hr;
  • the flow rate of the spray dryer aspirator will vary between 20 and 40 m 3 / h, preferably between 30 and 40 m 3 / h; x.
  • the inlet temperature of the carrier in the spray dryer ranges from 30 to 200 ° C, preferably from 120 to 150 ° C; xi
  • the outlet temperature of the system dry material ranges from 40 to 65 ° C; and,
  • bioactive agent is to 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 201 1, entitled "drugs for human use”).
  • bioactive agents may be proteins and peptides, the former being defined as macromolecules formed by chaining 100 or more amino acid residues, while the latter represented by structures having less than 100 amino acid residues.
  • bioactive macromolecule peptides and proteins 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 to cyclodextrins using the proposed process ( Figure 1).
  • the cyclodextrin (S1) solution at a concentration between 1.0 x 10 "3 to
  • 1.0 mol / L is inserted through a pump (B1) according to the molar ratio, while the solution of the drug to be complexed (S2) at a concentration between 1.0 x 10 "3 to 1.0 mol / L, non-limiting, is simultaneously pumped by pump B2 ( Figure 1a)
  • the two pumping lines from (B1) and (B2) flow through tubes to a controller (C1) where the solutions are premixed in a spiral system, over a temperature range of at least 0 ° C to a maximum of 100 ° C, with a pumping flow of at least 1.0 and a maximum of 28.0 mL / min,
  • the limiting of the two solutions leaves the controller (C1) and moves under pressure to another spiral or controller system (C2) where the temperature of the drug / cyclodextrin mixture can be controlled.
  • Temperature control is a critical step for the preparation of the inclusion compound by the continuous flow system, since it changes the thermodynamics of the inclusion process, favoring the interaction between two chemical species, preferably sertraline hydrochloride and cyclodextrins. and or potassium losartan and cyclodextrins.
  • the solution containing inclusion compound leaves the controller (C2) in continuous flow at a given temperature and pressure and is injected into the spray dryer (SD) by pump (B3) with a flow ranging from 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 as a dry powder.
  • the pumping flow of B1, B2 or B3 comprises a range between 1 and 28 mL / min; the spray flow pressure ranged from 5 to 8 bar, with a gas flow from 100 to 800 L / hr, preferably from 300 to 400 L / h and the spray dryer vacuum flow ranged from 0 to 40 m 3 / h is preferably a flow between 30 and 40 m 3 / h.
  • the formation of the spray jet can be performed by rotary, kinetic, ultrasonic, electrostatic atomizers, preferably pneumatic atomizers.
  • the temperature of the C 2 mixture temperature comprises a range of from -5 to 30 ° C, preferably from 0 to 5 ° C.
  • Injection temperature may be reduced for drug / CD systems if the process is exothermic and or elevated when the system is endothermic, in both cases favoring interaction according to the thermodynamics of the inclusion process.
  • the continuous flow spray drying (SD.LT) process used sertraline hydrochloride (SRT) as an example of low solubility drug (4.0 mg / kg). mL), a serotonin reuptake inhibitor antidepressant (SSRI) (Johnson, BM (1996). "Sertraline Hydrochloride.” Analytical Profiles of Drug Substances and Excipients, 24: 443-486) and as a high solubility drug model Losartan potassium (LS) and ⁇ -cyclodextrin ( ⁇ -CD) with solubility of 18.5 mg / mL (Brewster, 2006; Salustio, 2009). In vivo biological tests were performed to evaluate the pharmacological activity of free SRT, CD, and inclusion compounds prepared by the process of treated matter.
  • SRT sertraline hydrochloride
  • SSRI serotonin reuptake inhibitor antidepressant
  • LS Losartan potassium
  • ⁇ -CD ⁇ -cyclodextrin
  • Drug or cyclodextrin solutions used in the present invention may be prepared having as solvents water, buffered aqueous solutions, organic solvents and co-solvents (organo / aqueous mixtures).
  • Organic solvents may be alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, hexanol; or dichloromethane, dimethylsufoxide, chloroform, ether, ethyl acetate, methyl tert-butyl ether; not limiting.
  • the subject matter can be better understood from the following non-limiting examples:
  • Example 1 Preparation of the inclusion complex between sertraline hydrochloride drug (SRT) and ⁇ -cyclodextrin (pCD) via lyophilization (LF) and conventional spray drying process (SD.MC).
  • SRT sertraline hydrochloride drug
  • pCD ⁇ -cyclodextrin
  • LF lyophilization
  • SD.MC conventional spray drying process
  • the first aliquot was frozen in liquid nitrogen and then subjected to lyophilization.
  • Example 2 Preparation of the inclusion complex between sertraline hydrochloride drug (SRT) and ⁇ -cyclodextrin (PCD) by spray drying-SD.LT by double injection and continuous flow.
  • SRT sertraline hydrochloride drug
  • PCD ⁇ -cyclodextrin
  • the preparation of the inclusion complex consists of the following steps:
  • aqueous drug solutions of 1, 0 x 10 "3:01, 0 x 10" 2 mol / L aqueous or non 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 3.0 mol / l; ii.
  • the drug solution, 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 SRT / cyclodextrin molar ratio, preferably 1., was maintained; iii.
  • the solutions on both lines were found in controller C1, preferably in the form of a coil, at a temperature between 0 to
  • the resulting solution was directed to the controller C2, preferably in the form of a coil, 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; v.
  • the solution was then directed to the spray dryer equipment through a B3 pump in a flow range ranging from 1.0 to 28.0 mL / min, preferably from 4.0 to 8.0 mL / min .;
  • the spray dryer air flow pressure ranged from 5 to 8 bar with a gas flow between 100 and 800 L / hr, preferably between 300 and 400 L / hr; vii.
  • the spray dryer vacuum flow varied between 50 and 100%, preferably corresponding to a flow between 30 and 40 m 3 / h; viii.
  • the inlet temperature of the spray dryer gas ranged from 30 to 220 ° C, preferably from 100 to 150 ° C; ix.
  • the outlet temperature of the system dry material ranged from 40 to 65 ° C, preferably from 50 to 60 °; x.
  • the preparation of the inclusion compound in the following steps: i. Aqueous solutions of the Losartan potassium drug and cyclodextrin at a concentration of 1.6 x 10 -3 mole / L were prepared in advance; ii. The drug solution and cyclodextrin were respectively pumped through pump B1 and B2, respectively. independently and in separate flow lines ( Figure 1a) . The pumping pressure of B1 and B2 was adjusted to a flow ranging from 1.0 to 28.0 mL / min.
  • controller C1 preferably in the form of a coil, at a temperature between 40 - 65 ° C to allow homogenization; After mixing the solutions in C1, the resulting solution was directed to controller C2, where the temperature of the mixture was controlled within a range of 0 to 4 ° C, v. The solution was then directed to the spray dryer through of a B3 bomb in a range of f luxury ranging from 8.5 to 11.5 mL / min .; saw.
  • the spray dryer air flow pressure ranged from 5 to 8 bar with a gas flow from 100 to 800 L / h; vii.
  • the spray dryer vacuum flow varied between 50 and 100%, corresponding to a flow between 20 and 40 m 3 / h; viii.
  • the inlet temperature of the carrier in the spray dryer ranged from 120 to 150 ° C; ix.
  • the outlet temperature of the system dry material ranged from 40 - 50 ° C; x.
  • Example 4 Preparation of the inclusion complex between the drug Sertraline Hydrochloride and ⁇ -cyclodextrin (PCD) by the SD.LT process, alternatively by premixing the solutions.
  • premix container (C3 - Figure 1b) described in item “ii” alternatively replaces in the scheme of Figure 1a the controller (C1), preferably in the form of a cylindrical conical bottom tank;
  • the temperature of C3 is from 0 to 100 ° C, preferably from 30 - 60 ° C;
  • the agitation of the container described in “ii” ranges between 100 and 2000rpm, preferably between 300 and 500rpm;
  • the drug / CD molar ratio of the premix described in item "ii" ranged from 1: 0.1 to 1: 5, preferably 1: 1;
  • the temperature of the mixture was controlled at C 2 and ranged from -5,0 to 5,0 ° C, preferably from 0 to 2 ° C; ix.
  • the solution leaves the C2 controller and is directed to the spray dryer by means of a B3 pump in a flow range ranging from 1.0 to 28.0 ml / min, preferably between 4.0 and 8.0 ml / min .;
  • the spray dryer air flow pressure ranged from 5 to 8 bar with a gas flow between 100 and 800 L / hr, preferably between 300 and 400 L / hr;
  • the spray dryer vacuum flow varied between 20 and 40 m 3 / h, preferably between 30 and 40 m 3 / h;
  • the inlet temperature of the spray dryer gas in the range varied between 30 and 200 ° C, preferably between 120 and 150 ° C;
  • the outlet temperature of the system dry material ranged from 40 to 65 ° C;
  • the product obtained was in the form of a dry powder, which was characterized by physicochemical analysis.
  • Example 5 Product characterization and comparison of the obtained data.
  • the characterization of the inclusion compound formed between SRT and ⁇ -CD at the 1: 1 molar ratio was performed by different physicochemical techniques; either solid state such as X-ray powder diffraction (XRD) spectroscopy, infrared spectroscopy (FTIR), thermal analysis (TG / DTA), scanning electron microscopy (SEM), scattered particle size measurement as well as in solution by nuclear magnetic resonance (NMR) techniques.
  • XRD X-ray powder diffraction
  • FTIR infrared spectroscopy
  • TG / DTA thermal analysis
  • SEM scanning electron microscopy
  • scattered particle size measurement as well as in solution by nuclear magnetic resonance (NMR) techniques.
  • Figure 2 shows the XRD analyzes of the inclusion compound prepared between SRT and ⁇ -CD, which showed that the process claimed here led to the formation of an amorphous profile compound (Figure 2f), similar to that observed for the same prepared system. lyophilization processes ( Figure 2d) and SD.MC ( Figure 2.e), but different from the sample containing only the physical mixture of SRT and ⁇ -CD, which presented a summation profile of the diffractograms isolated.
  • Figure 3 shows the TG curves of the inclusion compound prepared by the claimed process (Figure 3e); which showed a different profile than observed for the free molecules SRT ( Figure 3a), ⁇ -CD ( Figure 3b) and the physical mixture (Figure 3c), suggesting the formation of the inclusion compound.
  • Complex formation by the claimed process is reinforced by the similar profile compared to the curve of the lyophilized complex ( Figure 3d).
  • the residual moisture of the prepared complex was 6.1% at 30 to 100 ° C, close to the 6.0% observed in the TG curve of the complex prepared by lyophilization ( Figure 3d).
  • Figure 5 presents the particle size distribution curves, which showed that the complexes prepared by spray drying presented unimodal distribution, with particle size around 5.0 ⁇ , by the process now claimed (Figure 5e). significantly lower than the 265 ⁇ observed for complexes prepared by lyophilization ( Figure 5c). Control of the particle size by the claimed process may facilitate homogenization of the drug with excipients during the preparation of oral pharmaceutical formulations as well as facilitate the dissolution process.
  • 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 ⁇ -cyclodextrin where a large number of spatial correlations between the SRT and the hydrogens can be seen.
  • 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 correlation signals between SRT and CD similar to those observed in the contour map of the same compound prepared by the lyophilization process ( Figure 6c).
  • 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 shown in Figures 6a and 6c.
  • This result shows the efficacy of the present process for preparation of inclusion compounds involving low solubility drugs and which can be used in the preparation of inclusion compounds involving drugs and cyclodextrins to replace the freeze drying (LF) process 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.
  • Figure 1a1a shows the 2D-ROESY contour maps of the LS: CD complex at the 1: 1 molar ratio prepared by the conventional lyophilization process, which shows spots indicating scalar coupling between Losartan and CD hydrogens.
  • Figure 1a1b shows the contour map of the LS: PCD complex at the 1: 1 molar ratio prepared by the SD.LT process, which has numerous patches of indicative correlations of scalar couplings, with a profile similar to that observed in Figure 1a1a freeze drying).
  • the preparation process claimed may also be applied to the preparation of complexes involving also soluble drugs.
  • In vivo tests were performed on adult male CF1 mice weighing between 20 and 30 g. Prior to the experiments, the animals were adapted for at least 05 days in a passage vivarium. The animals were kept in 17x28x 3 cm plastic boxes with a maximum of eight mice. The animals were kept under 12 hours light / dark cycle (lights on from 7 am to 7 pm), with constant temperature (23 ⁇ 2 ° C), under exhaust system (ventilated shelves) and monitored humidity, with free access to water. and food. The experiments were performed from 10 am to 4 pm, with the animals adapting 1 hour to the experiment room.
  • mice received orally (Figure 8 (a)) a dose of 20 mg / kg from aqueous free sertraline solutions and or their inclusion compounds (concentration of 2.0 mg / mL) prepared by different procedures. described. As a control group, only water (vehicle) was administered without the drug.
  • the tail suspension test (TSC) was performed according to
  • mice were immediately transferred to the acrylic box ( Figure 7) for the open field test (TCA test), being observed for a period of 6 minutes and the number of intersections between quadrants ( "crossings") registered.
  • TSC test open field test
  • crossings the number of intersections between quadrants
  • Figures 9 and 10 show, respectively, the results of the TSC and TCA tests in mice for antidepressant activity; using the vehicle, the SRT, the ⁇ -CD, the inclusion compounds prepared by the freeze drying process (LF), the conventional spray drying process (SD.MC) and the claimed spray drying process (SD.LT).
  • LF freeze drying process
  • SD.MC conventional spray drying process
  • SD.LT claimed spray drying process
  • FIG 10 presents the results of the open field exposure spontaneous locomotor activity tests (TCA test) for the vehicle, free SRT, ⁇ -CD, and inclusion compounds prepared by the different processes described above.
  • TCA test open field exposure spontaneous locomotor activity tests
  • a Newman-Keuls Multiple Comparison Test post-hoc pathway showed no significant differences between the number of crossings of the groups of animals that received only the vehicle and those treated with free SRT, ⁇ -CD, and the inclusion compounds prepared by the different processes previously reported.
  • 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) stimulating action, thus showing that administration of the inclusion compound did not affect the ability of motor of the animals.
  • CNS central nervous system

Abstract

The present technology describes a process for preparing inclusion compounds in continuous flow enclosing drugs and cyclodextrins, which is coupled to spray-dryer equipment. This process allows better control of the injection and of the flow of the drug, which is preferably sertraline hydrochloride or sertraline base; and of a vehicle, it being possible for the latter to be natural cyclodextrins (a (alpha), β(beta) or γ (gamma) cyclodextrins) or semi-synthetic cyclodextrins, alkyl, hydroxyalkyl, hydroxypropyl, acyl or polycyclodextrin derivatives, preferably β-cyclodextrin. Furthermore, the process allows better control of temperature, which is fundamental for inclusion to occur, and also operational control of the pre-mixing thereof.

Description

PROCESSO DE PREPARAÇÃO DE COMPOSTOS DE INCLUSÃO ENVOLVENDO CICLODEXTRINAS E FÁRMACOS, USANDO UM SISTEMA  PREPARATION FOR INCLUSION COMPOUNDS INVOLVING CYCLODEXTRINS AND DRUGS, USING A SYSTEM
DE FLUXO CONTÍNUO  CONTINUOUS FLOW
A presente tecnologia descreve um processo de preparação de compostos de inclusão em fluxo contínuo envolvendo fármacos e ciclodextrinas acoplado a um equipamento de spray dryer. Esse processo permite um melhor controle da injeção e do fluxo do fármaco, preferencialmente, cloridrato de sertralina e ou a sertralina base; e de um veículo, este podendo ser as ciclodextrinas naturais (a (alfa), β (beta) ou γ (gama) ciclodextrinas) ou ciclodextrinas semissintéticas, derivados alquil, hidroxialquil, hidroxi-propil, acil, ou poli-ciclodextrinas, preferencialmente a β-ciclodextrina. Além disso, o processo permite melhor controle da temperatura, que é fundamental para que ocorra a inclusão, bem como um controle opcional da pré-mistura dos mesmos. The present technology describes a process for the preparation of continuous flow inclusion compounds involving drugs and cyclodextrins coupled to a spray dryer equipment. This process allows better control of injection and drug flow, preferably sertraline hydrochloride and / or base sertraline; and a vehicle, which may be natural cyclodextrins (a (alpha), β (beta) or γ (gamma) cyclodextrins) or semi-synthetic cyclodextrins, alkyl, hydroxyalkyl, hydroxypropyl, acyl derivatives, or preferably polycyclodextrins, preferably β-cyclodextrin. In addition, the process allows for better temperature control, which is critical for inclusion as well as optional premix control.
As técnicas modernas de desenvolvimento de novos fármacos, tais como o "High-throughput screening" associadas a química combinatória e a síntese tem permitido o aumento no número de fármacos lipofílicos, os quais são difíceis de liberar, ocasionando uma baixa biodisponibilidade. Por outro lado, quase um terço dos medicamentos em desenvolvimento e a metade dos que estão em testes clínicos são insolúveis em água. A baixa solubilidade está aliada a baixa absorção, levando a uma biodisponibilidade variável e uma toxicidade gastrintestinal (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).  Modern drug development techniques such as high-throughput screening associated with combinatorial chemistry and synthesis have allowed the increase in the number of lipophilic drugs, which are difficult to release, resulting in low bioavailability. On the other hand, almost a third of drugs in development and half of those in clinical trials are insoluble in water. Low solubility is allied with low absorption, leading to variable bioavailability and gastrointestinal toxicity (Patil, JS, DV Kadam, et al. (2010). "Inclusion complexes system; A novel technique to improve the solubility and bioavailability of poorly soluble" drugs: A review. "International Journal of Pharmaceutical Sciences Review and Research, 2 (2): 29-34).
