Transdermal delivery of sodium nonivamide acetate from volatile vehicles: effects of polymers

The permeation of sodium nonivamide acetate (SNA), a newly designed analogue of capsaicin, from ethanol/pH 4.2 buffer solutions containing antinucleant polymers across rat skin, was investigated. The in vitro release of SNA was determined under an open condition at 25°C and 65% relative humidity. Therefore, the influence of the evaporation of vehicle components on the permeation of SNA was examined. Evaporation of the vehicle led to so drastic compositional changes that supersaturation is attained quickly. However, supersaturated solutions started to crystallize reducing the thermodynamic activity of SNA. Antinucleant polymers were used in the preparation of volatile vehicles in order to maintain the increased activity state of the drug. Methyl cellulose (MC) and hydroxypropyl cellulose (HPC) were both the efficient antinucleant polymers to increase the permeation of SNA. The permeation of SNA determined from volatile vehicles with 2% MC showed the result that the flux of SNA reached maximum at a certain ethanol proportion. A part of ethanol in the vehicle may penetrate into the skin causing the dehydration of stratum corneum and, therefore, the reduction of SNA permeation. The permeation of SNA was increased when ethanol in the volatile vehicle was replaced by n-propanol which could be due to the increased SNA solubility and reduction of diffusional barrier of stratum corneum in the presence of n-propanol.     

Transdermal delivery of diclofenac using microemulsions

A transdermal preparation containing diclofenac diethylammonium (DDA) was developed using an O/W microemulsion system. Of the oils tested, lauryl alcohol was chosen as the oil phase of the microemulsion, as it showed a good solubilizing capacity and excellent skin permeation rate of the drug. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant and cosurfactant for microemulsion formation, and the effect of these additives on skin permeation of DDA was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 1.16% of DDA, 5% of lauryl alcohol, 60% of water in combination with the 34.54% of Labrasol (surfactant)/ethanol (cosurfactant) (1:2). The efficiency of formulation in the percutaneous absorption of DDA was dependent upon the contents of water and lauryl alcohol as well as Labrasol:ethanol mixing ratio. It was concluded that the percutaneous absorption of DDA from microemulsions was enhanced with increasing the lauryl alcohol and water contents, and with decreasing the Labrasol:ethanol mixing ratio in the formulation.     

Transdermal delivery of ketoprofen using microemulsions

A transdermal preparation containing ketoprofen was developed using O/W microemulsion system. Of the oils tested, oleic acid was chosen as the oil phase of the microemulsion, as it showed a good solubilizing capacity and excellent skin permeation rate of the drug. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant and cosurfactant for microemulsion formation, and the effect of these additives on skin permeation of ketoprofen was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 3% ketoprofen, 6% oleic acid, 30% Labrasol/Cremophor RH 40 (1:1) and water. Terpenes were added to the microemulsion at the level of 5% and their effect on the skin permeation of ketoprofen from the microemulsion was evaluated. Of the four terpenes used, only limonene resulted in a powerful enhancing activity (3-fold increase over control).     

Transdermal delivery of piroxicam using microemulsions

To improve the skin permeability of piroxicam, a new oil-in-water microemulsion containing 0.5% piroxicam was developed. Among various oils investigated for their suitability as an oil phase for the microemulsion system, oleic acid showed both excellent solubility and skin permeation enhancing effect for piroxicam. Microemulsion existence ranges were identified through the construction of the pseudo-ternary phase diagram. The effect of the content of oleic acid and the ratio of the surfactant/cosurfactant on skin permeation of piroxicam were evaluated with excised rat skins. The optimum formulation with the highest skin permeation rate (47.14 microg/cm2/h) consisted of 0.5% piroxicam, 10% oleic acid, 60% Labrasol/ethanol (1:5) and water.     

Transdermal iontophoresis of sodium nonivamide acetate I. Consideration of electrical and chemical factors

Transdermal iontophoresis is a process which enhances skin permeation of ionized species by an electrical field as driving force. The aim of this present study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide acetate (SNA). Studies of electrical and physicochemical factors acting on the kinetics of in vitro iontophoresis were performed. Iontophoresis increased the transdermal penetration flux of SNA as compared to the passive diffusion in this study. Several application modes which possessed the same electrical energy had been researched. The iontophoretic flux of SNA increased following the decrease of donor buffer pH values. This trend could be due to the physiological property of skin and electro-osmotic flow presented. Comparing the various application modes, the discontinuous on/off cyclic current mode showed higher penetration capacity than did continuous mode which was due to the intensity of effective current which would not decay for on/off cyclic application of iontophoresis. The result of the present study is particularly helpful in the development of a SNA transdermal iontophoretic delivery system.     

