Method for preparing stable nanoparticles and compositions thereof

Abstract

The present invention relates to a method for preparing stable nanoparticles and pharmaceutical compositions thereof. Furthermore, the nanoparticles prepared by this method have a stable and controlled mean particle size and particle size distribution.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing nanoparticles having a stable and controlled mean particle size and particle size distribution. More specifically, the nanoparticles of the present invention are prepared by annealing a suspension of an active pharmaceutical ingredient to a specific temperature profile to grow crystals in a controlled manner with a desired stable morphology and a stable final particle size distribution. Furthermore, the present invention also relates to the use of nanoparticles in the preparation of pharmaceutical compositions. [Background technology]

[0002] In the pharmaceutical industry, the development of drug products with increased safety and efficacy is of paramount importance. In the successful formulation of drug products, variables such as solubility, stability, compatibility with solvents, excipients and photostability play an important role. Another important intrinsic parameter is particle size, because particle size largely determines the bioavailability of drugs. Controlling these variables helps to obtain uniform blood level drug release, thereby greatly enhancing the clinical effectiveness of the product.

[0003] To date, many newly developed active pharmaceutical ingredients are lipophilic or poorly water-soluble compounds. There are many challenges in designing such active pharmaceutical ingredients to obtain successful drug delivery systems. However, many conventional approaches available to solve the problems of low solubility, low bioavailability, and drug stability include micronization, the use of fatty solutions, the use of penetration enhancers or cosolvents, surfactant dispersion methods, salt formation, precipitation, etc. However, even with these techniques, their usefulness in enhancing the solubility of poorly soluble drugs is limited. Additional approaches, such as liposomes, solid dispersions, emulsions and microemulsions, and inclusion complexes with cyclodextrins, have shown beneficial effects as drug delivery systems, but the main problem with these techniques is that they cannot be universally used for all drugs.

[0004] Nanotechnology, particularly the production of nanoparticles, offers a viable alternative due to its unique and often advantageous properties. The production of nanoparticles of active pharmaceutical ingredients in the nanorange enhances water solubility, dissolution rate, and bioavailability because smaller particles result in an increased surface area to volume ratio. Traditionally, nanoparticles are prepared using a variety of techniques, including milling, liquid antisolvent precipitation, high-pressure homogenization, sol-gel processes, spray pyrolysis, combustion, electrochemical synthesis, and emulsification.

[0005] Milling converts large macro- or micro-sized particles into smaller ones by applying mechanical energy, and the resulting particles are then air-classified to recover nanoparticles. Various mills, such as ball mills, planetary ball mills, air jet mills, hammer mills, and pin mills, can be used for this purpose. This is the most commonly used technology in the pharmaceutical industry for particle size reduction. However, this technology suffers from low efficiency due to, for example, high energy consumption, non-uniform particle size distribution, and heterogeneous particle shape.

[0006] EP1620193 B1 discloses a method for solidifying inorganic or organic compounds using a novel antisolvent solidification technique, in which a liquid medium containing at least one dissolved organic or inorganic compound is forced through a membrane arranged in a membrane module into one or more antisolvents, or vice versa, to obtain solid particles of the organic and / or inorganic compound.

[0007] Ghaffarian, Hamid Reza et al. (Iran. J. Chem. Chem. En., 30(1):1-6, 2011) disclose a method for preparing ZnO nanoparticles. To synthesize ZnO nanoparticles, a precursor solution was first atomized using a nebulizer under atmospheric pressure (7 bar) to form droplets, which were then decomposed in a reactor at a temperature of 1200°C. The resulting nanoparticles were collected in a cooled precipitation tank and dried in an oven at 100°C. However, the instability and poor particle size distribution of the nanoparticles are major drawbacks of this method, resulting in poor physical and chemical characteristics.

[0008] Nurul Nadia Mohd Zorkiplia et al. (Procedia Chemistry, 19: 626-631, 2016) describe a method for synthesizing NiO nanoparticles. In this process, nickel(II) nitrate hexahydrate was first dissolved in isopropanol and PEG, stirred, and the pH of the solution was then adjusted and gradually heated to form a gel. The gel was dried at 200°C and then crushed to obtain NiO nanoparticles. However, the drawback of this method is the large volume of solvents and chemicals required.

[0009] V. Jenning et al. (J. Microencapsulation, 19 (1);1-10, 2002) disclose the preparation of retinol solid lipid nanoparticles (SLNs). In this method, lipids were melted at 85°C and retinol was added thereto. The hot lipid phase was dispersed in a surfactant solution to form a premix. The coarse premix was passed through a high-pressure homogenizer to obtain retinol-loaded solid lipid nanoparticles. However, maintaining a high temperature to melt the lipids, the cooling rate, particle aggregation, and the compatibility of the drug with the lipids are important parameters of this method.

[0010] Rashid A. Khaydarov et al. (J Nanopart Res, 11:1193-1200, 2009) described a method for synthesizing silver nanoparticles using an electrochemical method. In this method, two polished silver plates were used as the anode and cathode. These were immersed in an electrochemical cell filled with distilled water. The silver nanoparticle solution thus produced was stored under ambient conditions in a glass container. However, this technique only allows the preparation of metal nanoparticles using the electrochemical properties of the metal. Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, it is essential to develop more efficient methods for preparing stable nanoparticles to overcome the problems of the prior art and to satisfy the basic needs for solubility and stability and the development of successful drug delivery systems. More specifically, there is a need to develop improved methods for preparing nanoparticles with stable and controlled mean particle size and particle size distribution. [Means for solving the problem]

[0012] The present inventors have unexpectedly identified a method for preparing stable nanoparticles by annealing a suspension of an active pharmaceutical ingredient to a specific temperature profile. Nanoparticles prepared using the method of the present invention have been found to be stable even after long-term storage. The inventors have further found that annealing a suspension of an active pharmaceutical ingredient to a specific temperature profile directly affects the resulting particle size distribution and dissolution rate, allowing for controlled particle growth and precise tailoring of particle size. The method of the present invention has also been found to promote well-defined single-crystal morphology and separate agglomerates. The inventors have found that the nanoparticles of the present invention have significantly improved stability compared to nanoparticles formed without annealing at a specific temperature profile.

