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1.
Chem Pharm Bull (Tokyo) ; 69(8): 727-733, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334516

RESUMO

Recently, a novel humidifier that sprays water fine droplets equipped with a copolymer, poly(3,4-ethylene dioxythiophene)-poly(styrene sulfonate) (PEDOT/PSS) was developed. PEDOT/PSS in the humidifier absorbs water from the environment and releases fine water droplets by heating. In the present study, the effect of hydration on the skin barrier, stratum corneum, was first determined by the application of fine water droplets using the humidifier. The skin-penetration enhancement effect of a model hydrophilic drug, caffeine, was also investigated using the humidifier and compared with a conventional water-evaporative humidifier. More prolonged skin hydration effect was observed after application of the fine water droplet release humidifier using PEDOT/PSS than that using a conventional humidifier. In addition, markedly higher skin permeation of caffeine was observed in both infinite and finite dose conditions. Furthermore, higher skin permeation of caffeine from oil/water emulsion containing caffeine was observed in finite dose conditions by pretreatment with the humidifier using PEDOT/PSS. This device can provide water droplets without replenishing water, so it is more convenient for enhancing the skin permeation of chemical compounds from topical drugs and cosmetic formulations.


Assuntos
Cafeína/farmacologia , Umidificadores , Pele/efeitos dos fármacos , Administração Cutânea , Ar , Animais , Cafeína/administração & dosagem , Cafeína/química , Umidade , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Pelados , Absorção Cutânea/efeitos dos fármacos , Temperatura , Água/química
2.
Chem Pharm Bull (Tokyo) ; 69(8): 806-810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334526

RESUMO

Effect of rubbing application on the skin permeation of a hydrophilic drug caffeine (CAF) and lipophilic drug rhododendrol (RD) from lotion and cream were investigated. Skin permeation of CAF was markedly increased by rubbing action independent of the formulation type. In addition, the skin penetration-enhancement effect was affected by the rubbing direction: rubbing application against the direction of hair growth showed the highest permeation compared with rubbing applications along the direction of hair growth and in a circular pattern on the skin. On the other hand, no enhancement effect was observed by the rubbing actions on the skin permeation of RD, regardless of formulation type. Change in the infundibula orifice size of hair follicles by the rubbing and following skin stretching may be related to the higher skin permeation for CAF. In contrast, high RD distribution into the stratum corneum may be a reason why no enhancement effect was observed by the rubbing action. These results can be helpful to predict safety and effectiveness of topically applied formulations.


Assuntos
Butanóis/farmacologia , Cafeína/farmacologia , Pomadas/farmacologia , Creme para a Pele/farmacologia , Pele/efeitos dos fármacos , Animais , Butanóis/química , Cafeína/química , Interações Hidrofóbicas e Hidrofílicas , Pomadas/química , Permeabilidade/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Creme para a Pele/química , Suínos
3.
Chem Pharm Bull (Tokyo) ; 69(7): 639-645, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193712

RESUMO

The purpose of the present study was to evaluate whether iontophoresis (IP) accelerates the intradermal migration rate of medium molecular weight drugs. Sodium polystyrene sulfonate (PSA) and fluorescein isothiocyanate-dextran (FD) were used as model medium molecular weight acidic and non-electrolyte drugs, respectively. Low molecular weight acid and non-electrolyte drugs were also used for comparison. Drug-loaded excised split-layered skin (SL skin) was used in the experiment. SL skin was prepared using (i) whole skin was split once, (ii) the drug solution was applied on the lower skin, and (iii) the upper skin was layered onto the lower skin containing the drug solution as in the original skin. The effect of constant-current cathodal or anodal IP was applied to the SL skin, and the time course of the cumulative amount of drug migration from the SL skin through the dermis to the receiver was followed. In cases without IP and with anodal IP, the intradermal migration rates of medium molecular weight drugs were much lower than those of small molecules. The driving force for drug migration was thought to be simple diffusion through the skin layer. In contrast, cathodal IP significantly increased the intradermal migration rate of PSA not but of FD or low molecular weight drugs. This IP-facilitated migration of PSA was probably due to electrorepulsion. These results suggest that IP can be used to increase the intradermal migration of medium molecular weight charged drugs.


