RESUMO
Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to-drug mass ratio of 4.5 and at an inlet temperature of 120 °C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox®. No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method.
Assuntos
Antifúngicos/administração & dosagem , Excipientes/química , Itraconazol/administração & dosagem , Manitol/química , Administração Oral , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Disponibilidade Biológica , Química Farmacêutica/métodos , Cristalização , Cães , Estudos de Viabilidade , Itraconazol/química , Itraconazol/farmacocinética , Masculino , Nanopartículas , Tamanho da Partícula , Pós , Solubilidade , Comprimidos , Água/química , Difração de Raios XRESUMO
In this study, the in vivo oral absorption of a nanocrystal tablet formulation of a BCS II poorly water-soluble drug was compared with that of its water-soluble salt form. Silybin is used as the model drug, and its nanosuspension was prepared by high-pressure homogenization. Effect of process and formulation parameters on properties of the nansuspensions was investigated. Dried powder of the nanosuspension was prepared by spray drying and used for preparing tablets. A pharmacokinetic study was performed in Beagle dogs to compare the absorption for tablets of silybin nanocrystals and silybin meglumine. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was determined. X-ray powder diffraction results indicated that silybin existed in a crystalline state after homogenization. In vivo absorption study in rats showed that the peroral absorption of silybin was enhanced remarkably by decreasing particle size. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was comparable with that of the commercially available tablet of the water-soluble salt form of silybin. In conclusion, it is possible to increase the bioavailability of poorly soluble drugs by preparing its water-soluble derivative.
Assuntos
Antioxidantes/farmacocinética , Nanopartículas/química , Absorção pela Mucosa Oral , Silimarina/farmacocinética , Animais , Animais Endogâmicos , Antioxidantes/análise , Antioxidantes/química , Disponibilidade Biológica , Cães , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Excipientes/química , Masculino , Meglumina/química , Microscopia Eletrônica de Varredura , Nanopartículas/ultraestrutura , Tamanho da Partícula , Pós , Ratos Wistar , Silibina , Silimarina/sangue , Silimarina/química , Suspensões , ComprimidosRESUMO
To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility.
Assuntos
Composição de Medicamentos/métodos , Lovastatina/química , Nanopartículas/química , Varredura Diferencial de Calorimetria , Dessecação , Estabilidade de Medicamentos , Estudos de Viabilidade , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Difração de Pó , Pós , Solubilidade , Propriedades de Superfície , SuspensõesRESUMO
In recent years, nanosuspensions have been accepted as a valuable drug delivery system for poorly water-soluble drugs. Topdown and bottom-up technologies are the two main approaches for generating nanosuspensions. Several products manufactured by the top-down technologies have been successfully commercialized demonstrating that the processing features of the technologies are adaptable to industrial scale operation and meeting high pharmaceutical quality control standards. Nanosuspensions of poorly soluble drugs have shown to achieve dramatic improvements on the in vivo performance of the drugs including the enhancement of bioavailability and elimination of food effect when administered orally. This review will focus on the preparation of nanosuspensions by the top-down technologies. The influence of drug physicochemical properties on the nanosuspension forming process and the subsequent conversion into a dry powder form will be discussed with proposed mechanisms. In addition, the criteria for selection of stabilizers will be reviewed. The characteristics of drugs and stabilizers as well as their interaction effects on the redispersion properties of a dry powder prepared from a nanosuspension will be highlighted. The different administration routes of nanosuspensions are also presented with their potential therapeutic benefits.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Disponibilidade Biológica , Desenho de Equipamento , Modelos Químicos , Tamanho da Partícula , Solubilidade , Suspensões , Tecnologia Farmacêutica/instrumentação , Água/químicaRESUMO
