Chemical Enhancers for the Absorption of Substances Through the Skin: Laurocapram and Its Derivatives

ABSTRACT

Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components (lipids or proteins) or by increasing the membrane/vehicle partition coefficient. This article presents the results of biophysical and permeability studies performed with Laurocapram and its analogues. As shown, Laurocapram and its analogues present different enhancing efficacies, for most of both hydrophilic and lipophilic substances. The enhancing effect of Laurocapram (Azone®) is attributed to different mechanisms, such as insertion of its dodecyl group into the intercellular lipidic bilayer, increase of the motion of the alkylic chains of lipids, and fluidization of the hydrophobic regions of the lamellate structure. Toxicological studies reveal a low toxicity for Laurocapram, and for some derivatives, a relationship exists between toxicity and the number of carbons in the alkylic chain. Very important, when applied to human skin, Laurocapram shows a minimal absorption, being quickly eliminated from circulation. However, although Laurocapram and its derivatives have been shown to provide enhancement, they have not been widely accepted because of their suspected pharmacological activity or questions about their safety.     

Effect of borneol on the transdermal permeation of drugs with differing lipophilicity and molecular organization of stratum corneum lipids

The aim of the present paper was to investigate the promoting activity of borneol on the transdermal permeation of drugs with differing lipophilicity, and probe its alterations in molecular organization of stratum corneum (SC) lipids. The toxicity of borneol was evaluated in epidermal keratinocyte HaCaT and dermal fibroblast CCC-HSF-1 cell cultures and compared to known enhancers, and its irritant profile was also assessed by transepidermal water loss (TEWL) evaluation. The promoting effect of borneol on the transdermal permeation of five model drugs, namely 5-fluorouracil, antipyrine, aspirin, salicylic acid and ibuprofen, which were selected based on their lipophilicity denoted by logp value, were performed using in vitro skin permeation studies. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to monitor the borneol-induced alteration in molecular organization of SC lipids. The enhancer borneol displayed lower cytotoxicity or irritation in comparison to the well-established and standard enhancer Azone. Borneol could effectively promote the transdermal permeation of five model drugs, and its enhancement ratios were found to be parabolic curve with the logp values of drugs, which exhibited the optimum permeation activity for relatively hydrophilic drugs (an estimated logp value of??0.5 ～0.5). The molecular mechanism studies suggested that borneol could perturb the structure of SC lipid alkyl chains, and extract part of SC lipids, resulting in the alteration in the skin permeability barrier.     

Comparative Permeability of Some Acyclovir Derivatives Through Native Mucus and Crude Mucin Dispersions

The permeability of some guanine derivatives (acyclovir [ACV], deoxyacyclovir [DCV], and their N-acetyl congeners) through native porcine mucus and crude porcine mucin dispersions (30% and 50% w/v) was investigated in two-compartment dialysis cells. High correlation between apparent permeability coefficients P_app of tested substances determined in these two models was observed, although the examined compounds permeated faster through the native mucus. It was also established that P_app values decrease with increasing hydrophilicity and molecular mass of the tested substances. Furthermore, the influence of some substances that affect mucus structure (cysteine, N-acetylcysteine [NCY], sodium taurocholate [ST], and sodium chloride) on the permeation rate of the examined compounds through mucus and mucin dispersions was examined. It was shown that the P_app values of guanine derivatives were generally lower after the addition of these substances to the native mucus and mucin dispersions, although the lowering effect was more pronounced in the case of native mucus.     

Comparative Permeability of Some Acyclovir Derivatives Through Native Mucus and Crude Mucin Dispersions

The permeability of some guanine derivatives (acyclovir [ACV], deoxyacyclovir [DCV], and their N-acetyl congeners) through native porcine mucus and crude porcine mucin dispersions (30% and 50% w/v) was investigated in two-compartment dialysis cells. High correlation between apparent permeability coefficients P_app of tested substances determined in these two models was observed, although the examined compounds permeated faster through the native mucus. It was also established that P_app values decrease with increasing hydrophilicity and molecular mass of the tested substances. Furthermore, the influence of some substances that affect mucus structure (cysteine, N-acetylcysteine [NCY], sodium taurocholate [ST], and sodium chloride) on the permeation rate of the examined compounds through mucus and mucin dispersions was examined. It was shown that the P_app values of guanine derivatives were generally lower after the addition of these substances to the native mucus and mucin dispersions, although the lowering effect was more pronounced in the case of native mucus.     