Assuntos
Dextranos/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Iontoforese/métodos , Poliestirenos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Dextranos/análise , Fluoresceína-5-Isotiocianato/análise , Fluoresceína-5-Isotiocianato/metabolismo , Fluorometria , Peso Molecular , Poliestirenos/análise , Absorção Cutânea , Suínos
4.
Chem Pharm Bull (Tokyo) ; 69(7): 674-680, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193716

RESUMO

Quality by design (QbD) is an essential concept for modern manufacturing processes of pharmaceutical products. Understanding the science behind manufacturing processes is crucial; however, the complexity of the manufacturing processes makes implementing QbD challenging. In this study, structural equation modeling (SEM) was applied to understand the causal relationships between variables such as process parameters, material attributes, and quality attributes. Based on SEM analysis, we identified a model composed of the above-mentioned variables and their latent factors without including observational data. Difficulties in fitting the observed data to the proposed model are often encountered in SEM analysis. To address this issue, we adopted Bayesian estimation with Markov chain Monte Carlo simulation. The tableting process involving the wet-granulation process for acetaminophen was employed as a model case for the manufacturing process. The results indicate that SEM analysis could be useful for implementing QbD for the manufacturing processes of pharmaceutical products.


Assuntos
Análise de Classes Latentes , Comprimidos/química , Acetaminofen/química , Teorema de Bayes , Composição de Medicamentos/métodos , Cadeias de Markov , Método de Monte Carlo , Análise de Componente Principal
5.
Toxicol In Vitro ; 75: 105197, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34062233

RESUMO

Following the global trend of reducing animal testing, various reconstructed human epidermis (RHE) models for skin irritation test (SIT) have been developed, verified, validated and included in OECD TG 439. We developed a new RHE called EPiTRI and a SIT method using EPiTRI (EPiTRI-SIT model) following the OECD guidelines. EPiTRI possesses morphological, biochemical and physiological properties similar to human epidermis with well-differentiated multilayered viable cells with barrier function. The EPiTRI-SIT model was tested for 20 reference chemicals in Performance Standard of OECD TG 439 (GD 220), showing good predictive capacity with 100% sensitivity, 70% specificity and 85% accuracy. EPiTRI had sensitivity in detecting di-n-propyl disulphate, as an irritant chemical (UN GHS Category 2), whereas most validated reference methods detected it as a non-irritant. An international validation study of EPiTRI-SIT was conducted in four laboratories to confirm the within- and between-laboratory reproducibility, as well as predictive capacity. The phase I/II within-laboratory and between-laboratory reproducibility was 100%/95% and 95%, respectively. The overall sensitivity, specificity and accuracy of EPiTRI-SIT was 96%, 70% and 83%, respectively, which fulfilled the OECD criteria. Thus, EPiTRI, meets the criteria of Performance Standards of OECD TG 439 (GD 220) and is suitable for screening irritating chemicals in vitro.

6.
Chem Pharm Bull (Tokyo) ; 69(5): 481-487, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952857

RESUMO

Ionic liquid (IL) was prepared by mixing lidocaine and ibuprofen as a cation and anion, respectively, at various ratios. We determined the permeation of both compounds from the IL through a silicone membrane selected as a model biological membrane, and mathematically analyzed the permeation data from the viewpoint of the thermodynamic activities of lidocaine, ibuprofen, and the IL. As a result, IL and ibuprofen diffusely permeated through the membrane in the case of applying IL preparations with a molar fraction of ibuprofen of 0.5 or higher. The IL was thought to separate into lidocaine and ibuprofen in the receiver. On the other hand, when applying IL preparations with a molar fraction of lidocaine of 0.5 or higher, IL and lidocaine permeated. The permeation rate of IL itself was maximized when the applied IL was prepared using equimolar amounts of lidocaine and ibuprofen, and it decreased when the fraction of lidocaine or ibuprofen increased by more than 0.5. Their membrane permeation rates increased with an increase in their activity, and no more increase was found when the drugs were saturated in the IL. These membrane permeation profiles reflected well the mathematically calculated ones according to the concept of activity.