Alguns estudos mostraram que cerca de 40% dos insucessos observados no desenvolvimento de novos fármacos estão relacionados a problemas de dissolução e permeabilidade do princípio ativo; sendo que, dentre os 200 medicamentos mais vendidos no mundo, cerca de 75% apresentaram algum problema de solubilidade (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). Diante disso, surge a necessidade de desenvolvimento de novas formulações farmacológicas, com o intuito de melhorar a solubilidade e as propriedades físico-químicas e/ou biológicas dos fármacos. Some studies have shown that about 40% of the failures observed in the development of new drugs are related to active ingredient dissolution and permeability problems; Of the 200 best-selling drugs in the world, about 75% had some solubility problem (Davis, ME and ME 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 oral top 200 Molecular Pharmaceutics, 3 (6): 631-643). In view of this, there is a need for the development of new pharmacological formulations in order to improve solubility and the physicochemical and / or biological properties of drugs.
O aumento na solubilidade e a melhora nas propriedades físico-químicas dos fármacos podem ser obtidos através de modificações nas estruturas químicas, por exemplo, pela inserção de grupos substituintes. Outra alternativa é a modificação das formulações farmacêuticas, as quais, em geral, envolvem o uso de solventes orgânicos, surfactantes, variações no pH do meio e/ou mudanças nas formas polimórficas dos mesmos. Embora essas estratégias aumentem a solubilidade dos fármacos, elas ainda apresentam limitações no seu uso, em geral, devido à baixa biocompatibilidade dos excipientes utilizados, causando irritação e/ou efeitos adversos (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).  Increased solubility and improved physicochemical properties of drugs can be achieved by modifications in chemical structures, for example by the insertion of substituent groups. Another alternative is modification of pharmaceutical formulations, which generally involve the use of organic solvents, surfactants, changes in pH of the medium and / or changes in polymorphic forms thereof. Although these strategies increase drug solubility, they still have limitations in their use, generally 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, EMM (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39 (9): 1033-1046; Brewster, ME and T. Loftsson (2007). "Cyclodextrins as pharmaceutical solubilizers." Advanced Drug Delivery Reviews, 59 (7): 645-666).
Uma alternativa a essas estratégias tem sido o uso de ciclodextrinas An alternative to these strategies has been the use of cyclodextrins.
(CD's), as quais podem melhorar a solubilidade e consequentemente, a biodisponibilidade e a atividade farmacológica dos medicamentos. As CD's são sintetizadas a partir da degradação do amido e formam macrociclos de unidades glicopiranosídicas, contendo de 6 a 8 unidades de glicose. Devido às restrições configuracionais, as CD's formam uma estrutura cónica, as quais apresentam uma cavidade hidrofóbica e a parte externa, hidrofílica (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). Essas características permitem as CD's formarem compostos de inclusão, recebendo, em sua cavidade, parte ou o todo de moléculas biologicamente ativas. Considerando um fármaco pouco solúvel em meio aquoso, este, ao interagir com a CD, pode ser solvatado mais facilmente, elevando a sua solubilidade, sem modificações na sua estrutura química. (CD's), which may improve the solubility and consequently the bioavailability and pharmacological activity of medicines. CD's are synthesized from starch degradation and form macrocycles of glycopyranoside units containing from 6 to 8 glucose units. Due to the configurational constraints, the CD's form a conical structure which has a hydrophobic cavity and the hydrophilic exterior (Del Valle, EMM (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39 (9) : 1033-1046; Brewster, ME and T. Loftsson (2007). "Cyclodextrins as pharmaceutical solubilizers." Advanced Drug Delivery Reviews, 59 (7): 645-666). These features allow the CD 's form inclusion compounds, receiving in its cavity, part or all of biologically active molecules. Considering a poorly soluble drug in Aqueous medium, when interacting with CD, can be solvated more easily, increasing its solubility, without changes in its chemical structure.
Embora a interação CD/fármaco possa acontecer naturalmente, o processo de preparação do composto de inclusão influencia suas características físico-químicas, tais como solubilidade, ponto de fusão, ponto de ebulição, polaridade, dentre outras propriedades.  Although CD / drug interaction can occur naturally, the preparation process of the inclusion compound influences its physicochemical characteristics, such as solubility, melting point, boiling point, polarity, among other properties.
Diversos processos são empregados na preparação de compostos de inclusão, tais como, fusão, extrusão, co-precipitação, pasta, mistura seca, atomização ou "spray drying" (SD) e liofilização (LF) dentre outros (Hedges, A. R. (1998). "Industrial applications of cyclodextrins." ChemicalReviews, 98(5): 2035-2044; Loftsson, T. and D. Duchene (2007). "Cyclodextrinsand their pharmaceutical applications." International Journal of Pharmaceutics, 329(1-2): 1-11 ; 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). . Os métodos de co-precipitação, pasta e fusão apresentam diversas limitações como uso de solventes orgânicos, o estado físico das amostras e limitações termodinâmicas devido à necessidade de aquecimento e elevação das temperaturas na fase de secagem (Hedges, A. R. (1998). "Industrial applications of cyclodextrins." ChemicalReviews, 98(5): 2035-2044) Embora os compostos de inclusão possam ser preparados em meios semi-sólidos e sólidos, em geral a preparação em solução é mais utilizada devido à maior probabilidade e velocidade de interação entre as moléculas. O processo consiste basicamente em misturar e homogeneizar, a uma dada razão molar, soluções previamente preparadas de CD e da molécula hóspede, deixando a solução final sob agitação a uma dada temperatura por um período de tempo, até atingir o equilíbrio. A água é o solvente preferencial, entretanto solventes orgânicos ou misturas organo-aquosas podem ser utilizadas para solubilização prévia das moléculas (Hedges, A. R. (1998). "Industrial applications of cyclodextrins." ChemicalReviews, 98(5): 2035-2044; Del Valle, E. M. M. (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39(9): 1033- 1046). Após atingir o equilíbrio, o solvente presente no meio reacional seja ele água, solvente orgânico ou misturas precisam ser removidos por um processo de secagem (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).. Several processes are employed in the preparation of inclusion compounds, such as melting, extrusion, co-precipitation, slurry, dry mixing, spray drying (SD) and freeze drying (LF) among others (Hedges, AR (1998)). "Industrial applications of cyclodextrins." ChemicalReviews, 98 (5): 2035-2044; Loftsson, T. and D. Duchene (2007). "Cyclodextrinsand their pharmaceutical applications." International Journal of Pharmaceutics, 329 (1-2): 1-11; Del Valle, EMM (2004). "Cyclodextrins and their uses: a review." Process Biochemistry 39 (9): 1033-1046; De Sousa, FB, AML 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, PJ, 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). . The co-precipitation, paste and melt methods have several limitations such as use of organic solvents, the physical state of the samples and thermodynamic limitations due to the need for heating and rising temperatures in the drying phase (Hedges, AR (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 mostly used due to the higher probability and speed of interaction between the 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 to stir 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 may be used for solubilization. preview of molecules (Hedges, AR (1998). "Industrial applications of cyclodextrins." ChemicalReviews, 98 (5): 2035-2044; Del Valle, EMM (2004). "Cyclodextrins and their uses: a review." Process Biochemistry, 39 (9): 1033-1046). After equilibrium, the solvent present in the reaction medium, be it water, organic solvent or mixtures, must be removed by a drying process (Del Valle, EMM (2004). "Cyclodextrins and their uses: a review." Process Biochemistry 39 ( 9): 1033-1046; Salustio, PJ, 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).
A secagem consiste basicamente na conversão de um líquido, soluto dissolvido, suspensão e ou semissólido em um produto sólido seco de baixa umidade, envolvendo em geral consumo de energia térmica para evaporação da água (Ratti, C. (2001). "Hot air and freeze-drying 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): 769-781). Os processos de secagem também apresentam elevados custos financeiros e energéticos, exigem equipamentos especializados, sendo que a escolha dos mesmos dependentes da relação custo benefício, da produtividade e qualidade do produto final (Boss;, E. A. (2004). Modelagem e otimização do processo de liofilização.Aplicação para leite desnatado e café solúvel. Faculdade de Engenharia Química. Campinas, Universidade de Campinas. Doutorado: 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).  Drying basically consists of converting a liquid, dissolved solute, suspension and / or semi-solid into a low moisture dry solid product, generally involving thermal energy consumption for water evaporation (Ratti, C. (2001). "Hot air and freeze-drying of high-value foods: a review. "Journal of Food Engineering 49 (4): 311-319; Rane, MV, SVK Reddy, et al. (2005)." Energy efficient liquid desiccant-based dryer. " Applied Thermal Engineering, 25 (5-6): 769-781). Drying processes also present high financial and energy costs, requiring specialized equipment, and their choice depends on the cost-benefit ratio, productivity and quality of the final product (Boss ;, EA (2004). Lyophilization.Application for skimmed milk and instant coffee. Faculty of Chemical Engineering. Campinas, University of Campinas. PhD: 129; Misiuk, W. and M. Zalewska (2011). "Spectroscopic investigations on the interaction between hydroxypropyl-beta-cyclodextrin and bupropion. Journal of Molecular Liquids, 159 (3): 220-225).
Dentre esses processos de preparação e secagem disponíveis na área industrial, a liofilização é um dos métodos mais utilizados nas áreas de alimentos, biotecnologia, química fina e farmacêutica (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). A liofilização também tem sido muito empregada em escala laboratorial, devido à facilidade de execução, sendo muito útil na preparação de compostos de inclusão de substâncias termolábeis. Among these preparation and drying processes available in the industrial area, lyophilization is one of the most widely used methods in the areas of food, biotechnology, fine chemistry 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, JJ, LM Hardwick, et al. (2005)." Practical formulation and process development of freeze-dried products. "Pharmaceutical Development and Technology, 10 (2): 151-173; Abdul-Fattah, AM, DS 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, EV and SB 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 its ease of execution and is very useful in the preparation of inclusion compounds for thermolabile substances.
Em contrapartida, processos mais complexos, tais como fluído supercrítico, spray drying ou que envolvam equipamentos de custos mais elevados tem sido pouco explorados para a preparação de compostos de inclusão entre fármacos e CDs.  In contrast, more complex processes such as supercritical fluid, spray drying or involving higher cost equipment have been little explored for the preparation of drug and CD inclusion compounds.
A liofilização e o spray drying são processos de secagem que permitem a remoção do solvente utilizado na preparação dos compostos de inclusão, sendo o solvente no primeiro retirado por sublimação, e no segundo por evaporação (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). Os processos de preparação em sua maioria, apresentam alguma limitação técnica para o escalonamento industrial, sendo a escolha dos mesmos, dependente da relação custo/benefício, da qualidade do produto a ser obtido e da produtividade (Boss;, E. A. (2004). Modelagem e otimização do processo de liofilização: Aplicação para leite desnatado e café solúvel. Faculdade de Engenharia Química. Campinas, Universidade de Campinas. Tese Doutorado: 129).  Lyophilization and spray drying are drying processes that allow the removal of the solvent used in the preparation of the inclusion compounds, the former being removed by sublimation and the second by evaporation (Schwegman, JJLM; 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 Predictive Control Techniques Model. "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 have some technical limitation for industrial scheduling, and their choice depends on the cost / benefit ratio, the quality of the product to be obtained and the productivity (Boss ;, EA (2004). and optimization of the lyophilization process: Application for skim milk and instant coffee Faculty of Chemical Engineering Campinas University of Campinas Thesis Doctorate: 129).
O processo de liofilização é um dos mais empregados na preparação de compostos de inclusão, envolvendo fármacos e ciclodextrinas. Esse processo consiste na mistura prévia de duas soluções, em geral aquosas, do fármaco e da ciclodextrina, a qual, após a homogeneização, é congelada. Posteriormente à etapa de congelamento, o material é introduzido em um liofilizador, sendo a água no estado sólido removida por sublimação até a obtenção do material seco (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). As principais vantagens do processo de liofilização são o aumento da estabilidade físico-química do produto seco, a facilidade de estocagem do pó obtido, a formação de poros e a manutenção das características organolépticas (Boss;, E. A. (2004). Modelagem e otimização do processo de liofilização: Aplicação para leite desnatado e café solúvel. Faculdade de Engenharia Química. Campinas, Universidade de Campinas. Doutorado: 129). The lyophilization process is one of the most used in the preparation of inclusion compounds, involving drugs and cyclodextrins. This process consists of premixing two generally aqueous solutions of the drug and cyclodextrin, which, after homogenization, is frozen. Subsequent to the freezing step, the material is introduced into a lyophilizer and solid state water is removed by sublimation until dry material is obtained (Abdul-Fattah, AM, DS 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, MJ 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 lyophilization process are the increased physicochemical stability of the dry product, the ease of storage of the obtained powder, the formation of pores and the maintenance of organoleptic characteristics (Boss ;, EA (2004). lyophilization process: Application for skim milk and instant coffee Faculty of Chemical Engineering Campinas University of Campinas Doctorate: 129).
Estudos mostram que de um total de 129 produtos biofarmacêuticos comercializados no mercado até 2002, cerca de 41% são preparados por liofilização, o que indica a importância desse processo na área farmacêutica e biotecnológica (Schwegman, J. J., L. M. Hardwick, et al. (2005). "Practical formulation and process development of freeze-dried products." Pharmaceutical Development and Technology, 10(2): 51-173). No entanto, algumas limitações no uso do processo de liofilização podem ser observadas:  Studies show that of a total of 129 biopharmaceuticals marketed by 2002, about 41% are prepared by lyophilization, indicating the importance of this process in the pharmaceutical and biotechnology field (Schwegman, JJ, LM Hardwick, et al. (2005 ). "Practical formulation and process development of freeze-dried products." Pharmaceutical Development and Technology, 10 (2): 51-173). However, some limitations in the use of the lyophilization process can be observed:
• O congelamento de grandes volumes de soluções contendo compostos de inclusão é tecnicamente limitado e pode inviabilizar a sua preparação, podendo gerar o "stress" térmico nas amostras. Isto produz diferentes formas cristalinas (dependendo da velocidade do resfriamento) afetando o tamanho das partículas. Além disso, utilizam-se refrigeradores de grande porte, de alto custo, podendo inviabilizar o processo de preparação de forma contínua.  • Freezing large volumes of solutions containing inclusion compounds is technically limited and may make their preparation unfeasible and may generate thermal stress on samples. This produces different crystalline forms (depending on the cooling rate) affecting the particle size. In addition, large, high-cost refrigerators are used, which may make the preparation process unfeasible continuously.
• O método de liofilização, assim como em outros métodos, é necessário fazer a mistura prévia das soluções. Assim é necessário estocar grandes volumes da mistura até o congelamento; • O tempo necessário para a completa secagem do material pode tornar o processo financeiramente oneroso, podendo inviabilizar o custo produtivo de um determinado composto de inclusão; • The lyophilization method, as in other methods, is necessary to premix solutions. Thus it is necessary to store large volumes of the mixture until freezing; • The time required for the complete drying of the material can make the process financially costly and may make the production cost of a particular inclusion compound unviable;
• Além disso, o custo operacional é cerca de 4 a 8 vezes maior que o processo de secagem por ar quente, devido principalmente ao longo tempo do ciclo de liofilização até obtenção do produto desidratado (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).  • In addition, the operational cost is about 4 to 8 times higher than the hot air drying process, mainly due to the long lyophilization cycle until the dehydrated product is obtained (Maltesen, MJ 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).
• O uso de solventes orgânicos no processo de liofilização, muitas vezes necessários para a solubilização de determinados fármacos, pode inviabilizar o processo tecnicamente. Determinadas misturas organo-aquosas podem não congelar a uma dada temperatura ou necessitam de equipamentos especiais; e · A remoção, por sublimação, de solventes orgânicos, pode danificar os equipamentos de liofilização.  • The use of organic solvents in the lyophilization process, often necessary for solubilization of certain drugs, may make the process technically unfeasible. Certain organo-aqueous mixtures may not freeze at a given temperature or require special equipment; and · Sublimation removal of organic solvents can damage freeze drying equipment.
Dessa forma, um processo alternativo à liofilização é o processo de secagem por spray drying, muito utilizado na indústria alimentícia e farmacêutica (Gibbs, B. F., S. Kermasha, et al. (1999). "Encapsulation in the food 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).  Thus, an alternative process to lyophilization is the spray drying process, widely used in the food and pharmaceutical industry (Gibbs, BF, S. Kermasha, et al. (1999). "Encapsulation in the food industry: a review. "International Journal of Food Sciences and Nutrition, 50 (3): 213-224; Abdul-Fattah, AM, DS 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).
O processo spray drying consiste na pulverização de uma solução ou suspensão em uma câmara cilíndrica, em uma corrente de ar quente não saturada, a qual remove o solvente, permitindo obter na forma de pó, em apenas uma etapa, o soluto que estava dissolvido ou em suspensão (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). Dentre os processos de secagem descritos na literatura, o spray drying é o único processo em que a remoção do solvente é acompanhada imediatamente da definição da forma das partículas, sendo esta, uma característica distinta desse processo (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). The spray drying process consists of spraying a solution or suspension into a cylindrical chamber in an unsaturated hot air stream, which removes the solvent, allowing the solute that was dissolved or dissolved to be powdered in one step. in suspension (Abdul-Fattah, AM, DS 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 particle shape. , a distinct feature 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).