Caco-2 cells permeability evaluation of nifuroxazide derivatives with potential activity against methicillin-resistant Staphylococcus aureus (MRSA)

Throughout the period of evaluation and selection in drug development, the assessment of the permeability potential of a compound to achieve an efficient refinement of the molecular structure has been widely appraised by the transport of substances across cell monolayers. This study aims to develop in vitro assays through Caco-2 cells in order to analyze the permeability of 5-nitro-heterocyclic compounds analogues to nifuroxazide with antimicrobial activity, especially showing promising activity against multidrug-resistant Staphylococcus aureus (MRSA). Caco-2 cell monolayers cultivated for 21 days in Transwell® plates were used for the in vitro permeability assays. The quantification of the nifuroxazide derivatives in the basolateral chambers was performed by a validated high performance liquid chromatography with UV (HPLC-UV) method. Apparent permeability values (Papp) show that these compounds can be considered as new drug candidates with the potential to present high absorption in vivo, according to the classifications of Yee and Biganzoli. The thiophenic derivatives showed permeability values higher than the furanic ones, being AminoTIO the compound with the greatest potential for the development of a new drug against MRSA, since it showed the best cytotoxicity, permeability and solubility ratio among all the derivatives.     

Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle

Calcipotriol and betamethasone dipropionate are widely used effective treatments for psoriasis. Combined therapy is known to be superior to monotherapy, but current formulations do not permit simultaneous application as the drug substances will degrade when mixed. The purpose of the study was to develop a formulation which combines calcipotriol and betamethasone dipropionate in a single vehicle hereby achieving optimal delivery of both substances into the skin. As the two substances are incompatible in aqueous and alcoholic medias, different non-aqueous formulations were prepared. Skin permeation studies were investigated using Franz-type diffusion cells. Formulations based on isopropyl myristate were found to decrease the permeation rate (25-35%) as compared with marketed monotherapy products (set to 100%). Lanolin had no overall effect on skin permeability. However, polyoxypropylene-15 stearyl ether (PSE) had a marked effect. A 5% PSE formulation resulted in a permeation rate comparable to the marketed products. Thus, by using PSE as solvent, it was possible to combine calcipotriol and betamethasone dipropionate in a single formulation while optimal skin permeability was attained. Recently, the efficiency of this formulation (Daivobet®) has been verified in clinical studies showing an improved efficacy in the treatment of psoriatic patients.     

Surface Coating‐Dependent Cytotoxicity and Degradation of Graphene Derivatives: Towards the Design of Non‐Toxic,Degradable Nano‐Graphene

With the increasing interests of using graphene and its derivatives in the area of biomedicine, the systematic evaluation of their potential risks and impacts to biological systems is becoming critically important. In this work, we carefully study how surface coatings affect the cytotoxicity and extracellular biodegradation behaviors of graphene oxide (GO) and its derivatives. Although naked GO could induce significant toxicity to macrophages, coating those two‐dimensional nanomaterials with biocompatible macromolecules such as polyethylene glycol (PEG) or bovine serum albumin (BSA) could greatly attenuate their toxicity, as independently evidenced by several different assay approaches. On the other hand, although GO can be gradually degraded through enzyme induced oxidization by horseradish peroxidase (HRP), both PEG and BSA coated GO or reduced GO (RGO) are rather resistant to HRP‐induced biodegradation. In order to obtain biocompatible functionalized GO that can still undergo enzymatic degradation, we conjugate PEG to GO via a cleavable disulfide bond, obtaining GO‐SS‐PEG with negligible toxicity and considerable degradability, promising for further biomedical applications.     

