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1.
J Chromatogr Sci ; 57(10): 931-938, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31642896

RESUMO

Paclitaxel (PTX) and sulforaphane (SFN) are known anticancer molecules. Their activity was found to be potentiated when tested concurrently. Only recently, however, a novel SFN enabled PTX self-microemulsifying formulation (SMEDDS) was developed for their simultaneous delivery. This necessitated the development of an analytical method for the simultaneous detection and quantitation of PTX and SFN. In this study, a simple and sensitive isocratic high performance liquid chromatography-ultraviolet (HPLC-UV) analytical method was developed and validated per International Conference on Harmonization guidelines to satisfy this objective. Its application was demonstrated when quantifying the amount of PTX and SFN released from the SMEDDS in various dissolution media. The separation of the analytes was performed with the aid of a reversed phase C18 column at ambient temperature using a 60:40 mixture of acetonitrile and KH2PO4 buffer (pH 5.0) as the mobile phase. PTX and SFN peaks were detected at 202 nm with high resolution without interference from excipients. This method showed linearity within 2.5-100 µg/mL range with r2 > 0.999. The limit of detection and lower limit of quantitation were 0.1638 and 0.4964 µg/mL for PTX and 0.4419 and 1.3389 µg/mL for SFN, respectively. A total of 98-101% of the injected samples was recovered with RSD of 0.06-0.68% indicating the suitability of the method for the simultaneous detection and quantitation of the molecules in dissolution media.

2.
Pharm Dev Technol ; : 1-7, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31858867

RESUMO

Tocosol™ is a tocopherol-based paclitaxel (PTX) nanoemulsion consisting of α-tocopherol (α-T) isomer of vitamin E as a solubilizer and vitamin E TPGS as the primary emulsifier. Despite its positive attributes in early clinical studies, it failed the pivotal phase III clinical trials. The long-term goal of this work was to reformulate Tocosol™. In this study, Tocosol™ formulation was optimized by replacing the α-T isomer with the more pharmacological active isomer γ-tocotrienol (γ-T3), and the surfactant vitamin E TPGS was replaced with in-house designed PEGylated γ-T3 surfactant. The reformulated paclitaxel γ-T3/PEGylated γ-T3 -based nanoemulsion was significantly more active against pancreatic tumor cell lines than α-T/Vitamin E TPGS based formulation (IC50 = 0.5 µM and 1.1 µM, respectively). Furthermore, the reformulated product showed an average size of 220 ± 6 nm with surface charge equal to -42 ± 2 mV. The optimized product was physically and chemically stable over 6 months per ICH storage condition guidelines.

3.
Mol Cancer Ther ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645443

RESUMO

Ceramide (Cer) is an active cellular sphingolipid that can induce apoptosis or proliferation-arrest of cancer cells. Nanoparticle-based delivery offers an effective approach for overcoming bioavailability and biopharmaceutics issues attributable to the pronounced hydrophobicity of Cer. Missense mutations of the protein p53, which have been detected in approximately 42% of cancer cases, not only lose the tumor suppression activity of wild-type p53, but also gain oncogenic functions promoting tumor progression and drug resistance. Our previous works showed that cellular Cer can eradicate cancer cells that carry a p53 deletion-mutation by modulating alternative pre-mRNA splicing, restoring wild-type p53 protein expression. Here, we report that new ceramide-rubusoside (Cer-RUB) nanomicelles considerably enhance Cer in vivo bioavailability and restore p53-dependent tumor suppression in cancer cells carrying a p53 missense mutation. Natural RUB encapsulated short-chain C6-Cer so as to form Cer-RUB nanomicelles (∼32 nm in diameter) that substantially enhanced Cer solubility and its levels in tissues and tumors of mice dosed intraperitoneally. Intriguingly, Cer-RUB nanomicelle treatments restored p53-dependent tumor suppression and sensitivity to cisplatin in OVCAR-3 ovarian cancer cells and xenograft tumors carrying p53 R248Q mutation. Moreover, Cer-RUB nanomicelles showed no signs of significant nonspecific toxicity to noncancerous cells or normal tissues, including bone marrow. Furthermore, Cer-RUB nanomicelles restored p53 phosphorylated protein and downstream function to wild-type levels in p53 R172H/+ transgenic mice. Altogether, this study, for the first time, indicates that natural Cer-RUB nanomicelles offer a feasible approach for efficaciously and safely targeting cancers carrying p53 missense mutations.