Comparado a outros processos de remoção de solvente o processo spray drying é mais económico, devido à elevada expansão da área superficial específica que aumenta a taxa de evaporação e reduz o tempo de secagem. A redução do tempo de secagem protege o agente ativo, uma vez que reduz o contato entre as microgotículas e o ar aquecido do spray dryer. O contato fármaco (agente ativo)/ar pode variar de alguns segundos em escala laboratorial até minutos em escala industrial. Além da secagem rápida e eficiente, o processo spray drying apresenta outras vantagens em relação à liofilização tais como obtenção de partículas com tamanho uniforme, aumento da área superficial específica, eficiência energética, utilização de solventes orgânicos, escalonamento industrial, alta produtividade, fluxo contínuo na preparação dos materiais, dentre outros (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).  Compared to other solvent removal processes the spray drying process is more economical due to the high expansion of the specific surface area which increases the evaporation rate and reduces the drying time. Reducing the drying time protects the active agent as it reduces the contact between the microtropules and the spray dryer heated air. The drug (active agent) / air contact may range 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 over freeze drying such as obtaining uniformly sized particles, increasing specific surface area, energy efficiency, use of organic solvents, industrial scaling, high productivity, continuous flow in preparation of materials, among others (Maltesen, MJ 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).
O processo spray drying tem sido muito utilizado na preparação e s secagem de substâncias termosensíveis, tais como proteínas, peptídeos, hormônios, antibióticos, dentre outros (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(1-2): 209-216; Blanco, M. D., R. L. Sastre, et al. (2006). "Degradation behaviour 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 Acta, 467(1-2): 91-98). Esse processo tem sido cada vez mais utilizado para aplicações na área farmacêutica, principalmente na preparação de microesferas, envolvendo fármacos e polímeros biodegradáveis, preparação de partículas (poliméricas e não poliméricas) para inalação, alteração de formas polimórficas, preparação de compostos de inclusão envolvendo fármacos/ciclodextrinas, dentre outras aplicações (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 behaviour 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): 39- 147; Blanco, . 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). "Optimisation 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; 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). Assim, o processo spray drying apresenta-se como uma alternativa ao processo de liofilização na preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos em escala laboratorial e pode ser uma alternativa para aplicação em processos industriais, principalmente ser um processo de secagem ambientalmente mais compatível, devido à economia de energia. Estimativas indicam que cerca de 12% de toda energia consumida no setor industrial do mundo está associado à processos de secagem, representando um custo elevado, haja vista que grande parte é produzida a partir do petróleo uma fonte de energia instável do ponto de vista económico (Rane, M. V., S. V. K. Reddy, et al. (2005). "Energy efficient liquid desiccant-based dryer." Applied Thermal Engineering, 25(5-6): 769-781). Entretanto, grande parte dos trabalhos encontrados na literatura relata a preparação de compostos de inclusão apenas pela pré-mistura das soluções de fármaco e CD, seguido pela secagem, não sendo introduzidas inovações nas preparações (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 engineering via spray drying." Pharmaceutical 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). "Optimisation 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). Em outro aspecto, a preparação de compostos de inclusão envolvendo fármacos e ciclodextrinas, pelo processo spray drying convencional (MC), consiste basicamente em preparar soluções e ou suspensãos, isoladas de CD's e dos fármacos, as quais são posteriormente misturadas e deixadas sob agitação por um dado período de tempo, sendo a mistura resultante injetada no equipamento spray d/yer (Bootsma , H. P. R., H. W. Frijlink, et al. (1989). "Beta- ciclodextrin an excipient in solid oral dosage forms - in vitro and in vivo evaluation of spray-dried diazepam-beta-ciclodextrin 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). O processo spray drying assim como os demais processos de secagem apresentam algumas limitações, tais como: 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 (1-2): 209-216; Blanco, MD, RL 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-Junior, AA, MV Scarpa, et al. (2008). "Thermal analysis of biodegradable microparticles containing ciprofloxacin hydrochloride obtained by spray drying technique." Thermochimica Acta, 467 (1-2): 91-98). This process has been increasingly used for pharmaceutical applications , mainly in the preparation of microspheres, involving biodegradable drugs and 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, CM, MT Vieira , et 1. (2002). "Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds." European Journal of Pharmaceutical Sciences, 15 (1): 79-88; EsclusaDiaz, MT, M. GayoOtero, et al. (1996). "Preparation and evaluation of ketoconazole-beta-cyclodextrin multicomponent complexes." International Journal of Pharmaceutics, 142 (2): 183-187; Blanco, MD, RL Sastre, et al. (2006). "Degradation behavior of microspheres prepared by spray-drying poly (D, L-lactide) and poly (D, L-lactide-glycolide) polymers." International Journal of Pharmaceutics 326 (1-2): 39-147; Blanco,. D., MV 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): 121-129; Salustio, PJ, G. Feio, et al. (2009). "The influence of preparation methods on the inclusion of model drugs in a beta-cyclodextrin cavity." European Journal of Pharmaceutics and Biopharmaceutics, 71 (2): 377-386). Thus, the spray drying process is presented as an alternative to the lyophilization process in the preparation of inclusion compounds involving laboratory scale cyclodextrins and drugs and can be an alternative for application in industrial processes, mainly being a more environmentally compatible drying process, due to energy saving. Estimates indicate that about 12% of all energy consumed in the industrial sector in the world is associated with drying processes, which is a high cost, since much of it is produced from petroleum as an economically unstable energy source ( Rane, MV, SVK Reddy, et al. (2005). "Energy efficient liquid desiccant-based dryer." Applied Thermal Engineering, 25 (5-6): 769-781). However, most studies found in the literature report the preparation of inclusion compounds only by premixing the drug and CD solutions, followed by drying, and no innovations were introduced in the preparations (EsclusaDiaz, MT, M. GayoOtero, et al. (1996). "Preparation and evaluation of multicomponent ketoconazole-beta-cyclodextrin complexes." International Journal of Pharmaceutics, 142 (2): 183-187; Vehring, R. (2008). "Pharmaceutical particle engineering via spray drying." Research, 25 (5): 999-1022; Koester, LS ( JB 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, CM, MT 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., RA Carvalho, et al. (2007). "Solid-state characterization and dissolution profiles of complex inclusion 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). In another aspect, the preparation of inclusion compounds involving drugs and cyclodextrins, by conventional spray drying (MC) process, basically consists of preparing solutions and or suspensions, isolated from CD's and drugs, which are then mixed and left under stirring by a given time period, the resulting mixture being injected into the spray d / yer equipment (Bootsma, HPR, HW 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, LS, JB 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., RA Carvalho, et al. (2007)." Solid-state characterization and dissolution profiles of the inclusion complexe s 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:
• Preparação de uma pré-mistura de duas soluções fora do equipamento, antes da injeção, levando a concepção da produção em batelada;  • Preparation of a premix of two off-equipment solutions prior to injection, leading to batch production design;
· Injeção da amostra contendo o composto de inclusão à temperatura ambiente,  · Injection of the sample containing the inclusion compound at room temperature,
• Não consideram a termodinâmica do processo de inclusão, uma vez que os processos podem ser exotérmicos (maior parte) e em certos casos endotérmicos;  • Do not consider the thermodynamics of the inclusion process, as the processes may be exothermic (for the most part) and in some cases endothermic;
· Ausência de controle da temperatura da solução a ser injetada o que pode reduzir a eficiência processo inclusão;  · Lack of temperature control of the solution to be injected which may reduce the inclusion process efficiency;
• Precipitação seletiva do fármaco e ou da CD devido a diferenças de solubilidade entre eles dificultando inclusão;  • Selective drug and / or CD precipitation due to solubility differences between them making inclusion difficult;
• Aumento da temperatura da amostra dentro das microgotículas formadas no "spray" devido a corrente de ar quente, alterando a termodinâmica do processo de inclusão fármaco/CD; • Perda de atividade biológica de compostos bioativos, tais como proteínas e peptídeos, por desnaturação térmica, dentre outros problemas pontuais. • Increased sample temperature within the spray-formed microtropules due to hot air flow, changing the thermodynamics of the drug / CD inclusion process; • Loss of biological activity of bioactive compounds, such as proteins and peptides, by thermal denaturation, among other specific problems.
Essas limitações são mais bem evidenciadas através da análise dos pedidos de patentes, CN 1546145 e CN 1247080, além da patente EA005111 relatam a preparação de compostos de inclusão com a utilização do processo spray drying. A patente US6720003B1 , intitulada "Serotonin reuptake inhibitor formulations" relata um processo de preparação de uma dispersão sólida, compreendendo um ingrediente ativo e um polímero solúvel em água. É reivindicado o uso do spray dryer para a secagem do complexo de inclusão fármaco-veículo. Também é reivindicada, como veículo carreador, a alfa-, beta- e gama-ciclodextrinas, além do fármaco a ser carreado, podendo este ser a sertralina. Entretanto, não é reivindicado um sistema de fluxo modificado, semelhante ao proposto na presente invenção, tampouco uma faixa de temperatura que favoreça a inclusão. Essa faixa de temperatura, por sua vez, compreendeu entre 40 e 50°C; bem superior à reivindicada no presente pedido.  These limitations are best evidenced by the analysis of patent applications, CN 1546145 and CN 1247080, and patent EA005111 report the preparation of inclusion compounds using the spray drying process. US6720003B1 entitled "Serotonin reuptake inhibitor formulations" discloses a process for preparing a solid dispersion comprising an active ingredient and a water-soluble polymer. The use of the spray dryer for drying the drug-carrier inclusion complex is claimed. As carrier carrier, alpha-, beta- and gamma-cyclodextrins are also claimed 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, or a temperature range that favors inclusion is not claimed. This temperature range, in turn, comprised between 40 and 50 ° C; well above that claimed in this application.
O pedido de patente BRPI0510382A, intitulado "Complexo de inclusão e preparação farmacêutica" se refere a um complexo de inclusão contendo um derivado de benzimidazol e seu processo de preparação, usando ciclodextrina e um polímero solúvel em água. No entanto, não é utilizado o fármaco sertralina e sim, derivados de benzimidazol. Além disso, o sistema e processo de preparação do composto de inclusão se diferem da matéria tratada.  Patent application BRPI0510382A entitled "Pharmaceutical Inclusion and Inclusion Complex" refers to an inclusion complex containing a benzimidazole derivative and its preparation process using cyclodextrin and a water soluble polymer. However, sertraline is not used, but benzimidazole derivatives. In addition, the system and process of preparation of the inclusion compound differ from the treated matter.
O pedido de patente US20080200533, intitulado "Drug or pharmaceutical compounds and a preparation thereof" relata processos de preparação de compostos de inclusão, usando a ciclodextrina e sertralina, não limitante a estes. Já o pedido de patente US20050250738A1 , intitulado "Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin" relata o processo de preparação de formulações orais aquosas contendo sertralina ou um sal farmaceuticamente aceitável, e a ciclodextrina. Entretanto, nesses pedidos não são relatados a utilização de um sistema modificado de fluxo acoplado a um spray dryer que permita a inclusão do fármaco na ciclodextrina. O pedido de patente US20090004262A1 intitulado "Nanoparticulate formuiations and methods for the making and use therof" descreve o processo de preparação de composições nanoparticuladas, os quais estão incluídos os compostos de inclusão que utilizam ciclodextrina. No entanto, não se refere ao processo de preparação do composto de inclusão ciclodextrina-sertralina, tampouco é reivindicada a etapa de secagem por spray dryer. US20080200533, entitled "Drug or pharmaceutical compounds and the preparation thereof", reports processes for preparing inclusion compounds using cyclodextrin and sertraline, not limiting them. 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 cyclodextrin. US20090004262A1 entitled "Nanoparticulate formulations and methods for the making and use of therof" describes the process for 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.
O pedido de patente US5376645, intitulado "Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof" descreve um processo de preparação de compostos de inclusão envolvendo ciclodextrinas em uma base aquosa. No entanto, a faixa de temperatura considerada apropriada pelo inventor é de 70 a 80°C. A matéria tratada, por sua vez, compreende um controle de temperatura em uma faixa bem inferior.  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 deemed appropriate by the inventor is 70 to 80 ° C. The treated matter, in turn, comprises temperature control in a much lower range.
A patente US7037928B2, intitulada "Compositions of N- (methylethylaminocarbonyl)-4-(-3-methylphenylamino)-3-pyridylsulfonamide and cyclic oligosaccharides" descreve um método de preparação de compostos de inclusão à base de torasemida e ciclodextrinas, ou derivados desta, onde são utilizados alguns equipamentos de secagem; dentre eles, o spray dryer. Nessa patente, no entanto, é reivindicada uma faixa de temperatura que compreende um intervalo de 10 a 100°C. A matéria tratada, por sua vez, utiliza temperaturas inferiores e também utiliza somente o spray dryer como um equipamento de secagem.  US7037928B2, entitled "Compositions of N- (methylethylaminocarbonyl) -4 - (- 3-methylphenylamino) -3-pyridylsulfonamide and cyclic oligosaccharides" describes a method of preparing torasemide and cyclodextrin-based inclusion compounds, or derivatives thereof, where some drying equipment is used; Among them, the spray dryer. In that patent, however, a temperature range comprising a range of 10 to 100 ° C is claimed. The treated material, in turn, uses lower temperatures and also uses only the spray dryer as a drying equipment.
A patente EP1793862B1 intitulada "A process for the preparation of a piroxicam: Beta-cyclodextrin inclusion compound" descreve um método de preparação do composto de inclusão entre o fármaco piroxicam e β- ciclodextrina à razão molar 1 :2.5 por spray drying aplicado a uma escala piloto para melhorar as propriedades físico-químicas e biofarmacêuticas de preparações para administração via oral. Essa patente reivindica a utilização de um aditivo, hidróxido de amónio, na concentração entre 28 - 30% para solubilizar o piroxicam e trabalha com escala piloto de 12kg de fármaco. As temperaturas de entrada do equipamento entre 175°C e 195°C, temperatura de saída de 110°C, temperatura da solução a ser injetada entre 70°C e 80°C. A matéria ora tratada não utiliza aditivos para solubílização do fármaco, bem como difere das temperaturas de entrada, saída e da solução, as quais são diferentes dessa patente. 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 1: 2.5 molar ratio by spray drying applied on a scale. pilot 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 of 28-30% to solubilize piroxicam and works with a pilot scale of 12kg of drug. Equipment inlet temperatures between 175 ° C and 195 ° C, outlet temperature 110 ° C, temperature of solution to be injected between 70 ° C and 80 ° C. The material now treated does not use additives for solubilization of the drug, as well as as it differs from inlet, outlet and solution temperatures which are different from this patent.
O pedido de patente PI06120326A2 intitulado "Complexos de inclusão de ciclodextrina e métodos de preparação dos mesmos" descreve a preparação de compostos de inclusão entre flavorizantes, substâncias voláteis e derivados, além das ciclodextrinas, utilizando alguns processos para secagem, inclusive secagem por pulverização ou spray drying. O pedido mostra a preparação de complexos pela mistura seca de dois ou mais compostos, sendo um deles a ciclodextrina, e posterior dissolução, emulsificação e ou suspensão por adição de solventes. A mistura do componente ativo e a ciclodextrina pode ser formada em um reator, fechado ou aberto, com ou sem aquecimento. O processo descrito no pedido de patente não descreve o uso de um sistema de fluxo contínuo e por dupla injeção conforme a matéria ora tratada. Além disso, a mistura do composto ativo e da ciclodextrina é feita em batelada e o resfriamento do reator é realizado em faixas de temperatura diferente daqueles mostradas no processo da matéria tratada neste pedido. Adicionalmente, a redução da temperatura da solução é realizada de forma estática no reator, divergente do controle em fluxo contínuo proposto pelo presente pedido. Na matéria ora tratada o tempo de homogeneização é menor do que a faixa estabelecida pelo pedido de patente citado anteriormente, mostrando assim que as duas tecnologias são distintas e divergentes.  Patent application PI06120326A2 entitled "Cyclodextrin Inclusion Complexes and Methods of Preparing Them" describes the preparation of inclusion compounds between flavorants, volatile substances and derivatives, in addition to cyclodextrins, using some drying processes, including spray or spray drying drying. The application shows the preparation of complexes by dry mixing of two or more compounds, one being cyclodextrin, and further dissolving, emulsifying and or suspending by addition of solvents. The active ingredient mixture and cyclodextrin may be formed in a closed or open reactor, with or without heating. The process described in the patent application does not describe the use of a continuous flow and double injection system according to the subject matter herein. In addition, the active compound and cyclodextrin are mixed in batches and the reactor is cooled in different temperature ranges than those shown in the process material treated in this application. Additionally, the solution temperature reduction is performed statically in the reactor, different from the continuous flow control proposed by the present application. In the subject matter 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.
Diferentemente dos documentos supracitados, a matéria tratada apresenta modificações no processo utilizado para preparar os compostos de inclusão. As modificações introduzidas permitem um melhor controle da injeção e do fluxo dos fármacos e da ciclodextrina, bem como da pré-mistura dos mesmos; além do controle da temperatura em faixas mais reduzidas, necessário para ocorrer à inclusão.  Unlike the above documents, the subject matter has modifications 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 premixing; in addition to the temperature control in smaller ranges required for inclusion.
DESCRIÇÃO DAS FIGURASDESCRIPTION OF THE FIGURES
A Figura 1 mostra (a) representação esquemática do processo de preparação dos compostos de inclusão, usando um sistema de fluxo contínuo (SD.LT), (b) representação esquemática do processo SD.LT, alternativamente ao fluxo contínuo, com pré-mistura das soluções de fármaco e CD para preparação dos compostos de inclusão. Figure 1 shows (a) schematic representation of the process of preparing inclusion compounds using a continuous flow system (SD.LT), (b) schematic representation of the SD.LT process, alternatively continuous flow, with premixing of drug and CD solutions for preparation of the inclusion compounds.
A Figura 2 mostra os difratogramas de raios-X de pó, (a) SRT, (b) PCD, (c) mistura física (MM) 1 :1 e dos compostos inclusão preparados a razão molar 1 :1 (d) CI.SRT: CD1 :1 LF, (e) CI.SRT: CD1 :1 SD.MC e (f) CI.SRT: CD1 :1SD.LT. Figure 2 shows the X-ray powder diffractograms, (a) SRT, (b) PCD, (c) 1: 1 physical mixture (MM) and inclusion compounds prepared at 1: 1 (d) CI molar ratio. SRT: CD1: 1 LF, (e) CI.SRT: CD1: 1 SD.MC and (f) CI.SRT: CD1: 1SD.LT.