[0013] An aspect of the present invention is to provide a method for preparing stable nanoparticles. Another aspect of the present invention is to provide a method for preparing nanoparticles with a stable and controlled average particle size and particle size distribution. Another aspect of the present invention is to provide a method for preparing nanoparticles by annealing a suspension of an active pharmaceutical ingredient to a specific temperature profile. Another aspect of the present invention is to provide a method for preparing nanoparticles by annealing a suspension of an active pharmaceutical ingredient to a specific temperature profile to provide nanoparticles having an average particle size of less than 30,000 nm. Yet another aspect of the present invention is to provide a method for preparing stable nanoparticles by annealing a suspension of an active pharmaceutical ingredient to a specific temperature profile such that the method results in the production of sterile nanoparticles.

[0014] One aspect of the present invention is a method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 99°C for 0.5 hours to 2 weeks at a rate ranging from 0.01°C / min to 50.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0015] One aspect of the present invention is a method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 40°C for 0.5 hours to 2 weeks at a rate of 0.01°C / min to 50.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0016] Another aspect of the present invention is a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 45°C to 65°C for 24 hours to 1 week at a rate of 0.1°C / min to 1.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0017] Yet another aspect of the present invention is a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 75°C to 95°C for 24 hours to 1 week at a rate of 0.2°C / min to 0.8°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0018] Another aspect of the present invention provides a method for preparing stable nanoparticles, wherein step (a) and / or step (b) optionally includes a surfactant. One aspect of the present invention is to provide a pharmaceutical composition comprising nanoparticles obtainable by the method of the present invention. Yet another aspect of the present invention provides a pharmaceutical composition comprising the nanoparticles obtainable by the method of the present invention, the composition being selected from oral, parenteral, transdermal, rectal, urethral, ​​intranasal, intrarespiratory, intraocular or conjunctival. Yet another aspect of the present invention is to provide a pharmaceutical composition comprising the nanoparticles obtainable by the method of the present invention and, optionally, one or more pharmaceutically acceptable excipients. [Brief explanation of the drawings]

[0019] [Figure 1] Figure 1 shows the effect of annealing (40°C) at different times on the particle size distribution (PSD) performed using the laser diffraction method (SALD). [Figure 2] Figure 2 shows SEM images at 2000x and 4000x magnification of the unannealed and annealed forms of the nanoparticles produced in Example 3. Figures 2A and 2C show the unannealed and annealed forms, respectively, at 2000x magnification, and Figures 2B and 2D show the unannealed and annealed forms, respectively, at 4000x magnification. [Figure 3] FIG. 3 shows the release profile of the non-annealed paliperidone palmitate composition at accelerated conditions (40° C. / 75% RH). [Figure 4]FIG. 4 shows the release profile of the non-annealed paliperidone palmitate composition at standard conditions (25° C. / 60% RH). [Figure 5] FIG. 5 shows the release profile of the annealed paliperidone palmitate composition at accelerated conditions (40° C. / 75% RH). [Figure 6] FIG. 6 shows the release profile of the annealed paliperidone palmitate composition at standard conditions (25° C. / 60% RH). [Figure 7] FIG. 7 shows the effect of different annealing temperatures on particle size distribution using disc centrifugation (CPS). [Figure 8] FIG. 8 shows the release profile of the annealed aripiprazole composition at accelerated conditions (40° C. / 75% RH). [Figure 9] FIG. 9 shows the release profile of the annealed aripiprazole composition at standard conditions (25° C. / 60% RH). DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention relates to a method for preparing stable nanoparticles and pharmaceutical compositions thereof. The present invention relates to a method for preparing stable nanoparticles having a stable and controlled average particle size and particle size distribution. In particular, the present invention relates to a method for preparing nanoparticles by subjecting a suspension of an active pharmaceutical ingredient to a specific temperature profile. The method of the present invention, which includes temperature treatment, promotes nanoparticles with a well-defined single crystalline morphology and separates agglomerates.

[0021] More specifically, the present invention provides a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 99°C for 0.5 hours to 2 weeks at a rate ranging from 0.01°C / min to 50.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention relates to a method for preparing a compound of formula (I) comprising the steps of:

[0022] As used herein, the term "stable" refers to particles obtained by the method of the present invention that do not undergo statistically significant changes in particle size or particle size distribution over time.Stability is demonstrated by specific stability tests, in which the key quality properties of the product, including but not limited to, the appearance of the suspension, the appearance of the container closure, visible particulates in the injection, assay and related materials, dissolution, and particle size distribution, are measured over time during storage under predefined conditions.

[0023] As used herein, the term "dissolution rate" refers to the rate at which an active pharmaceutical ingredient dissolves in a dissolution medium. As used herein, the term "average particle size" refers to particles with the same size in the total mass of a particulate system. It is the weighted average volume average diameter or surface area average of the entire representative population of particles. The particle size distribution of the present invention can be measured using laser light scattering (LLS), disk centrifuge, Zetasizer and dynamic light scattering (DLS), and the average particle size is calculated from the particle size distribution. The term "nanoparticles" includes particles having an average size of less than 30,000 nm, preferably less than 25,000 nm, 20,000 nm, 15,000 nm, 10,000 nm or 5,000 nm. Most preferably, the nanoparticles have an average size of less than 5,000 nm.

[0024] As used herein, the term "annealing" refers to a temperature treatment that changes the physical and sometimes chemical properties of a material. The annealing process helps the particles achieve their final state, morphology, and size.

[0025] The term "active pharmaceutical ingredient" is used broadly to include pharmaceutically acceptable derivatives thereof. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes, and the like.

