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1.
AAPS PharmSciTech ; 19(3): 1358-1366, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29352403

RESUMO

The following research study focuses on improving the solubility of zaleplon (BCS class II drug) via micronization technique in order to enhance its oral delivery in orodispersible formulations. Zaleplon along with a surfactant solution was micronized by ultrasonication. The micronization process reduced the particle size of the crystalline drug about six-fold from its original size of 155.5 µm. The micronized zalepon dispersion was lyophilized to allow for a change in the state of matter (to a powder). The superior dissolution parameters (Q5, Q30, IDR, MDR, MDT, DE, and RDR) of zaleplon in microcrystalline form over the original crystalline form in in vitro dissolution studies had unraveled that micronization technique is an efficient tool in enhancing drug solubility. The micronized zaleplon solid dispersion (after lyophilization) was loaded into orodispersible tablet (ODT) and orodispersible film (ODF) formulations. The positive quality of ODT with adequate hardness and smooth texture was attributing to the presence of Pearlitol Flash® as a ready to use ODT platform. On the other hand, the ODF loaded with micronized zaleplon and prepared with Lycoat® RS 720 (as a film former) ensured adequate tensile strength. The disintegration time of ODT and ODF was 30 ± 5 and 35 ± 5 s, respectively. Thus, the orodispersible formulations containing micronized zaleplon have a strong potential for rapid disintegration following superior absorption in solution state through oral cavity into the blood stream, envisaging better oral delivery.


Assuntos
Acetamidas/química , Acetamidas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Pirimidinas/química , Pirimidinas/metabolismo , Acetamidas/administração & dosagem , Administração Oral , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Composição de Medicamentos/métodos , Dureza , Tamanho da Partícula , Pirimidinas/administração & dosagem , Solubilidade , Comprimidos/química , Resistência à Tração , Difração de Raios X/métodos
2.
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
3.
AAPS PharmSciTech ; 14(4): 1333-40, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23990120

RESUMO

Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25°C and 60% relative humidity (RH), or under accelerated conditions, 40°C and 75% RH. Benzocaine degradation was monitored by liquid chromatography-mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25°C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions.


Assuntos
Anestésicos Locais/análise , Benzocaína/análise , Anestésicos Locais/administração & dosagem , Benzocaína/administração & dosagem , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Estabilidade de Medicamentos , Excipientes , Solubilidade , Espectrofotometria Ultravioleta , Comprimidos
4.
Int J Pharm ; 627: 122209, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36162609

RESUMO

The United States Food and Drug Administration (USFDA) demands that the generic industry prove topical ocular products' pharmaceutical and bioequivalence (BE). In contrast to generic oral drugs, topical ocular product BE testing has proved difficult. New generic versions are compared to an authorized drug product known as a Reference Listed Drug (RLD) to demonstrate their bioequivalence. If the excellent in-vitro results may support the presumption of equivalence in-vivo performance and the only clinically significant difference between the generic and RLD is in its physicochemical qualities and drug release rate, then in-vivo BE studies may be waived. Proving BE through dissolution tests is a golden standard for most conventional dosage forms. However, due to the limited number of biorelevant in-vitro drug release testing (IVRT) approaches capable of differentiating their performance based on product quality and physicochemical properties, the development of generic ophthalmic products has been slow and time-consuming. Often, BE of topical ophthalmic formulations cannot be proved using a single in-vitro test; therefore, an elaborated discussion on various IVRT methods performed to demonstrate bioequivalence of complex generis like ophthalmic emulsions, suspensions, ointments, and gels is necessary. This manuscript aims to review the status of biowaiver criteria for complex ophthalmic products concerning the product-specific FDA guidance to the generic industry.