A Figura 3 mostra as curvas TG: (a) SRT, (b) CD, (c) mistura física (MM) 1 :1 e dos compostos inclusão preparados a razão molar 1 :1 (d) CI.SRT:pCD1 :1 LF, (e) CI.SRT:pCD1 :1SD.LT. Figure 3 shows TG curves: (a) SRT, (b) CD, (c) 1: 1 physical mixture (MM) and inclusion compounds prepared at 1: 1 molar ratio (d) CI.SRT:pCD1: 1 LF, (e) CI.SRT:pCD1: 1SD.LT.
A Figura 4 mostra micrografias por MEV do composto de inclusão preparado a razão molar 1 :1 pelo processo SD.LT (a) aumento 2000x, (b) 7000x, (c) 10000X, e preparado pelo processo de liofilização (d) 2000x, (e) 3000x e (f) 10000X.  Figure 4 shows SEM by micrographs of the inclusion compound prepared at 1: 1 molar ratio by SD.LT process (a) 2000x magnification, (b) 7000x, (c) 10000X, and prepared by lyophilization process (d) 2000x, (e) 3000x and (f) 10000X.
A Figura 5 mostra as curvas de distribuição de tamanho de partículas das moléculas livres (a) SRT, (b) CD e dos compostos inclusão (c) CI.SRT: CD1 :1 LF, (d) CI.SRT:pCD1 :1 SD.MC e (e) CI.SRT:pCD1 :1SD.LT preparados pelos diferentes processos a razão molar 1 :1.  Figure 5 shows the particle size distribution curves of the free molecules (a) SRT, (b) CD and the inclusion compounds (c) CI.SRT: CD1: 1 LF, (d) CI.SRT :pCD1: 1 SD.MC and (e) CI.SRT:pCD1: 1SD.LT prepared by different processes at 1: 1 molar ratio.
A Figura 6 mostra os espectros de ressonância magnética nuclear 2D ROESY, dos compostos de inclusão formados entre a sertralina (SRT) e a β- CD: (a) através do uso de um sistema de fluxo modificado, usando um equipamento de spray dryer com controle da temperatura do processo spray drying (SD.LT), (b) através do processo convencional por spray drying (SD.MC), e (c) através do processo de liofilização (LF). Figure 6 shows the 2D ROESY nuclear magnetic resonance spectra of the 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 freeze drying process (LF).
A Figura 7 mostra a imagem de uma caixa acrílica com 24 quadrantes para a realização do teste de atividade locomotora espontânea -"crossing" - e avaliação da influência da SRT, da β-CD, e dos compostos de inclusão na atividade motora dos camundongos, usando doses de 20 mg/kg.  Figure 7 shows the image of a 24-quadrant acrylic box for the spontaneous locomotor activity test - "crossing" - and evaluation of the influence of SRT, β-CD, and inclusion compounds on the motor activity of mice, using doses of 20 mg / kg.
A Figura 8 mostra em (a) a administração por via oral (gavagem) das soluções aquosas de SRT livre, de β-CD, e dos compostos de inclusão nos camundongos; (b) teste de suspensão pela cauda (TSC) para avaliação preditiva da atividade antidepressiva da SRT livre, da β-CD, e dos compostos de inclusão, preparados por diferentes processos, usando doses de 20 mg/kg. Figure 8 shows in (a) oral administration (gavage) of free SRT, β-CD aqueous solutions, and inclusion compounds in mice; (b) tail suspension test (TSC) for evaluation predictive of antidepressant activity of free SRT, β-CD, and inclusion compounds prepared by different processes using doses of 20 mg / kg.
A Figura 9 mostra o gráfico dos resultados do TSC com as medidas de imobilidade dos grupos de animais após tratamento com SRT livre, β-CD, e os compostos de inclusão preparados pelos diferentes processos. Figure 9 shows the graph of TSC results with the immobility measures of the animal groups following treatment with free SRT, β-CD, and the inclusion compounds prepared by the different processes.
A Figura 10 mostra o gráfico da avaliação da atividade locomotora (número de cruzamentos) de cada grupo de animais após tratamento com SRT livre, β-CD, e os compostos de inclusão preparados pelos diferentes processos.  Figure 10 shows the graph of the assessment of locomotor activity (number of crossings) of each animal group after treatment with free SRT, β-CD, and the inclusion compounds prepared by the different processes.
A Figura 11 mostra os espectros de ressonância magnética nuclear 2D ROESY, dos compostos de inclusão formados entre o Losartan potássico e a β-CD: (a) através do processo convencional de liofilização (LF), (b) através do uso de um sistema de fluxo modificado, usando um equipamento de spray dryer com controle da temperatura do processo spray drying (SD.LT). 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 freeze drying (LF) process, (b) using a system flow modified using a spray drying equipment with temperature control of the spray drying process (SD.LT).
DESCRIÇÃO DETALHADA DA INVENÇÃO A matéria tratada compreende um processo de preparação de compostos de inclusão que utiliza um sistema de fluxo contínuo, conforme esquematizado na Figura 1a. DETAILED DESCRIPTION OF THE INVENTION The subject matter comprises a process of preparing inclusion compounds using a continuous flow system as outlined in Figure 1a.
O Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos, usando um sistema de fluxo (Figura 1a), caracteriza- se por compreender as seguintes etapas: The process of preparing inclusion compounds involving cyclodextrins and drugs using a flow system (Figure 1a) is characterized by the following steps:
a. Preparação das soluções aquosas do fármaco solúvel losartan, de fármacos pouco solúveis, preferencialmente a sertralina, e da ciclodextrina, a uma concentração entre 1 ,0 x 10"3 e 1 ,0 x10'2 mol/L, preferencialmente 5,0 x 10"3; The. Preparation of aqueous solutions of losartan soluble drug of poorly soluble drugs, preferably sertraline, and cyclodextrin at a concentration between 1.0 x 10 -3 and 1.0 x 10 -2 mol / L, preferably 5.0 x 10 "3 ;
b. Bombeamento da solução do fármaco e da solução de ciclodextrina, respectivamente, através das bombas B1 e B2, em fluxo contínuo, independente e em linhas de fluxo separadas (Figura 1a);  B. Pumping drug solution and cyclodextrin solution, respectively, through pumps B1 and B2, in continuous, independent flow and in separate flow lines (Figure 1a);
c. Ajuste do fluxo de bombeamento de B1 e B2; d. Mistura das soluções no controlador C1 , podendo ser um recipiente ou uma tubulação, esta preferencialmente no formato de uma serpentina, podendo também ter um controle de temperatura; ç. Adjustment of pumping flow of B1 and B2; d. Mixture of solutions in controller C1, which may be a container or a pipe, preferably in the form of a coil, may also have a temperature control;
e. Direcionamento da solução resultante para o controlador C2, este preferencialmente no formato de uma serpentina;  and. Directing the resulting solution to the controller C2, preferably in the form of a coil;
f. Controle da temperatura da mistura em C2; podendo ser um recipiente ou uma tubulação, esta preferencialmente no formato de uma serpentina;  f. Control of mixture temperature in C2; it may be a container or a pipe, it is preferably in the shape of a coil;
g. Direcionamento da solução para um equipamento de spray dryer através de uma bomba B3, a uma dada temperatura;  g. Directing the solution to a spray dryer equipment through a B3 pump at a given temperature;
h. Ajuste dos parâmetros de controle do equipamento de spray dryer, i. Produção de um pó seco.  H. Adjustment of spray dryer control parameters, i. Production of a dry powder.
O Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo (Figura 1a) também se caracteriza por utilizar, como solventes, água, solventes orgânicos, misturas de co-solventes, do fármaco e das CDs; caracteriza-se pelo fluxo de bombeamento de B1 , B2 e B3 compreender um intervalo entre 1 e 28 mL/min, preferencialmente entre 8 e 12 mL/min; caracteriza-se pela manutenção da razão molar fármaco/CDs compreender um intervalo entre 1 :0.001 e 1 :10, preferencialmente entre 1 :0.1 e 1 :5; e caracteriza-se pelo controle da temperatura da mistura em C1 compreender o intervalo entre 0 e 100°C, preferencialmente entre 20 e 30°C, e em C2, compreender um intervalo entre -5,0 e 30°C, preferencialmente, entre 0o e 5°C. 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, co-solvent mixtures, drug and CD. ; 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 in that the maintenance of the drug / CD molar ratio comprises a range between 1: 0.001 and 1: 10, preferably between 1: 0.1 and 1: 5; and characterized in that the temperature control of the mixture in C1 comprises the range between 0 and 100 ° C, preferably between 20 and 30 ° C, and in C2, comprises a range between -5.0 and 30 ° C, preferably between 0 and 5 ° C.
Os parâmetros de controle do equipamento de spray dryer (SD, Figura 1a) que devem ser ajustados caracterizam-se por compreender:  Control parameters of spray dryer equipment (SD, Figure 1a) to be adjusted are characterized by:
i. Controle do fluxo de ar do spray dryer, podendo variar a uma pressão entre 5 a 8 bar e a um fluxo que pode variar entre 600 e 800 L/h;  i. Control of spray dryer air flow, ranging from 5 to 8 bar pressure and from 600 to 800 L / h;
ii. Controle do fluxo do aspirador do spray dryer, podendo variar entre 50 e 100%, com um fluxo que pode variar entre 0 e 40 m3/h, preferencialmente 30 e 40 m3/h; iii. Controle da temperatura de entrada no spray dryer, podendo variar entre 100 e 200 °C, preferencialmente entre 120 - 150°C; ii. Control of spray dryer vacuum flow, which can vary between 50 and 100%, with a flow that can vary between 0 and 40 m 3 / h, preferably 30 and 40 m 3 / h; iii. Control of the inlet temperature in the spray dryer, ranging from 100 to 200 ° C, preferably between 120 - 150 ° C;
iv. Controle da temperatura de saída spray dryer, podendo variar entre 40 e 65 °C, preferencialmente entre 50 e 60°C. As ciclodextrinas que podem ser utilizadas na presente invenção (Figura iv. Control of spray dryer outlet temperature, which may vary between 40 and 65 ° C, preferably between 50 and 60 ° C. Cyclodextrins which may be used in the present invention (Figure
1a) compreendem as ciclodextrinas naturais α (alfa), β (beta) ou Y(gama) ciclodextrinas e ou ciclodextrinas semi-sintéticas, derivados alquil, hydroxialquil, hidroxi-propil (ex: hidroxi-propil-aciclodextrinas, hidroxi-propil-Pciclodextrinas hidroxi-propil-Yciclodextrinas), acil, ou poli-ciclodextrinas ou poli-ciclodextrinas com ligações cruzadas, preferencialmente a β-ciclodextrina e ou combinações com outras ciclodextrinas. 1a) include natural α (alpha), β (beta) or Y (gamma) cyclodextrins and / or semi-synthetic cyclodextrins, alkyl, hydroxyalkyl, hydroxypropyl derivatives (eg hydroxypropyl acyclodextrins, hydroxypropyl-Pcyclodextrins hydroxypropyl-γ-cyclodextrins), acyl, or cross-linked polycyclodextrins or polycyclodextrins, preferably β-cyclodextrins and or combinations with other cyclodextrins.
Os fármacos que podem ser utilizados na presente invenção compreende um antidepressivo da classe dos inibidores seletivos da recaptura de serotonina tais como a fluoxetina, sertralina, paroxetina, citalopram, fluvoxamina; ou inibidores seletivos de recaptura de serotonina/noradrenalina como, duloxetina, venlafaxina; ou inibidores de recaptura de serotonina e antagonistas alfa-2, nefazadona, tradazona; ou estimulante da recaptura de serotonina, tianeptina, inibidores não seletivos da recaptura de monoaminas (Serotonina/Noradernalina) ou também conhecidos como antidepressivos tricíclicos), amitriptilina, nortriptilina, clomipramina, imipramina, desipramina, doxepina, maprotilina; ou inibidores da monoaminoxidase, tranilcipromina, isocarboxazida, iproniazida, fenelzina, clorgilina, moclobemida, toloxatona, brofaromina, befloxatona; ou antagonistas dos adrenoreceptores alfa-2, mirtazapina, mianserina; ou inibidores seletivos de recaptura de dopamina, minaprina, bupropiona, amineptina; ou inibidores seletivos de recaptura de noradrenalina.viloxazina e reboxetina, preferencialmente o cloridrato de sertralina. Drugs which may be used in the present invention comprise an antidepressant of the class of selective serotonin reuptake inhibitors 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, thianeptin, non-selective monoamine reuptake inhibitors (Serotonin / Noradernaline) or otherwise known as tricyclic antidepressants), amitriptyline, nortriptyline, clomipramine, imipramine, desipramine, doxepine, maprotiline; or monoaminoxidase, tranylcypromine, isocarboxazide, iproniazide, phenelzine, clorgiline, moclobemide, toloxatone, bropharomine, befloxatone inhibitors; or alpha-2 adrenoreceptor antagonists, mirtazapine, myanserine; or selective dopamine, minaprine, bupropion, amineptine reuptake inhibitors; or selective noradrenaline.viloxazine and reboxetine reuptake inhibitors, preferably sertraline hydrochloride.
Além dos antidepressivos, os fármacos que também podem ser utilizados na presente invenção compreendem os antagonistas do receptor AT1 , sendo eles: telmisartan, valsartan, candersartan, azilsartan, eprosartan, ibersartan, olmesartan, ou o tasosartan; preferencialmente, o losartan potássico, não limitante. · In addition to antidepressants, drugs that may also be used in the present invention include AT1 receptor antagonists, namely: telmisartan, valsartan, candersartan, azilsartan, eprosartan, ibersartan, olmesartan, or tasosartan; preferably non-limiting losartan potassium. ·
Em função dos aspectos físico-químicos, os fármacos que podem ser utilizados na presente invenção compreende um composto de alta solubilidade e alta permeabilidade (Classe I), segundo a classificação biofarmacêutica (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) tais como; amilorida, cloroquina, ciclofosfamida, diazepam, digoxina, doxiciclina, fluconazol, levodopa+carbidopa, levonorgestrel, metronidazol, fenobarbital, fenoxi-metilpenicilina, prednisolona, primaquina, propranolol, pirazinamida, riboflavina, salbutamol, stavudina, teofilina, zidovudina, amoxicilina, benzinidazol, dietil-carbamazina, DL-metionina, etossuximida, isoniazida, carbonato de lítio, nicotinamida, noretisterona, piridoxima, cloridrato de proguanil, clorfeniramina, sulfato de atropina, dexametasona, etinilestradiol, trinitrado de glicerila, dinitrato de isossorbida, lamivudina, levamisol, sulfato de morfina, metoclopramida, quinina, iodeto de sódio, verapamil, warfarina; ou compostos de baixa solubilidade e alta permeabilidade (Classe II) da BCS como, amiodarona, atorvastatina, ácido fólico, albendazol, azitromicina, ácido nalidixico, nevirapina, carbamazepina, clorpromazina, cisapridas, ciprofloxacina, clofazimina, diloxanida, ciclosporina, diclofenaco, diflunisal, digoxina, eritromicina, efavirenz, flurbiprofeno, danazol, dapsona, glipazida, glibenclamida, griseofulvina, haloperidol, ivermectina, lopinavir ibuprofeno, indanavir, indometacina, itraconazol, cetoconazol, lanzoprazol, lovastatina, mefloquina, mebendazol, naproxeno, niclosamida, nitrofurantoína, nifedipina, ofloxaciona, fenitoína, pirantel, pirimetamina, piroxicam, raloxifeno, rifamicina, retinol, ritonavir, saquinavir, spironolactona, sulfametoxazol, sulfadizaina, sulfassalazina, tracrolimo, tamoxifeno, terfenadina, trimetropina, ácido valpróico, fenazopiridina, nelfinavir, glipizida, glibenclamida, oxprozina, raloxifeno, sirolimus, talinolol; ou compostos de alta solubilidade e baixa permeabilidade (Classe III) da BCS tais como, abacavir, aciclovir, acido acetil salicílico, alupurinol, ácido ascórbico, atenolol, biperideno, captopril, clorafenicol, cimetidina, cloxacilina sódica, didanosina, ergocalciferol, ergometrina, eritromicina, etambutol, fosfato de codeína, colchicina, ergotamina, hidralazina, hidroclorotiazida, levotiroxina sódica, metotrexato, metformina, metildopa, neostigmina, nistatina, nifurtimox, paracetamol (acetaminofeno), prometazina, propiltiouracil, piridostigmina, reserpina, tiamina; ou compostos de baixa solubilidade e baixa permeabilidade (Classe IV) da BCS tais como, acetazolamida, azatioprina, amfotericina, clortalidona, clortiazida, ciprofloxacino, furosemida, hidróxido de alumínio, hidroclorotiazdia, indanavir, mebendazol, metrotexato, neomicina, nelfinavir, ritonavir, ou saquinavir, não limitante. Depending on the physicochemical aspects, the drugs which may 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 abipharmaceutical 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, benzofluidine, benzofluidine, diethylcarbamazine, DL-methionine, ethosuximide, isoniazid, lithium carbonate, nicotinamide, norethisterone, pyridoxime, proguanyl hydrochloride, chlorpheniramine, atropine sulfate, dexamethasone, ethinyl estradiol, glyceryl trinitate, isosolide dinitrate, lamivolide morphine, metoclopramide, quinine, sodium iodide, verapamil, warfarin; or BCS Class II low solubility and high permeability compounds such as amiodarone, atorvastatin, folic acid, albendazole, azithromycin, nalidixic acid, nevirapine, carbamazepine, chlorpromazine, cisaprides, ciprofloxacin, clofazimine, diloxanide, cyclosporin, cyclosporine, cyclosporine, digoxin, erythromycin, efavirenz, flurbiprofen, danazol, dapsone, glipazide, glibenclamide, griseofulvin, haloperidol, ivermectin, lopinavir ibuprofen, indanavir, indomethacin, itraconazole, ketoconazole, nanzoprazol, lovofatin, nophosphamine, nefloxacin , phenytoin, pirantel, pyrimethamine, piroxicam, raloxifene, rifamycin, retinol, ritonavir, saquinavir, spironolactone, sulfamethoxazole, sulfadizaine, sulfasalazine, tracrolimus, tamoxifen, terfenadine, trimetropine, valproic acid, glenaziridine, phenenazine, sirolimus, talinolol; or BCS high solubility and low permeability compounds (Class III) such as abacavir, acyclovir, acetyl salicylic acid, alupurinol, ascorbic acid, atenolol, biperiden, captopril, chlorafenicol, cimetidine, cloxacillin sodium, didanosine, ergocalciferol, ergometrine, erythromycin, ethambutol, codeine phosphate, colchicine, ergotamine, hydralazine, hydrochlorothiazide, levothyroxine sodium, methotrexate, metformin nephromethane, acetaminophen propylthiouracil, pyridostigmine, reserpine, thiamine; or BCS low solubility and low permeability compounds (Class IV) such as acetazolamide, azathioprine, amphotericin, chlortalidone, chlortiazide, ciprofloxacin, furosemide, aluminum hydroxide, hydrochlorothiazdia, indanavir, mebendazole, methotrexate, neomycin, ritonavir, nelfinir, saquinavir, not limiting.
