Basil Oil is a Promising Skin Penetration Enhancer for Transdermal Delivery of Labetolol Hydrochloride

Thepresent work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER?=?46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.     

Two steps modification for improvement of cyclobenzaprine transdermal delivery: releasing from patch and penetrating through skin

The aim of this study was to improve the transdermal delivery of cyclobenzaprine (CBZ) from drug-in-adhesive patch which showed less side effects and better compliance. CBZ base was prepared and then characterized using differential scanning calorimetry (DSC). The interaction between CBZ and pressure-sensitive adhesive (PSA) was determined by Fourier Transform Infrared Spectroscopy (FT-IR). The influences of PSAs, penetration enhancers, patch thickness and drug content on the transdermal delivery of CBZ were studied thoroughly in vitro. Both CBZ releasing from patch and penetrating through the skin showed very great effect on the transdermal delivery of CBZ. The percentage of drug released from patch was increased with the decreasing of patch thickness, and so did the permeation percentage. The stratum corneum (SC) contributed approximately 57% resistance of total skin permeation resistance, and Span 20 increased the transdermal permeation by approximately 1.59-fold. The pharmacokinetic parameters were obtained through in vivo experiments of the optimized formulation using rabbit. Furthermore, the in vitro skin permeation results of CBZ patch correlated well with the in vivo absorption results in rabbit.     

Preparation and Evaluation of Pranoprofen Gel for Percutaneous Administration

ABSTRACT

The percutaneous delivery of nonsteroidal anti-inflammatory drug (NSAID) has the advantages of avoiding the hepatic first pass effect and delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropyl methylcellulose (HPMC) and poloxamer 407 were used in an attempt to develop new topical formulations of pranoprofen. The effects of the drug concentration (0.04, 0.08, 0.12, 0.16, and 0.20%) on the rate of drug release from HPMC-poloxamer 407 gels were examined using a synthetic cellulose membrane at 37±0.5°C. The rate of drug permeation increased significantly with increasing drug concentration in the gels until the concentration reached 0.16%, and increased slightly thereafter. The effects of temperature on the rate of drug release from the 0.16% pranoprofen gels were evaluated at 32, 37, and 42°C. The rate of drug release from the 0.16% pranoprofen gels increased with increasing temperature with activation energy (E_a) of 8.88 kcal/mol. Various penetration enhancers, such as nonionic surfactants and fatty acids, were incorporated in the gel formulation in an attempt to increase the level of drug permeation. Among the enhancers used, octanoic acid had the strongest enhancing effects with an enhancement factor of 3.09. The anti-inflammatory effect of the pranoprofen gel was evaluated using a rat paw-edema model. The 0.16% pranoprofen gel containing octanoic acid as an enhancer reduced the edema size by approximately 73% compared with that of the control group. These results highlight the feasibility of a topical gel formulation of pranoprofen containing an enhancer.     

In vitro percutaneous absorption enhancement of granisetron by chemical penetration enhancers

Granisetron (GRN), a potent antiemetic agent, is frequently used to prevent nausea and vomiting induced by cancer cytotoxic chemotherapy and radiation therapy.

Objective: As part of our efforts to further modify the physicochemical properties of this market drug, with the ultimate goal to formulate a better dosage form for GRN, this work was carried out to improve its permeability in vitro.

Methods: The permeation behavior of GRN in isopropyl myristate (IPM) was investigated across excised rabbit abdominal skin and the enhancing activities of three novel O-acylmenthol derivatives synthesized in our laboratory as well as five well-known chemical enhancers were evaluated.

Results: It was found that the steady-state flux of granisetron free base (GRN-B) was about 26-fold higher than that of granisetron hydrochloride (GRN-H). The novel enhancer, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP), was observed to provide the most significant enhancement for the absorption of GRN-B. When incorporated in the donor solution with the optimal enhancer M-HEP, the steady-state flux of GRN-B increased from (196.44?±?12.03) μg·cm^?2·h^?1 to (1044.95?±?71.99) μg·cm^?2·h^?1 (P?<?0.01).

Conclusion: These findings indicated that the application of chemical enhancers was an effective approach to increase the percutaneous absorption of GRN in vitro.     

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.     