Assuntos
Medicamentos Genéricos , Estados Unidos , Equivalência Terapêutica , United States Food and Drug Administration , Técnicas In Vitro , Composição de Medicamentos
5.
Drug Dev Ind Pharm ; 37(11): 1306-10, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21702731

RESUMO

The purpose of this study was to investigate the plausibility of delivery of cefotaxime to the brain via intranasal administration. In vitro permeation studies were carried out using Franz diffusion cells, and the effect of different concentrations of chitosan (0.1% w/v and 0.25% w/v) on drug permeation across the bovine olfactory mucosa was determined. Samples were collected from the receiver compartment at different time points and analyzed using HPLC. The amount of cefotaxime that permeated across the olfactory mucosa when 0.25% w/v of chitosan was used as a permeation enhancer was ~1.5- and ~2-fold higher at the end of the first hour and second hour, respectively, over control (29.56 ± 6.18 µg/cm(2)). There was no significant enhancement in drug permeation when 0.1% w/v chitosan was used as the permeation enhancer. Pharmacokinetic studies were carried out using Sprague-Dawley rats. Cefotaxime solution with 0.25% w/v chitosan (40 mg/kg) was administered intravenously (i.v.) to rats in groups 1 and 3 and intranasally to those in group 2 and 4. The time course of drug in the brain was investigated by performing microdialysis in rats of groups 1 and 2. Blood samples were withdrawn from rats in groups 3 and 4, and cefotaxime in plasma was analyzed using HPLC after extraction with a hydrochloric acid-chloroform:1-pentanol (3:1) and phosphate buffer solvent system. Pharmacokinetic parameters were calculated using the trapezoidal rule. The results imply that the drug levels attained in the brain following i.v. and intranasal administrations were comparable. These results suggest that intranasal administration of cefotaxime could be a potential method of delivering antibacterial agents because of it being noninvasive and patient compliant.


Assuntos
Antibacterianos/administração & dosagem , Encéfalo/efeitos dos fármacos , Cefotaxima/administração & dosagem , Mucosa Nasal/metabolismo , Administração Intranasal , Animais , Disponibilidade Biológica , Bovinos , Quitosana/química , Sistemas de Liberação de Medicamentos , Masculino , Microdiálise , Permeabilidade , Ratos , Ratos Sprague-Dawley
6.
Int J Pharm ; 527(1-2): 151-160, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28549972

RESUMO

The present investigation was carried out to understand the impact of formulation and process variables on the quality of oral disintegrating films (ODF) using Quality by Design (QbD) approach. Lamotrigine (LMT) was used as a model drug. Formulation variable was plasticizer to film former ratio and process variables were drying temperature, air flow rate in the drying chamber, drying time and wet coat thickness of the film. A Definitive Screening Design of Experiments (DoE) was used to identify and classify the critical formulation and process variables impacting critical quality attributes (CQA). A total of 14 laboratory-scale DoE formulations were prepared and evaluated for mechanical properties (%elongation at break, yield stress, Young's modulus, folding endurance) and other CQA (dry thickness, disintegration time, dissolution rate, moisture content, moisture uptake, drug assay and drug content uniformity). The main factors affecting mechanical properties were plasticizer to film former ratio and drying temperature. Dissolution rate was found to be sensitive to air flow rate during drying and plasticizer to film former ratio. Data were analyzed for elucidating interactions between different variables, rank ordering the critical materials attributes (CMA) and critical process parameters (CPP), and for providing a predictive model for the process. Results suggested that plasticizer to film former ratio and process controls on drying are critical to manufacture LMT ODF with the desired CQA.


Assuntos
Química Farmacêutica , Dessecação , Composição de Medicamentos , Plastificantes , Temperatura , Administração Oral , Desenho de Fármacos
7.
J Control Release ; 224: 69-76, 2016 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-26732557

RESUMO

The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.


Assuntos
Analgésicos/líquido cefalorraquidiano , Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , ômega-Conotoxinas/líquido cefalorraquidiano , ômega-Conotoxinas/uso terapêutico , Administração Intranasal , Administração Intravenosa , Analgésicos/administração & dosagem , Animais , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Géis , Injeções Espinhais , Masculino , Mucosa Olfatória/metabolismo , Soluções Farmacêuticas , Ratos , Ratos Sprague-Dawley , Viscosidade , ômega-Conotoxinas/administração & dosagem
8.
J Control Release ; 210: 58-66, 2015 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-25979329

RESUMO

The objective of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6mg (delivery rates of 25, 50 and 100µg/day, respectively) was deconvoluted using Wagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R(2)=1.0) with a polynomial regression of Y=-0.227X(2)+0.331X-0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100µg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for Cmax and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100µg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100µg/day.