Transdermal delivery of theophylline from alcohol vehicles

The fluxes of theophylline (Th) through hairless mouse skin from suspensions in straight alkyl chain alcohols have been measured (J_i). The fluxes of theophylline from these first applications was least from methanol (C₁), increased by almost 100-fold for fluxes of theophylline from pentanol (C₅), hexanol (C₆), heptanol (C₇) octanol (C₈) and nonanol (C₉), then decreased 10-fold for the flux of theophylline from undecanol (C₁₁). The second application of a standard solute–solvent, theophylline–propylene glycol (Th–PG), was used to assess damage to the skin caused by the first application. The flux from this subsequent application of Th–PG (J_j) was least after application of Th–C₁, increased almost 60-fold after application of Th–C₅, then remained relatively constant after application of theophylline in the longer chain alcohols. The trend in the fluxes of Th–PG in the second application was the same as the trend in the fluxes of Th–PG subsequent to the application of the neat alcohols previously reported. The ratios J_i/J_j showed that there were no significant increases in fluxes of theophylline from the first application without concomitant increases in fluxes of theophylline from the second application (J_i/J_j=1.3–2.2) except for the application of Th–C₃ where J_i/J_j=7.7. Control experiments showed that the fluxes of the alcohols from the suspensions and the back-diffusion of water into the donor phases in the first application, determined using ¹H NMR spectroscopy, were of the same magnitude and gave the same trend as from the application of the neat alcohols previously reported.     

Sodium nonivamide acetate: A non-pungently antinociceptive capsaicin derivative with unusual anti-inflammatory properties

• 1.1. Bradykinin-induced vascular pain in conscious rats, hyperalgesia in the rat hind paw, rat hind paw edema induced by compound 48/80 and carrageenin and dye exudation induced by intraperitoneal injection of 0.7% acetic acid in mice were all inhibited by sodium nonivamide acetate (SNA).
• 2.2. Collagen and arachidonic acid-induced rabbit platelet aggregations were inhibited by SNA and capsaicin. In human platelet microsomes, prostaglandin E₂ formation in arachidonic acid metabolite was not inhibited by SNA but was inhibited by capsaicin and indomethacin; thromboxane B₂ formation and its synthetase activity were inhibited by SNA and capsaicin.
• 3.3. In the extracellular recording, SNA could not decrease the action potential amplitude of the vagus nerve.
• 4.4. The motor activity of mice induced by caffeine (1.0 mg/kg) was inhibited by SNA and capsaicin.

     

Electrically-assisted skin permeation of two synthetic capsaicin derivatives, sodium nonivamide acetate and sodium nonivamide propionate, via rate-controlling polyethylene membranes

The objective of this study was to examine the transdermal delivery of sodium nonivamide acetate (SNA) using iontophoresis and electroporation with ultra high molecular weight polyethylene membranes (Solupor) to achieve controlled transdermal drug delivery. A derivative of SNA, sodium nonivamide propionate (SNP), was also used as a model drug in this investigation. Iontophoresis increased the transdermal permeation of SNA as compared to passive diffusion. Most Solupor membranes were rate-limiting for the iontophoretic permeation of SNA except for Solupor 8P07, which showed negligible resistance to SNA delivery. The tortuosity (Gurley number), pore size, and the current density-induced attachments on the surface of the Solupor membranes may have been important for their rate-controlling effect. The trends for inhibiting or controlling SNA permeation were similar for both iontophoretic and electroporation applications. The higher molecular size and lower hydrophilicity of SNP compared to SNA resulted in lower permeation of SNP using electrically-assisted methods. Moreover, the various types of Solupor membranes showed similar trends for both SNA and SNP. This present study indicates that Solupor membranes act as rate-limiting membranes for controlling the release and skin permeation of both SNA and SNP by electrically-assisted methods.     

Transdermal delivery of methotrexate: iontophoretic delivery from hydrogels and passive delivery from microemulsions

In vitro assays were performed to investigate the effectiveness of transdermal administration of methotrexate (MTX) by iontophoretic delivery from two types of hydrogel and passive delivery from two types of microemulsion. Both iontophoretic delivery of MTX from hydrogels and passive delivery from microemulsions were more effective than passive delivery from aqueous solutions of the drug. In the iontophoretic delivery assays, the type of hydrogel used and the concentration of the drug in the loading solution had little influence on effectiveness of delivery. In the passive delivery assays, we used both water/oil (w/o) and oil/water (o/w) microemulsions: effectiveness of delivery was higher from o/w systems. At the end of all assays, significant amounts of MTX were detected in the skin. These results suggest that both hydrogels and microemulsions may be of value for the topical administration of MTX in the treatment of psoriasis.     