应用于化妆品的水杨酸微胶囊载体系统的制备及表征

以阿拉伯胶和麦芽糊精为微胶囊壁材,采用喷雾干燥法制备水杨酸微胶囊,并用傅里叶红外光谱及扫描电子显微镜对包埋行为进行鉴定,还研究了最佳阿拉伯胶／麦芽糊精比、微胶囊溶解度、释放机制及体外透皮性,实验结果表明,最佳阿拉伯胶／麦芽糊精比为1：1,微胶囊化后水杨酸溶解度能够提高至26mg/mL。水杨酸微胶囊呈现球状结构,并具有一定的缓释性,体外透皮结果显示微胶囊化后水杨酸透皮速率减慢并且无突释现象,与未包埋水杨酸相比,水杨酸微胶囊具有更高的皮表保留量和较低的皮肤驻留量。     

The Effect of Clove Oil on the Transdermal Delivery of Ibuprofen in the Rabbit by In Vitro and In Vivo Methods

The study was designed to evaluate skin permeation enhancement effect of essential oils from Eugenia caryophyllata (clove oil) in rabbits and to compare the in vitro absorption and in vivo permeation using ibuprofen as a model drug. The in vitro results indicated a significant permeation enhancement effect of the clove oil. The group with 1% oil appeared to the flux (239 μg/cm²/hr), and 3% oil was 293 μg/cm²/hr to some extent similar with 2% azone group (327 μg/cm²/hr). The enhancement ratio of clove oil was 7.3. In vivo results also demonstrated that clove oil showed a significant permeation enhancement effect, but the enhancement of clove oil was relatively weak than in vitro. The group with 3% oil exhibited the higher value of area under the curve (AUC) of 80.8 μg/mL·hr, which was 2.4 times the high of control. The AUC value of 3% oil group was similar to that of 2% azone group (89.8 μg/mL·hr). The GC-MS results indicated eugenol and acetyleugenol identified from clove oil might mainly contribute to enhance in vitro and in vivo absorption of ibuprofen because of its large quantities (90.93%).     

Percutaneous Absorption of Metopimazine and Effect of Cyclodextrins

Metopimazine (MPZ) is used to prevent emesis during chemotherapies. A transdermal delivery system of MPZ may present a great advantage in patients to improve compliance. Hydroxypropyl β cyclodextrin (HPβCD) and partially methylated β cyclodextrin (PMβCD) were tested to enhance the percutaneous absorption of MPZ through pig skin using Franz's cells. The MPZ hydrochloride flux was low with 0.176 ± 0.054 μg/h/cm² and no flux was detected with a suspension of MPZ (base). The used characterization analyses demonstrated the formation of an inclusion complex with cyclodextrin and this complex improved percutaneous absorption of MPZ. Flux was increased to 0.240 ± 0.032 μg/h/cm² and 0.566 ± 0.057 μg/h/cm² for HPβCD and PMβCD, respectively, with a concentration of 20%. This study has shown that HPβCD and PMβCD improved the percutaneous penetration of MPZ. Cyclodextrin complexes increased MPZ bioavailability at the skin surface and PMβCD was also able to extract cutaneous fatty acids.     

Investigation on the synergistic effect of a combination of chemical enhancers and modulated iontophoresis for transdermal delivery of insulin

Purpose: The main objective of this study was to assess the flux enhancement of insulin transdermally by utilizing a complex of chemical enhancers in combination with modulated iontophoresis. Methods: The experiments were performed on porcine epidermis model under three different circumstances, namely, (a) 1-hour modulated iontophoresis alone; (b) pretreatment with vehicle and chemical enhancer combinations and (c) combination of (a) and (b). The mechanism of action of the enhancers was studied using infra-red spectra by derivative and curve-fitting techniques and Confocal laser scanning microscopy. The efficacy of the optimized combination was tested in vivo in streptozocin-diabetic Wistar rats. Results: A blend of 1,8 cineole, oleic acid and sodium deoxycholate in propylene glycol : ethanol (7:3) resulted in 45% enhancement, when permeation was performed in combination with iontophoresis as compared to the latter alone. In-depth analysis of infra-red spectra revealed that each of the enhancers acted differentially on lipid-protein domains of the stratum corneum thereby supporting the observed synergism. Movement of fluorescently labeled insulin depicted highlighted follicular regions and paracellular accumulation of the probe after iontophoresis and chemical enhancer treatment respectively. Presence of the fluorescent peptide in these regions 4 hour after treatment with the combination reinforced the results of the permeation studies. Finally the combination of modulated iontophoresis with chemical enhancer blend resulted in lowering of blood glucose for 8 hour in vivo. Conclusions: The study proved the applicability of modulated iontophoresis with chemical pretreatment in delivering insulin transdermally.     

