WO2013155586A1 - Procédé de préparation de composés d'inclusion faisant intervenir des cyclodextrines et des substances pharmaceutiques, au moyen d'un système à flux continu - Google Patents

Procédé de préparation de composés d'inclusion faisant intervenir des cyclodextrines et des substances pharmaceutiques, au moyen d'un système à flux continu Download PDF

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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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English (en)
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

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Abstract

La présente technologie décrit un procédé de préparation de composés d'inclusion en flux continu faisant intervenir des substances pharmaceutiques et des cyclodextrines, couplé à un équipement de séchage par pulvérisation. Ce procédé permet une meilleur régulation de l'injection et du flux de la substance pharmaceutique, de préférence du chlorhydrate de sertraline et/ou de la sertraline de base, et d'un véhicule, celui-ci pouvant être des cyclodextrines naturelles (α- (alpha-), β- (bêta-) ou γ- (gamma-) cyclodextrines) ou des cyclodextrines semi-synthétiques, des dérivés alkyle, hydroxyalkyle, hydroxypropyle, acyle, ou des polycyclodextrines, de préférence la β-cyclodextrine. Ce procédé permet en outre d'améliorer la régulation de la température, ce qui essentiel pour que se produise l'inclusion, outre une régulation optionnelle de leur pré-mélange.
PCT/BR2013/000135 2012-04-20 2013-04-22 Procédé de préparation de composés d'inclusion faisant intervenir des cyclodextrines et des substances pharmaceutiques, au moyen d'un système à flux continu WO2013155586A1 (fr)

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CN112190498A (zh) * 2020-10-31 2021-01-08 华南理工大学 一种具有水溶性的茶碱和环糊精包合物及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104445325A (zh) * 2014-12-05 2015-03-25 福州大学 一种从含钾、铝矿石中提取氢氧化铝的方法
CN112190498A (zh) * 2020-10-31 2021-01-08 华南理工大学 一种具有水溶性的茶碱和环糊精包合物及其制备方法

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