Transdermal iontophoresis of sodium nonivamide acetate evaluated by in vivo microdialysis and histologic study

By using an intradermal microdialysis technique 22 h after the transdermal iontophoretic delivery of sodium nonivamide acetate (SNA), a synthetic derivative of capsaicin, the amount of SNA in the extracellular space was measured. Transdermal iontophoresis is a process that enhances skin permeation of ionized species by using an electric field as a driving force. Iontophoresis increased the amount of SNA in dialysate compared with passive diffusion in this study. By using various polymers incorporated in formulations, indicated hydrogels showed higher capacity for SNA delivery than solution formulations. This result was possibly attributable to the antinucleant ability of polymers resulting in the increase of thermodynamic activity of SNA in formulations. Pretreatment with isopropyl myristate, a lipophilic penetration enhancer, on rat skin enhanced transdermal delivery of SNA both for passive and iontophoretic penetration, indicating the possibility of reducing the surface area of the administrations site in clinical use. Microscopic examination revealed no or slight changes in the skin after iontophoretic treatment compared with penetration enhancer pretreatment. The histologic results also suggested iontophoretic treatment with 0.5 mA/cm² current density of not more than 7‐h application duration may be acceptable clinically. Drug Dev. Res. 46:87–95, 1999. © 1999 Wiley‐Liss, Inc.     

Transdermal iontophoresis of sodium nonivamide acetate. V. Combined effect of physical enhancement methods

The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium-aluminum-garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.     

Transdermal delivery of insulin using trypsin as a biochemical enhancer

Trypsin has been extensively used in laboratory settings for in vitro epidermal separation and keratinocyte isolation for over 50 years. The aim of this study was to assess the enhancing effect of trypsin on the transdermal delivery of insulin by applying its specific biochemical properties to react with the stratum corneum (SC) of skin. Bovine insulin was used as a model peptide to investigate in vitro permeation through rat skin and in vivo hypoglycemic effects of bovine insulin with or without the trypsin pretreatment. Trypsin significantly increased the transdermal permeability of bovine insulin in pH 3.0 solution, but no effect was observed in pH 6.0 solution. The permeation flux of bovine insulin from pH 3.0 solution was promoted 5.2-fold with 0.25% trypsin pretreatment when compared with the control. The enhancement of trypsin was dependent on the concentration in the range of 0.5-2.5%. Furthermore, with trypsin pretreatment, the plasma glucose level was reduced to less than 60% of the initial value after 8 h of in vivo permeation of bovine insulin with pH 3.0 solution, but did not return to the initial value during an 8-h experiment. Mechanistic studies with Fourier transform-infrared and attenuated total reflectance analysis and electrical resistance measurements suggest that trypsin alters the SC protein structure from the alpha- to the beta-form and decreases the electrical resistance of skin, thereby decreasing the SC barrier and enhancing the permeation of insulin. We conclude that trypsin would be effective as a biochemical enhancer for the transdermal delivery of peptide and protein drugs such as insulin.     

In vivo percutaneous absorption of capsaicin,nonivamide and sodium nonivamide acetate from ointment bases: Skin erythema test and non-invasive surface recovery technique in humans

Nonivamide (NVA) and sodium nonivamide acetate (SNA) are both synthetic analogues of capsaicin. In this present study, the in vivo skin erythema test and non-invasive surface recovery techniques were performed in humans for capsaicin, NVA and SNA after transdermal ointment application. In order to quantify the skin erythema and irritation caused by capsaicin and its analogues, laser Doppler flowmetry (LDF) was utilized for determining the cutaneous blood flow to assess the degree of irritant reaction. In the study of surface recovery technique, NVA hydrophilic ointment base showed higher flux and cumulative absorbed amount than the other formulations. In the study of skin erythema test, capsaicin caused severer skin irritation than NVA in humans. Moreover, there was no significant difference between the erythema levels of SNA and control group indicating that SNA produced no skin irritation or pungent sensation. In addition, increased skin temperatures were detected after transdermal application of capsaicin, NVA and SNA ointment bases. The trend of the skin temperature profiles was consistent with that of skin erythema test by laser Doppler flowmetry suggesting that increased skin temperatures may reflect the degree of vasodilation produced by irritation in the treated skin area. In the study of the skin erythema test using various concentration levels of capsaicin and NVA, the various doses from hydrophilic ointment did not markedly influence the pungent and irritant skin reactions after transdermal application.     