Assuntos
Ibuprofeno/química , Líquidos Iônicos/química , Lidocaína/química , Silicones/química , Termodinâmica , Ânions , Cátions , Líquidos Iônicos/síntese química , Estrutura Molecular
7.
Pharm Res ; 38(3): 503-513, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33638122

RESUMO

PURPOSE: Non-lamellar liquid crystal (NLLC)-forming lipids have gained attention as a novel component because of their ability to self-assemble upon contact with body fluids. In this study, a novel NLLC-forming lipid, mono-O-(5, 9, 13-trimethyl-4-tetradecenyl) glycerol ester (C17MGE), and a model drug with a middle molecule weight, leuprolide acetate (LA), were used to confirm the usefulness of C17MGE as an excipient for depot formulations with sustained release properties. METHODS: A self-constructed depot formulation was prepared by mixing C17MGE and different types of phospholipids. The constructed NLLC structure was evaluated using small angle X-ray analysis and cryo-transmission electron microscopy. In vitro release and blood concentration profiles of LA were investigated. RESULTS: The NLLC structure was confirmed by small angle X-ray analysis. LA release was able to be modified by adding different ratios of various phospholipids to C17MGE. Formulations containing 1, 2-dioleoyl-sn-glycero-3-phosphoglycerol sodium salt with a mixing ratio of 12% or 24% (MDOPG12 or MDOPG24, respectively) exhibited sustained release profiles of LA. In addition, the blood concentration of LA was detected over 21 days or more after administration of MDOPG12, and the absolute bioavailability was calculated to be about 100%. CONCLUSIONS: A depot formulation using C17MGE was useful to achieve sustained release of LA.

8.
Pharm Res ; 38(2): 289-299, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33515137

RESUMO

PURPOSE: Penetration enhancers are necessary to overcome a formidable barrier function of the stratum corneum in the development of topical formulations. Recently, non-lamella liquid crystal (NLLC)-forming lipids such as glycerol monooleate and phytantriol (PHY) are gaining increasing attention as a novel skin permeation enhancer. In the present study, fluorescein sodium (FL-Na) was used as a model hydrophilic drug, and acryl-base pressure-sensitive adhesive (PSA) tape containing NLLC forming lipids, mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE) or PHY, was prepared to enhance drug permeation through the skin. METHODS: A PSA patch containing FL-Na was prepared by mixing FL-Na entrapped in NLLC and acrylic polymer. FL permeation through excised hairless rat skin, and also human skin, was investigated. Changes in lipid structure, folding/unfolding state of keratin in the stratum corneum, and penetration of MGE into the stratum corneum were investigated using confocal Raman microscopy. RESULTS: Enhanced FL permeation was observed by the application of a PSA patch containing MGE and PHY. Especially, dramatically enhancement effect was confirmed by 15% of MGE contained formulation. Penetration of MGE provided diminished orthorhombic crystal structure and a peak shift of the aliphatic CH3 vibration of keratin chains toward lower wavenumbers. CONCLUSION: The present results suggested that the formulation development by adding MGE may be useful for improving the skin permeation of mal-permeable drugs such as hydrophilic drugs.

9.
Chem Pharm Bull (Tokyo) ; 68(11): 1025-1033, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132369

RESUMO

We examined the physicochemical and biochemical properties of mono-O-(5,9,13-trimethyl-4-tetradecenyl)glycerol ester (MGE), including ease of handling, high bioadhesiveness, quick and stable in vivo self-organization (forming a non-lamellar lyotropic liquid crystal [NLLC]), and high biomembrane permeation enhancement. We prepared MGE oral mucosa-applied spray preparations containing triamcinolone acetonide (TA), which is widely used in the treatment of stomatitis, and we examined the usefulness of the MGE preparations compared with commercially available oral mucosal application preparations containing 2,3-dihydroxypropyl oleate (1-mono(cis-9-octadecenoyl)glycerol (GMO) (previously studied as an NLLC-forming lipid) preparation. As a result, the MGE preparation applied to the oral mucosa can rapidly formed an NLLC with reverse hexagonal or cubic structures, or a mixture, on contact with water. In addition, by adding hydroxypropyl cellulose to the MGE preparation, similar retention properties on the oral mucous membrane were obtained to that using marketed drug preparations. Furthermore, the MGE spray formulation on the oral mucosa showed an equivalent or higher TA release as well as oral mucous membrane permeability compared with commercial formulations. Because MGE forms a stable NLLC and is easy to handle compared with GMO, MGE was considered to be a useful pharmaceutical additive for a spray preparation applied to the oral mucosa in combination.