4.
Int J Nanomedicine ; 14: 7643-7663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571869

RESUMO

Angiogenesis is the formation of new blood vessels from pre-existing vessels. It is a highly regulated process as determined by the interplay between pro-angiogenic and anti-angiogenic factors. Under certain conditions the balance between angiogenesis stimulators and inhibitors is altered, which results in a shift from physiological to pathological angiogenesis. Therefore, the goal of therapeutic targeting of angiogenic process is to normalize vasculature in target tissues by enhancing angiogenesis in disease conditions of reduced vascularity and blood flow, such as tissue ischemia, or alternatively to inhibit excessive and abnormal angiogenesis in disorders like cancer. Gold nanoparticles (AuNPs) are special particles that are generated by nanotechnology and composed of an inorganic core containing gold which is encircled by an organic monolayer. The ability of AuNPs to alter vasculature has captured recent attention in medical literature as potential therapeutic agents for the management of pathologic angiogenesis. This review provides an overview of the effects of AuNPs on angiogenesis and the molecular mechanisms and biomedical applications associated with their effects. In addition, the main synthesis methods, physical properties, uptake mechanisms, and toxicity of AuNPs are briefly summarized.


Assuntos
Tecnologia Biomédica/métodos , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Endocitose , Ouro/toxicidade , Humanos , Nanopartículas Metálicas/toxicidade
5.
Int J Pharm ; 569: 118596, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394181

RESUMO

Epidemiological studies have compellingly documented the ability of the Mediterranean diet rich in extra-virgin olive oil to reduce the incidence of certain malignancies, and cardiovascular diseases, and slow the Alzheimer's disease progression. S-(-)-Oleocanthal (OC) was identified as the most bioactive olive oil phenolic with documented anti-inflammatory, anticancer, and anti-Alzheimer's activities. OC consumption causes irritating sensation at the oropharynx via activation of TRPA1. Accordingly, a taste-masked formulation of OC is needed for its future use as a nutraceutical while maintaining its bioactivity and unique chemistry. Therefore, the goal of this study was to prepare a taste-masked OC solid formulation with improved dissolution and pharmacodynamic profiles, by using (+)-xylitol as an inert carrier. Xylitol was hypothesized to serve as an ideal vehicle for the preparation of OC solid dispersions due to its low melting point and sweetness. The optimized OC-(+)-xylitol solid dispersion was physically and chemically characterized and showed effective taste masking and enhanced dissolution properties. Furthermore, OC-(+)-xylitol solid dispersion maintained potent in vivo anti-breast cancer activity. It effectively suppressed the human triple negative breast cancer development, growth, and recurrence after primary tumor surgical excision in nude mice orthotopic xenograft models. Collectively, these results suggest the OC-(+)-xylitol solid dispersion formulation as a potential nutraceutical for effective control and prevention of human triple negative breast cancer.


Assuntos
Aldeídos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Azeite de Oliva , Fenóis/administração & dosagem , Xilitol/administração & dosagem , Administração Oral , Aldeídos/química , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , Modelos Moleculares , Fenóis/química , Paladar , Xilitol/química
6.
PLoS One ; 14(4): e0214798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964898

RESUMO

Epidemiological and clinical studies compellingly documented the ability of Mediterranean diet rich in extra-virgin olive oil (EVOO) to reduce breast and colon cancers incidence, cardiovascular diseases, and aging cognitive functions decline. (-)-Oleocanthal (OC) and other EVOO phenolics gain progressive research attention due to their documented biological effects against cancer, inflammations, and Alzheimer's disease. There is no simple, reliable, and cost-effective isolation protocol for EVOO phenolics, which hinder their therapeutic applications. This study develops novel methods to isolate OC and other EVOO phenolics. This includes the use of ultra-freezing to eliminate most EVOO fats and the successful water capacity to efficiently extract OC and EVOO phenolics as self-emulsified nano-emulsion. Subsequent resin entrapment and size exclusion chromatography afforded individual EVOO phenolics in high purity. OC in vitro and in vivo oral anti-breast cancer (BC) activities validated its lead candidacy. Effective isolation of EVOO phenolics provided in this study will facilitate future preclinical and clinical investigations and stimulate the therapeutic development of these important bioactive natural products.