Oral delivery of capsaicin using MPEG-PCL nanoparticles

Aim:

To prepare a biodegradable polymeric carrier for oral delivery of a water-insoluble drug capsaicin (CAP) and evaluate its quality.

Methods:

CAP-loaded methoxy poly (ethylene glycol)-poly(ε-caprolactone) nanoparticles (CAP/NPs) were prepared using a modified emulsification solvent diffusion technique. The quality of CAP/NPs were evaluated using transmission electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared techniques. A dialysis method was used to analyze the in vitro release profile of CAP from the CAP/NPs. Adult male rats were orally administered CAP/NPs (35 mg/kg), and the plasma concentrations of CAP were measured with a validated HPLC method. The morphology of rat gastric mucosa was studied with HE staining.

Results:

CAP/NPs had an average diameter of 82.54±0.51 nm, high drug-loading capacity of 14.0%±0.13% and high stability. CAP/NPs showed a biphasic release profile in vitro: the burst release was less than 25% of the loaded drug within 12 h followed by a more sustained release for 60 h. The pharmacokinetics study showed that the mean maximum plasma concentration was observed 4 h after oral administered of CAP/NPs, and approximately 90 ng/mL of CAP was detected in serum after 36 h. The area under the curve for the CAP/NPs group was approximately 6-fold higher than that for raw CAP suspension. Histological studies showed that CAP/NPs markedly reduced CAP-caused gastric mucosa irritation.

Conclusion:

CAP/NPs significantly enhance the bioavailability of CAP and markedly reduce gastric mucosa irritation in rats.     

Percutaneous absorption of capsaicin,nonivamide and sodium nonivamide acetate from gel and ointment bases: In vitro formulation evaluations in pigs and in vivo bioengineering methods in humans

Nonivamide (NVA) and non-pungent sodium nonivamide acetate (SNA) are synthetic derivatives of capsaicin. In this study, in vitro formulation evaluations in pigs and in vivo bioengineering methods in humans were performed to obtain the information on percutaneous absorption for capsaicin, NVA and SNA. After the consideration of penetration capacity, skin irritation and physicochemical properties of the formulations in vitro, 0.6% Carbopol 940® gel form for capsaicin and NVA as well as 3.8% isopropyl myristate-added hydrophilic o/w ointment for SNA were utilized to study the following in vivo test in humans. In the study of in vivo surface recovery techniques, SNA showed an equivalent therapeutic capability to that of NVA after calculation of the antinociceptive index. After the quantification of skin erythema by laser Doppler flowmetry (LDF), capsaicin caused more severe irritation than NVA in humans. In addition, SNA showed no skin irritation, toxicity and pungent sensation. The transepidermal water loss (TEWL) values were determined using an evaporimeter. A comparison of the gel form showed there was significantly higher TEWL AUC values in capsaicin and NVA than in the control group. The AUC value of the hydrophilic ointment control group was significantly higher than that of the gel control group. The reason was that isopropyl myristate and sodium laurylsulfate, two additives incorporated in the hydrophilic base, could cause slight skin irritation resulting in the increase of TEWL. The results of this study suggest that SNA possesses potent antinociceptive activities after transdermal application. Furthermore, SNA can be used extensively in clinical therapy because it avoids any pungent skin sensation and burning pain to improve patients' compliance.     

Transdermal delivery of indomethacin and levonorgestrel using clofibric acid amides as penetration enhancers