Assuntos
Composição de Medicamentos/métodos , Lipídeos/química , Cristais Líquidos/química , Mucosa Bucal/metabolismo , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Glicerol/química , Lipídeos/farmacologia , Masculino , Mucosa Bucal/efeitos dos fármacos , Ratos , Ratos Pelados , Triancinolona Acetonida/química , Triancinolona Acetonida/farmacologia
10.
Chem Pharm Bull (Tokyo) ; 68(9): 832-836, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879223

RESUMO

Rubbing actions are often conducted to apply topical formulations onto the skin. Although rubbing was found to increase the skin permeation of drugs, few reports have revealed whether rubbing enhanced either drug permeation through the stratum corneum (SC) or hair follicles (HFs) pathways, or through both. In the present study, we investigated the effects of rubbing on caffeine (CAF) distribution in the SC and HFs. The effect of rubbing direction on the skin penetration of CAF was also investigated. The skin concentration of CAF and its cumulative permeation amount were increased clearly by rubbing. More than six times higher CAF concentrations in the viable epidermis and dermis were observed 5 min after rubbing application compared with no rubbing. On the other hand, slightly increased CAF concentrations were observed in the SC, suggesting that CAF was delivered through the HF pathway by rubbing. Rubbing against the natural hair direction provided the highest skin permeation as well as skin concentrations. Changes in the morphology of the HF opening area might be related to the enhancement effect. These results may provide useful information to understand the effect of rubbing on the skin permeation of applied drugs.


Assuntos
Cafeína/química , Folículo Piloso/química , Pele/química , Administração Cutânea , Animais , Permeabilidade , Absorção Cutânea , Suínos
11.
Chem Pharm Bull (Tokyo) ; 68(8): 779-783, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741920

RESUMO

Tranilast, a lipophilic drug with various ophthalmic applications, was used as a model drug to establish the possibility of delivering lipophilic drugs through the eyelid skin. Pharmacokinetics and tissue distribution studies were conducted employing three application methods (topical application onto eyelid skin, eye drops, and intravenous injection in rats) to broaden the significance of delivering drugs through the eyelids. A two-compartment open model analysis was used for intravenous route while a non-compartmental evaluation was used for topical applications to estimate the pharmacokinetic parameters. Eyelid skin application, eye drops, and intravenous administration had mean residence times (MRTs) of 8.07, 1.79, and 3.25 h in the eyeball and 10.8, 1.29, and 2.97 h in the conjunctiva, correspondingly. In the eyeball, topical application of tranilast onto the eyelids corresponded to a 4.5- and 2.5-fold higher MRT compared with eye drops and intravenous administration, respectively. An 8.4- or 3.6-fold higher MRT was observed in the conjunctiva after topical application compared with eye drops or intravenous administration, respectively. This indicated a gradual penetration of tranilast into the eyeball and conjunctiva, subsequently a slow elimination from these target tissues.


Assuntos
Pele/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Administração Intravenosa , Administração Tópica , Animais , Cromatografia Líquida de Alta Pressão , Túnica Conjuntiva/metabolismo , Portadores de Fármacos/química , Pálpebras/metabolismo , Meia-Vida , Masculino , Soluções Oftálmicas/química , Soluções Oftálmicas/farmacocinética , Soluções Oftálmicas/farmacologia , Ratos , Ratos Pelados , Pele/metabolismo , Espectrometria de Massas em Tandem , Distribuição Tecidual , ortoaminobenzoatos/sangue , ortoaminobenzoatos/farmacocinética
12.
J Control Release ; 325: 1-9, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32598958

RESUMO

Intranasal administration is poised as a competent method in delivering drugs to the brain, because the nasal route has a direct link with the central nervous system bypassing the formidable blood-brain barrier. C17-monoglycerol ester (MGE) and glyceryl monooleate (GMO) as liquid crystal (LC)-forming lipids possess desirable formulation characteristics as drug carriers for intranasally administered drugs. This study investigated the effect of LC formulations on the pharmacokinetics of tranilast (TL), a lipophilic model drug, and its distribution in the therapeutic target regions of the brain in rats. The anatomical biodistribution of LC formulations was monitored using micro-computed tomography tandem in vivo imaging systems. MGE and GMO effectively formed LC with suitable particle size, zeta potential, and viscosity supporting the delivery of TL to the brain. MGE and GMO LC formulations enhanced brain uptake by 10- to 12-fold and 2- to 2.4- fold, respectively, compared with TL solution. The olfactory bulb had the highest TL concentration and fluorescent signals among all the brain regions, indicating a direct nose-to-brain delivery pathway of LC formulations. LC-forming lipids, MGE and GMO, are potential biomaterials in formulations intended for intranasal administration.