Assuntos
Aldeídos/química , Aldeídos/farmacologia , Neoplasias da Mama/tratamento farmacológico , /farmacologia , Emulsões/química , Azeite de Oliva/química , Azeite de Oliva/farmacologia , Fenóis/química , Fenóis/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Emulsões/farmacologia , Feminino , Humanos , Extração Líquido-Líquido/métodos , Células MCF-7 , Camundongos , Camundongos Nus
7.
BMJ Case Rep ; 12(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30709890

RESUMO

We herein describe a case of acute myocarditis which may mimic myocardial infarction, since affected patients experience 'typical' chest pain, the ECG changes are identical to those observed in acute coronary syndromes, and serum markers are increased. This case emphasises the importance of performing appropriate cardiac MRI to help in the differential and definitive diagnosis as well as the extent of myocardial involvement. ST elevation myocardial infarction is rare in young adults and when it is encountered, it should raise the differential diagnosis of its mimickers.


Assuntos
Dor no Peito/diagnóstico , Miocardite/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Adulto , Dor no Peito/etiologia , Diagnóstico Diferencial , Eletrocardiografia/métodos , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Miocardite/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações
8.
Int J Pharm ; 553(1-2): 210-219, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30347275

RESUMO

Curcumin (CUR) chewing gums have potential therapeutic benefits to head and neck cancer patients. The objective of this work was to develop medicated chewing gums (MCGs) with high CUR loading and desirable mastication properties. This was accomplished by evaluating the effect of five gum ingredients: (X1) polyisobutene, (X2) polyvinyl acetate, (X3) wood rosin, (X4) wax, and (X5) CUR on the mechanical properties of the MCGs using a 25-run, five-factor, two-level D-Optimal mixture design. CUR MCGs were prepared by the conventional fusion method for making chewing gums. They were characterized by a two-bites texture and uniaxial tension tests to generate force-displacement curves from which the cohesiveness (Y1), springiness (Y2), chewiness (Y3), compressibility (Y4), resistance to extension (Y5), and extensibility (Y6) were measured. Observed responses were used to generate polynomial models correlating the independent with the dependent variables. Elasticity and stiffness of the gums were found to be readily impacted by PIB and CUR levels. Fitted models were then used to predict a gum composition that has comparable mechanical properties to commercially procured chewing gums. The optimized MCG was loaded with 50% of either CUR or CUR/SBE-ß-CD inclusion complex and tested in vitro for drug release. Although no differences in mechanical properties were observed, substituting CUR with the inclusion complex was found to significantly enhance drug release. This study highlighted the impact of each gum ingredient on the quality of the MCGs and demonstrated the feasibility of preparing chewing gums with up to 50% drug loading.


Assuntos
Antineoplásicos/administração & dosagem , Goma de Mascar , Curcumina/administração & dosagem , Excipientes/química , Antineoplásicos/química , Química Farmacêutica/métodos , Curcumina/química , Liberação Controlada de Fármacos , Elasticidade , Elastômeros/química , Estudos de Viabilidade , Modelos Teóricos , Polienos/química , Polímeros/química , beta-Ciclodextrinas/química
9.
Int J Pharm ; 552(1-2): 378-387, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30308273

RESUMO

Soluplus® is an amphiphilic graft copolymer used in hot melt extrusion applications and electrospinning. Very little information is available on the use of Soluplus® as a film former and in the development of film-based formulations. The overall aim of this work was to study the mechanical and adhesive properties of Soluplus® films prepared by the solvent casting technique. More specifically, we discovered that vitamin E can serve as a plasticizer for the Soluplus® polymer and to significantly modulate its mechanical and adhesive properties. Vitamin E (0-75% w/w) and Soluplus® were dissolved in ethanol and cast on liners to produce transparent films. Cast films were tested for their physiochemical properties by IR, XRD, and MDSC, and for their adhesive and mechanical properties by texture analysis. Vitamin E was found to be miscible with Soluplus® and to reduce the crystallinity of the films. Vitamin E also decreased the films' tensile strength and Young's modulus while significantly increasing their percent elongation. The most notable effect was the observed increase in the adhesiveness (tackiness) and hydrophobicity of the films, which was evidenced by a significant increase in their water contact angle and a decrease in their swelling capacity and disintegration. These observations indicated that vitamin E/Soluplus® blends might be used for the preparation of highly pliable films, especially when made with 30-50% vitamin E, and in the development of a new type of pressure sensitive adhesive films when prepared with ≥65% vitamin E load.