Enhancement of in vitro skin permeation of verapamil

A number of compounds including aliphatic esters, alkanols and amides were investigated for their ability to enhance the in vitro permeation rate of verapamil across hairless mouse skin. While several of them did enhance the permeation rate, the best results were obtained with the lauric acid derivatives. On analysis of the permeation rate data it was found that while most of the compounds increased the solubility of verapamil in skin and hence its partition coefficient from the delivery system, the lauric acid derivatives also increased its diffusivity in skin. Permeation of verapamil from delivery systems containing these lauric derivatives was further investigated through delipidized and stripped skin. It was found that most of these derivatives enhanced the permeation of verapamil across both whole and delipidized skin, indicating that in addition to their action on the skin lipids, they must also have some effect on the proteins in the stratum corneum.     

Enhancement of in vitro skin permeation of verapamil

Abstract

A number of compounds including aliphatic esters, alkanols and amides were investigated for their ability to enhance the in vitro permeation rate of verapamil across hairless mouse skin. While several of them did enhance the permeation rate, the best results were obtained with the lauric acid derivatives. On analysis of the permeation rate data it was found that while most of the compounds increased the solubility of verapamil in skin and hence its partition coefficient from the delivery system, the lauric acid derivatives also increased its diffusivity in skin. Permeation of verapamil from delivery systems containing these lauric derivatives was further investigated through delipidized and stripped skin. It was found that most of these derivatives enhanced the permeation of verapamil across both whole and delipidized skin, indicating that in addition to their action on the skin lipids, they must also have some effect on the proteins in the stratum corneum.     

Microneedles for transdermal drug delivery: a systematic review

Transdermal route has been explored for various agents due to its advantage of bypassing the first pass effect and sustained release of drug. Due to strong barrier properties of the skin, mainly stratum corneum (SC), the delivery of many therapeutic agents across the skin has become challenging. Few drugs with specific physicochemical properties (molecular weight <500?Da, adequate lipophilicity, and low melting point) can be effectively administered via transdermal route. However, delivery of hydrophilic drugs and macromolecular agents including peptides, DNA and small interfering RNA is challenging. Drug penetration through the SC may involve bypass or reversible disruption of SC layer by various means. Recently, the use of micron-scale needles has been proposed in increasing skin permeability and shown to dramatically increase permeation, especially for macromolecules. Microneedles (MNs) can penetrate through the SC layer of the skin into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. This review summarizes the types of MNs and fabrication techniques of different types of MNs. The safety aspects of the materials used for fabrication have been discussed in detail. Biological applications and relevant phase III clinical trials are also highlighted.     

Critical evaluation of permeation enhancers for oral mucosal drug delivery

Background: Drug delivery via oral mucosa is an alternative method of systemic administration for various classes of therapeutic agents. Among the oral mucosae, buccal and sublingual mucosae are the primary focus for drug delivery. Buccal delivery offers a clear advantage over the peroral route by avoidance of intestinal and hepatic first-pass metabolism. However, despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. One of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. To date, the information available on oral mucosal permeation enhancement is much less than transdermal enhancement, though oral mucosa is more resistant to damage than other mucosal membranes. This article reviews the various categories of permeation enhancers for oral mucosal drug delivery, their mechanism of action, their usefulness, and the limitations associated with their use. Conclusion: To optimize the concentration of enhancer to limit its toxicity while facilitating an enhancing effect reproducibly will be a big challenge for future developments. Advances in permeability modulation and formulation with appropriate enhancers can provide for effective and feasible buccal drug delivery for many drugs, which otherwise have to be injected or ingested with water.     