The enhancing properties of clofibric acid amides on the transdermal delivery of indomethacin and levonorgestrel were studied in vitro using full-thickness hairless mouse skin. The enhancers possessed alkyl side chains varying from 2 (1) to 16 (7) carbons. Indomethacin was applied in propylene glycol and levonorgestrel in 1-butanol, and all enhancers were applied at 0.4 M in propylene glycol 1 h prior to drug treatment. 1-Butanol was chosen as the vehicle for levonorgestrel since it was found to deliver more drug transdermally than propylene glycol. Since this was a volatile solvent, all experiments with levonorgestrel were performed under occlusion. The greatest increases in permeability coefficients and skin retention of model drugs were observed with compounds 4, 5, and 6. The permeability coefficient enhancement ratio (ER) for indomethacin and 4 was 3.1, for 5 was 10.9, and for 6 was 14.6. Skin content ER values were 4.6, 5.3, and 1.8, respectively. Levonorgestrel permeability coefficient ER values were lower, 1.6 for 4, 2.6 for 5, and 1.9 for 6. Skin content ER values for this model drug were 1.7, 4.3, and 2.3, respectively. Azone, however, was less effective than 5 and 6 for both model drugs with respect to permeability coefficients and 24-h receptor concentrations. For skin contents and indomethacin, 2-7 were more effective than Azone, and for levonorgestrel, 5, 6, and 7. Indomethacin enhancement was dependent on concentration of enhancer 6 (0.1, 0.2, 0.4, 0.6, 0.8 M), the maximum being observed for 0.4, 0.6, and 0.8 M. Permeation enhancement of both drugs was dependent on the length of the alkyl side chain of the enhancer. It is proposed that these compounds may be useful for transdermal drug delivery, although further testing needs to be performed.     

Transdermal delivery of insulin in mice by using lecithin vesicles as a carrier

The present study was undertaken to characterize the preparation of flexible lecithin vesicles containing insulin and to assess the enhancing effect of these flexible vesicles on the transdermal delivery of a hydrophilic protein. Both conventional and flexible vesicles were prepared by reverse-phase evaporation and treated further by sonication. The free drug was separated from vesicles by column chromatography and analyzed by HPLC. Both conventional and flexible vesicles were transparent colloidal dispersions. The particle size of the conventional and flexible vesicles was 73.5 nm and 87.1 nm with a polydispersity index of 44.5% and 15.6%, respectively. The entrapment efficiencies of conventional and flexible vesicles were 35% and 81%, respectively. When vesicles were nonocclusively applied onto the abdominal mice skin at a dose of 0.90 IU/cm2, in vivo hypoglycemic study showed the drop percentage of blood glucose by flexible vesicles was 21.42 +/- 10.19% at 1 hr, reached 61.48 +/- 8.97% at 5 hr, and was larger than 50% within 18 hr. Conventional vesicles, insulin solution, and saline had no hypoglycemic effect. Probably due to the incorporation or adsorption of a certain amount of insulin into the flexible vesicles during the mixing process, blank flexible vesicles mixed with insulin solution had a certain degree of hypoglycemic effect, though much less than the effect of flexible vesicles containing insulin (p < 0.05). Flexible vesicle may become a promising carrier for the transdermal delivery of hydrophilic polypeptides.     

HPV pseudovirions as DNA delivery vehicles

"The ability of HPV pseudovirions to efficiently deliver DNA into cells suggests several potential applications in basic biology, including the characterization of virion biology and measurement of protective neutralizing antibody titers in vitro and in vivo, as well as their employment for more direct medical applications".     

不锈钢微针经皮给药的研究

目的：将不锈钢微针阵列应用于经皮给药。考察离体大鼠皮肤经不同针形微针预处理相同时间、相同针形微针预处理不同时间后，模型药物鬼臼毒素经大鼠皮肤的透皮能力。方法：微针预处理大鼠皮肤后，用改进的Franz扩散池研究鬼臼毒素对皮肤的透皮速率。高效液相色谱法测定鬼臼毒素的含量。结果：皮肤经微针预处理后进行鬼臼毒素透皮，其透皮速率比未经微针处理时有明显提高。三角形微针、梯形微针、矛形微针对鬼臼毒素的促渗能力依次增强；三者所引起的鬼臼毒素在皮肤中的滞留量有显著差异。同种针形微针预处理皮肤时间越长，鬼臼毒素的透皮速率越大；但微针预处理时间对皮肤中的药物滞留量无显著影响。结论：微针用于药物经皮给药时，微针针形、微针的预处理时间对药物的经皮渗透具有重要影响。     

Bacterial ghosts as antigen delivery vehicles

The bacterial ghost system is a novel vaccine delivery system unusual in that it combines excellent natural intrinsic adjuvant properties with versatile carrier functions for foreign antigens. The efficient tropism of bacterial ghosts (BG) for antigen presenting cells promotes the generation of both cellular and humoral responses to heterologous antigens and carrier envelope structures. The simplicity of both BG production and packaging of (multiple) target antigens makes them particularly suitable for use as combination vaccines. Further advantages of BG vaccines include a long shelf-life without the need of cold-chain storage due to their freeze-dried status, they are safe as they do not involve host DNA or live organisms, they exhibit improved potency with regard to target antigens compared to conventional approaches, they are versatile with regards to DNA or protein antigen choice and size, and as a delivery system they offer high bioavailability.