Assuntos
Adesivos/química , Antioxidantes/química , Plastificantes/química , Polietilenoglicóis/química , Polivinil/química , Vitamina E/química , Adesividade , Módulo de Elasticidade , Etanol/química , Interações Hidrofóbicas e Hidrofílicas , Solventes/química , Resistência à Tração
10.
AAPS PharmSciTech ; 19(8): 3742-3750, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30255470

RESUMO

Curcumin chewing gums could be therapeutically beneficial if used by the head and neck cancer patients. High curcumin loading in chewing gums however is needed to achieve desired therapeutic effect. Preparing gums with high drug load is nonetheless challenging because of the negative impact of solids on their masticatory properties. The use of liquid flavors was found to partially solve this problem. The objectives of this study were to (1) determine the maximum amount of curcumin that can be loaded into co-compressed chewing gums made from Health in Gum® as the base and flavored with 1.5% peppermint oil, (2) determine if addition of sweeteners can improve the yield strength and compressibility of the gums when examined by a texture analyzer, (3) examine the effect of temperature over a storage period of one month on the physical stability of the chewing gums, and (4) study the impact of substituting curcumin with its inclusion complex with SBE-ß-CD on drug release. It was found that when flavored, Health in Gum® could load up to 25% curcumin by weight without compromising its masticatory properties. When tested for drug release, SBE-ß-CD was found to significantly increase the amount of curcumin dissolved within 30 min. Despite poor drug release from gums loaded with insoluble curcumin, the fragmentation of the gums during mastication by the Erweka tester is nonetheless expected to produce a suspension for absorption in the lower GIT. This study demonstrated how modulating gum composition and storage conditions can impact the mechanical properties of chewing gums with high solids content.


Assuntos
Química Farmacêutica/métodos , Goma de Mascar , Força Compressiva , Curcumina/síntese química , Excipientes/síntese química , beta-Ciclodextrinas/síntese química , Curcumina/metabolismo , Liberação Controlada de Fármacos , Excipientes/metabolismo , Solubilidade , Comprimidos , beta-Ciclodextrinas/metabolismo
11.
AAPS PharmSciTech ; 19(7): 2908-2920, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30088152

RESUMO

Medicated chewing gums (MCGs) represent a unique platform for drug delivery. They have been defined as solid single-dose preparations, which may contain more than one active pharmaceutical ingredient (API) with base consisting primarily of gum that has to be chewed for a certain period of time. They mainly contain a tasteless masticatory gum base as the core with other minor nonmasticatory ingredients, such as flavors and sweeteners. Despite their advantages in drug delivery, MCGs remain a niche product due to the complexity of their formulation, lack of acceptable testing methods, and intricacy of their manufacturing. Few studies have been reported on their use, and most of the information on their composition and production could be found in patent search. The aim of this review is to provide an overview of gum composition, manufacturing process, and characterization. Due to the scarcity of studies concerning the evaluation of the mechanical properties of MCGs, greater emphasis was placed on the available performance tests and procedures for the estimation of their mechanical and textural properties. While very few tests have been recommended by the official pharmacopeias, several tests have been suggested for assessing the mechanical properties of MCGs in vitro. Properties, such as chewiness, elasticity, and firmness, of chewing gums during mastication are imperative quality attributes that have been found to strongly correlate with gum composition and mouth feel.


Assuntos
Goma de Mascar/análise , Goma de Mascar/normas , Sistemas de Liberação de Medicamentos/normas , Sistemas de Liberação de Medicamentos/métodos , Elasticidade , Emulsificantes/análise , Emulsificantes/síntese química , Emulsificantes/normas , Fenômenos Mecânicos , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/normas , Resistência à Tração
12.
Int J Pharm ; 546(1-2): 255-262, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29792987

RESUMO

Soluplus® is a graft amphiphilic copolymer that is frequently used as an excipient in solid dosage forms as a dissolution and a solubility enhancer. We discovered that Soluplus® can be dissolved in vitamin E. The result is a tacky and highly adhesive material. Our research objective was to evaluate the rheological, adhesive, and textural properties of the Soluplus®/Vitamin E composites. In this study, Soluplus® was dissolved under heat in vitamin E at increasing concentrations from 0 to 40% (by weight). The flow behavior of the Soluplus®/Vitamin E composites was determined by applying shear stress using an advanced AR2000 rheometer. Under the linear viscoelastic region (LVR), the rheological properties of the blends such as dynamic viscosity (η'), storage modulus (G'), loss modulus (G″), and the phase angle tangent (tan δ) were measured. Hardness, adhesiveness, and cohesiveness of the blends were also measured with a TA.XT plus texture analyzer. Rheological analysis showed that the viscosity of the Soluplus®/Vitamin E composites increased with an increase in Soluplus® concentration but decreased as the temperature increased from 20 to 90 °C. The adhesiveness of the blends also significantly increased with an increase in Soluplus® concentration. The results from this study indicated that Soluplus®/Vitamin E composites have the potential to be exploited in applications where the use of highly adhesive material is desirable.