[0026] In the present invention, the active pharmaceutical ingredient is selected from the group consisting of abdominal aortic aneurysm, Acanthamoeba infection, adverse childhood experiences, Acinetobacter infection, acquired immunodeficiency syndrome, acute flaccid myelitis, adenovirus infection, attention deficit hyperactivity disorder, atrial fibrillation, African trypanosomiasis, Alhamra hemorrhagic fever, amyotrophic lateral sclerosis, intestinal amebiasis, American trypanosomiasis, amyotrophic lateral sclerosis, anaplasmosis, hookworm Zubini infection, hookworm American infection, Angiosstrongius infection, anisakiasis, anthrax, arenavirus infection, childhood arthritis, fibromyalgia, gout, and roundworm. Infectious diseases, aseptic meningitis, aspergillosis, asthma, autism, avian influenza, Burkholderia cepacia infection, babesiosis, bacterial vaginosis, Balamuthia mandrillus infection, balantidiosis, Bartonella bacilliformis infection (carionosis), Bartonella henselae infection (cat-scratch disease), Bartonella quintana infection (trench fever), Baylisascaris infection (raccoon roundworm disease), bilharzia (schistocytosis), bioterrorism diseases, melanopneumoconiosis (coal workers' pneumoconiosis), human blastocystis infection, blastomycosis, blood clotting Disorders, body lice (Pediculus humanus colpolis), Borrelia burgdorferi infection (Lyme disease), louse-borne borreliosis, tick-borne borreliosis, botulism, bovine spongiform encephalopathy, Brainard's diarrhea, bronchiolitis, bronchitis, brucellosis, Bunyaviridae infection, Burkholderia cepacia infection, Burkholderia mallei (glanders), Burkholderia pseudomallei infection (melioidosis), herpes B virus infection, Candida auris infection, Clostridium difficile infection, Clostridium perfringens infection fringens infection, Clostridium tetani infection (tetanus), Cryptococcus gattii cryptococcosis, Cryptococcus neoformans cryptococcosis, campylobacteriosis, cancer (colorectal cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, breast cancer, esophageal cancer, endometrial cancer, pancreatic cancer, liver cancer, etc.), Candida auris infection, canine influenza, capillariasis, carbapenem-resistant Enterobacteriaceae infection, carbapenem-resistant Klebsiella pneumonia, carpal tunnel syndrome, cat flea tapeworm, Crimean-Congo hemorrhagic fever, cercarial dermatitis, cerebral palsy,Chagas' disease (Trypanosoma cruzi infection), Chapare hemorrhagic fever, chickenpox (varicella), chikungunya fever, childhood overweight and obesity, Chlamydia pneumoniae infection, Chlamydia psittaci infection, Chlamydia trachomatis disease, Vibrio cholerae infection, chronic fatigue syndrome, chronic obstructive pulmonary disease, chronic traumatic encephalopathy, chronic wasting disease, ciguatera fish poisoning, classic Creutzfeldt-Jakob disease, liver fluke disease, cytomegalovirus infection, coccidioidomycosis, common cold, Colorado tick fever, concussion (brain trauma), congenital deafness, congenital heart disease, conjunctivitis (pink eye), Kouri - Anemia, Coronavirus Disease 2019, Corynebacterium diphtheriae infection (diphtheria), Coxiella burnetti infection (Q fever), Crimean-Congo hemorrhagic fever, Cronobacter infection, Cryptosporidiosis, Cryptosporidium infection (cryptosporidiosis), Blue-green algae bloom-related illness, Cyclosporiasis, Cysticercosis, Cystoisosporiasis, Deep vein thrombosis, Dementia, Dengue fever, Dermatophyte infection, Developmental disorders, Diuretic amoeba infection, Diphyllobothriasis, Dipyridium infection, Canine heartworm disease, Down syndrome (trisomy 1) 21), Dracunculiasis, Small Tapeworm (Striped Tapeworm Infection), Escherichia coli Infection, Ear Infection (Otitis Media), Eastern Equine Encephalitis, Ebola Virus Disease, Epstein-Barr Virus Infection, Echinococcosis, Human Ehrlichiosis, Elephantiasis (Lymphatic Filariasis), Elizabethkingia Infection, Fungal Endophthalmitis, Endometritis, Entamoeba Histolytica Infection, Enterovirus D68, Non-Polioenterovirus Infection, Typhus, Epilepsy, Esophageal Candidiasis (Thrush), Exserohilum Rostratum (Other Pathogenic Fungi), Extensively Drug-Resistant TB, Necrotizing Fasciitis, Fascioliasis, Clonorchiasis, fetal alcohol spectrum disorder, fibromyalgia, fifth disease (parvovirus B19 infection), filovirus infection, flavivirus infection, folliculitis (bathtub folliculitis), fragile X syndrome, Francisella turaensis infection (tularemia), fungal meningitis, granulomatous amebic encephalitis (Acanthamoeba), group A streptococcal infection, group B streptococcal infection, vulvar candidiasis, genital herpes (herpes simplex virus infection), human papillomavirus infection, rubella (rubella virus), giardiasis, gnathostomiasis, gonorrhea (Neisseria gonorrhea infection), gout,Guillain-Barré syndrome, Guinea worm infection (Dracunculiasis), H3N2V influenza, harmful algal bloom-related illnesses, Haemophilus influenzae serotype B, hand, foot and mouth disease, leprosy, Hantavirus pulmonary syndrome, head lice (Pediculus humanus capitis), Heartland virus infection, hemoglobinopathies, hemophilia, viral hemorrhagic fever, Hendra virus disease, viral hepatitis, hepatitis A, hepatitis B, shingles, heterophyiasis, Histoplasma capsulatum infection (histoplasmosis), human hookworm infestation, zoonotic infection Hookworm infection, human parainfluenza virus, inflammatory bowel disease, impetigo, infectious mononucleosis, infertility, H1N1 influenza, intestinal amebic infection, non-pathogenic (harmless) gastrointestinal protozoan infection, invasive candidiasis, isospora infection (Cystoisospora infection), Jamestown Canyon virus infection, Japanese encephalitis, jaundice, Klebsiella pneumoniae infection, kala-azar (Leishmaniasis), Kawasaki disease, Acanthamoeba keratitis, fungal keratitis, kernicterus, Kyasanur Forest disease, chronic kidney disease, La Crosse encephalitis, Lassa fever, louse-borne relapsing fever, Leishmaniasis, Lymphocytic choriomeningitis, Legionnaires' disease, Leishmaniasis, Hansen's disease (leprosy), leptospirosis, listeriosis, Lou Gehrig's disease, Luho hemorrhagic fever, systemic lupus erythematosus, lymphocytic choriomeningitis, Mycobacterium avium complex, malaria, Marburg hemorrhagic fever, seafood toxins, muscular dystrophy, multidrug-resistant TB, myalgic encephalomyelitis / chronic fatigue syndrome, measles, melioidosis (Burkholderia pseudomallei infection), Middle East respiratory syndrome coronavirus, methicillin-resistant Staphylococcus aureus, microcephaly, microcephaly Sporozoan infections, molluscum contagiosum, simian B virus infection, monkeypox, mucormycosis, mumps, Mycobacterium abscessus infection, spinal meningeal carcinoma, mycosis, primary amebic meningoencephalitis, amyotrophic lateral sclerosis, necrotizing fasciitis (group A streptococcal infection), neglected tropical diseases, Neisseria gonorrhoeae infection, neurocysticercosis, Nocardia asteroides infection, non-polio enterovirus infection, osteoarthritis, Omsk hemorrhagic fever, onchocerciasis (ocular onchocerciasis), liver fluke infection, orpharyngeal candidiasis (thrush),Peripheral arterial disease, Paragonimiasis, Parainfluenza, Parvovirus B19 infection (fifth disease), Pneumocystis pneumonia, Pulmonary thromboembolism, Whooping cough (pertussis), Pinworm infection (pinworm infection), Plague (Yersinia pestis infection), Pneumonia, Polio infection (poliomyelitis infection), Pontiac fever (Legionnaires' disease), Powassan virus infection, Poxvirus infection, Primary amebic meningoencephalitis (Naegleria infection), Prion disease (transmissible spongiform encephalopathy), Pseudomonas aeruginosa infection, Psittacosis (Chlamydia psittaci infection), Psoriasis, Rheumatoid arthritis, Rabies, Rat-bite fever (Schizophrenia), Streptobacilus moniliforme infection), recreational water illness, respiratory syncytial virus infection, spotted fever group rickettsiae, Rickettsia rickettsii infection (Rocky Mountain spotted fever), Rift Valley fever, Salmonella typhi infection (typhoid fever), sappinia infection, severe acute respiratory syndrome, scabies, scarlet fever (group A streptococcal infection), schistosome infection (schistosomiasis), trichomoniasis, sudden infant death syndrome, sinusitis, sleeping sickness (African trypanosomiasis), smallpox, erythema migrans associated with Amblyomma testudinarium bites, Sporothrix, Strongyloides disease, schizophrenia disease, tapeworm disease, thalassemia (Cooley's anemia), thrombophilia, toxoplasmosis, brain trauma, trichinellosis (trichinosis), trichomoniasis, trichuriasis (whipworm infection), Trypanosoma cruzi infection (Chagas' disease), African trypanosomiasis (sleeping sickness), Tourette's syndrome, tularemia (Francisella turaensis infection), ulcerative colitis, undulant fever (brucellosis infection), unexplained respiratory disease outbreaks, vaginal candidiasis, Valley fever (coccidioidomycosis), vancomycin-intermediately resistant Staphylococcus aureus infection, vancomycin-resistant enterococcus infection, variant Kreutzfeldt-Jakob disease Selected from drugs used to treat a disease / disorder selected from, but not limited to, Erdt-Jakob disease, varicella-zoster virus infection, viral hemorrhagic fever, Alhamra hemorrhagic fever, Chapare hemorrhagic fever, Crimean-Congo hemorrhagic fever (Nairovirus infection), Kyasanur Forest disease, Luho hemorrhagic fever, Marburg hemorrhagic fever, von Willebrand disease, West Nile virus infection, whipworm infection (trichuria), Whitmore disease (melioidosis), yeast infection, yellow fever, Yersinia enterocolitica infection (yersiniosis), Zika virus infection.