Assuntos
Cristais Líquidos , Administração Intranasal , Animais , Encéfalo/diagnóstico por imagem , Sistemas de Liberação de Medicamentos , Ratos , Distribuição Tecidual , Microtomografia por Raio-X , ortoaminobenzoatos
13.
Pharmaceutics ; 12(5)2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384778

RESUMO

: A highly viscous substance was prepared by evaporating an ethanol solution containing two hydrophilic vitamins; vitamin C, and vitamin B6. The viscous substance and physical mixture of the two vitamins were tested using a differential scanning calorimeter and an X-ray diffractometer. The highly viscous substance was found to be a liquid crystal (LC) made of these two hydrophilic vitamins. Determination by proton nuclear magnetic resonance measurement suggested that intramolecular hydrogen bonding in vitamin B6 was eliminated by the LC formation. This LC compound showed high solubility in 1,3-butanediol (almost 87%). Much higher skin permeation of both vitamin C and B6 was also observed from the LC compound than that from the physical mixture. The present LC compound containing vitamin C and vitamin B6 may be useful for pharmaceutical and cosmeceutical applications.

14.
Int J Pharm ; 578: 119186, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32112931

RESUMO

Finite dose experiments represent clinical use wherein depletion of dose, evaporation of excipients, and gradual change in vehicle composition may occur. In the present study, we attempted a mathematical approach for predicting skin permeation and concentration of a cosmetic active, rhododendrol (RD), from complex vehicle-based formulations applied in finite dose. In vitro skin permeation and concentration studies of RD were conducted from formulations containing water and polyols with concentrations ranging from 10 to 100% under infinite and finite dose conditions using vertical Franz diffusion cells. Observed data for skin permeation and the viable epidermis and dermis (VED) concentration of RD were estimated by the differential equations under Fick's second law of diffusion together with water evaporation kinetics and changes in the partition coefficient from vehicles to the stratum corneum. As a result, a goodness-of-fit was observed allowing accurate estimation of skin permeation and VED concentration of RD. This mathematical approach could become a useful tool to estimate the skin permeation and concentration of actives from topical formulation applied in finite dose conditions likened in actual use.


Assuntos
Butanóis/metabolismo , Cosméticos/metabolismo , Derme/metabolismo , Epiderme/metabolismo , Administração Cutânea , Animais , Química Farmacêutica/métodos , Difusão/efeitos dos fármacos , Cinética , Permeabilidade , Polímeros/metabolismo , Absorção Cutânea/fisiologia , Suínos , Água/metabolismo
15.
Pharmaceutics ; 12(2)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32092954

RESUMO

The ban on the use of animals in testing cosmetic products has led to the development of animal-free in vitro methods. Strat-M® is an artificial membrane engineered to mimic human skin and is recommended as a replacement for skin. However, its usefulness in the assessment of the permeation of cosmetics in in-use conditions remains unverified. No data have been published on its comparative performance with the membrane of choice, porcine skin. The comparative permeability characteristics of Strat-M® and porcine skin were investigated using Franz diffusion cells. Caffeine (CF) and rhododendrol (RD) in complex vehicles with varying concentrations of polyols were applied as finite and infinite doses. Good rank orders of permeation from finite dose experiments were observed for RD. High correlations were observed in RD permeation between Strat-M® and porcine skin under finite and infinite dose conditions, whereas only finite dose conditions for CF were associated with good correlations. Permeation from formulations with high polyol content and residual formulations was enhanced due to the disruption of the integrity of the Strat-M® barrier. The usefulness of Strat-M® in the assessment of dermal permeation may be limited to finite dose conditions and not applicable to infinite dose conditions or formulations applied in layers.