Assuntos
Adesivos/química , Polietilenoglicóis/química , Polivinil/química , Vitamina E/química , Adesividade , Elasticidade , Excipientes/química , Dureza , Reologia , Temperatura Ambiente , Viscosidade
13.
Int J Pharm ; 539(1-2): 147-156, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29414123

RESUMO

Self-emulsifying drug delivery systems (SEDDS) have been used as a formulation strategy to overcome the challenges in formulating poorly water soluble drugs. The objective of the present study was to report on the solubilizing capacity of sulforaphane (SFN) and its utilization to formulate SEDDS of poorly water soluble drugs. A set of 24 drugs was tested for their solubility in SFN of which Cyclosporine A, Celecoxib, Paclitaxel, Docetaxel, and Curcumin were selected for subsequent SEDDS formulation development utilizing SFN as common solubilizer. SFN-SEDDS formulations were developed utilizing a step-wise screening method that enabled the selection of the most efficient surfactants and co-surfactants to yield transparent microemulsions by microscopic analysis and absorbance data. The optimized SEDDS formulation for curcumin was selected for further investigation by DSC and FTIR, and was subjected to a dissolution study where more than 95% of the drug was found to dissolve within 10 min in both simulated gastric and intestinal fluids. The physical stability of the SEDDS was also confirmed in both media when monitored at three different temperatures (4, 25 and 37 °C) up to 30 days. This study introduced a new approach to formulating SEDDS by utilizing the solubilizing capacity of SFN and introduced high throughput screening approach to formulation development and stability study.


Assuntos
Curcumina/química , Sistemas de Liberação de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Isotiocianatos/química , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos
15.
Int J Pharm ; 536(1): 146-157, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29195915

RESUMO

Vitamin E TPGS is a tocopherol (α-T) based nonionic surfactant that was used in the formulation of the Tocosol™ paclitaxel nanoemulsion, which was withdrawn from phase III clinical trials. Unlike tocopherols, however, the tocotrienol (T3) isomers of vitamin E were found to have innate anticancer activity and were shown to potentiate the antitumor activity of paclitaxel. The primary objective of the present study was therefore to develop a paclitaxel nanoemulsions by substituting α-T oil core of Tocosol™ with γ-T3 in, and vitamin E TPGS with PEGylated γ-T3 as the shell, and test the nanoemulsions against Bx-PC-3 and PANC-1 pancreatic tumor cells. A secondary objective was to test the activity of paclitaxel when directly conjugated with the γ-T3 isomer of vitamin E. The synthesis of the conjugates was confirmed by NMR and mass spectroscopy. Developed nanoemulsions were loaded with free or lipid conjugated paclitaxel. Nanoemulsions droplets were <300 nm with fastest release observed with formulations loaded with free paclitaxel when γ-T3 was used as the core. Substituting α-T with γ-T3 was also found to potentiate the anticancer activity of the nanoemulsions. Although marginal increase in activity was observed when nanoemulsions were loaded with free paclitaxel, a significant increase in activity was observed when lipid conjugates were used. The results from this study suggest that the developed paclitaxel nanoemulsions with either γ-T3, PEGylated γ-T3, or paclitaxel lipid conjugates may represent a more promising option for paclitaxel delivery in cancer chemotherapy.