Percutaneous Absorption of Capsaicin and Its Derivatives

Nonivamide (NVA), sodium nonivamide acetate (SNA) and sodium nonivamide propionate (SNP) are analogues of Capsaicin (CAP). The structure and pungent property of NVA are similar to CAP. The solubilities of SNA in different pH value buffer solution were higher than that of NVA and CAP. For the NVA and SNA, the n-octanol/buffer partition coefficients decreased with increasing pH value. The fluxes of CAP and its analogues were determined using excised rat skin and the effect of pH was also investigated. The flux of NVA and SNA mixture was higher than individually NVA or SNA, and the ratio of 70:30 was a better choice. Sodium lauryl sulfate (SLS), an anionic surfactant, had significant effect on SNA skin permeation.     

非均质表皮层径向双层承压井流数学模型的半解析解

考虑表皮层和未扰动承压层的非均质性、各向异性以及竖向越流补给作用,建立了径向双层承压三维井流的数学模型,采用Laplace变换和矩阵理论求得表皮层和未扰动承压层的水头降以及井壁流量的半解析解.应用所求解编制计算程序,分析了表皮层沿竖向随机变化的渗透性对承压层井流的影响,结果表明:表皮层非均质变化形态决定了表皮层内和其附近处的水头降以及井壁流量的竖向分布规律,表皮层对承压层渗流产生的影响范围与承压层的竖向渗透系数大小有关;改善井周岩土介质渗透性或增大"负表皮层"厚度可提高抽水井产量;表皮层径向渗透系数较小时,承压层的水头降幅度主要取决于承压层径向渗透系数的大小,而当表皮层径向渗透系数较大时,承压层径向渗透系数和竖向渗透系数均对承压层水头降有较大影响.     

Polymer-based nanoparticles for the delivery of nucleoside analogues

Nucleoside analogues, together with nucleobases and nucleotide analogues, are commonly used in the treatment of cancer and viral infections. In both cases, they act as antimetabolite agents and interfere with the synthesis of cellular or viral nucleic acids. However, the need of high doses due to the rapid elimination of these compounds, to their poor activation, and/or to their non-specific distribution, often leads to side effects and resistances. The present paper aims to review the different types of polymer nanoparticles which have been designed as drug delivery devices to address these issues. Thus, poly(alkylcyanoacrylate) nanoparticles have been demonstrated as potential carriers for antiviral nucleoside analogues, especially for anti-HIV agents, regarding both intravenous and oral routes. Nanoparticles based on polyesters such as poly(lactic acid) and poly(lactide-co-glycolide) have been used as nanocarriers for nucleosides analogues too, and especially for their ocular delivery. Albumin has shown interesting properties in the design of nanoparticles for the same application, but also for the oral administration of anticancer analogues. Finally, new hydrophilic nanoparticles consisting of cross-linked polymer network ('Nanogels') open the perspective to deliver nucleoside analogues within their active triphosphate form.     

A simple method of microneedle array fabrication for transdermal drug delivery

Abstract

The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 µg to 450 µg per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin.     

C60 fullerene derivatized nanoparticles and their application to therapeutics

Fullerenes can be formed into many new materials and devices. They have a wide range of applications in medicine, electronics, biomaterials, and energy production. An overview of the nanostructure and the physical and chemical characteristics of fullerene-drug derivatives is given. The biological behavior of fullerene derivatives shows their potential to medical application fields because C(60) is rapidly absorbed by tissues and is excreted through urinary tract and enterons, which reveals low toxicity in vitro and in vivo studies. Nanomedicine has become one of the most promising areas of nanotechnology, while many have claimed its therapeutic use against cancer, human immunodeficiency virus (HIV), and neurodegenerative disorders. Water-soluble C(60) fullerene derivatives that come from chemical modification largely enhance the biological efficacy. The blood-brain barrier (BBB) is a physical barrier composed of endothelial tight junctions that restrict the paracellular permeability. A major challenge facing neuropharmacology is to find compounds that can be delivered into the brain through the bloodstream. Fullerene C(60) was demonstratively able to cross the BBB by hybridizing a biologically active moiety dyad, which provides a promising clue as a pharmacological therapy of neural disorders.     