The effect of clove oil on the transdermal delivery of ibuprofen in the rabbit by in vitro and in vivo methods

The study was designed to evaluate skin permeation enhancement effect of essential oils from Eugenia caryophyllata (clove oil) in rabbits and to compare the in vitro absorption and in vivo permeation using ibuprofen as a model drug. The in vitro results indicated a significant permeation enhancement effect of the clove oil. The group with 1% oil appeared to the flux (239 μg/cm²/hr), and 3% oil was 293 μg/cm²/hr to some extent similar with 2% azone group (327 μg/cm²/hr). The enhancement ratio of clove oil was 7.3. In vivo results also demonstrated that clove oil showed a significant permeation enhancement effect, but the enhancement of clove oil was relatively weak than in vitro. The group with 3% oil exhibited the higher value of area under the curve (AUC) of 80.8 μg/mL·hr, which was 2.4 times the high of control. The AUC value of 3% oil group was similar to that of 2% azone group (89.8 μg/mL·hr). The GC-MS results indicated eugenol and acetyleugenol identified from clove oil might mainly contribute to enhance in vitro and in vivo absorption of ibuprofen because of its large quantities (90.93%).     

Development and evaluation of nanosized niosomal dispersion for oral delivery of Ganciclovir

Encapsulation of Ganciclovir in lipophilic vesicular structure may be expected to enhance the oral absorption and prolong the existence of the drug in the systemic circulation. So the purpose of the present study was to improve the oral bioavailability of Ganciclovir by preparing nanosized niosomal dispersion. Niosomes were prepared from Span40, Span60, and Cholesterol in the molar ratio of 1:1, 2:1, 3:1, and 3:2 using reverse evaporation method. The developed niosomal dispersions were characterized for entrapment efficiency, size, shape, in vitro drug release, release kinetic study, and in vivo performance. Optimized formulation (NG8; Span60:Cholesterol 3:2 molar ratio) has shown a significantly high encapsulation of Ganciclovir (89?±?2.13%) with vesicle size of 144?±?3.47?nm (polydispersity index [PDI]?=?0.08). The in vitro release study signifies sustained release profile of niosomal dispersions. Release profile of prepared formulations have shown that more than 85.2?±?0.015% drug was released in 24?h with zero-order release kinetics. The results obtained also revealed that the types of surfactant and Cholesterol content ratio altered the entrapment efficiency, size, and drug release rate from niosomes. In vivo study on rats reveals five-time increment in bioavailability of Ganciclovir after oral administration of optimized formulation (NG8) as compared with tablet. The effective drug concentration (>0.69 µg/mL in plasma) was also maintained for at least 8?h on administration of the niosomal formulation. In conclusion, niosomes can be proposed as a potential oral delivery system for the effective delivery of Ganciclovir.     

Influence of ion-pairing and chemical enhancers on the transdermal delivery of meloxicam

Purpose: To investigate the influence of ion pairing and chemical enhancers on the transdermal delivery of meloxicam. Method: We examined the increased permeation of meloxicam produced by ion pair formation with six organic bases, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, and N-(2′-hydroxyethanol)-piperidine, and four normal permeation enhancers, oleic acid, menthol, azone, and N-methyl-2-pyrrolidone. The cumulative permeation was markedly increased in the presence of either a counter ion or chemical enhancers. In particular, we proved the formation of a meloxicam/amine ion-pair in solution by ¹³C-NMR (nuclear magnetic resonance). Results and conclusion: The cumulative permeation was markedly increased in the presence of either a counter ion or chemical enhancers. These results suggest that the degree of enhancement possibly depends on the structure and hydrophilicity of the counter ions.     

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers

Context: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. Objective: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. Materials and Methods: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. Results: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34–46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 ± 2.1 ng/mL, which was attained at 15.5 ± 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. Conclusion: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.     