16.
Int J Pharm ; 577: 118944, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31870952

RESUMO

Skin offers an easily accessible and convenient site for the administration of drugs. Therefore, the development of injectable formulations with controlled drug release properties are now expected to deliver middle- and large-size biomolecules. In the present study, formulations mainly composed of a novel polyol ester with an isoprenoid side chain; mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE), that was capable of forming a non-lamellar liquid crystal (NLLC), were prepared with different types of phospholipid. Then, factors that affected the release of a model entrapped drug, fluorescein-isothiocyanate dextran (FD-4, M.W. 4,000), from the MGE formulations were analyzed with multi-regression analysis. In addition, self-assembly of the NLLC structure was investigated using small-angle X-ray scattering analysis after contacting the MGE formulations with water. NLLC-forming ability of the formulations after s.c. injection into rats was also confirmed using microscopic observations. FD-4 concentrations in blood were determined after s.c. injection of the MGE formulations. The injectable MGE formulations successfully constructed NLLC structures to form a sponge-like gel after contact with water in vitro and in vivo (in rats) as well. In in vitro conditions, the amount of FD-4 released from the formulations was altered by changing the type and concentration of phospholipid in the MGE formulations and can be expressed with parameters such as MGE content and interplanar spacing of the NLLC. A significantly sustained FD-4 level in the blood was observed after s.c. injection of the formulations. These results suggested that injectable MGE formulations may have the potential to achieve controlled release profiles of drugs after s.c. injection.


Assuntos
Ésteres/química , Glicerol/química , Cristais Líquidos/química , Fosfolipídeos/química , Animais , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Fluoresceínas/administração & dosagem , Fluoresceínas/química , Interações Hidrofóbicas e Hidrofílicas , Injeções Subcutâneas , Masculino , Ratos
17.
AAPS PharmSciTech ; 20(7): 264, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342293

RESUMO

The humidity was a well-known method to hydrate the skin; however, the published data were varied, and systemic experiments in the previous papers were few. Therefore, the in vitro permeation of excised porcine ear skin by drugs with different polarities [aminopyrine (AMP), antipyrine (ANP), methylparaben (MP), and ibuprofen (IP)] was analyzed under a constant skin surface temperature with different temperatures and humidities to reveal the effects of temperature and humidity on the skin permeation enhancement effects. Applied formulations were prepared by mixing the drug and a hydrophilic vehicle containing glycerin. The disposition-distance profiles of water and the humectant glycerin in the stratum corneum were also investigated using confocal Raman microscopy. High absolute humidity (AH) significantly contributed to the high skin penetration of the hydrophilic penetrants AMP, ANP, and MP but not the hydrophobic penetrant IP. An increase in the partition parameter and a decrease in the diffusivity parameter occurred with an increase in AH, independent of drug polarity. Moreover, we found that dew condensation induced by high AH on temperature-controlled skin surface may effectively increase water content and may provide higher glycerin distribution in the skin barrier, the stratum corneum. Increasing the amount of water and hydrophilic vehicles such as glycerin in the stratum corneum may enhance the permeation of hydrophilic penetrants AMP, ANP, and MP. These data suggested a dew condensation on the skin surface induced by high AH at a constant skin surface temperature would be important to enhance hydrophilic penetrants.


Assuntos
Absorção Cutânea , Pele/metabolismo , Temperatura , Aminopirina/farmacocinética , Animais , Antipirina/farmacocinética , Epiderme , Umidade , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/farmacocinética , Parabenos/farmacocinética , Suínos
18.
J Pharm Sci ; 108(9): 2942-2948, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31002809

RESUMO

Extending the delivery of drugs into the eyes while reducing systemic bioavailability is of utmost importance in the management of chronic ocular diseases. Topical application onto the lower eyelid skin, as an alternative to eye drops, is seen to be a valuable strategy in the treatment of chronic eye diseases. To elucidate the critical value of delivering drugs in solution onto the eyeball through the eyelid skin, pharmacokinetic studies of pilocarpine were conducted, and the results were verified using a direct pharmacodynamic study in rats. The mean residence time of pilocarpine after topical eyelid application to the eyelid skin, conjunctiva, eyeball, and plasma were 14.9, 8.50, 6.29, and 8.11 h, respectively. Conjunctiva and eyeball concentrations of pilocarpine at 8 h were 80-fold and 8-fold higher after topical eyelid application, respectively, than those for eye drops. Pupillary constriction was sustained over 8 h after topical eyelid application. Topical eyelid skin application exhibited a localized drug absorption and specific drug accumulation in the ocular tissues. Hence, it is rational to prepare topical formulations directed onto the eyelid skin, which is suitable for drugs required for long-term treatment.