Alternativamente, o processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos, usando também um sistema de fluxo e com pré-mistura das soluções (Figura 1b), caracteriza-se por compreender: i. A etapa C3 representar um recipiente para pré-mistura e homogeneização das soluções de fármaco (S1) e ciclodextrina (S2), preferencialmente no formato de um tanque;  Alternatively, the process of preparing inclusion compounds involving cyclodextrins and drugs, also using a flow system and premixing the solutions (Figure 1b), comprises: i. Step C3 represents a container for premixing and homogenizing drug (S1) and cyclodextrin (S2) solutions, preferably in the form of a tank;
ii. A agitação do tanque em "ii" por sistema de bombeamento, pá rotativa, rotação do recipiente, agitação por balanço, preferencialmente agitação mecânica por hélice;  ii. "Ii" tank agitation by pumping system, rotary blade, container rotation, rocking agitation, preferably mechanical propeller agitation;
iii. A velocidade de agitação em "iii" variar entre 100 e 2000rpm, preferencialmente entre 300 e 500rpm, por um período de tempo entre 1 e 60 minutos, preferencialmente entre 5 e 20 minutos;  iii. The stirring rate at "iii" will range from 100 to 2000rpm, preferably from 300 to 500rpm, for a period of time from 1 to 60 minutes, preferably from 5 to 20 minutes;
iv. A razão molar fármaco/CD da pré-mistura em "ii" variar entre 1:0.001 e 1 :5, preferencialmente entre 1 :0.01 e 1 :5;  iv. The drug / CD molar ratio of premix in "ii" will range from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 5;
v. O bombeamento da pré-mistura do recipiente C3 para C2 por B1 com fluxo variando entre 1 ,0 e 28,0 mL/min, preferencialmente entre 4 e 8,0 ml/min;  v. Pumping the premix from container C3 to C2 by B1 with flow ranging from 1.0 to 28.0 mL / min, preferably from 4 to 8.0 mL / min;
vi. O controle da temperatura da pré-mistura em C2 por um sistema de tubulação, preferencialmente no formato de uma serpentina; vii. O controle da temperatura da pré-mistura em C2 por um sistema de fluxo contínuo na faixa entre -5,0 e 5,0°C, preferencialmente entre 0 e 2°C; viii. O fluxo do gás do spray dryer (spray flow) variar entre 100 e 800 L/h, preferencialmente entre 300 e 400 L/h; saw. Control of the premix temperature in C2 by a piping system, preferably in the form of a coil; vii. Controlling the temperature of the premix in C2 by a continuous flow system in the range of -5.0 to 5.0 ° C, preferably between 0 and 2 ° C; viii. The spray dryer gas flow varies between 100 and 800 L / hr, preferably between 300 and 400 L / hr;
ix. O fluxo do aspirador do spray dryer variar entre 20 e 40 m3/h, preferencialmente entre 30 e 40 m3/h; x. A temperatura de entrada (inlet temperaturé) do gás de arraste no spray dryer variar na faixa entre 30 e 200 °C, preferencialmente entre 120 e 150°C; xi. A temperatura de saída (outlet temperaturé) do material seco do sistema variar entre 40 e 65°C; e, ix. The flow rate of the spray dryer aspirator will vary between 20 and 40 m 3 / h, preferably between 30 and 40 m 3 / h; x. The inlet temperature of the carrier in the spray dryer ranges from 30 to 200 ° C, preferably from 120 to 150 ° C; xi The outlet temperature of the system dry material ranges from 40 to 65 ° C; and,
xii. Obtenção do produto na forma de um pó seco.  xii. Obtaining the product as a dry powder.
O processo (Figura 1) pode ainda ser aplicado à preparação de complexos entre ciclodextrinas e agentes bioativos. O termo "agente bioativo" deve ser entendido no sentido mais amplo, não se limitando aos compostos de origem biológico; sendo considerada qualquer substância que tenha atividade farmacológica com função terapêutica, profilática ou curativa em humanos (Code of Federal Regulations 21 , FDA, part 330.05 (drug categories), part 331 through 361 ; 440- 460, revised in em abril 201 1 , entitled "drugs for human use"). Esses agentes bioativos podem ser proteínas e peptídeos, definindo-se a primeira como macromoléculas formadas pelo encadeamento de 100 ou mais resíduos de aminoácidos, enquanto a segunda representada por estruturas com menos de 100 resíduos de aminoácidos. Além de peptídeos e proteínas macromoléculas bioativas com diferentes composições químicas tais como polissacaríedos, açucares, DNA, RNA, genes, parte de sequências gênicas de ácidos nucléicos, lipídeos, enzimas, antígenos, compostos naturais (extraídos de sistemas vivos), semissintéticos (modificadas após extração) ou sintéticos (preparadas artificialmente), podem ser conjugados com as ciclodextrinas utilizando o processo proposto (Figura 1). A preparação de uma solução de um veículo; sendo este ciclodextrinas e/ou derivados, a uma dada temperatura, concentração e em diferentes proporções molares deste fármaco e da ciclodextrina; por exemplo, 1 :1 a 1 :10, 2:1 a 2:10 ou 3:1 , preferencialmente, 1 :1 a 1 :5, não limitante. The process (Figure 1) can also be applied to the preparation of complexes between cyclodextrins and bioactive agents. The term "bioactive agent" is to 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 201 1, entitled "drugs for human use"). Such bioactive agents may be proteins and peptides, the former being defined as macromolecules formed by chaining 100 or more amino acid residues, while the latter represented by structures having less than 100 amino acid residues. In addition to bioactive macromolecule peptides and proteins 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 to cyclodextrins using the proposed process (Figure 1). The preparation of a solution of a vehicle; this being cyclodextrins and / or derivatives at a given temperature, concentration and in different molar ratios of this drug and cyclodextrin; for example, 1: 1 to 1: 10, 2: 1 to 2:10 or 3: 1, preferably 1: 1 to 1: 5, not limiting.
A solução de ciclodextrina (S1) em uma concentração entre 1,0 x 10"3 aThe cyclodextrin (S1) solution at a concentration between 1.0 x 10 "3 to
1 ,0 mol/L é inserida através de uma bomba (B1), de acordo com a proporção molar, enquanto a solução do fármaco a ser complexado (S2) em uma concentração entre 1 ,0 x 10"3 a 1 ,0 mol/L, não limitante, é bombeada, simultaneamente pela bomba (B2) (Figura 1a). As duas linhas de bombeamento, advindas de (B1) e (B2) confluem-se através de tubos para um controlador (C1), onde as soluções são previamente misturadas em um sistema em espiral; sob uma faixa de temperatura de, no mínimo, 0°C e no máximo 100°C, com fluxo de bombeamento de no mínimo 1 ,0 e no máximo 28,0 mL/min, não limitante. A mistura das duas soluções deixa o controlador (C1) e desloca-se, sob pressão, para outro sistema em espiral ou controlador (C2), no qual a temperatura da mistura fármaco/ciclodextrina pode ser controlada. Em C2 a temperatura da mistura pode ser elevada de 0°C a 100°C se o processo de interação entre as espécies químicas é endotérmico e ou pode ser reduzida em no mínimo -5°C e no máximo +5°C no caso de sistemas sistemas exotérmicos, de acordo com sistema fármaco/CDs envolvido. O controle da temperatura é uma etapa crítica para a preparação do composto de inclusão pelo sistema de fluxo contínuo, uma vez que altera a termodinâmica do processo de inclusão, favorecendo a interação entre duas espécies químcias, preferencialmente, o fármaco cloridrato de sertralina e a ciclodextrinas e ou losartan potássico e ciclodextrinas. Em seguida, a solução contendo composto de inclusão deixa o controlador (C2), em fluxo contínuo, a uma dada temperatura e pressão e é injetada no equipamento de spray dryer (SD) pela bomba (B3) com um fluxo variando entre 1 ,0 e 28,0 mL/min de acordo com a razão molar fármaco/CD utilizado. A pressão de bombeamento, temperatura de entrada do equipamento e a pressão do aspirador foram controladas para obter o produto na forma de pó seco. O fluxo de bombeamento de B1 , B2 ou B3 compreende um intervalo entre 1 e 28 mL/min; a pressão do pulverizador (spray flow) variou entre 5 a 8 bar, com um fluxo de gás entre 100 e 800 L/h, preferencialmente entre 300 e 400 L/h e o fluxo do aspirador do spray dryer variou entre 0 e 40 m3/h, preferencialmente, um fluxo entre 30 e 40 m3/h. A formação do jato spray pode ser realizada por bico atomizadores rotativos, cinéticos, ultra-som, eletrostáticos, preferencialmente atomizadores pneumáticos. 1.0 mol / L is inserted through a pump (B1) according to the molar ratio, while the solution of the drug to be complexed (S2) at a concentration between 1.0 x 10 "3 to 1.0 mol / L, non-limiting, is simultaneously pumped by pump B2 (Figure 1a) The two pumping lines from (B1) and (B2) flow through tubes to a controller (C1) where the solutions are premixed in a spiral system, over a temperature range of at least 0 ° C to a maximum of 100 ° C, with a pumping flow of at least 1.0 and a maximum of 28.0 mL / min, The limiting of the two solutions leaves the controller (C1) and moves under pressure to another spiral or controller system (C2) where the temperature of the drug / cyclodextrin mixture can be controlled. of the mixture may be raised from 0 ° C to 100 ° C if the process of interaction between chemical species is endothermic and or may be reduced by at least -5 ° C and maximum + 5 ° C for exothermic systems, according to drug / CD system involved. Temperature control is a critical step for the preparation of the inclusion compound by the continuous flow system, since it changes the thermodynamics of the inclusion process, favoring the interaction between two chemical species, preferably sertraline hydrochloride and cyclodextrins. and or potassium losartan and cyclodextrins. Then the solution containing inclusion compound leaves the controller (C2) in continuous flow at a given temperature and pressure and is injected into the spray dryer (SD) by pump (B3) with a flow ranging from 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 as a dry powder. The pumping flow of B1, B2 or B3 comprises a range between 1 and 28 mL / min; the spray flow pressure ranged from 5 to 8 bar, with a gas flow from 100 to 800 L / hr, preferably from 300 to 400 L / h and the spray dryer vacuum flow ranged from 0 to 40 m 3 / h is preferably a flow between 30 and 40 m 3 / h. The formation of the spray jet can be performed by rotary, kinetic, ultrasonic, electrostatic atomizers, preferably pneumatic atomizers.
A temperatura da temperatura da mistura em C2 compreende um intervalo entre -5 e 30°C, preferencialmente, entre 0o e 5°C. A temperatura de injeção pode ser reduzida para sistemas fármaco/CD caso o processo seja exotérmico e ou elevada quando o sistema for endotérmico, em ambos os casos favorecendo a interação de acordo com a termodinâmica do processo de inclusão. The temperature of the C 2 mixture temperature comprises a range of from -5 to 30 ° C, preferably from 0 to 5 ° C. Injection temperature may be reduced for drug / CD systems if the process is exothermic and or elevated when the system is endothermic, in both cases favoring interaction according to the thermodynamics of the inclusion process.
A fim de demonstrar o processo de preparação do composto de inclusão, pelo processo spray drying em fluxo contínuo (SD.LT) usou-se o fármaco cloridrato de sertralina (SRT), como exemplo de fármaco de baixa solubilidade (4,0 mg/mL), um antidepressivo inibidor da recaptação de serotonina (SSRI) (Johnson, B. M. (1996). "Sertraline Hydrochloride." Analytical Profiles of Drug Substances and Excipients, 24: 443-486) e como modelo de fármaco de alta solubilidade o Losartan potássico (LS) e a β-ciclodextrina (β- CD) com solubilidade de 18,5 mg/mL (Brewster, 2006; Salustio, 2009). Foram realizados testes biológicos in vivo, para avaliar a atividade farmacológica da SRT livre, CD, e dos compostos de inclusão preparados pelo processo em que consiste a matéria tratada.  In order to demonstrate the process of preparation of the inclusion compound, the continuous flow spray drying (SD.LT) process used sertraline hydrochloride (SRT) as an example of low solubility drug (4.0 mg / kg). mL), a serotonin reuptake inhibitor antidepressant (SSRI) (Johnson, BM (1996). "Sertraline Hydrochloride." Analytical Profiles of Drug Substances and Excipients, 24: 443-486) and as a high solubility drug model Losartan potassium (LS) and β-cyclodextrin (β-CD) with solubility of 18.5 mg / mL (Brewster, 2006; Salustio, 2009). In vivo biological tests were performed to evaluate the pharmacological activity of free SRT, CD, and inclusion compounds prepared by the process of treated matter.
As soluções de fármacos ou das ciclodextrinas utilizadas na presente invenção podem ser preparadas, tendo como solventes, água, soluções aquosas tamponadas, solventes orgânicos e co-solventes (misturas organo/aquosas). Os solventes orgânicos podem ser álcoois, tais como o etanol, metanol, propanol, isopropanol, butanol, hexanol; ou o diclorometano, dimetilsufóxido, clorofórmio, éter, acetato de etila, metil-ter-butil-éter; não limitante. A matéria tratada pode ser mais bem compreendida a partir dos seguintes exemplos, não limitantes: Drug or cyclodextrin solutions used in the present invention may be prepared having as solvents water, buffered aqueous solutions, organic solvents and co-solvents (organo / aqueous mixtures). Organic solvents may be alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, hexanol; or dichloromethane, dimethylsufoxide, chloroform, ether, ethyl acetate, methyl tert-butyl ether; not limiting. The subject matter can be better understood from the following non-limiting examples:
Exemplo 1 - Preparação do complexo de inclusão entre o fármaco cloridrato de sertralina (SRT) e a β-ciclodextrina (pCD), via liofilização (LF) e spray drying processo convencional (SD.MC). Example 1 - Preparation of the inclusion complex between sertraline hydrochloride drug (SRT) and β-cyclodextrin (pCD) via lyophilization (LF) and conventional spray drying process (SD.MC).
Inicialmente foram preparadas isoladamente duas soluções, uma de SRT e outra de PCD, a uma concentração variando de 1 ,0 x 10"3 a 1 ,0 x 10"2 mol/L. Uma alíquota de no mínimo 100 mL de cada solução foi misturada previamente, mantendo uma razão molar de no mínimo de 1 :1 de SRT: CD, sendo que a solução final resultante da mistura foi mantida sob agitação (2000 rpm) por um período de no mínimo de 6 horas. A solução final foi então dividida em duas alíquotas. Initially we were prepared separately two solutions, one of SRT and another PCD at a concentration ranging from 1 x 10 0 "3-1, 0 x 10" 2 mol / L. An aliquot of at least 100 mL of each solution was premixed, maintaining a minimum molar ratio of 1: 1 SRT: CD, and the resulting final mixture was stirred (2000 rpm) for a period of at least 6 hours. The final solution was then divided into two aliquots.
A primeira alíquota foi congelada em nitrogénio líquido, e posteriormente submetida à liofilização.  The first aliquot was frozen in liquid nitrogen and then subjected to lyophilization.
A segunda alíquota foi injetada no equipamento de spray dryer segundo a metodologia convencional (SD.MC) relatada na literatura (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). mantendo os parâmetros de operação do aparelho.  The second aliquot was injected into the spray dryer according to the conventional methodology (SD.MC) reported in the literature (Lin ;, SY and YH 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.
O pó seco obtido foi, então, caracterizado por Ressonância Magnética Nuclear (Figuras 2(b) e 2(c)).  The obtained dry powder was then characterized by Nuclear Magnetic Resonance (Figures 2 (b) and 2 (c)).
Exemplo 2 - Preparação do complexo de inclusão entre o fármaco cloridrato de sertralina (SRT) e β-ciclodextrina (PCD) pelo processo spray drying- SD.LT, por dupla injeção e em fluxo contínuo. Example 2 - Preparation of the inclusion complex between sertraline hydrochloride drug (SRT) and β-cyclodextrin (PCD) by spray drying-SD.LT by double injection and continuous flow.