Assuntos
Sistemas de Liberação de Medicamentos , Estradiol/administração & dosagem , Estradiol/farmacocinética , Estrogênios/administração & dosagem , Estrogênios/farmacocinética , Modelos Biológicos , Administração Cutânea , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Estradiol/sangue , Estrogênios/sangue , Feminino , Terapia de Reposição Hormonal , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Pele/metabolismo , Absorção Cutânea , Adulto Jovem
9.
Int J Pharm ; 493(1-2): 412-25, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26231106

RESUMO

Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance.


Assuntos
Aciclovir/química , Antivirais/química , Aciclovir/administração & dosagem , Administração Oftálmica , Animais , Antivirais/administração & dosagem , Química Farmacêutica , Córnea/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Masculino , Pomadas , Tamanho da Partícula , Permeabilidade , Controle de Qualidade , Coelhos , Reologia , Viscosidade
10.
J Pharm Sci ; 103(6): 1638-42, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24648369

RESUMO

Topical treatment of hypertrophic scars is challenging because of poor penetrability of drugs into the scar tissue. The objective of the study was to investigate the effectiveness of iontophoresis to deliver medicaments across the scar epidermis. Initially, biophysical studies were performed to investigate the differences between scar and normal skin epidermis obtained from cadaver. In case of scar skin epidermis, the transepidermal water loss was not significantly different from the normal skin epidermis, whereas the electrical resistivity was significantly higher. The passive permeation flux of sodium fluorescein was approximately one-third of that across the normal skin epidermis. Scanning electron microscopy studies revealed that the two membranes were alike except that the scar skin epidermis lacked follicles. Cathodal iontophoresis enhanced the delivery of sodium fluorescein across the scar skin epidermis by approximately 46 folds [51.90 ± 8.82 ng/(cm(2) h)]. However, the transport of sodium fluorescein across the scar skin epidermis was about an order of magnitude less than the normal skin epidermis. Overall, the studies suggest that iontophoresis could be utilized to overcome the barrier resistance of scar skin epidermis and treat the scar regionally.


Assuntos
Cicatriz/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Iontoforese , Adulto , Feminino , Humanos , Microscopia Eletrônica de Varredura
11.
J Pharm Sci ; 101(7): 2392-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22487899

RESUMO

The main objective of the present study was to investigate the plausibility of iontophoretic delivery of drugs to the nail matrix via proximal nail fold. The in vitro drug transport studies were performed in Franz diffusion cells across folded epidermis, which is used as a model for the proximal nail fold. The amount of drug transported into the receiver compartment following iontophoresis for 3 h at 0.5 mA/cm(2) was 150-fold higher than the control (0.008 ± 0.002 µg/cm(2)). The amount of drug present in the skin after iontophoresis (0.45 ± 0.12 µg/mg) was approximately fivefold higher as compared with that of the control (0.08 ± 0.01 µg/mg). Iontophoresis of terbinafine across the proximal nail fold was assessed using excised cadaver toe model as well. A custom-designed foam-pad-type patch system was used for iontophoresis in cadaver toes. The amount of the drug delivered into the nail matrix following iontophoresis for 3 h was significantly higher than the minimum inhibition concentration of terbinafine. However, on the contrary, passive delivery for about 24 h did not result in any detectable drug levels in the nail matrix. Iontophoresis across the proximal nail fold could be developed as a potential method to target drugs to nail matrix.


Assuntos
Antifúngicos/administração & dosagem , Sistemas de Liberação de Medicamentos/instrumentação , Iontoforese/instrumentação , Unhas/metabolismo , Naftalenos/administração & dosagem , Antifúngicos/farmacocinética , Epiderme/metabolismo , Desenho de Equipamento , Humanos , Naftalenos/farmacocinética , Permeabilidade , Terbinafina
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