Permeability and retention studies of (-)epicatechin gel formulations in human cadaver skin

(-)Epicatechin (EC) is a major antioxidant component of grape seed extract which has become increasingly popular in topical skin preparations. This study assessed the following: (1) the permeability through cellulose membranes of EC in three different gel formulations (Carbopol 940, Klucel, and Ultrez 10); (2) the effect of three different antioxidants (butylated hydroxytoluene (BHT), alpha-tocopherol (VE), and ascorbic acid (AA)) on the stability and penetration properties of EC; and (3) the permeability and retention of EC in Ultrez 10 gels, supplemented with BHT or VE, on human cadaver skin. Permeability studies through cellulose membranes showed that different gelling agents do not significantly affect the permeability of EC (n = 7/gel; p > 0.05). BHT and VE have antioxidant properties superior to AA (p < 0.05) and preserve 100% of the initial content of EC for 28 days. Permeation studies on cadaver human skin, following application of two anhydrous gel formulations (0.5% EC in Ultrez 10 containing BHT or VE), showed that EC was not detectable in the receiving solution. However, the EC amount in viable skin increased with time, indicating that EC penetrated and was retained in the upper part of the skin for approximately 1% and 3% of the dose for the formulations containing BHT and VE, respectively.     

Improved optical properties of CdS quantum dots by ligand exchange

High-quality CdS nanocrystals with highly efficient and narrow band edge emission have been prepared by means of decomposition of suitable precursors in non-coordinating solvents at high temperature. The role played by capping ligands, solvents and their interactions has been investigated by optical measurements. Capping layer exchange treatments with different amines have been carried out suggesting a possible influence of alkylic chain length in modifying the optical properties of CdS nanocrystals. Enhancement of band edge emission has been demonstrated with octylamine ligand.     

Transdermal delivery of physostigmine: effects of enhancers and pressure-sensitive adhesives

The purpose of this study was to investigate the effects of various pressure- sensitive adhesives (PSA) on the percutaneous absorption of physostigmine across hairless mouse skin. In addition, the influences of various vehicles and polyvinylpyrrolidone (PVP) on the percutaneous absorption of physostigmine from PSA matrix across hairless mouse skin were evaluated using a flow-through diffusion cell system at 37°C. Physostigmine showed the highest permeability from silicone adhesive matrix, followed by polyisobutylene (PIB), styrene- isoprene-styrene (SIS), acrylic, and styrene-butadiene-styrene (SBS) matrix. Among acrylic adhesives, the permeability of physostigmine was the highest from grafted acrylic adhesive. Polyvinyl pyrrolidone inhibited the crystallization of physostigmine in the PIB adhesive matrix and enhanced the permeability of physostigmine from the PIB adhesive matrix. When esters of sorbitol and fatty acid, polyethylene glycol (PEG) alkyl esters, and caprylic/capric triglycerides were tested, the more lipophilic was a surfactant, the higher the permeation rate within the same group of surfactants. The enhancement effect of PEG derivatives was lower than that of non-PEG derivatives. Among non-linear fatty acid derivatives, linoleate derivatives showed higher permeability of physostigmine than oleate derivatives. This study showed that several non-ionic surfactants, including PEG-20 evening primrose glyceride, enhanced the permeation of physostigmine across hairless mouse skin better than oleic acid.     

淀粉基食品包装膜材料的研究进展

目的将淀粉应用于绿色包装领域,开发出具有良好生物降解性的淀粉基食品包装膜材料。方法综述淀粉种类、增塑剂、多糖、脂质及类脂物质、蛋白质、交联剂、无机物和活性物质等对淀粉膜性能的影响。结果在淀粉膜的制备中,选用高直链淀粉含量的淀粉,并加入增塑剂和交联剂可以改善淀粉膜的力学性能,降低薄膜的水蒸气渗透性;淀粉与多糖或蛋白质复合后,不同成膜材料优势互补,薄膜性能会得到改善,加入脂质或类脂物质可改善薄膜的阻水性。结论随着研究的深入,淀粉基食品包装膜材料在很多领域都会有广阔的应用前景。