Basicamente, a preparação do complexo de inclusão consiste nas seguintes etapas: Basically, the preparation of the inclusion complex consists of the following steps:
i. Foram preparadas, previamente, as soluções aquosas do fármaco entre 1 ,0 x 10"3 e 1 ,0 x 10"2 mol/L, ou não aquosas quando o fármaco é pouco solúvel, preferencialmente cloridrato de sertralina, entre 1 ,0 x 10~3 a 1 ,0 x 10"2 mol/L, e da ciclodextrina, a uma concentração entre 1 ,0 x 10"3 a ,0 mol/L; ii. A solução do fármaco, preferencialmente, o cloridrato de sertralina e da ciclodextrina foram bombeadas, respectivamente, através da bomba B1 e B2, de forma independente e em linhas de fluxo separadas (Figura 1a). A pressão de bombeamento de B1 e B2 foi ajustada para um fluxo que entre 1 ,0 a 28,0 mL/min. para cada linha de bombeamento, de modo que fosse mantida a razão molar da SRT/ciclodextrina, preferencialmente de 1. ; iii. As soluções nas duas linhas se encontraram no controlador C1 , preferencialmente no formato de uma serpentina, a uma temperatura entre 0 ai. Were prepared in advance, the aqueous drug solutions of 1, 0 x 10 "3:01, 0 x 10" 2 mol / L aqueous or non 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 3.0 mol / l; ii. Preferably, the drug solution, 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 SRT / cyclodextrin molar ratio, preferably 1., was maintained; iii. The solutions on both lines were found in controller C1, preferably in the form of a coil, at a temperature between 0 to
100°C, preferencialmente 20 e 30°C, a fim de permitir a homogeneização entre as soluções advindas de B1 e B2; iv. Após a mistura das soluções em C1 , a solução resultante foi direcionada ao controlador C2, preferencialmente no formato de uma serpentina, onde a temperatura da mistura foi controlada numa faixa de -5,0 a 5,0°C, preferencialmente, entre 0 e 5,0°C; v. A solução, então, foi direcionada ao equipamento spray dryer, através de uma bomba B3 em uma faixa de fluxo que variou entre 1 ,0 e 28,0 mL/min preferencialmente entre 4,0 e 8,0 mL/min.; 100 ° C, preferably 20 and 30 ° C, to allow homogenization between solutions from B1 and B2; iv. After mixing the solutions in C1, the resulting solution was directed to the controller C2, preferably in the form of a coil, 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; v. The solution was then directed to the spray dryer equipment through a B3 pump in a flow range ranging from 1.0 to 28.0 mL / min, preferably from 4.0 to 8.0 mL / min .;
vi. A pressão do fluxo de ar do spray dryer (spray flow) variou entre 5 a 8 bar com um fluxo de gás entre 100 e 800 L/h, preferencialmente entre 300 e 400 L/h; vii. O fluxo do aspirador do spray dryer variou entre 50 e 100%, correspondendo preferencialmente a um fluxo entre 30 e 40 m3/h; viii. A temperatura de entrada (inlet temperature) do gás no spray dryer variou na faixa entre 30 e 220 °C, preferencialmente entre 100 e 150°C; ix. A temperatura de saída (outlet temperature) do material seco do sistema variou entre 40 e 65°C, preferencialmente entre 50 e 60°; x. Finalmente, produziu-se um pó seco, o qual foi caracterizado através de técnicas de análises físico-químicas. Exemplo 3 - Preparação do complexo de inclusão entre o fármaco Losartan potássico (LS) e β-ciclodextrina (PCD) pelo processo spray drying .LT, por dupla injeção e em fluxo contínuo. saw. The spray dryer air flow pressure ranged from 5 to 8 bar with a gas flow between 100 and 800 L / hr, preferably between 300 and 400 L / hr; vii. The spray dryer vacuum flow varied between 50 and 100%, preferably corresponding to a flow between 30 and 40 m 3 / h; viii. The inlet temperature of the spray dryer gas ranged from 30 to 220 ° C, preferably from 100 to 150 ° C; ix. The outlet temperature of the system dry material ranged from 40 to 65 ° C, preferably from 50 to 60 °; x. Finally, a dry powder was produced which was characterized by physicochemical analysis techniques. Example 3 - Preparation of the inclusion complex between the drug Losartan potassium (LS) and β-cyclodextrin (PCD) by the spray drying .LT process by double injection and continuous flow.
Basicamente, a preparação do composto de inclusão nas seguintes etapas: i. Foram preparadas, previamente, soluções aquosas do fármaco Losartan potássico e da ciclodextrina na concentração de 1 ,6 x 10"3 mol/L; ii. A solução do fármaco e da ciclodextrina foram bombeadas, respectivamente, através da bomba B1 e B2, de forma independente e em linhas de fluxo separadas (Figura 1a). A pressão de bombeamento de B1 e B2 foi ajustada para um fluxo que variou entre 1 ,0 a 28,0 mL/min., para cada linha de bombeamento, mantendo a razão molar da LS/ciclodextrina, preferencialmente de 1 :1 ; iii. As soluções nas duas linhas se encontraram no controlador C1 , preferencialmente no formato de uma serpentina, a uma temperatura entre 40 - 65°C, a fim de permitir a homogeneização; iv. Após a mistura as soluções em C1 , a solução resultante foi direcionada ao controlador C2, onde a temperatura da mistura foi controlada numa faixa de entre 0 e 4°C; v. A solução, então, foi direcionada ao equipamento spray dryer, através de uma bomba B3 em uma faixa de fluxo que variou entre 8,5 e 11 ,5 mL/min.; vi. A pressão do fluxo de ar do spray dryer (spray flow) variou entre 5 a 8 bar com um fluxo de gás entre 100 e 800 L/h; vii. O fluxo do aspirador do spray dryer variou entre 50 e 100%, correspondendo a um fluxo entre 20 e 40 m3/h; viii. A temperatura de entrada {inlet temperaturé) do gás de arraste no spray dryer variou na faixa entre 120 e 150°C; ix. A temperatura de saída (outlet temperaturé) do material seco do sistema variou entre 40 - 50°C; x. Finalmente, produziu-se um pó seco, o qual foi caracterizado através da RMN 2D-ROESY. Basically, the preparation of the inclusion compound in the following steps: i. Aqueous solutions of the Losartan potassium drug and cyclodextrin at a concentration of 1.6 x 10 -3 mole / L were prepared in advance; ii. The drug solution and cyclodextrin were respectively pumped through pump B1 and B2, respectively. independently and in separate flow lines (Figure 1a) .The pumping pressure of B1 and B2 was adjusted to a flow ranging from 1.0 to 28.0 mL / min. for each pumping line, maintaining the ratio molar LS / cyclodextrin, preferably 1: 1 iii The solutions on both lines were found in controller C1, preferably in the form of a coil, at a temperature between 40 - 65 ° C to allow homogenization; After mixing the solutions in C1, the resulting solution was directed to controller C2, where the temperature of the mixture was controlled within a range of 0 to 4 ° C, v. The solution was then directed to the spray dryer through of a B3 bomb in a range of f luxury ranging from 8.5 to 11.5 mL / min .; saw. The spray dryer air flow pressure ranged from 5 to 8 bar with a gas flow from 100 to 800 L / h; vii. The spray dryer vacuum flow varied between 50 and 100%, corresponding to a flow between 20 and 40 m 3 / h; viii. The inlet temperature of the carrier in the spray dryer ranged from 120 to 150 ° C; ix. The outlet temperature of the system dry material ranged from 40 - 50 ° C; x. Finally, a dry powder was produced which was characterized by 2D-ROESY NMR.
Exemplo 4 - Preparação do complexo de inclusão entre o fármaco Cloridrato de Sertralina e β-ciclodextrina (PCD) pelo processo SD.LT, alternativamente com pré-mistura das soluções.  Example 4 - Preparation of the inclusion complex between the drug Sertraline Hydrochloride and β-cyclodextrin (PCD) by the SD.LT process, alternatively by premixing the solutions.
i. Foram preparadas soluções aquosas do fármaco (S1) e da ciclodextrina (S2) (Figura 1b), preferencialmente cloridrato de sertralina e β- ciclodextrina, em uma concentração entre 5,0 x 0"3 e 1 ,0 x 10"2 mol/L, preferencialmente 5,0 x 10"3 mol/L; i. Aqueous solutions of the drug (S1) and cyclodextrin (S2) (Figure 1b), preferably sertraline hydrochloride and β-cyclodextrin, were prepared at a concentration between 5.0 x 0 "3 and 1.0 x 10 " 2 mol / L, preferably 5.0 x 10 -3 mol / L;
ii. As duas soluções do item "i" foram previamente misturadas e agitadas em um recipiente (Figura 1b - (C3)), por um período de tempo que variou entre 1 minuto e 60 minutos, preferencialmente entre 10 e 30 minutos;  ii. The two solutions of item "i" were previously mixed and shaken in a container (Figure 1b - (C3)) for a period of time ranging from 1 minute to 60 minutes, preferably from 10 to 30 minutes;
iii. O recipiente de pré-mistura (C3 - Figura 1b) descrito no item "ii" substitui alternativamente no esquema da Figura 1a o controlador (C1), preferencialmente em formato de um tanque cilíndrico, com fundo cónico;  iii. The premix container (C3 - Figure 1b) described in item "ii" alternatively replaces in the scheme of Figure 1a the controller (C1), preferably in the form of a cylindrical conical bottom tank;
iv. A temperatura de C3 varia entre 0 e 100°C, preferencialmente entre 30 - 60°C;  iv. The temperature of C3 is from 0 to 100 ° C, preferably from 30 - 60 ° C;
v. A agitação do recipiente descrita em "ii" varia entre 100 e 2000rpm, preferencialmente entre 300 e 500rpm;  v. The agitation of the container described in "ii" ranges between 100 and 2000rpm, preferably between 300 and 500rpm;
vi. A razão molar fármaco/CD da pré-mistura descrita no item "ii" variou entre 1 :0.1 e 1 :5, preferencialmente 1 :1;  saw. The drug / CD molar ratio of the premix described in item "ii" ranged from 1: 0.1 to 1: 5, preferably 1: 1;
vii. A mistura de soluções preparada de acordo com item "i" a "v" foi direcionada ao controlador C2, preferencialmente no formato de uma serpentina, através da bomba B1 , conforme mostrado na Figura 1b, com fluxo que variou entre 1 ,0 e 28,0 mL/min; vii. The solution mixture 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 flow ranging from 1.0 to 28. 0.0 mL / min;
viii. A temperatura da mistura foi controlada em C2 e variou na faixa entre -5,0 e 5,0°C, preferencialmente entre 0 e 2°C; ix. A solução deixa o controlador C2 e é direcionada ao equipamento spray dryer, através de uma bomba B3 em uma faixa de fluxo que variou entre 1 ,0 e 28,0 mlJmin, preferencialmente entre 4,0 e 8,0 mIJmin.; viii. The temperature of the mixture was controlled at C 2 and ranged from -5,0 to 5,0 ° C, preferably from 0 to 2 ° C; ix. The solution leaves the C2 controller and is directed to the spray dryer by means of a B3 pump in a flow range ranging from 1.0 to 28.0 ml / min, preferably between 4.0 and 8.0 ml / min .;
x. A pressão do fluxo de ar do spray dryer (spray flow) variou entre 5 a 8 bar com um fluxo de gás entre 100 e 800 L/h, preferencialmente entre 300 e 400 L/h;  x. The spray dryer air flow pressure ranged from 5 to 8 bar with a gas flow between 100 and 800 L / hr, preferably between 300 and 400 L / hr;
xi. O fluxo do aspirador do spray dryer variou entre 20 e 40 m3/h, preferencialmente entre 30 e 40 m3/h; xi The spray dryer vacuum flow varied between 20 and 40 m 3 / h, preferably between 30 and 40 m 3 / h;
xii. A temperatura de entrada (inlet temperature) do gás, de arraste no spray dryer variou na faixa entre 30 e 200 °C, preferencialmente entre 120 e 150°C;  xii. The inlet temperature of the spray dryer gas in the range varied between 30 and 200 ° C, preferably between 120 and 150 ° C;
xiii. A temperatura de saída (outlet temperature) do material seco do sistema variou entre 40 e 65°C; xiii. The outlet temperature of the system dry material ranged from 40 to 65 ° C;
xiv. O produto obtido foi na forma de um pó seco, o qual foi caracterizado através de análises físico-químicas. xiv. The product obtained was in the form of a dry powder, which was characterized by physicochemical analysis.
Exemplo 5 - Caracterização dos produtos e comparação dos dados obtidos. Example 5 - Product characterization and comparison of the obtained data.
A caracterização do composto de inclusão formado entre a SRT e a β- CD, na razão molar 1 :1 foi realizada por diferentes técnicas físico-químicas; tanto em estado sólido, como espectroscopia difração de raios-X de pó (DRX), espectroscopias na região do infravermelho (FTIR), análise térmica (TG/DTA), microscopia eletronica de varredura (MEV), medida de tamanho de partículas por espalhamento de luz, bem como em solução pelas técnicas de ressonância magnética nuclear (RMN).  The characterization of the inclusion compound formed between SRT and β-CD at the 1: 1 molar ratio was performed by different physicochemical techniques; either solid state such as X-ray powder diffraction (XRD) spectroscopy, infrared spectroscopy (FTIR), thermal analysis (TG / DTA), scanning electron microscopy (SEM), scattered particle size measurement as well as in solution by nuclear magnetic resonance (NMR) techniques.
Na Figura 2 são apresentadas as análises DRX do composto de inclusão preparado entre SRT e β-CD, a qual mostrou que o processo ora reivindicado levou a formação de um composto com perfil amorfo (Figura 2f), semelhante ao observado para o mesmo sistema preparado pelos processos de liofilização (Figura 2d) e SD.MC (Figura 2.e), mas diferente da amostra contendo apenas a mistura física da SRT e β-CD, a qual apresentou um perfil somatório dos difratogramas isoladas. Figure 2 shows the XRD analyzes of the inclusion compound prepared between SRT and β-CD, which showed that the process claimed here led to the formation of an amorphous profile compound (Figure 2f), similar to that observed for the same prepared system. 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 summation profile of the diffractograms isolated.
Na Figura 3 são apresentadas as curvas TG do composto de inclusão preparado pelo processo reivindicado (Figura 3e); a qual mostrou um perfil diferente dó observado para as moléculas livres SRT (Figura 3a), β-CD (Figura 3b) e a mistura física (Figura 3c), sugerindo a formação do composto de inclusão. A formação do complexo pelo processo reivindicado é reforçada pelo perfil semelhante comparado à curva do complexo liofilizado (Figura 3d). A umidade residual do complexo preparado foi de 6,1% entre 30 a 100°C valor próximo aos 6,0% observado na curva TG do complexo preparado por liofilização (Figura 3d).  Figure 3 shows the TG curves of the inclusion compound prepared by the claimed process (Figure 3e); which showed a different profile than observed for the free molecules SRT (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 reinforced by the similar profile compared to the curve of the lyophilized complex (Figure 3d). The residual moisture of the prepared complex was 6.1% at 30 to 100 ° C, close to the 6.0% observed in the TG curve of the complex prepared by lyophilization (Figure 3d).
Na Figura 4 pode ser visto as micrografias obtidas por MEV das partículas, a qual apresentou formas esféricas, com invaginações, sugerindo formação de microcápsulas (Figuras 4a a 4c); diferentemente do observado ara as partículas obtidas pelo processo de liofilização que apresentaram formas laminares (Figuras 4d e 4e).  In Figure 4 we can see the SEM micrographs of the particles, which presented spherical shapes with invaginations, suggesting microcapsule formation (Figures 4a to 4c); unlike that observed for the particles obtained by the lyophilization process that presented laminar forms (Figures 4d and 4e).
Na Figura 5 são apresentadas as curvas de distribuição de tamanho das partículas, as quais mostraram que os complexos preparados por spray drying, apresentaram distribuição unimodal, com tamanho de partículas em torno de 5,0 μηι, pelo processo ora reivindicado (Figura 5e), valor significativamente menor do que os 265μιη observados para os complexos preparados por liofilização (Figura 5c). O controle do tamanho de partículas pelo processo reivindicado pode facilitar a homgeneização do fármaco com excipientes durante a preparação de formulações farmacêuticas de uso oral, bem como facilitar o processo de dissolução.  Figure 5 presents the particle size distribution curves, which showed that the complexes prepared by spray drying presented unimodal distribution, with particle size around 5.0 μηι, by the process now claimed (Figure 5e). significantly lower than the 265μιη observed for complexes prepared by lyophilization (Figure 5c). Control of the particle size by the claimed process may facilitate homogenization of the drug with excipients during the preparation of oral pharmaceutical formulations as well as facilitate the dissolution process.
A efetiva interação entre o fármaco SRT e a β-ciclodextrina pode ser observada por técnicas de RMN (Figura 6); confirmando, assim, a formação dos compostos de inclusão.  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.
Na Figura 6(a) é apresentado o mapa de contorno 2D ROESY do composto de inclusão preparado pelo processo reivindicado na presente invenção, envolvendo a SRT e β-ciclodextrina onde pode ser visto um grande número de correlações espaciais entre os hidrogênios da SRT e da CD. Comparando as expansões dos mapas de contornos 2D ROESY mostrados nas Figuras 6(a), (b) e (c) observa-se que o mapa de contorno do composto inclusão preparado pelo processo spray drying na presente invenção (Figura 6a) apresenta um número de sinais de correlação entre SRT e CD semelhantes àqueles observados no mapa de contorno do mesmo composto preparado pelo processo de liofilização (Figura 6c). Por outro lado, o mapa de contorno do composto de inclusão preparado pelo processo spray drying convencional (SD.MC) (Figura 6b) é diferente dos dois mapas de contornos apresentados nas Figuras 6a e 6c. Esse resultado mostra a eficácia do presente processo para preparação de compostos de inclusão envolvendo fármacos de baixa solubilidade e o qual pode ser utilizado na preparação de compostos de inclusão envolvendo fármacos e ciclodextrinas em substituição ao processo de liofilização (LF) e ao processo spray dryer convencional (SD.MC), com a vantagem de ser um processo de produção rápida e contínua. Exemplo 7 - Caracterização do complexo formado entre Losartan e ciclodextrina pelo processo SD.LT. 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 SRT and the hydrogens can be seen. 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 correlation signals between SRT and CD 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 shown in Figures 6a and 6c. This result shows the efficacy of the present process for preparation of inclusion compounds involving low solubility drugs and which can be used in the preparation of inclusion compounds involving drugs and cyclodextrins to replace the freeze drying (LF) process 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.