溶剂/非溶剂组合对聚醚砜分离膜结构与性能的影响

采用沉浸相转化法制备聚醚砜分离膜,研究了具有不同溶解度参数的溶剂/非溶剂组合对膜亚层结构与性能的影响.结果表明,溶剂/非溶剂组合是影响聚醚砜分离膜亚层结构性能的关键因素,溶剂与聚醚砜的溶解度参数越接近,即|△δ|越小,越易形成海绵状致密结构,而溶剂与非溶剂的|△δ|越大,相转化时间越短,越容易得到指状的大空腔结构;实验中异丙醇为非溶剂时膜的截留和通量效果较好,这是由于在形成致密膜的同时增加了膜的亲水性的缘故.     

Enhanced In Vitro Percutaneous Absorption and In Vivo Anti-Inflammatory Effect of a Selective Cyclooxygenase Inhibitor Using Microemulsion

Celecoxib, a specific COX-2 inhibitor, was recently approved for the treatment of rheumatoid and osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. Oral administration of celecoxib is effective against ultraviolet B radiation (UVB)-induced skin carcinogenesis; however, its clinical use is restricted because of its failure to block the characteristic cutaneous inflammatory response and lower availability at the site of inflammation. Topical application of celecoxib has been effective compared with oral in certain clinical conditions. The present study was undertaken to develop and investigate the development of microemulsion system (isopropyl myristate/medium-chain glyceride/polysorbate 80/water) for topical delivery of celecoxib. The pseudoternary phase diagram was constructed with constant surfactant concentration, and several compositions were identified and characterized by using dynamic light scattering. The in vitro permeation rate of celecoxib through rat skin was determined for microemulsions, microemulsion gel, and cream by using the modified Franz-type diffusion cell. In all formulations tested, celecoxib permeated more quickly, and the microemulsions increased the permeation rate of celecoxib up to 5 and 11 times compared with those of microemulsion gel and cream, respectively. Increasing the concentration of medium-chain mono-/di-glyceride in microemulsion imparted increased droplet size and viscosity and decreased diffusion coefficient. In vivo anti-inflammatory study suggested that the developed microemulsion formulations might serve as potential drug vehicle for the prevention of UVB-induced skin cancer.     

Al_2O_3对稀土配合物掺杂有机改性凝胶玻璃结构及荧光性能的影响

以γ-缩水甘油氧基三甲氧基硅烷作为有机改性先驱体,采用原位合成技术,用溶胶-凝胶法制备稀土离子(Eu3+或Tb3+)、配位体β-二酮噻吩甲酰三氟丙酮或苯甲酸及协同体1,10-菲啰啉共掺的两种有机改性二氧化硅玻璃,测量它们的发射光谱和红外光谱,并进行X射线衍射分析和扫描电镜观察,探讨Al2O3的掺量对凝胶玻璃结构及性能的影响。结果表明:Al3+对稀土离子发射峰的位置没有明显的影响,并使凝胶在室温时的荧光减弱,但它能使稀土离子及原位合成的配合物在较高温度保持相对稳定,提高凝胶玻璃的热稳定性和荧光强度;在制备较实用的具有较强荧光的含稀土离子的凝胶玻璃时,要根据实际需要选取适宜掺量的Al2O3。     

Enhanced In Vitro Percutaneous Absorption and In Vivo Anti-Inflammatory Effect of a Selective Cyclooxygenase Inhibitor Using Microemulsion

Celecoxib, a specific COX-2 inhibitor, was recently approved for the treatment of rheumatoid and osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. Oral administration of celecoxib is effective against ultraviolet B radiation (UVB)-induced skin carcinogenesis; however, its clinical use is restricted because of its failure to block the characteristic cutaneous inflammatory response and lower availability at the site of inflammation. Topical application of celecoxib has been effective compared with oral in certain clinical conditions. The present study was undertaken to develop and investigate the development of microemulsion system (isopropyl myristate/medium-chain glyceride/polysorbate 80/water) for topical delivery of celecoxib. The pseudoternary phase diagram was constructed with constant surfactant concentration, and several compositions were identified and characterized by using dynamic light scattering. The in vitro permeation rate of celecoxib through rat skin was determined for microemulsions, microemulsion gel, and cream by using the modified Franz-type diffusion cell. In all formulations tested, celecoxib permeated more quickly, and the microemulsions increased the permeation rate of celecoxib up to 5 and 11 times compared with those of microemulsion gel and cream, respectively. Increasing the concentration of medium-chain mono-/di-glyceride in microemulsion imparted increased droplet size and viscosity and decreased diffusion coefficient. In vivo anti-inflammatory study suggested that the developed microemulsion formulations might serve as potential drug vehicle for the prevention of UVB-induced skin cancer.     