Assuntos
Agonistas Muscarínicos/farmacocinética , Soluções Oftálmicas/farmacocinética , Pilocarpina/farmacocinética , Administração Cutânea , Administração Intravenosa , Administração Oftálmica , Animais , Túnica Conjuntiva/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Pálpebras/metabolismo , Masculino , Agonistas Muscarínicos/administração & dosagem , Agonistas Muscarínicos/efeitos adversos , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/efeitos adversos , Pilocarpina/administração & dosagem , Pilocarpina/efeitos adversos , Ratos , Pele/metabolismo , Distribuição Tecidual
19.
Int J Pharm ; 565: 41-49, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31022503

RESUMO

The aim of the present study was to assess the potential of biocompatible polymeric nanosheets as topical and transdermal drug-delivery devices. Nanosheets are two-dimensional nanostructures with a thickness in the nanometer order, and their extremely large aspect ratios result in unique properties, including high transparency, flexibility, and adhesiveness. Nanosheet formulations containing betamethasone valerate (BV) as a model drug and consisting of poly (L-lactic acid) or poly (lactic-co-glycolic) acid were fabricated through a spin-coating-assisted layer-by-layer method using a water-soluble sacrificial membrane. The fabricated formulations could incorporate and release higher amounts of BV compared with a commercial ointment, and the amounts could be controlled by the polymers used, the amount of BV added, and the use of controlled-release membranes. The presence of BV had a minimal effect on thickness, transparency, adhesiveness, and moisture permeability of nanosheets, permitting their application to any area of skin for a long period of time. Therefore, this biocompatible polymeric nanosheet formulation represents a novel and promising topical and transdermal drug delivery device, which has potential to deliver drugs regardless of the area of skin.


Assuntos
Sistemas de Liberação de Medicamentos , Nanoestruturas/administração & dosagem , Poliésteres/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Administração Tópica , Adulto , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Valerato de Betametasona/administração & dosagem , Valerato de Betametasona/química , Liberação Controlada de Fármacos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/química , Humanos , Masculino , Nanoestruturas/química , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos Pelados , Pele/metabolismo , Suínos , Adulto Jovem
20.
J Toxicol Sci ; 44(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30626775

RESUMO

Cosmetics containing rhododendrol (RD) were voluntarily recalled after incidents of leukoderma related to their use. Users reported using up to five different RD-containing products by layered application. In this study, we investigated the effects of layered application, formulations, and their components on the skin permeation of cosmetics containing RD. Experiments were designed to simulate actual in-use conditions, such as varying application volumes, physical mixing of formulations, sequence of cosmetics application and time interval between applications, to establish their effect on the skin permeation of RD. Milk and lotion RD-containing cosmetics (2%), 1% aqueous RD, and preparations of formulation components were applied as the first or second layers as finite doses of 10 or 20 µL/cm2. Permeation experiments were performed through excised porcine ear skin using Franz diffusion cells with an effective diffusion area of 1.77 cm2. Cosmetics applied by layered application exhibited lower skin permeation of RD compared with a single application despite having the same application dose. High initial volume (20 µL at 0 or 5 sec) did not exhibit any significant reduction in the permeation of RD. Formulations and their components caused varying reductions in RD permeation, probably due to changes in thermodynamic activity of the active component. Layered application, formulation components, application volume, time interval and sequence of application had significant influences on the skin permeation of the active component. Moreover, this study established a method of investigating the influence of formulations and their components on the skin permeation of actives after layered application.


Assuntos
Butanóis/administração & dosagem , Cosméticos/administração & dosagem , Absorção Cutânea , Administração Cutânea , Animais , Butanóis/química , Composição de Medicamentos , Técnicas In Vitro , Pele/metabolismo , Suínos
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