Assuntos
Emulsões/química , Lipídeos/química , Nanopartículas/química , Paclitaxel/química , Tocotrienóis/química , Antineoplásicos/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Humanos , Polietilenoglicóis/química , Vitamina E/química
16.
Int J Pharm ; 536(1): 187-198, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-29195916

RESUMO

Paclitaxel (PTX) and docetaxel (DTX) are highly effective chemotherapeutic agents against breast cancer cells. Existing PTX and DTX formulations, however, contain excipients that result in a multitude of side-effects. The objective of the present study was to develop novel self-microemulsifying formulations of PTX and DTX with significantly lower excipient content by utilizing the high solubility of taxanes in sulforaphane (SFN). SFN-enabled microemulsions were developed by a screening process in which optical microscopy and absorbance data were used to monitor the physical stability of the dispersions. Optimized formulations contained vitamin E TPGS and transcutol to aid in taxane dissolution in water and the formation of transparent microemulsions (< 20 nm). SFN microemulsions were stable in different dilution media and storage temperatures and had no hemolytic effect on RBCs. When tested in vitro against MDA-MB-231 and MCF7 cancer cells by IncuCyte® live cell analysis and CellTiter-Blue® assay, taxanes/SFN microemulsions showed similar activity as the commercial taxanes injection solutions. SFN was only found to potentiate the activity of taxanes when used at high concentrations. This study highlighted the unique properties of SFN and its potential use in reformulating taxanes with high drug load and significantly lower excipient content than the commercial products.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Emulsões/administração & dosagem , Emulsões/química , Isotiocianatos/administração & dosagem , Isotiocianatos/química , Taxoides/administração & dosagem , Taxoides/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Docetaxel , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Feminino , Humanos , Células MCF-7 , Paclitaxel/administração & dosagem , Paclitaxel/química , Solubilidade/efeitos dos fármacos
17.
J Texture Stud ; 49(1): 30-37, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28776678

RESUMO

Medicated chewing gum tablets (CGTs) represent a unique platform for drug delivery. Loading directly compressible gums with high concentrations of powdered medication, however, results in compacts with hybrid properties between a chewable gum and a brittle tablet. The aim of the present study was to develop textural tests that can identify the point at which CGTs begin to behave like a solid tablet upon drug incorporation. Curcumin (CUR) CGTs made with Health in gum were prepared with increasing CUR load from 0 to 100% and were characterized for their mechanical properties by a single-bite (knife) and a two-bite tests. From each test several parameters were extracted and correlated with drug loading. In the single-bite test, the change in the resistance of the compacts to plastic deformation was found to give a definitive guide on whether they behave as gums or tablets. A more in depth analysis of the impact of CUR loading on the chewability of the CGTs was provided by the two-bite test where CUR loading was found to have a nonlinear impact on the mechanical properties of compacts. An upper limit of 10% was found to yield compacts with gum-like properties, which were abolished at higher CUR loads. The textural test procedure outlined in this study are expected to assist those involved in the formulation of medicated gums for pharmaceutical applications in making an informed decision on the impact of drug loading on gum behavior before proceeding with clinical testing. PRACTICAL APPLICATIONS: There is a growing interest in utilizing medicated chewing gums for drug delivery, especially those made using directly compressible gum bases, such as Health in gum. Directly compressing a gum base with high amounts of solid drug powder, however, poses a challenge as it may result in compressed compacts with hybrid properties between a chewing gum and a hard tablet. Currently, official Pharmacopeias do not specify a testing procedure for the estimation of the mechanical and textural properties of chewing gum tablets. To fill in the knowledge gap, we demonstrated in the present study how complementing a single-bite (knife) test with a modified two-bite test could be used to discriminate between chewing gums and hard tablets that were prepared by directly compressing Health in gum base with increasing concentration of curcumin powder in the blend. By utilizing these two tests, it was possible to identify clear demarcations between conventional tablets and chewing gums. In this study, we found that a 10% load by weight is the upper limit for curcumin loading in a binary blend with Health in gum to maintain the mastication properties of the compacts, which become brittle tablets at 30% load.


Assuntos
Goma de Mascar/análise , Sistemas de Liberação de Medicamentos/métodos , Comprimidos/química , Química Farmacêutica/métodos , Força Compressiva , Saliva Artificial , Tecnologia Farmacêutica
18.
Int J Pharm ; 529(1-2): 75-86, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28627454