INTRODUCTION: Currently marketed microsphere products are manufactured with the use of organic solvents which have a negative impact on the environment and stability of biological molecules. With recent advances in fabrication technologies, solvent free methods have demonstrated potential for the preparation of microspheres. AREAS COVERED: New technical advances recently achieved in solvent based microsphere manufacturing processes have allowed for major improvement in product quality and properties. Novel solvent free fabrication methods combined with newly functionalized biodegradable polymers have been explored for their application in the preparation of microspheres containing biological molecules. EXPERT OPINION: Novel fabrication methods for microspheres have been recently reported but technical challenges and development risks remain high for scale up from bench to industrial commercialization. While the applications of microspheres for delivery of proteins, genes and vaccines have shown promise for clinical use, the approval of newly functionalized polymers as carriers may still face scrutiny on safety and biocompatibility, which can be key factors in securing the regulatory approval of the product.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Microesferas , Polímeros , Tecnologia Farmacêutica/métodos , Portadores de Fármacos , Técnicas de Transferência de Genes , Humanos , Preparações Farmacêuticas/administração & dosagem , Polímeros/química , Proteínas/administração & dosagem , Vacinas/administração & dosagemRESUMO
INTRODUCTION: Polymeric microspheres have been established as a valuable parenteral drug delivery system for sustained release of therapeutic agents via subcutaneous or intramuscular injection. AREAS COVERED: Biodegradable polymers which are either synthetic or from natural sources are reviewed with respect to recent advances in exploring their applications for microsphere fabrications. New information on the impact of formulation variables on the properties of microspheres formed by an emulsion method was also presented. The characterization of microspheres using advanced physical analytical techniques was also reviewed and the utilization of the information in assessing in vivo performance of the product was also highlighted. EXPERT OPINION: The broad clinical use of microspheres for delivery of therapeutic agents in particular biologics such as proteins has not been realized commercially. The limited availability of biodegradable polymers with a long history of regulatory approval and the challenges in gaining regulatory approval of a new polymer have hindered the development of microspheres for parenteral drug delivery.
Assuntos
Sistemas de Liberação de Medicamentos , Infusões Parenterais , Microesferas , Polímeros/química , Animais , HumanosRESUMO
This study was performed to optimize stabilizer systems used in itraconazole (ITZ) nanosuspensions to achieve the greatest extent of size reduction and investigate the effect of particle size on the in vitro dissolution and oral absorption of ITZ. The nanosuspensions were prepared by high pressure homogenization and characterized for particle size, zeta potential, and surface morphology. A central composite method was applied to identify a multiple stabilizer system of Lutrol F127 and sodium lauryl sulfate for optimal particle size reduction. By using the optimized system, an ITZ nanosuspension was prepared that showed the particle size results in good agreement with the values predicted by the model. The nanosuspension was physically stable at 25°C for 1 week. The crystalline form of ITZ was not altered. The ITZ dissolution rate is directly correlated to its particle size, and a smaller particle size yields a faster dissolution rate. Pharmacokinetics study was performed using four ITZ suspensions with various particle sizes in rats (n = 3). A significant increase in both maximal plasma concentration of drug and area under the drug concentration-time curve (AUC) was shown when the particle size was reduced from micrometer to nanometer. However, the AUC was not significantly affected by further reduction of the particle size within the nano-size range.
Assuntos
Antifúngicos , Portadores de Fármacos/química , Itraconazol , Mucosa Bucal/metabolismo , Nanopartículas/química , Absorção , Animais , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Composição de Medicamentos , Estabilidade de Medicamentos , Itraconazol/administração & dosagem , Itraconazol/química , Itraconazol/farmacocinética , Masculino , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Pressão , Ratos , Ratos Wistar , Solubilidade , Propriedades de Superfície , Termografia , Difração de Raios XRESUMO
In recent years, with the widespread application of high-throughput screening technologies in drug discovery, an increasing number of new chemical entities with extremely poor aqueous solubility have been generated. Their poor solubility represents a major challenge for formulation of these compounds for both oral and parenteral administration. Formulations for intravenous (i.v.) application are of significant importance because they are frequently used in several key therapeutic areas, such as oncology and anesthesia. Furthermore, i.v. formulations of new compounds are often needed to determine basic biopharmaceutical parameters and to obtain proof of concept results in the early phase of product development. This review provides an overview of the recent advances in formulation approaches and drug delivery technologies for poorly water-soluble compounds applicable to i.v. administration. The advantages and disadvantages of different strategies are highlighted and an expert opinion on each technical field is presented.
Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Preparações Farmacêuticas/administração & dosagem , Animais , Química Farmacêutica/métodos , Humanos , Infusões Intravenosas , Preparações Farmacêuticas/química , Solubilidade , Tecnologia Farmacêutica/métodosRESUMO
Taking ABT627 as a hydrophobic model drug, poly-(lactic-co-glycolic acid) (PLGA) microspheres were prepared by an emulsion solvent evaporation method. Various process parameters, such as continuous phase/dispersed phase (CP/DP) ratio, polymer concentration, initial drug loading, polyvinyl alcohol concentration and pH, on the characteristics of microspheres and in vitro drug release pattern of ABT627 were investigated. Internal morphology of the microspheres was observed with scanning electron microscopy by stereological method. CP/DP is a critical factor in preparing microspheres and drug loading increased significantly with increasing CP/DP ratios accompanied by a remarkably decreased burst release. At CP/DP ratio 20, microspheres with a core-shell structure were formed and the internal porosity of the microspheres decreased with increasing CP/DP ratio. Increase in PLGA concentration led to increased particle sizes and decreased drug release rates. ABT627 release rate increased considerably with increasing PVA concentrations in the continuous phase from 0.1% to 0.5%. The maximum solubility of ABT627 in PLGA was approximately 30%, under which ABT627 was dispersed in PLGA matrix in a molecular state. Increase in initial drug loading had no significant influence on particle size, drug encapsulation efficiency, burst release and internal morphology. However, drug release rate decreased at higher drug loading. Independent of process parameters, ABT627 was slowly released from the PLGA microspheres over 30 days, by a combination of diffusion and polymer degradation. During the first 13 days, ABT627 was mainly released by the mechanism of diffusion demonstrated by the unchanged internal morphology. In contrast, a core-shell structure of the microspheres was observed after being incubated in the release medium for 17 days, independent of drug loading, implying that the ABT627/PLGA microspheres degraded by autocatalytic effect, starting from inside of the matrix. In conclusion, hydrophobic drug release from the PLGA microspheres is mainly dependent on the internal morphology and drug distribution state in the microspheres.
Assuntos
Ácido Láctico/química , Ácido Poliglicólico/química , Polímeros/química , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Solventes/químicaRESUMO
Major progresses in the development of parenteral sustained-release systems have been made in recent years as evidenced by the regulatory approval and market launch of several new products. Both the availability of novel carrier materials and the advances in method of fabrication have contributed to these commercial successes. With the formulation challenges associated with biologics, new delivery systems have also been evolved specifically to address the unmet needs in the parenteral sustained release of proteins. In this review paper, different new carriers systems and preparation methods are discussed with special focus on their applications to biologicals.
Assuntos
Preparações de Ação Retardada/química , Sistemas de Liberação de Medicamentos , Polímeros/química , Proteínas/administração & dosagem , Animais , Química Farmacêutica , Composição de Medicamentos , Implantes de Medicamento/química , Géis , Glicolatos/química , Humanos , Injeções , Ácido Láctico , Lipossomos , Microesferas , Nanoestruturas , Polianidridos/química , Poliésteres/química , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas/químicaRESUMO
Bupivacaine lipid microparticles were prepared and evaluated as a parenteral sustained-release dosage form for postoperative pain management. Bupivacaine free base was incorporated into a molten tristearin matrix and lipid micro-particles were subsequently formed from this molten mixture by a spray-congealing process. A 3% injectable bupivacaine lipid microparticle suspension was prepared by dispersing 30% bupivacaine lipid microparticles in an aqueous medium containing carboxymethylcellulose (CMC), mannitol, and Tween 80. Upon room temperature storage, the fluid suspension gradually changed into a nonflowing semisolid (gelation) as a result of crystal growth of bupivacaine. However, suspensions prepared with bupivacaine lipid microparticles that were previously annealed at an elevated temperature remained fluid upon long-term storage. Differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and isoperibol solution calorimetry were used to investigate the changes in the solid-state properties of tristearin and bupivacaine in the lipid microparticles before and after the heat treatment. The DSC and XRPD results indicate that after 24 hours of heating at 40 degrees C, tristearin was completely converted from the unstable alpha form to the stable beta form. Using the isoperibol solution calorimetric method, bupivacaine was found to transform into a more stable form after the lipid microparticles were heated at 60 degrees C for 24 hours. The generation of the unstable solid forms of tristearin and bupivacaine was attributed to the resolidification of both components from the molten mixture during the spray-congealing process.