[0027] In the present invention, the organic solvent and the other solvent are partially to completely miscible with each other, and the active pharmaceutical ingredient has poor solubility in the other solvent. Organic solvents according to the present invention include, but are not limited to, tetrahydrofuran (THF), acetone, dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, triethanolamine, N-methyl-2-pyrrolidone, and acetic acid, alcohols such as methanol, ethanol, propanol, butanol, alkali esters such as ethyl acetate, and the like, or combinations thereof.

[0028] The active pharmaceutical ingredient may be dissolved in the organic solvent or another solvent in an amount of 0.1 to 50 w / w %. The organic solvent and another solvent can be mixed in a ratio ranging from 1:2 to 1:100, preferably from 1:4 to 1:20, and more preferably from 1:5 to 1:15.

[0029] Surfactants according to the invention include nonionic, ionic, cationic and amphoteric surfactants, such as cetylpyridinium chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, carrageenan, diethanolamine, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters (Span 20, Span 80), polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, such as polysorbates. 20 or 80 (polysorbate); ethylene glycol, glycol esters, ethylene glycol esters, polyethylene glycol, dodecyltrimethylammonium bromide, fatty alcohols, lanolin and its alcohols, fatty acids, mineral oil, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, ethylene oxide and formaldehyde-containing 4-(1,1,3,3-tetramethylbutyl acrylate) )-phenolic polymers (also known as tyloxapol, sperinone, and triton), poloxamers, poloxamines; charged phospholipids, such as dimyristoylphosphatidylglycerol, dioctyl sulfosuccinate (DOSS), dialkyl esters of sodium sulfosuccinate, sodium lauryl sulfate, alkylaryl polyethers; p-isononylphenoxypoly-(glycidol); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside;Examples of surfactants include, but are not limited to, nonanoyl-N-methylglucamide, n-nonyl β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl β-D-glucopyranoside, octyl β-D-thioglucopyranoside, and the like, or combinations thereof. Preferably, the surfactant used in accordance with the present invention is selected from polysorbate 20 or 80, Span 20 or 80, SDS, and poloxamer. The surfactant component can be present in either the organic solvent, another solvent, or both. The surfactant component can be present in an amount of up to 15 w / w% of the organic solvent or another solvent, preferably less than 4 w / w%, more preferably less than 2.5 w / w%.

[0030] In the process of the present invention, the organic solvent is removed using a method selected from purging with a gas, distillation, extraction or supercritical fluid extraction. In the method of the present invention, the suspension is concentrated using a method selected from tangential flow filtration, centrifugation / sedimentation or dead-end filtration.

[0031] In one embodiment, the present invention provides a method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 99°C for 0.5 hours to 2 weeks at a rate ranging from 0.01°C / min to 50.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention relates to a method for preparing a compound of formula (I) comprising the steps of:

[0032] In another embodiment, the present invention provides a method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 40°C for 0.5 hours to 2 weeks at a rate of 0.01°C / min to 50.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention relates to a method for preparing a compound of formula (I) comprising the steps of:

[0033] In one embodiment, the present invention provides a method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 45°C to 65°C for 24 hours to 1 week at a rate of 0.1°C / min to 1.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention relates to a method for preparing a compound of formula (I) comprising the steps of:

[0034] In a preferred embodiment, the present invention provides a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents selected from tetrahydrofuran (THF), acetone, dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, triethanolamine, N-methyl-2-pyrrolidone and acetic acid, alcohols such as methanol, ethanol, propanol, butanol, or alkali esters such as ethyl acetate, optionally containing a surfactant; b. adding the solution of step (a) to another solvent selected from water, water for injection, acetone or alcohol, such as methanol, ethanol, propanol, butanol, to produce a suspension of the active pharmaceutical ingredient, wherein the other solvent optionally contains one or more surfactants; c. removing the organic solvent by purging with a gas; d. concentrating the suspension obtained in step (c) by tangential flow filtration; e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 55°C for 48 hours at a rate of 0.8°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0035] In a preferred embodiment, the present invention provides a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents selected from tetrahydrofuran (THF), acetone, dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, triethanolamine, N-methyl-2-pyrrolidone and acetic acid, alcohols such as methanol, ethanol, propanol, butanol, or alkali esters such as ethyl acetate, optionally containing a surfactant; b. adding the solution of step (a) to another solvent selected from water, water for injection, acetone or alcohol, such as methanol, ethanol, propanol, butanol, to produce a suspension of the active pharmaceutical ingredient, wherein the other solvent optionally contains one or more surfactants; c. removing the organic solvent by purging with a gas; d. concentrating the suspension obtained in step (c) by tangential flow filtration; e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 65°C for 48 hours at a rate of 0.8°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0036] In one embodiment, the present invention provides a method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 75°C to 95°C for 24 hours to 1 week at a rate of 0.2°C / min to 0.8°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention relates to a method for preparing a compound of formula (I) comprising the steps of:

[0037] In a preferred embodiment, the present invention provides a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents selected from tetrahydrofuran (THF), acetone, dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, triethanolamine, N-methyl-2-pyrrolidone and acetic acid, alcohols such as methanol, ethanol, propanol, butanol, or alkali esters such as ethyl acetate, optionally containing a surfactant; b. adding the solution of step (a) to another solvent selected from water, water for injection, acetone or alcohol, such as methanol, ethanol, propanol, butanol, to produce a suspension of the active pharmaceutical ingredient, wherein the other solvent optionally contains one or more surfactants; c. removing the organic solvent by purging with a gas; d. concentrating the suspension obtained in step (c) by tangential flow filtration; e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 80°C for 24 hours to 1 week at a rate of 0.2°C / min to 0.8°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0038] In a preferred embodiment, the present invention provides a method for preparing stable nanoparticles, said nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents selected from tetrahydrofuran (THF), acetone, dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, triethanolamine, N-methyl-2-pyrrolidone and acetic acid, alcohols such as methanol, ethanol, propanol, butanol, or alkali esters such as ethyl acetate, and one or more surfactants; b. adding the solution of step (a) to another solvent selected from water, water for injection, acetone or alcohol, such as methanol, ethanol, propanol, butanol, to produce a suspension of the active pharmaceutical ingredient, wherein the other solvent comprises one or more surfactants; c. removing the organic solvent by purging with a gas; d. concentrating the suspension obtained in step (c) by tangential flow filtration; e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 40°C to 80°C for 24 to 72 hours at a rate of 0.3°C / min to 1.0°C / min; f. Optionally, drying the nanoparticles of step (e); The present invention provides a method for preparing a composition comprising the steps of:

[0039] The annealing step in the above embodiment of the present invention is essential for obtaining nanoparticles with a stable, desired particle size distribution and stable particle morphology. The annealing process allows for controlled particle growth, allowing for precise control of particle size and, thereby, the physicochemical parameters of the active pharmaceutical ingredient. It also promotes a well-defined single crystal morphology and separates agglomerates. The desired particle size of the present invention is achieved by exposing the active pharmaceutical ingredient to temperatures ranging from 30°C to 99°C for a specific period of time ranging from about 0.5 hours to 2 weeks.

[0040] The particle size of the active pharmaceutical ingredient produced according to the present invention is also dependent on the heating and cooling rates, which range from 0.01°C / min to 50.0°C / min, preferably from 0.1°C / min to 5°C / min, and more preferably from 0.3°C / min to 1°C / min. According to the present invention, the size of the resulting nanoparticles is less than 30,000 nm, preferably particles having an average size of less than 25,000 nm, 20,000 nm, 15,000 nm, 10,000 nm or 5,000 nm. Most preferably, the nanoparticles have an average size of less than 5,000 nm.

[0041] Another embodiment of the present invention relates to a pharmaceutical composition comprising nanoparticles produced using the method of the present invention, the composition being selected from, but not limited to, oral, parenteral, transdermal, rectal, urethral, ​​intranasal, intrarespiratory, intraocular or conjunctival.

[0042] More specifically, the stable nanoparticles of the present invention can be further used to prepare pharmaceutical compositions including, but not limited to, chewable tablets, coated tablets, effervescent tablets, gastroresistant tablets, orodispersible tablets, modified-release tablets, sublingual tablets, floating tablets, hard capsules, soft capsules, gastroresistant capsules, chewable capsules, modified-release capsules, effervescent powders, effervescent granules, gastroresistant granules, lozenges, gels, pastes, pastilles, creams, ointments, compresses, lotions, sponges, foams, patches, suspensions, emulsions, solutions, syrups, mouthwashes, sprays, eye drops, implants, vaginal suppositories, suppositories, parenteral suspensions, parenteral emulsions, and parenteral solutions.

[0043] In one embodiment of the present invention, the nanoparticles produced by the method of the present invention can be used to prepare a pharmaceutical composition that is a parenteral or injectable preparation in the form of a solution or suspension, where the route of administration can be intravenous, intramuscular or subcutaneous or any other route of administration depending on the needs of the treatment.

[0044] In another embodiment of the invention, a solution or suspension for parenteral administration is prepared by diluting the resulting nanoparticles with a pharmaceutically acceptable excipient, wherein the method does not include isolation and drying of the precipitated nanoparticles, or lyophilization. Additionally, excipients used in preparing the parenteral compositions of the present invention include, but are not limited to, solubility enhancers, buffers, osmolality adjusting agents, viscosity adjusting agents, preservatives, bulking agents, wetting agents, pH adjusting agents or fillers. Buffers according to the present invention include, but are not limited to, phosphate, tartrate, ascorbate, acetate, succinate, citrate, borate, lactate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate monohydrate, and the like, or combinations thereof.

[0045] Tonicity adjusting agents according to the present invention include, but are not limited to, dextrose, glycerol, mannitol, sorbitol, sodium chloride, and the like, or combinations thereof. Viscosity enhancers according to the present invention include, but are not limited to, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate, and the like, or combinations thereof. Preservatives according to the present invention include, but are not limited to, benzoic acid, benzyl alcohol, butylhydroxyanisole, butylhydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-gamma-picolinium chloride, phenylmercuric acetate, and thimerosal. Tonicity agents include, for example, sodium chloride, dextrose, mannitol, sorbitol, lactose, and sodium sulfate. Examples of antioxidants that may be present include, but are not limited to, acetone sodium bisulfate, ascorbate, α-tocopherol, sodium bisulfate, butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteine ​​hydrochloride (cysteine ​​HCl), sodium dithionite, gentisic acid, gentisic acid ethanolamine, monosodium glutamate, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, monothioglycerol, propyl gallate, sodium sulfite, tocopherol alpha, sodium thioglycolate, and mixtures thereof.