RESUMO

The anticancer activity of water soluble methoxy polyethylene glycol (mPEG) derivatives of tocotrienol (T3) isomers of vitamin E was previously found to be reduced when compared to the parent free isomers. This could be due to the ester bond formation between the mPEG and the 6-OH group on the chroman moiety of the T3 isomer. To further investigate, the objectives of the current study were to (1) synthesize and characterize stable amide and cleavable hydrazone conjugates between mPEG and carbon-5 on the chroman moiety of T3, and (2) examine the cytotoxicity of the newly synthesized mPEG conjugates against breast (MCF-7 and MDA-MB-231) and pancreatic (BxPC-3 and PANC-1) cancer cells. Conjugates were synthesized by direct conjugation of succinyl chloride derivatives of mPEG to the α-tocopherol and γ-tocotrienol isomers of vitamin E, and were characterized by 1H NMR, FT-IR, and mass spectrometry. The micelles of the amide and hydrazone self-assembled conjugates were characterized for size, zeta, CMC, and stability at different pH media. The hydrolysis of the hydrazone conjugate was pH dependent with highest release at acidic (pH 5.5) conditions, whereas the amide conjugate was stable in all tested media. The amide conjugate nonetheless showed greater cytotoxicity than the hydrazone conjugate, which suggested that maintaining solubility and the presence of free 6-OH group are important for γ-T3 to exert anticancer activity in vitro. The results from the current study demonstrated the importance of considering the nature of the chemical bond between T3 and mPEG when designing functional ingredients for use in drug delivery.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Cromanos/farmacologia , Portadores de Fármacos/química , Hidrazonas/farmacologia , Vitamina E/análogos & derivados , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Micelas , Polietilenoglicóis/química , Espectroscopia de Infravermelho com Transformada de Fourier , Vitamina E/farmacologia
19.
Int J Pharm ; 528(1-2): 463-470, 2017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28627455

RESUMO

Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the γ-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienol isomers of vitamin E can potentiate the anticancer activity of gemcitabine. To accomplish this objective, a full synthesis scheme for gemcitabine conjugation to fatty acids (stearic and linoleic) and the tocopherol and tocotrienol isomers of vitamin E (α-T and γ-T3) was presented. The conjugates were characterized by 1H NMR and mass spectrometry analysis and tested for their susceptibility to deamination. Also discussed is the impact of entrapping the conjugates into nanoemulsions on the physiochemical properties of the delivery system and the in vitro anticancer activity of gemcitabine against Bx-PC-3 and PNAC-1 pancreatic cancer cells. In-vitro enzymatic deamination study showed that the γ-T3 conjugate of gemcitabine was least affected by deamination deactivation reaction when compared with the free and conjugated gemcitabine in solution. Furthermore, in-vitro cytotoxicity study demonstrated that entrapment of gemcitabine-lipid conjugates into nanoemulsions significantly enhanced their anticancer activity when compared to the free drug. It was concluded that conjugation to the γ-T3 isomer is a viable option for gemcitabine delivery and is worthy of further investigation.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Nanopartículas/química , Vitamina E/farmacologia , Linhagem Celular Tumoral , Cromanos , Desaminação , Desoxicitidina/farmacologia , Humanos , Tocotrienóis , Vitamina E/análogos & derivados
20.
Int J Pharm ; 520(1-2): 173-180, 2017 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-28167265

RESUMO

One approach to enhance curcumin (CUR) aqueous solubility is to use cyclodextrins (CDs) to form inclusion complexes where CUR is encapsulated as a guest molecule within the internal cavity of the water-soluble CD. Several methods have been reported for the complexation of CUR with CDs. Limited information, however, is available on the use of the autoclave process (AU) in complex formation. The aims of this work were therefore to (1) investigate and evaluate the AU cycle as a complex formation method to enhance CUR solubility; (2) compare the efficacy of the AU process with the freeze-drying (FD) and evaporation (EV) processes in complex formation; and (3) confirm CUR stability by characterizing CUR:CD complexes by NMR, Raman spectroscopy, DSC, and XRD. Significant differences were found in the saturation solubility of CUR from its complexes with CD when prepared by the three complexation methods. The AU yielded a complex with expected chemical and physical fingerprints for a CUR:CD inclusion complex that maintained the chemical integrity and stability of CUR and provided the highest solubility of CUR in water. Physical and chemical characterizations of the AU complexes confirmed the encapsulated of CUR inside the CD cavity and the transformation of the crystalline CUR:CD inclusion complex to an amorphous form. It was concluded that the autoclave process with its short processing time could be used as an alternate and efficient methods for drug:CD complexation.


Assuntos
Curcumina/química , Ciclodextrinas/química , Composição de Medicamentos/métodos , Temperatura Alta , Esterilização/métodos , Estabilidade de Medicamentos , Substâncias Macromoleculares/química , Solubilidade
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