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1.
AAPS PharmSciTech ; 18(6): 2131-2140, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28028793

RESUMO

Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P < 0.001) higher than that with product-C, product-A, gel, and spray. However, products-A and C, gel, and spray showed almost the same (P > 0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug-retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P < 0.001) higher than those with products-A and B, gel, and spray. The in vitro study results indicate a high potential of skin-to-skin drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined.


Assuntos
Estradiol , Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Epiderme/fisiologia , Estradiol/administração & dosagem , Estradiol/farmacologia , Estrogênios/administração & dosagem , Estrogênios/farmacologia , Géis/administração & dosagem , Humanos , Absorção Cutânea
2.
Int J Pharm ; 475(1-2): 110-22, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25089511

RESUMO

The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3.


Assuntos
Aciclovir/metabolismo , Antivirais/metabolismo , Aprovação de Drogas/métodos , Medicamentos Genéricos/metabolismo , Epiderme/metabolismo , Creme para a Pele/metabolismo , Aciclovir/análise , Aciclovir/química , Antivirais/análise , Antivirais/química , Cadáver , Fenômenos Químicos , Composição de Medicamentos , Medicamentos Genéricos/análise , Medicamentos Genéricos/química , Emulsões , Epiderme/química , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Tamanho da Partícula , Permeabilidade , Creme para a Pele/química , Solubilidade , Temperatura de Transição , Estados Unidos , United States Food and Drug Administration , Viscosidade
3.
J Pharm Sci ; 103(5): 1433-42, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24585397

RESUMO

Cold flow is a phenomenon occurring in drug-in-adhesive type of transdermal drug delivery systems (DIA-TDDS) because of the migration of DIA coat beyond the edge. Excessive cold flow can affect their therapeutic effectiveness, make removal of DIA-TDDS difficult from the pouch, and potentially decrease available dose if any drug remains adhered to pouch. There are no compendial or noncompendial methods available for quantification of this critical quality attribute. The objective was to develop a method for quantification of cold flow using stereomicroscopic imaging technique. Cold flow was induced by applying 1 kg force on punched-out samples of marketed estradiol DIA-TDDS (model product) stored at 25°C, 32°C, and 40°C/60% relative humidity (RH) for 1, 2, or 3 days. At the end of testing period, dimensional change in the area of DIA-TDDS samples was measured using image analysis software, and expressed as percent of cold flow. The percent of cold flow significantly decreased (p < 0.001) with increase in size of punched-out DIA-TDDS samples and increased (p < 0.001) with increase in cold flow induction temperature and time. This first ever report suggests that dimensional change in the area of punched-out samples stored at 32°C/60%RH for 2 days applied with 1 kg force could be used for quantification of cold flow in DIA-TDDS.


Assuntos
Adesivos/química , Sistemas de Liberação de Medicamentos/métodos , Microscopia/métodos , Administração Cutânea , Temperatura Baixa , Pele/efeitos dos fármacos
4.
Mol Pharm ; 11(4): 1140-50, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24579673

RESUMO

Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Fosfatidiletanolaminas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Vitamina E/análogos & derivados , Animais , Catepsina B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citidina Desaminase/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Feminino , Humanos , Camundongos , Micelas , Vitamina E/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
5.
Mol Pharm ; 11(3): 787-99, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24423028

RESUMO

Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products.


Assuntos
Ciclosporina/química , Sistemas de Liberação de Medicamentos , Emulsões , Imunossupressores/química , Soluções Oftálmicas/química , Controle de Qualidade , Tecnologia Farmacêutica/normas , Química Farmacêutica , Estabilidade de Medicamentos , Humanos , Tamanho da Partícula , Equivalência Terapêutica
6.
PLoS One ; 8(3): e58619, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505544

RESUMO

BACKGROUND: Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17-AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles. CONCLUSIONS/SIGNIFICANCE: We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.


Assuntos
Benzoquinonas/administração & dosagem , Portadores de Fármacos , Lactamas Macrocíclicas/administração & dosagem , Micelas , Nanopartículas , Paclitaxel/administração & dosagem , Animais , Benzoquinonas/química , Benzoquinonas/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Portadores de Fármacos/química , Feminino , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacocinética , Metaboloma , Metabolômica , Camundongos , Nanopartículas/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Espectroscopia de Luz Próxima ao Infravermelho , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Pharm ; 419(1-2): 281-6, 2011 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-21820041

RESUMO

The aim of this study was to develop micellar nanocarriers for concomitant delivery of paclitaxel and 17-allylamino-17-demethoxygeldanamycin (17-AAG) for cancer therapy. Paclitaxel and 17-AAG were simultaneously loaded into polymeric micelles by a solvent evaporation method. Two candidate nanocarrier constructs, polyethylene glycol-poly(D, L-lactic acid) (PEG-PLA) micelles and PEG-distearoylphosphatidylethanolamine/tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles, were assessed for the release kinetics of the loaded drugs. Compared to PEG-PLA micelles, entrapment of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles resulted in significantly prolonged release half-lives. The simultaneous incorporation of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles was confirmed by (1)H NMR analysis. Paclitaxel/17-AAG-loaded PEG-DSPE/TPGS mixed micelles were as effective in blocking the proliferation of human ovarian cancer SKOV-3 cells as the combined free drugs. PEG-DSPE/TPGS mixed micelles may provide a novel and advantageous delivery approach for paclitaxel/17-AAG combination therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Nanopartículas , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzoquinonas/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Feminino , Meia-Vida , Humanos , Lactamas Macrocíclicas/administração & dosagem , Micelas , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Fosfatidiletanolaminas , Polietilenoglicóis/química , Vitamina E/análogos & derivados , Vitamina E/química
8.
Int J Pharm ; 392(1-2): 170-7, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20363305

RESUMO

17-Allyamino-17-demethoxygeldanamycin (17-AAG) is a potent anticancer agent currently undergoing phases I and II clinical trials. However, the clinical development of 17-AAG has been hindered by its poor aqueous solubility and hepatotoxicity. This study aimed to devise novel micellar nanocarriers for 17-AAG that improve its solubility and retain the incorporated drug for a prolonged period of time. We have found that 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]/D-alpha-tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles (at a 1:2 molar ratio) can deliver 17-AAG at clinically relevant doses. By modulating the concentrations of micelle-forming copolymers, the burst release of 17-AAG from PEG-DSPE/TPGS mixed micelles was substantially reduced with a release half-life up to about 8h. Our (1)H NMR spectroscopy results revealed that the incorporation of TPGS into PEG-DSPE micelles restricted internal molecular motions of copolymers in both the corona and core regions of the micelles, leading to the delayed drug release. Cytotoxicity of 17-AAG formulated in PEG-DSPE/TPGS mixed micelles against human ovarian cancer SKOV-3 cells was comparable to that of free 17-AAG. 17-AAG-loaded PEG-DSPE/TPGS mixed micelles may offer a promising alternative to the current 17-AAG formulations for the treatment of solid tumors.


Assuntos
Antineoplásicos/administração & dosagem , Benzoquinonas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Desenho de Fármacos , Lactamas Macrocíclicas/administração & dosagem , Nanopartículas/química , Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Lactamas Macrocíclicas/farmacologia , Espectroscopia de Ressonância Magnética , Micelas , Tamanho da Partícula , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Solubilidade , Vitamina E/química
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