A interação entre o Losartan potássico e a β-ciclodextrina pode ser observada por técnicas de RMN (Figura 1a1); confirmando, assim, a formação do compostos de inclusão.  The interaction between Losartan potassium and β-cyclodextrin can be observed by NMR techniques (Figure 1a1); thus confirming the formation of the inclusion compounds.
Na Figura 1a1a são apresentados os mapas de contornos 2D-ROESY do complexo LS: CD na razão molar 1 :1 preparados pelo processo convencional de liofilização, o qual mostra manchas indicativas de acoplamento escalar entre os hidrogênios do Losartan e CD. A Figura 1a1b mostra o mapa de contornos do complexo LS: PCD na razão molar 1 :1 preparado pelo processo SD.LT, o qual apresenta inúmeras manchas de correlações indicativas de acoplamentos escalar, com um perfil semelhantes ao observado na Figura 1a1a (processo de liofilização). Assim, conforme demonstardo na Figuras 11a e 11b o processo de preparação reinvindicado também pode ser aplicado a preparação de complexos envolvendo fármacos também solúveis. Exemplo 7 - Testes biológicos in vivo. A fim de verificar a influência dos processos de preparação no perfil farmacológico antidepressivo dos compostos de inclusão formados entre a SRT e a CD, foram realizados testes in vivo. Figure 1a1a shows the 2D-ROESY contour maps of the LS: CD complex at the 1: 1 molar ratio prepared by the conventional lyophilization process, which shows spots indicating scalar coupling between Losartan and CD hydrogens. Figure 1a1b shows the contour map of the LS: PCD complex at the 1: 1 molar ratio prepared by the SD.LT process, which has numerous patches of indicative correlations of scalar couplings, with a profile similar to that observed in Figure 1a1a freeze drying). Thus, as shown in Figures 11a and 11b, the preparation process claimed may also be applied to the preparation of complexes involving also soluble drugs. Example 7 - In vivo biological testing. In order to verify the influence of the preparation processes on the antidepressant pharmacological profile of the inclusion compounds formed between SRT and CD, in vivo tests were performed.
Os testes in vivo foram realizados em camundongos machos, adultos, do tipo CF1 , pesando entre 20 e 30 g. Antes dos experimentos, os animais foram adaptados por, no mínimo, 05 dias em um biotério de passagem. Os animais foram mantidos em caixas plásticas de 17x28x 3 cm com, no máximo, oito camundongos. Os animais foram mantidos sob ciclo claro/escuro de 12 horas (luzes acesas das 07 às 19 horas), com temperatura constante (23±2°C), sob sistema de exaustão (estantes ventiladas) e umidade monitorada, com acesso livre à água e alimento. Os experimentos foram realizados no período das 10 às 16 horas, ocorrendo uma adaptação dos animais de 1 hora à sala de experimentação.  In vivo tests were performed on adult male CF1 mice weighing between 20 and 30 g. Prior to the experiments, the animals were adapted for at least 05 days in a passage vivarium. The animals were kept in 17x28x 3 cm plastic boxes with a maximum of eight mice. The animals were kept under 12 hours light / dark cycle (lights on from 7 am to 7 pm), with constant temperature (23 ± 2 ° C), under exhaust system (ventilated shelves) and monitored humidity, with free access to water. and food. The experiments were performed from 10 am to 4 pm, with the animals adapting 1 hour to the experiment room.
Antes da administração do fármaco, os animais passaram por um período de 3 horas de jejum. Para a realização dos experimentos foi usada uma caixa de acrílico transparente, medindo 40x30x30cm, com o fundo dividido em 24 quadrantes iguais (Figura 7).  Prior to administration of the drug, the animals went through a period of 3 hours of fasting. For the experiments, a transparent acrylic box measuring 40x30x30cm was used, with the bottom divided into 24 equal quadrants (Figure 7).
• Tratamentos • Treatments
Os camundongos receberam por via oral (Figura 8(a)), uma dose de 20 mg/Kg a partir de soluções aquosas de sertralina livre e ou respectivos compostos de inclusão (concentração de 2,0 mg/mL), preparados pelos diferentes processos descritos. Como grupo controle foi administrado apenas água (veículo), sem o fármaco.  Mice received orally (Figure 8 (a)) a dose of 20 mg / kg from aqueous free sertraline solutions and or their inclusion compounds (concentration of 2.0 mg / mL) prepared by different procedures. described. As a control group, only water (vehicle) was administered without the drug.
• Teste da suspensão pela cauda (severidade moderada) • Tail suspension test (moderate severity)
O teste de suspensão pela cauda (TSC) foi realizado de acordo com The tail suspension test (TSC) was performed according to
Steru e colaboradores, mediante adaptações (Steru, L, R. Chermat, et al. (1985). "The Tail Suspension Test - A new method for screening antidepressant in mice", Psychopharmacology, 85(3): 367-370). Assim como o teste do nado forçado (TNF), o TSC baseia-se no fato de que roedores (na maioria das vezes camundongos) desenvolvem uma postura imóvel quando colocados em uma situação estressante e inescapável. Essa imobilidade é significativamente reduzida com a administração prévia de antidepressivos, principalmente os que atuam sobre o sistema serotonérgico. O protocolo consistiu em pré-tratar os camundongos por via oral com os fármacos nas doses adequadas 1 hora antes de suspendê-los pela extremidade da cauda com auxílio de fita adesiva a 60 cm do solo (Figura 8(b)) por um período de 6 minutos, no qual foi registrado o tempo total de imobilidade para cada animal (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). Os animais tratados apenas com água, sem o principio ativo, foram utilizados como controle negativo a ser comparado com os animais tratados. Este procedimento é considerado moderadamente estressante para os animais, já que acarreta aumento transitório nos níveis séricos de corticosterona. No entanto, é uma característica intrínseca do modelo que o torna válido como um modelo animal de depressão, onde o estresse é conhecido como um fator desencadeante (Barbier, E. and J. B. Wang (2009). "Anti-depressant and anxiolytic like behaviors in PKCI/HINT1 knockout mice associated with elevated plasma corticosterone levei" 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). A maior parte dos modelos animais para avaliar a depressão, aceitos na literatura, envolve algum grau de estresse sendo. Então, este estresse fundamental para o estudo proposto (Willner, P. (1990). "Animal - Models of depression - An overview", Pharmacology & Therapeutics, 45(3): 425-455) O teste foi realizado em ambiente com controle de luminosidade e ruídos. Steru et al., By 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 swimming 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 stillness is significantly reduced with previous administration of antidepressants, especially those acting on the serotonergic system. The protocol consisted of pre-treating the mice orally with the drugs at the appropriate doses 1 hour before suspending them by the tail end with the aid of tape 60 cm from the ground (Figure 8 (b)) for a period of 10 minutes. 6 minutes, in which the total immobility time was recorded for each animal (Duarte, FS, 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). Animals treated only with water, without the active ingredient, were used as negative control to be compared with treated animals. This procedure is considered moderately stressful for 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 JB Wang (2009). "Anti-depressant and anxiolytic like behaviors in PKCI / HINT1 knockout mice associated with elevated plasma corticosteroids "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. 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 brightness and noise.
• Avaliação da atividade locomotora espontânea: teste de exposição ao campo aberto • Evaluation of spontaneous locomotor activity: open field exposure test
Os parâmetros motores são comumente avaliados em roedores nas etapas iniciais de investigação de um provável efeito central de compostos, principalmente devido a sua simplicidade (Steru, L, R. Chermat, et al. (1985). "The Tail Suspension Test - A new method for screening antidepressant in mice", Psychopharmacology, 85(3): 367-370). As alterações na atividade locomotora podem levar a interpretações equivocadas dos resultados obtidos no teste TSC, uma vez que a redução e ou aumento da locomoção podem ser causados por efeitos estimulatórios do SNC e não pelo efeito antidepressivo preditivo dos compostos testados (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). Assim, torna-se necessário avaliar a atividade locomotora, a qual pode ser realizada pelo teste de exposição ao campo aberto (TCA), um dos modelos mais utilizados devido sua simplicidade (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). 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, Chermat R., et al. (1985). "The Tail Suspension Test - A new method for screening antidepressant in mice ", Psychopharmacology, 85 (3): 367-370). Changes in locomotor activity may lead to misinterpretation of the results obtained in the TSC test, as the reduction and or increase in locomotion may be caused by CNS stimulatory effects. and not by the predictive antidepressant effect of the compounds tested (Porsolt, RD, G. Anton, et al. (1978). "Behavioral despair in rats - New model sensitive to antidepressant treatments." European Journal of Pharmacology, 47 (4): 379 Crowley, JJ, JA Blendy, et al. (2005). "Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test." Psychopharmacology 183 (2): 257-264). if necessary evaluate the locomotor activity, which can be performed by the open field exposure test (ACT), one of the most used models due to its simplicity (Porsolt, RD, G. Anton, et al. (1978). "Behavioral despair in rats - New model sensitive to antidepressant treatments. "European J ournal of Pharmacology, 47 (4): 379-391; Crowley, JJ, JA Blendy, et al. (2005). "Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test" Psychopharmacology, 183 (2): 257-264; Porsolt, RD, A. Bertin, et al. (1977), "Behavioral despair in mice - Primary screening test for antidepressants." Archives Internationales Pharmacodynamie Et De Therapie, 229 (2): 327-336).
Após o teste TSC, os camundongos foram imediatamente transferidos para a caixa de acrílico (Figura 7) para realização do teste de campo aberto (Teste TCA), sendo os mesmos observados por um período de 6 minutos e o número de cruzamentos entre os quadrantes ("crossings") registrados. O procedimento foi realizado em ambiente com reduzida luminosidade e sem ruídos.  After the TSC test, the mice were immediately transferred to the acrylic box (Figure 7) for the open field test (TCA test), being observed for a period of 6 minutes and the number of intersections between quadrants ( "crossings") registered. The procedure was performed in low light environment and without noise.
Posteriormente, os resultados observados foram compilados e analisados por ANOVA (análise de variância) de uma via com "pos-hoc" Newman-Keuls Multiple Comparison Test e/ou Dunnetfs Multiple Comparison Test para a determinação das observações, apresentadas nas Figuras 5 e 6.  Subsequently, the observed results were compiled and analyzed by one-way ANOVA with Newman-Keuls Multiple Comparison Test and / or Dunnetfs Multiple Comparison Test to determine the observations, shown in Figures 5 and 6. .
Assim, nas Figuras 9 e 10 são apresentados, respectivamente, os resultados dos testes TSC e teste TCA em camundongos para atividade antidepressiva; utilizando o veículo, a SRT, a β-CD, os compostos de inclusão preparados pelo processo de liofilização (LF), pelo processo spray drying convencional (SD.MC) e pelo processo spray drying reivindicado (SD.LT). Thus, Figures 9 and 10 show, respectively, the results of the TSC and TCA tests in mice for antidepressant activity; using the vehicle, the SRT, the β-CD, the inclusion compounds prepared by the freeze drying process (LF), the conventional spray drying process (SD.MC) and the claimed spray drying process (SD.LT).
Os resultados do teste TSC (Figura 9) mostraram que os compostos de inclusão preparados por liofilização (LF) e por spray drying-LT apresentaram atividade farmacológica estatisticamente significativa em relação ao veículo, (p <0,001). Neste caso, os compostos obtidos apresentaram atividade farmacológica, embora o composto de inclusão preparado pelo método spray dryer convencional (SD.MC) não apresentou diferença estatisticamente significativa (p > 0,05) em relação aos animais tratados apenas com o veículo (água) (Figura 9a). Além disso, a atividade antidepressiva dos compostos de inclusão preparados por liofilização e pelo método inovador (SD.LT) não foi estatisticamente significativa (p > 0,05), indicando a obtenção de compostos de inclusão semelhantes.  The TSC test results (Figure 9) showed that the inclusion compounds prepared by lyophilization (LF) and spray drying-LT showed statistically significant pharmacological activity relative to the vehicle, (p <0.001). In this case, the obtained compounds showed pharmacological activity, although the inclusion compound prepared by the conventional spray dryer method (SD.MC) showed no statistically significant difference (p> 0.05) compared to the animals treated with the vehicle (water) only. (Figure 9a). In addition, the antidepressant activity of the inclusion compounds prepared by lyophilization and the innovative method (SD.LT) was not statistically significant (p> 0.05), indicating that similar inclusion compounds were obtained.
Comparando a atividade farmacológica dos animais tratados com veículo e SRT livre, com aqueles tratados com o composto de inclusão preparado pelo processo spray dryer convencional (SD.MC) não foram observadas diferenças significativas entre eles (Figura 9a), indicando que o composto de inclusão preparado pelo processo convencional não deve ter sido formado entre a SRT e CD. Esse resultado é concordante com as análises 2D ROESY desses compostos de inclusão (Figura 7c) que não indicaram a presença de correlações espaciais significativas entre os hidrogênios da SRT e a os hidrogênios da cavidade da CD, o que foi observado tanto nos compostos preparados por liofilização quanto pelo processo spray dryer reivindicado SD.LT (Figura 7a e c).  Comparing the pharmacological activity of the vehicle and free SRT treated animals 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 should not have been formed between the SRT and CD. This result is consistent with 2D ROESY analyzes of these inclusion compounds (Figure 7c) which did not indicate the presence of significant spatial correlations between SRT and CD cavity hydrogens, which was observed in both compounds prepared by lyophilization. as for the spray dryer process claimed SD.LT (Figure 7a and c).
Na Figura 10 são apresentados os resultados dos testes de atividade locomotora espontânea por exposição ao campo aberto (Teste TCA) para o veículo, a SRT livre, a β-CD, e para os compostos de inclusão preparados pelos diferentes processos anteriormente descritos. Através das análises estatísticas ANOVA uma via com "pos-hoc" Newman-Keuls Multiple Comparison Test não foram observadas diferenças significativas entre o número de cruzamentos dos grupos de animais que receberam apenas o veículo e aqueles tratados com SRT livre, β-CD, e os compostos de inclusão preparados pelo diferentes processos relatados anteriormente. Esse resultado mostra que o efetio anti-imobilidade observado no teste TSC provém da atividade farmacológica da SRT e dos seus complexos e não de uma ação estimulante do sistema nervoso central (SNC), mostrando assim que a administração do composto de inclusão não afetou a capacidade motora dos animais. Figure 10 presents the results of the open field exposure spontaneous locomotor activity tests (TCA test) for the vehicle, free SRT, β-CD, and inclusion compounds prepared by the different processes described above. Through the ANOVA statistical analyzes, a Newman-Keuls Multiple Comparison Test post-hoc pathway showed no significant differences 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 previously reported. 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) stimulating action, thus showing that administration of the inclusion compound did not affect the ability of motor of the animals.

Claims

REIVINDICAÇÕES
1. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos, usando um sistema de fluxo, caracterizado por compreender as seguintes etapas: Process for preparing inclusion compounds involving cyclodextrins and drugs, using a flow system, comprising the following steps:
a. Preparação das soluções aquosas do fármaco solúvel losartan, de fármacos pouco solúveis, preferencialmente a sertralina, e da ciclodextrina, a uma concentração entre 1 ,0 x 10"3 e 1 ,0 x 0"2 mol/L, preferencialmente 5,0 x 10"3; The. Preparation of aqueous solutions of the soluble drug losartan, poorly soluble drug, preferably sertraline, and cyclodextrin at a concentration of 1 0 x 10 "3:01, 0 x 0" 2 mol / L, preferably 5.0 x 10 "3 ;
b. Bombeamento da solução do fármaco e da solução de ciclodextrina, respectivamente, através das bombas B1 e B2, em fluxo contínuo, independente e em linhas de fluxo separadas (Figura a);  B. Pumping drug solution and cyclodextrin solution, respectively, through pumps B1 and B2, in continuous, independent and separate flow lines (Figure a);
c. Ajuste do fluxo de bombeamento de B1 e B2;  ç. Adjustment of pumping flow of B1 and B2;
d. Mistura das soluções no controlador C1 , podendo ser um recipiente ou uma tubulação, esta preferencialmente no formato de uma serpentina, podendo também ter um controle de temperatura;  d. Mixture of solutions in controller C1, which may be a container or a pipe, preferably in the form of a coil, may also have a temperature control;
e. Direcionamento da solução resultante para o controlador C2, este preferencialmente no formato de uma serpentina;  and. Directing the resulting solution to the controller C2, preferably in the form of a coil;
f. Controle da temperatura da mistura em C2; podendo ser um recipiente ou uma tubulação, esta preferencialmente no formato de uma serpentina,  f. Control of mixture temperature in C2; which may be a container or a pipe, preferably in the form of a coil,
g. Direcionamento da solução para um equipamento de spray dryer através de uma bomba B3, a uma dada temperatura;  g. Directing the solution to a spray dryer equipment through a B3 pump at a given temperature;
h. Ajuste dos parâmetros de controle do equipamento de spray dryer, i. Produção de um pó seco.  H. Adjustment of spray dryer control parameters, i. Production of a dry powder.
2. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, etapa "a", caracterizado por utilizar como solventes, água, solventes orgânicos, misturas de co-solventes, misturas organo-aquosas do fármaco e das CDs; Process for preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system according to claim 1, step "a", characterized in that it uses as solvents water, organic solvents, mixtures of solvents, organo-aqueous drug and CD mixtures;
3. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, caracterizado pelo fluxo de bombeamento de B1 , B2 e B3 compreender um intervalo entre 1 e 28 mL/min, preferencialmente entre 8 e 12 mL/min. 3. Process of preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a flow system continuous flow according to claim 1, 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.
4. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, etapa "d" caracterizado pela manutenção da razão molar fármaco/CDs compreender um intervalo entre 1 :0,001 e 1:10, ou entre 2:0,001 e 2:10, ou entre 3:0,001 e 3:10, preferencialmente entre 1 :0,1 e 1 :5.  Process for preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system according to claim 1, step "d" characterized in that maintaining the drug / CD molar ratio comprises a range between 1: 0.001 and 1:10, or between 2: 0.001 and 2:10, or between 3: 0.001 and 3:10, preferably between 1: 0.1 and 1: 5.
5. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, caracterizado pelo controle da temperatura da mistura em C1 compreender o intervalo entre 0 e 100°C, preferencialmente entre 20 e 30°C, e em C2 compreender um intervalo entre - 5,0 e 30°C, preferencialmente, entre 0o e 5°C; Process for preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system according to claim 1, characterized in that the temperature control of the mixture at C1 comprises the range between 0 and 100 ° C, preferably 20 to 30 ° C, and at C 2 to comprise a range of from -5 to 30 ° C, preferably from 0 to 5 ° C;
6. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, etapa "h", caracterizado por compreender:  A process for preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system according to claim 1, step "h", comprising:
i. Controle do fluxo de ar do spray dryer, podendo variar a uma pressão entre 5 a 8 bar e a um fluxo que pode variar entre 600 e 800 L/h;  i. Control of spray dryer air flow, ranging from 5 to 8 bar pressure and from 600 to 800 L / h;
ii. Controle do fluxo do aspirador do spray dryer, podendo variar entre 50 e 100%, com um fluxo que pode variar entre 0 e 40 m3/h, preferencialmente 30 e 40 m3/h; ii. Control of spray dryer vacuum flow, which can vary between 50 and 100%, with a flow that can vary between 0 and 40 m 3 / h, preferably 30 and 40 m 3 / h;
iii. Controle da temperatura de entrada no spray dryer, podendo variar entre 100 e 200 °C, preferencialmente entre 120 e 150°C;  iii. Control of the spray dryer inlet temperature, which may vary between 100 and 200 ° C, preferably between 120 and 150 ° C;
iv. Controle da temperatura de saída, podendo variar entre 40 e 65 °C, preferencialmente entre 50 e 60°C.  iv. Control of the outlet temperature, which may vary between 40 and 65 ° C, preferably between 50 and 60 ° C.
7. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, etapa "b", caracterizado pela ciclodextrina compreender pelos menos uma das ciclodextrinas naturais α (alfa), β (beta) ou Y(gama) ciclodextrinas e ou ciclodextrinas semissintéticas, derivados alquil, hydroxialquil, hidroxi-propil (ex: hidroxi-propil-aciclodextrinas, hidroxi-propil-Pciclodextrinas hidroxi-propil-Yciclodextrinas), acil, ou poli- ciclodextrinas ou poli-ciclodextrinas com ligações cruzadas, preferencialmente a β-ciclodextrina e ou combinações com outras ciclodextrinas; 7. Process of preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a flow system continuous according to claim 1, step "b", characterized in that cyclodextrin comprises at least one of the natural cyclodextrins α (alpha), β (beta) or Y (gamma) cyclodextrins and or semi-synthetic cyclodextrins, alkyl, hydroxyalkyl, hydroxy derivatives -propyl (eg hydroxypropyl acyclodextrins, hydroxypropyl-Pcyclodextrins hydroxypropyl-Yciclodextrins), acyl, or cross-linked polycyclodextrins or polycyclodextrins, preferably β-cyclodextrins and or combinations with other cyclodextrins;
8. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com a reivindicação 1, caracterizado pelo fármaco compreender:  Process for preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system according to claim 1, characterized in that the drug comprises:
i. Um antidepressivo da classe dos inibidores seletivos da recaptura de serotonina tais como, fluoxetina, sertralina, paroxetina, citalopram, fluvoxamina; inibidores seletivos de recaptura de serotonina/noradrenalina como, duloxetina, venlafaxina; inibidores de recaptura de serotonina e antagonistas alfa-2, nefazadona, tradazona; estimulante da recaptura de serotonina, tianeptina, inibidores não seletivos da recaptura de monoaminas (Serotonina/Noradernalina) ou também conhecidos como antidepressivos tricíclicos), amitriptilina, nortriptilina, clomipramina, imipramina, desipramina, doxepina, maprotilina; Inibidores da monoaminoxidase, tranilcipromina, isocarboxazida, iproniazida, fenelzina, clorgilina, moclobemida, toloxatona, brofaromina, befloxatona; antagonistas dos adrenoreceptores alfa-2, mirtazapina, mianserina; Inibidores seletivos de recaptura de dopamina, minaprina, bupropiona, amineptina; Inibidores seletivos de recaptura de noradrenalina.viloxazina e reboxetina, preferencialmente o cloridrato de sertralina.  i. An antidepressant of the class of selective serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine; selective serotonin / norepinephrine reuptake inhibitors such as duloxetine, venlafaxine; serotonin reuptake inhibitors and alpha-2 antagonists, nefazadone, tradazone; serotonin reuptake stimulant, thianeptin, non-selective monoamine reuptake inhibitors (Serotonin / Noradernaline) or otherwise known as tricyclic antidepressants), amitriptyline, nortriptyline, clomipramine, imipramine, desipramine, doxepine, maprotiline; Monoaminoxidase, tranylcypromine, isocarboxazide, iproniazide, phenelzine, clorgiline, moclobemide, toloxatone, bropharomine, befloxatone inhibitors; alpha-2 adrenoreceptor antagonists, mirtazapine, myanserine; Selective reuptake inhibitors of dopamine, minaprine, bupropion, amineptine; Selective noradrenaline.viloxazine and reboxetine reuptake inhibitors, preferably sertraline hydrochloride.
ii. Antagonista do receptor AT1 , telmisartan, valsartan, candersartan, azilsartan, eprosartan, ibersartan, olmesartan, tasosartan, preferencialmente, losartan potássico;  ii. AT1 receptor antagonist, telmisartan, valsartan, candersartan, azilsartan, eprosartan, ibersartan, olmesartan, tasosartan, preferably losartan potassium;
iii. Um composto de alta solubilidade e alta permeabilidade, Classe I, segundo a classificação biofarmacêutica (CBS)tais como; amilorida, cloroquina, ciclofosfamida, diazepam, digoxina, doxiciclina, fluconazol, levodopa+carbidopa, levonorgestrel, metronidazol, fenobarbital, fenoxi- metilpenicilina, prednisolona, primaquina, propranolol, pirazinamida, riboflavina, salbutamol, stavudina, teofilina, zidovudina, amoxicilina, benzinidazol, dietil-carbamazina, DL-metionina, etossuximida, isoniazida, carbonato de lítio, nicotinamida, noretisterona, piridoxima, cloridrato de proguanil, clorfeniramina, sulfato de atropina, dexametasona, etinilestradiol, trinitrado de glicerila, dinitrato de isossorbida, lamivudina, levamisol, sulfato de morfina, metoclopramida, quinina, iodeto de sódio, verapamil, warfarina; compostos de baixa solubilidade e alta permeabilidade, Classe II da BCS como, amiodarona, atorvastatina, ácido fólico, albendazol, azitromicina, ácido nalidixico, nevirapina, carbamazepina, clorpromazina, cisapridas, ciprofloxacina, clofazimina, diloxanida, ciclosporina, diclofenaco, diflunisal, digoxina, eritromicina, efavirenz, flurbiprofeno, danazol, dapsona, glipazida, glibenclamida, griseofulvina, haloperidol, ivermectina, lopinavir ibuprofeno, indanavir, indometacina, itraconazol, cetoconazol, lanzoprazol, lovastatina, mefloquina, mebendazol, naproxeno, niclosamida, nitrofurantoína, nifedipina, ofloxaciona, fenitoína, pirantel, pirimetamina, piroxicam, raloxifeno, rifamicina, retinol, ritonavir, saquinavir, spironolactona, sulfametoxazol, sulfadizaina, sulfassalazina, tracrolimo, tamoxifeno, terfenadina, trimetropina, ácido valpróico, fenazopiridina, nelfinavir, glipizida, glibenclamida, oxprozina, raloxifeno, sirolimus, talinolol; compostos de alta solubilidade e baixa permeabilidade - Classe III da BCS tais como, abacavir, aciclovir, acido acetil salicílico, alupurinol, ácido ascórbico, atenolol, biperideno, captopril, clorafenicol, cimetidina, cloxacilina sódica, didanosina, ergocalciferol, ergometrina, eritromicina, etambutol, fosfato de codeína, colchicina, ergotamina, hidralazina, hidroclorotiazida, levotiroxina sódica, metotrexato, metformina, metildopa, neostigmina, nistatina,, nifurtimox, paracetamol (acetaminofeno), prometazina, propiltiouracil, piridostigmina, reserpina, tiamina; compostos de baixa solubilidade e baixa permeabilidade - Classe IV da BCS tais como, acetazolamida, azatioprina, amfotericina, clortalidona, clortiazida, ciprofloxacino, furosemida, hidróxido de alumínio, hidroclorotiazdia, indanavir, mebendazol, metrotexato, neomicina, nelfinavir, ritonavir, saquinavir. iii. A high solubility and high permeability compound, Class I, according to the biopharmaceutical classification (CBS) such as; amiloride, chloroquine, cyclophosphamide, diazepam, digoxin, doxycycline, fluconazole, levodopa + carbidopa, levonorgestrel, metronidazole, phenobarbital, phenoxymethylpenicillin, prednisolone, primaquine, propranolol, pyrazinamide, salbutamidazine, zavidine, benzodinyl, benzodinyl carbamazine, DL-methionine, ethosuximide, isoniazid, lithium carbonate, nicotinamide, norethisterone, pyridoxime, proguanyl hydrochloride, chlorpheniramine, atropine sulfate, dexamethasone, ethinylestradiol, glyceryl trinitate, isosorbide dinitrate, lamivol, lamphenate metoclopramide, quinine, sodium iodide, verapamil, warfarin; BCS Class II low solubility and high permeability compounds such as amiodarone, atorvastatin, folic acid, albendazole, azithromycin, nalidixic acid, nevirapine, carbamazepine, chlorpromazine, cisaprides, ciprofloxacin, clofazimine, diloxanide, cyclosporal, diphosphonine, cyclosporine, cyclosporine, cyclosporine, erythromycin, efavirenz, flurbiprofen, danazol, dapsone, glipazide, glibenclamide, griseofulvin, haloperidol, ivermectin, lopinavir ibuprofen, indanavir, indomethacin, itraconazole, ketoconazole, lanzoprazole, nephrofenate, meifinaurin, phenofinan , pirantel, pyrimethamine, piroxicam, raloxifene, rifamycin, retinol, ritonavir, saquinavir, spironolactone, sulfamethoxazole, sulfadizaine, sulfasalazine, trachrolimus, tamoxifen, terfenadine, trimetropine, valproic acid, phenazopyridine, glipyridine, glipyridine, glipyridine talinolol; BCS Class III high solubility and low permeability compounds such as abacavir, acyclovir, acetyl salicylic acid, alupurinol, ascorbic acid, atenolol, biperiden, captopril, chlorafenicol, cimetidine, cloxacillin sodium, didanosine, ergocalciferol, erambromine, ergometrine, ergometrine, , codeine phosphate, colchicine, ergotamine, hydralazine, hydrochlorothiazide, sodium levothyroxine, methotrexate, metformin, methyldopa, neostigmine, nystatin ,, nifurtimox, paracetamol (acetaminophen), promethazine, propylthiouracil, pyridostine, reseridine; low solubility and low permeability compounds - BCS Class IV such as acetazolamide, azathioprine, amphotericin, chlorthalidone, chlortiazide, ciprofloxacin, furosemide, aluminum hydroxide, hydrochlorothiazdia, indanavir, mebendazole, methotrexate, neomycin, nelfinavir, ritonavir, saquinavir.
9. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos pouco solúveis, usando um sistema de fluxo contínuo, de acordo com as reivindicações 1 e 8, caracterizado pela solução do fármaco ou da ciclodextrina ser preparado, tendo como solventes, água, soluções aquosas tamponadas, solventes orgânicos e co-solventes (misturas organo/aquosas); pelos solventes orgânicos serem álcoois, tais como o etanol, metanol, propanol, isopropanol, butanol, hexanol; ou o diclorometano, dimetilsufóxido, clorofórmio, éter, acetato de etila, metil-ter-butil-éter; não limitante. Process for preparing inclusion compounds involving cyclodextrins and poorly soluble drugs using a continuous flow system according to claims 1 and 8, characterized in that the drug or cyclodextrin solution is prepared having solvents, water, solutions buffered aqueous, organic solvents and co-solvents (organo / aqueous mixtures); the organic solvents are alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, hexanol; or dichloromethane, dimethylsufoxide, chloroform, ether, ethyl acetate, methyl tert-butyl ether; not limiting.
10. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos, usando um sistema de fluxo, de acordo com a reivindicação 1, caracterizado pelo fármaco compreender um agente bioativo, tais como proteínas, peptídeos e macromoléculas bioativas com diferentes composições químicas tais como polissacaríedos, açúcares, DNA, RNA, genes, parte de sequências gênicas de ácidos nucléicos, lipídeos, enzimas, antígenos, compostos naturais (extraídos de sistemas vivos), semissintéticos (modificadas após extração) ou sintéticos (preparadas artificialmente); podem ser conjugados com as ciclodextrinas utilizando o processo proposto (Figura 1).  Process for the preparation of inclusion compounds involving cyclodextrins and drugs using a flow system according to claim 1, characterized in that the drug comprises a bioactive agent, such as bioactive proteins, peptides and macromolecules with different chemical compositions such as polysaccharides. , sugars, DNA, RNA, genes, part of gene sequences of nucleic acids, lipids, enzymes, antigens, natural compounds (extracted from living systems), semi-synthetic (modified after extraction) or synthetic (artificially prepared); can be conjugated to cyclodextrins using the proposed process (Figure 1).
10. Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos, usando um sistema de fluxo, de acordo com a reivindicação 1, alternativamente com pré-mistura das soluções, caracterizado por compreender;  Process for preparing inclusion compounds involving cyclodextrins and drugs using a flow system according to claim 1, alternatively with premixing the solutions, characterized in that it comprises;
i. A mudança do processo de fluxo contínuo para batelada, preferencialmente na etapa (C1); ii. A etapa C3 representar um recipiente para pré-mistura e homogeneização das soluções de fármaco (S1) e ciclodextrina (S2), preferencialmente no formato de um tanque; iii. A agitação do tanque em "ii" por sistema de bombeamento, pá rotativa, rotação do recipiente, agitação por balanço, preferencialmente agitação mecânica por hélice; iv. A velocidade de agitação em "iii" variar entre 100 e 2000rpm, preferencialmente entre 300 e 500rpm, por um período de tempo entre 1 e 60 minutos, preferencialmente entre 5 e 20 minutos; i. Changing the process from continuous flow to batch, preferably in step (C1); ii. Step C3 represents a container for premixing and homogenizing drug (S1) and cyclodextrin (S2) solutions, preferably in the form of a tank; iii. "Ii" tank agitation by pumping system, rotary blade, container rotation, rocking agitation, preferably mechanical propeller agitation; iv. The stirring rate at "iii" will range from 100 to 2000rpm, preferably from 300 to 500rpm, for a period of time from 1 to 60 minutes, preferably from 5 to 20 minutes;
v. A razão molar fármaco/CD da pré-mistura em "ii" variar entre 1 :0.001 e 1 :5, preferencialmente entre 1 :0.01 e 1 :5; vi. O bombeamento da pré-mistura do recipiente C3 para C2 por B1 com fluxo variando entre 1 ,0 e 28,0 mL/min, preferencialmente entre 4 e 8,0 ml/min; vii. O controle da temperatura da pré-mistura em C2 por um sistema de tubulação, preferencialmente no formato de uma serpentina; viii. O controle da temperatura da pré-mistura em C2 por um sistema de fluxo contínuo na faixa entre -5,0 e 5,0°C, preferencialmente entre 0 e 2°C; ix. O fluxo do gás do spray dryer (spray flow) entre 100 e 800 L/h, preferencialmente entre 300 e 400 L/h; x. O fluxo do aspirador do spray dryer variou entre 20 e 40 m3/h, preferencialmente entre 30 e 40 m3/h; xi. A temperatura de entrada {inlet temperature) do gás de arraste no spray dryer variar na faixa entre 30 e 200 °C, preferencialmente entre 120 e 150°C; xii. A temperatura de saída (outlet temperature) do material seco do sistema variar entre 40 e 65°C; e, xiii. O produto obtido foi na forma de um pó seco. v. The drug / CD molar ratio of premix in "ii" will range from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 5; saw. Pumping the premix from container C3 to C2 by B1 with flow ranging from 1.0 to 28.0 mL / min, preferably from 4 to 8.0 mL / min; vii. Control of the premix temperature in C2 by a piping system, preferably in the form of a coil; viii. Controlling the temperature of the premix in C2 by a continuous flow system in the range of -5.0 to 5.0 ° C, preferably between 0 and 2 ° C; ix. The spray dryer gas flow between 100 and 800 L / hr, preferably between 300 and 400 L / hr; x. The spray dryer vacuum flow varied between 20 and 40 m 3 / h, preferably between 30 and 40 m 3 / h; xi The inlet temperature of the carrier gas in the spray dryer ranges from 30 to 200 ° C, preferably from 120 to 150 ° C; xii. The outlet temperature of the system dry material ranges from 40 to 65 ° C; and xiii. The product obtained was in the form of a dry powder.
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