[0046] Bulking agents according to the present invention include, but are not limited to, mannitol, sorbitol, maltose, sucrose, xylitol, glucose, starch, and the like, or combinations thereof. Humectants according to the present invention include, but are not limited to, glycerol, alcohol, propylene glycol, polyethylene glycol castor oil, polyethylene glycol, polyoxyethylene sorbitan fatty acid esters (polysorbates), povidone, and the like, or combinations thereof. pH adjusters according to the present invention include, but are not limited to, hydrochloric acid, fumaric acid, acetic acid, citric acid, malic acid, phosphoric acid, ammonia solution, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine, and the like, or combinations thereof.

[0047] The following examples illustrate specific aspects and embodiments of the present invention and demonstrate its practice and advantages. It is understood that these examples are given for illustrative purposes only and are not intended to limit the scope of the invention in any way. [Example]

[0048] Example 1: Method for preparing particles of paliperidone palmitate a. Paliperidone palmitate (54 g) was weighed into a 1 L glass Duran® bottle. 846 g of tetrahydrofuran was added to the Duran® bottle to create a 6% w / w solvent phase. The mixture was then stirred at room temperature until completely dissolved. b. 6.75 g of 0.09% w / w Tween® 20 in water for injection (7493.25 g) was weighed into a 10 L extraction vessel and cooled to 5° C. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 33 mL / min until a ratio of water for injection to tetrahydrofuran of 10:1 was reached. d. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 72 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. e. The suspension of step (d) was concentrated using tangential flow filtration to obtain a final concentrated suspension. Concentration was stopped when the desired concentration of paliperidone palmitate of 175 mg / g was reached. f. Annealing for step (e) was initiated at 40° C. for 16 days with a heating and cooling rate of 0.8° C. / min using a Julabo heater-cooler system. The nanoparticles produced in Example 1 were characterized for their particle size distribution (PSD) using laser diffraction (Shimadzu-SALD-2300).

[0049] PSD data were collected at different time points starting from day 5 to day 16. Table 8 and Figure 1 show the volume-averaged PSD results, D10, D50, and D90. The statistical parameters D10, D50, and D90 indicate the sizes at which 10%, 50%, and 90% of the particles are distributed, respectively. The average particle size was observed to be stable or slightly increased during the first 5 days of annealing. However, surprisingly, after day 5, the agglomerates began to dissociate, and the average particle size rapidly decreased.

[0050] Example 2: Method for preparing a pharmaceutical composition prepared using paliperidone palmitate particles prepared according to Example 1. [Table 1]

[0051] The paliperidone palmitate nanoparticle suspension prepared from Example 1 was diluted with a buffer containing other excipients to give a final drug product bulk at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials.

[0052] Example 3: Method for preparing particles of paliperidone palmitate a. Paliperidone palmitate (54 g) was weighed into a 1 L glass Duran® bottle. 846 g of tetrahydrofuran was added to the Duran® bottle to create a 6% w / w solvent phase. The mixture was then stirred at room temperature until completely dissolved. b. 6.75 g of 0.09% w / w Tween® 20 in water for injection (7493.25 g) was weighed into a 10 L extraction vessel and cooled to 5° C. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 33 mL / min until a ratio of water for injection to tetrahydrofuran of 10:1 was reached. d. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 72 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. e. The suspension of step (d) was concentrated by using tangential flow filtration to obtain the final concentrated suspension. Concentration was stopped when the desired paliperidone palmitate concentration of 175 mg / g was reached. f. Annealing for step (e) was initiated at 60° C. for 48 hours with a heating and cooling rate of 0.8° C. / min using a Julabo heater-cooler system. The morphology of Example 3 after annealing is captured in the scanning electron microscope (SEM) images in Figure 2. This figure shows the disaggregation of the agglomerates after the annealing treatment (Figure 2: A and B) and the resulting optimal morphology of the isolated single crystals (Figure 2: C and D).

[0053] Example 4: Method for preparing a pharmaceutical composition prepared using paliperidone palmitate particles prepared according to Example 3. [Table 2]

[0054] The paliperidone palmitate nanoparticle suspension prepared from Example 3 was diluted with buffer containing other excipients to give a final drug product bulk at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials. In addition to nanoparticle performance, their stability is also an important parameter. Nanoparticle formulations should remain stable at long-term ambient and accelerated conditions. Therefore, the pharmaceutical composition prepared from Example 4 was examined at accelerated conditions of 40°C / 75%RH and at 25°C / 60%RH for long-term stability. Samples were tested for various physicochemical properties, such as assay, related substances, PSD, and dissolution.

[0055] The results shown in Tables 9 and 10 (Figures 3-6) demonstrate a significant increase in stability for the annealed composition compared to the non-annealed composition of Example 9. The decrease in dissolution rate was particularly pronounced under accelerated conditions, while the non-annealed composition exhibited slower dissolution after aging. Furthermore, the annealed composition exhibited a more stable PSD compared to the non-annealed composition. The annealed composition exhibited a stability profile reflected in a more stable dissolution rate after aging, which represented a significant improvement in the product quality profile.

[0056] Example 5: Method for preparing particles of paliperidone palmitate a. Paliperidone palmitate (54 g) was weighed into a 1 L glass Duran® bottle. 846 g of tetrahydrofuran was added to the Duran® bottle to create a 6% w / w solvent phase. The mixture was then stirred at room temperature until completely dissolved. b. 6.75 g of 0.09% w / w Tween® 20 in water for injection (7493.25 g) was weighed into a 10 L extraction vessel and cooled to 5° C. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 33 mL / min until a ratio of water for injection to tetrahydrofuran of 10:1 was reached. d. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 72 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. e. The suspension of step (d) was concentrated using tangential flow filtration to obtain a final concentrated suspension. Concentration was stopped when the desired concentration of paliperidone palmitate of 175 mg / g was reached. f. Annealing for step (e) was initiated at 80° C. for 48 hours with a heating and cooling rate of 0.8° C. / min using a Julabo heater-cooler system.

[0057] The nanoparticles prepared in Examples 1, 3, and 5 were investigated for the effect of different annealing temperatures and their influence on the PSD. The PSD was determined using the CPS method. This method was used because agglomerates were dissociated and the CPS method provided a more accurate estimate of the particle size range of single crystals, ranging from 0.12 to 5 μm. The results are summarized in Table 11 and Figure 7. During processing, it was observed that de-agglomeration occurred faster (within 24 hours) at higher annealing temperatures of 60°C and 80°C compared to annealing at 40°C (5 days). Using higher annealing temperatures slightly increased the PSD, which may allow for fine tuning of the final particle size.