Assuntos
Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Anestésicos Locais/química , Bupivacaína/química , Varredura Diferencial de Calorimetria , Fenômenos Químicos , Físico-Química , Estabilidade de Medicamentos , Excipientes , Lipídeos , Microscopia Eletrônica de Varredura , Microesferas , Tamanho da Partícula , Suspensões , Triglicerídeos/química , Difração de Raios XRESUMO
A suspension formulation containing sarafloxacin HCl, triamcinolone acetonide, and clotrimazole was developed for the treatment of otitis externa in dogs. The potency for the three active ingredients in this suspension was monitored at 25 degrees C and 40 degrees C for up to 3 months. The potencies of triamcinolone and clotrimazole were found unchanged, but the potency of sarafloxacin HCl in the samples stored at 40 degrees C for 1 month varied significantly between samples. However, assay inconsistency for sarafloxacin HCl was not seen in samples stored at 25 degrees C. Under an optical microscope, large crystals were found in the 40 degrees C stability samples but not in the 25 degrees C samples. The large crystals in 40 degrees C samples were identified as sarafloxacin by high-performance liquid chromatography (HPLC). This finding suggests that crystal growth of sarafloxacin took place at 40 degrees C during storage, leading to the formation of larger crystals and the consequent sampling nonuniformity and assay inconsistency. The solid-state properties of these crystals were further evaluated using hot-stage microscopy and Fourier transform infrared (FTIR) analysis. The results indicate that the crystal growth of sarafloxacin was most likely attributed to a change in the hydration form of sarafloxacin.
Assuntos
Anti-Infecciosos Locais , Química Farmacêutica/métodos , Ciprofloxacina/análogos & derivados , Clotrimazol , Fluoroquinolonas , Glucocorticoides , Triancinolona Acetonida , Animais , Cromatografia Líquida de Alta Pressão , Cães , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Temperatura Alta , Otite Externa/tratamento farmacológico , SuspensõesRESUMO
Bupivacaine lipospheres were prepared as a parenteral sustained-release system for post-operative pain management. Bupivacaine free base was incorporated into micron-sized triglyceride solid particles coated with phospholipids, which were formed via a hot emulsification and cold resolidification process. The bupivacaine liposphere dispersions were characterized with respect to drug loading, particle-size distribution, and morphology. Gelation of the fluid liposphere dispersions was observed at different time intervals upon storage. The type of phospholipids used in the formulation was found to have a major impact on the gelation of the dispersion. The use of synthetic phospholipids instead of the natural phospholipids in the formulation yielded bupivacaine liposphere dispersions exhibiting prolonged gelation time. The addition of a hydrophilic cellulosic polymer can further improve the physical stability of the dispersion.
Assuntos
Bupivacaína/química , Microesferas , Química Farmacêutica , Lipossomos , Tamanho da PartículaRESUMO
Laboratory-scale spray-congealing equipment was utilized to fabricate injectable microparticles consisting of polyorthoester and bupivacaine. Operating conditions for the spray-congealing process were optimized to produce microparticles with the desired shape and particle size to yield acceptable syringeability and injectability. Characterizations were performed to determine the chemico-physical properties of polyorthoester before and after microparticle fabrication. Microparticles with different drug loadings and comparable particle sizes were produced, and their in vitro drug-release profiles were determined. The in vitro drug release of microparticles with a high drug loading was markedly faster than those with a low drug loading. This is partially attributed to a more significant initial burst-drug release of the microparticles with a high drug loading. The microparticles have demonstrated the potential to be used for long-acting postsurgery pain management by local injection.