Interaction of Tenoxicam with Cyclodextrins and Its Influence on the In Vitro Percutaneous Penetration of the Drug

Solid complexes of tenoxicam (TEN) with cyclodextrins (CDs), in a 1:1 molar ratio, were obtained by the coprecipitation method and characterized by x-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. The binding capacity of the CDs with TEN was also demonstrated in aqueous solution and in water-propylene glycol mixtures. The purpose of this study was to determine the effect of CDs on the in vitro percutaneous penetration of TEN from carbopol gels, taking into account the role of the CD cavity size and the nature of the substituents. The effect of pretreatment was studied too. In vitro permeation experiments were carried out on Franz diffusion cells using cellulose nitrate membranes and abdominal rat skin. In these results, the release rates of the drug scarcely decreased when the CDs were added, probably because of a lower concentration of the free drug and an increased gel viscosity. However, it was also found that CDs, particularly γ-CD and M-β-CD, can improve slightly TEN absorption through the skin. Pretreatment studies with CDs, however, provided no effects on TEN permeation, but lag time was markedly reduced, suggesting a faster partitioning of TEN into the skin. Therefore, the use of pretreatment with CDs would be interesting when a quick action of the drug is desired.     

Effect of intratumoral injection on the biodistribution and therapeutic potential of novel chemophor EL-modified single-walled nanotube loading doxorubicin

The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a doxorubicin (DOX)-loaded Polyoxyl 35 Castor Oil (Cremophor EL, CrEL) noncovalent modified single-walled carbon nanotubes (SWNTs) formulation in a sarcoma tumor model after intratumoral injection. The drug loaded SWNTs were successfully prepared via physical absorption, which was confirmed by UV-vis-NIR absorbance spectra and dynamic light scattering assay. Solid tumor models were obtained by injecting mouse sarcoma 180 cells into the thighs of ICR mice. CrEL-SWNTs-DOX, CrEL-SWNTs, free DOX and saline (control) were intratumorally injected after 5 days post transplantation. The biodistribution studies demonstrated that intratumoral delivery of CrEL-SWNTs-DOX resulted in longer drug retention time in tumor, higher tumor level (27.6-fold than that of free DOX), as well as less accumulation in other solid tissues, especially in heart. Furthermore, in vivo anti-tumor activity results showed that CrEL-SWNTs-DOX could effectively suppress the tumor growth than free DOX and the control, attributing to its enhanced intratumoral DOX level. The histopathological findings revealed that the new carbon nanomaterials were a safe vehicle for topical drug delivery systems. It is concluded that this noncovalent modification of carbon nanotubes by CrEL for anticancer agents might be a promising alternative for cancer treatment.     

Effect of O-acylmenthol and salt formation on the skin permeation of diclofenac acid

Purpose: To enhance the transdermal delivery of diclofenac acid (DA) by using O-acylmenthol as a penetration enhancer and complexing with amines, or by a combination of the two methods. Methods: The skin permeability of diclofenac was tested in vitro across rat skin with each of the evaluated permeants in a saturated isopropyl myristate (IPM) donor solution. Results: A 4.5-fold increase in the flux of diclofenac was observed by ion-pair formation with diethylamine; however, the cations with hydroxyl groups had negative effects on the transdermal delivery of diclofenac. 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate and 2-isopropyl-5-methylcyclohexyl heptanoate produced significant increase in the permeation of diclofenac potassium (D-K); however, both of them were ineffective for the other diclofenac salts, including diclofenac diethylamine (D-DETA), diclofenac ethanolamine (D-EA), diclofenac diethanolamine (D-DEA), diclofenac triethanolamine, and diclofenac N-(hydroxylethyl) piperidine. 2-isopropyl-5-methylcyclohexyl tetradecanoate was effective on the penetration of D-K, D-DETA, D-EA, and D-DEA. Also, it is exciting to note that the combined use of diethylamine with 2-isopropyl-5-methylcyclohexyl tetradecanoate produced a 9.74-fold increase in accumulation amount of diclofenac compared with DA in IPM. Conclusions: The use of ion pair in combination with O-acylmenthol is necessary to further increase the diclofenac flux to provide better compliance for the patients undergoing clinical therapy.