[0058] Example 6: Method for preparing a pharmaceutical composition prepared using paliperidone palmitate particles prepared according to Example 5. [Table 3]

[0059] The paliperidone palmitate nanoparticle suspension prepared from Example 5 was diluted with buffer containing other excipients to give a final drug product bulk at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials.

[0060] Example 7: Method for preparing particles of aripiprazole a. 6% w / w aripiprazole (75 g) was weighed into a glass Duran® bottle, and 0.15% w / w Tween® 20 (1.875 g) was weighed into a small beaker. 93.85% w / w tetrahydrofuran (1175 g) was weighed into a beaker and used to pour the Tween® 20 from the beaker into the Duran® bottle. The mixture was then stirred at room temperature until completely dissolved. b. Weighed water for injection (4166.7 g) was charged into an extraction vessel. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 83 mL / min until a ratio of water for injection to tetrahydrofuran of 5:1 was reached. d. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 72 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. e. The suspension of step (d) was concentrated using tangential flow filtration to obtain a final concentrated suspension. Concentration was stopped when the desired concentration of paliperidone palmitate of 270 mg / g was reached. f. Annealing for step (e) was initiated after solvent extraction at 55° C. for 48 hours with a heating and cooling rate of 0.8° C. / min using a Julabo heater-cooler system.

[0061] Example 8: Method for preparing a pharmaceutical composition prepared using the aripiprazole particles prepared according to Example 7. [Table 4]

[0062] The aripiprazole nanoparticle suspension prepared from Example 7 was diluted with two buffer solutions containing other excipients to give a final bulk drug product at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials. The stability of this formulation was monitored under long-term stability conditions at 25° C. / 60% RH and accelerated conditions at 40° C. / 75% RH. The results are shown in Tables 12 and 13 and Figures 8 and 9 and confirm that the batches made using the annealing process exhibit a significantly more stable profile.

[0063] Example 9: Method for preparing particles of paliperidone palmitate a. Paliperidone palmitate (54 g) was weighed into a 1 L glass Duran® bottle. 846 g of tetrahydrofuran was added to the Duran® bottle to create a 6% w / w solvent phase. The mixture was then stirred at room temperature until completely dissolved. b. 6.75 g of 0.09% w / w Tween® 20 in water for injection (7493.25 g) was weighed into a 10 L extraction vessel and cooled to 5° C. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 33 mL / min until a ratio of water for injection to tetrahydrofuran of 10:1 was reached. d. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 72 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. e. The suspension of step (d) was concentrated using tangential flow filtration to obtain a final concentrated suspension. Concentration was stopped when the desired concentration of paliperidone palmitate of 175 mg / g was reached.

[0064] Example 10: Preparation method of pharmaceutical composition prepared using aripiprazole particles prepared according to Example 9. [Table 5]

[0065] The paliperidone palmitate nanoparticle suspension prepared from Example 9 was diluted with buffer containing other excipients to give a final drug product bulk at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials.

[0066] Example 11a: Method for preparing particles of paliperidone palmitate a. Paliperidone palmitate (54 g) was weighed into a 1 L glass Duran® bottle. 846 g of tetrahydrofuran was added to the Duran® bottle to create a 6% w / w solvent phase. The mixture was then stirred at room temperature until completely dissolved. b. 6.75 g of 0.09% w / w Tween® 20 in water for injection (7493.25 g) was weighed into a 10 L extraction vessel and cooled to 5° C. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 33 mL / min until a ratio of water for injection to tetrahydrofuran of 10:1 was reached. d. Annealing for step (c) was initiated at 60° C. for 48 hours with a heating and cooling rate of 0.8° C. / min using a Julabo heater-cooler system. e. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 72 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. f. The suspension of step (e) was concentrated using tangential flow filtration to obtain a final concentrated suspension. Concentration was stopped when the desired concentration of paliperidone palmitate of 175 mg / g was reached.

[0067] Example 11b: Method for preparing particles of paliperidone palmitate a. Paliperidone palmitate (54 g) was weighed into a 1 L glass Duran® bottle. 846 g of tetrahydrofuran was added to the Duran® bottle to create a 6% w / w solvent phase. The mixture was then stirred at room temperature until completely dissolved. b. 6.75 g of 0.09% w / w Tween® 20 in water for injection (7493.25 g) was weighed into a 10 L extraction vessel and cooled to 5° C. c. A suspension was prepared by transferring step (a) from a pressurized vessel through a flow meter into step (b) at a constant flow rate of 33 mL / min until a ratio of water for injection to tetrahydrofuran of 10:1 was reached. d. The solvent from step (c) was extracted by passing nitrogen through the extraction vessel at 20 L / min for 24 hours while heating to 21° C., removing the gaseous solvent from the headspace of the extraction vessel and transferring it to an activated carbon vessel. e. Annealing for step (d) was carried out using a Julabo heater-cooler system at 60° C. for 48 hours at a heating and cooling rate of 0.8° C. / min during solvent extraction at 10 L / min. f. The suspension of step (e) was concentrated using tangential flow filtration to obtain a final concentrated suspension. Concentration was stopped when the desired concentration of paliperidone palmitate of 175 mg / g was reached.

[0068] The effect of annealing timing was investigated in Examples 11a and 11b, and the results are summarized in Table 14. It was observed that the presence of organic solvent affected particle growth during the annealing process: a higher solvent content in the suspension resulted in a larger average particle size for the same annealing temperature and time. Furthermore, both methods showed that if annealing was performed early in the process, e.g., when there was more solvent in the suspension, the PSD led to larger particles. This timing of annealing can also be used to precisely tune particle size.

[0069] Example 12a: Method for preparing a pharmaceutical composition prepared using paliperidone palmitate particles prepared according to Example 11a. [Table 6]

[0070] The paliperidone palmitate nanoparticle suspension prepared from Example 11a was diluted with a buffer containing other excipients to give a final drug product bulk at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials.

[0071] Example 12b: Method for preparing a pharmaceutical composition prepared using paliperidone palmitate particles prepared according to Example 11a. [Table 7]

[0072] The paliperidone palmitate nanoparticle suspension prepared from Example 11b was diluted with a buffer containing other excipients to give a final drug product bulk at the target API concentration containing the required excipients. The resulting bulk suspension was filled into syringes or vials. Pharmaceutical compositions prepared from Examples 12a and 12b were examined under accelerated conditions at 40° C. / 75% RH and for long-term stability at 25° C. / 60% RH. Samples were tested for various physicochemical properties, including assay, related substances, PSD, and dissolution. The results shown in Table 15 indicated that the annealed compositions of aripiprazole exhibited a satisfactory stability profile.