Assuntos
Bupivacaína/química , Poliésteres/química , Química Farmacêutica , Microesferas , Tamanho da PartículaRESUMO
A polyanhydride implant (Septacin) containing gentamicin sulfate was developed for sustained local delivery of the drug to the site of infection in the treatment of osteomyelitis. Laboratory-scale injection molding equipment was utilized to fabricate the implant for in vitro characterization. Molding conditions were optimized to produce implants with a skin-core structure which was found to be critical in preventing the initial cracking of the implant during in vitro drug release test in water. A manufacturing process consisting of twin-screw extrusion, pelletizing, and injection molding was developed. Polymer-drug pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The implants were terminally sterilized by gamma-radiation which was found to cause increase in copolymer molecular weight as a result of polymer chain extension. The stability of Septacin was evaluated as a function of storage temperature and time. A marked decline in copolymer molecular weight occurred in samples stored above freezing temperatures and significantly slower drug-release profiles were also exhibited by these samples. In vivo drug release from Septacin in rats showed that the gentamicin plasma levels were extremely low, indicating the low systemic exposure to gentamicin. Furthermore, Septacin samples have demonstrated efficacy in the rat skin-abscess and horse-joint infection models. Results from a human in vivo study also showed high local drug concentrations at implantation sites while systemic exposure to the drug was minimal.
Assuntos
Anidridos/administração & dosagem , Antibacterianos/administração & dosagem , Bombas de Infusão Implantáveis , Polímeros/administração & dosagem , Animais , HumanosRESUMO
A production-scale manufacturing process has been developed for polyanhydride/gentamicin sulfate implants for the treatment of osteomyelitis. Gentamicin sulfate was first dried to an acceptable moisture level by using a tumble vacuum dryer. Dried gentamicin sulfate powder and polyanhydride granules were separately fed into the twin-screw extruder at a pre-determined metering rate using a gravimetric feeding device. The extruded molten mixture was solidified to form strands which were subsequently cut into pellets by using a pelletizer. The pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The pellets were later fed into production-scale injection-molding equipment for implant fabrication. The injection-molding cycle was developed and evaluated in terms of cycle reproducibility. Implants were tested and shown to yield an oriented skin-core structure exhibiting a desirable in-vitro drug release profile.
Assuntos
Anidridos , Antibacterianos/administração & dosagem , Ácidos Decanoicos/química , Ácidos Graxos/química , Gentamicinas/administração & dosagem , Polímeros/química , Tecnologia Farmacêutica/métodos , Antibacterianos/uso terapêutico , Implantes de Medicamento , Gentamicinas/uso terapêutico , Técnicas In Vitro , Osteomielite/tratamento farmacológico , Tecnologia Farmacêutica/instrumentaçãoRESUMO
Septacin, a polyanhydride implant containing gentamicin sulfate, was sterilized by gamma-radiation. Its copolymer molecular weight (M(w) by GPC) was increased after this radiation. No cross-linking was shown in the radiated samples as no gel content was found by the filtration method. The chemical structure as detected by 1H NMR for non-radiated and radiated samples was comparable. For samples radiated at higher dose levels (70-100 kGy), the IR spectra showed that the intensity of absorbance attributable to the C-H stretching vibration (at 2852 and 2927 cm(-1)) was attenuated, indicating free-radical formation or loss of hydrogen atoms from C-H bonds. However, the mass spectra for the gamma-radiated and the non-radiated controls after they were completely depolymerized in methylene chloride were virtually identical. Therefore, it could be concluded that the increase in copolymer molecular weight for radiated Septacin was a result of chain extension in the copolymer backbone during radiation. In addition, wide-angle X-ray diffraction and polarizing light microscopy (PLM) revealed a change in the physical structure of the radiated copolymer. There was an increase in crystallinity of the copolymer with increasing radiation doses; the greatest increase in crystallinity occurred at the dose range of 70-80 kGy, which was also shown to result in the greatest molecular-weight increase. The crystalline morphology of the samples as detected by PLM was not altered by gamma-radiation, regardless of the dose levels.