[0073] [Table 8]

[0074] [Table 9]

[0075] [Table 10]

[0076] [Table 11]

[0077] Table 12

[0078] Table 13

[0079] Table 14

[0080] Table 15

Claims

1. 1. A method for preparing stable nanoparticles, the nanoparticles comprising: a. dissolving the active pharmaceutical ingredient in one or more organic solvents, optionally containing a surfactant; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient, the other solvent optionally containing a surfactant; c. removing the organic solvent; d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 99°C for 0.5 hours to 2 weeks at a rate ranging from 0.01°C / min to 50.0°C / min; f. Optionally, drying the nanoparticles of step (e); The method of claim 1, wherein the compound is prepared by a method comprising:

2. 10. The method of claim 1, wherein step e) comprises further annealing the suspension after any of step (b), step (c), or step (d) at a temperature ranging from 30° C. to 40° C. for 0.5 hours to 2 weeks at a rate of 0.01° C. / min to 50.0° C. / min.

3. 10. The method of claim 1, wherein step e) comprises further annealing the suspension after any of step (b), step (c), or step (d) at a temperature ranging from 45°C to 65°C for 24 hours to 1 week at a rate of from 0.1°C / min to 1.0°C / min.

4. 2. The method of claim 1, wherein step e) comprises further annealing the suspension after any of step (b), step (c), or step (d) at a temperature ranging from 75°C to 95°C for 24 hours to 1 week at a rate of from 0.2°C / min to 0.8°C / min.

5. A pharmaceutical composition comprising nanoparticles obtainable by the method according to any one of claims 1 to 4.

6. 6. The pharmaceutical composition of claim 5, selected from oral, parenteral, transdermal, rectal, urethral, ​​intranasal, intrarespiratory, intraocular or conjunctival compositions.

7. 7. The pharmaceutical composition according to claim 5 or 6, comprising one or more pharmaceutically acceptable excipients.

8. a. preparing a solution by dissolving an active pharmaceutical ingredient in one or more organic solvents; b. adding the solution of step (a) to another solvent to produce a suspension of the active pharmaceutical ingredient; c. removing the organic solvent from the suspension of step (b); d. concentrating the suspension obtained in step (c); e. further annealing the suspension after either step (b) or step (c) or step (d) at a temperature ranging from 30°C to 99°C for 0.5 hours to 2 weeks; 1. A method for preparing stable nanoparticles having an average particle size of less than about 30,000 nm, comprising:

9. 9. The method of claim 8, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, triethanolamine and acetic acid, acetaldehyde, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine, dimethoxyethane, 1,4-dioxane, ethylamine, ethylene glycol, formic acid, furfuryl alcohol, glycerol, methyldiethanolamine, methyl isocyanide, N-methyl-2-pyrrolidone, 1,3-propanediol, 1,5-pentanediol, propanoic acid, propylene glycol, pyridine, triethylene glycol, methyl t-butyl ether, diethyl ether, nitromethane, diethylene glycol, 2-butanone, methyl acetate, ethyl acetate, benzyl alcohol, water or a mixture of water, alcohols such as methanol, ethanol, propanol, butanol, and combinations thereof.

10. 10. The method of claim 8 or 9, wherein the further solvent is selected from the group consisting of water, water for injection, acetone, alcohols such as methanol, ethanol, propanol, butanol and combinations thereof.

11. 11. The method of any one of claims 8 to 10, wherein the organic solvent is removed using a method selected from purging with a gas, distillation, extraction or supercritical fluid extraction.

12. 12. The method of any one of claims 8 to 11, wherein the suspension is concentrated using a method selected from tangential flow filtration, centrifugation / sedimentation or dead-end filtration.

13. 13. The method of any one of claims 8 to 12, wherein the annealing step is carried out at a heating and cooling rate of from 0.01°C / min to 50.0°C / min.

14. 14. The method of any one of claims 8 to 13, wherein the organic solvent and the further solvent optionally comprise a surfactant.

15. Surfactants include cetylpyridinium chloride, gelatin, casein, lecithin (phosphatide), dextran, glycerol, acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, carrageenan, diethanolamine, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester (Polysorbate); ethylene glycol, glycol ester, ethylene glycol ester, polyethylene glycol, dodecyltrimethylammonium bromide, fatty alcohol, lanolin and its alcohol, fatty acid, mineral oil, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose, Magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, ethylene oxide and formaldehyde-containing 4-(1,1,3,3-tetramethylbutyl)-phenol polymer (also known as tyloxapol, sperinone, and triton), poloxamer, poloxamine; charged phospholipids, such as dimyristoyl phosphatidylglycerol, dioctyl sulfosuccinate (DOSS), dialkyl esters of sodium sulfosuccinate, sodium lauryl sulfate, alkylaryl polyethers; p-isononyl phenoxy Poly(glycidol); Decanoyl-N-methylglucamide; n-Decyl β-D-glucopyranoside; n-Decyl β-D-maltopyranoside; n-Dodecyl β-D-glucopyranoside; n-Dodecyl β-D-maltoside; Heptanoyl-N-methylglucamide; n-Heptyl-β-D-glucopyranoside; n-Heptyl β-D-thioglucoside; n-Hexyl β-D-glucopyranoside; Nonanoyl-N-methylglucamide; n-Nonyl β-D-glucopyranoside; Octanoyl-N-methylglucamide; n-Octyl-β-D-glucopyranoside;15. The method of claim 14, wherein the hydroxybenzoate is selected from the group consisting of octyl β-D-thioglucopyranoside, ... and the like, or a combination thereof.

16. 16. A composition comprising nanoparticles prepared as described in any one of claims 8 to 15, wherein the nanoparticles are formulated in a dosage form selected from oral, parenteral, transdermal, rectal, urethral, ​​intranasal, intrarespiratory, intraocular, intravenous, intraarterial, conjunctival, or any other form of local or systemic delivery.

17. 17. The composition of claim 16, wherein the dosage form is a parenteral preparation.

18. 18. The composition according to claim 16 or 17, wherein the parenteral preparation further comprises one or more suitable pharmaceutically acceptable excipients.

19. 20. The composition of claim 18, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of viscosity enhancing agents, bulking agents, osmolality adjusting agents, wetting agents, surfactants, buffering agents, pH adjusting agents and fillers.

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