Effect of Terpenes on the enhancement of skin permeation of lipophilic drugs: A systematic review

Objectives@#The stratum corneum (SC) remains an obstacle to the passage of drugs applied topically. Several investigations have focused on enhancing the penetration of drugs through the SC by integrating permeation enhancers (PE) into the drug formulation. Terpenes are among the PE utilized in formulations and are categorized by the regulatory bodies as generally recognized as safe (GRAS). This study aimed to comparatively analyze the skin permeation enhancing effect of terpenes on lipophilic drugs. @*Methods@#The present study reviewed the effects of terpenes on the permeation of lipophilic small-molecule drugs through the skin using original research published between 2000 - 2022 retrieved from PubMed®. The search phrase used was (lipophilic drug) AND (terpene) AND (permeation enhancer). @*Results@#Terpenes increase the percutaneous permeation of lipophilic small molecule drugs by 1.06 – 256.80-fold. Linear correlation analysis of terpenes’ cLog P with enhancement ratio (ER) revealed moderate and strong positive correlations in pig skin (r = 0.21) and mouse skin (r = 0.27), and rat skin (r = 0.41) and human skin (r = 0.67), respectively. Drug cLog P is a poor (r = -0.06) predictor of permeation enhancement. Terpenes with cLog P higher than 2.40 had ER greater than 10. Higher ERs (>30) were recorded for nerolidol, carvacrol, borneol, terpineol, limonene, menthone, pulegone, and menthol among the terpene-chemical penetration enhancers. @*Conclusion@#cLog P of terpene-based chemical permeation enhancers (CPE) is strongly correlated with ER of lipophilic drugs across human skin. Non-polar groups in terpenes and hydrogen bond interactions by terpenes with SC lipid enhance cutaneous drug penetration of lipophilic drugs.

Development and optimization of metoclopramide containing polymeric patches: impact of permeation enhancers

Abstract The study is aimed to develop a monolithic controlled matrix transdermal patches containing Metoclopramide as a model drug by solvent casting method. Eudragit L100, Polyvinylpyrrolidone K-30, and Methylcellulose were used in different ratios and Polyethylene glycol 400 added as a plasticizer. Resulting patches were evaluated for their physicochemical characters like organoleptic characters, weight variation, folding endurance, thickness, swelling index, flatness, drug content, swelling index, percentage erosion, moisture content, water vapor transmission rate and moisture uptake. Formed patches were also evaluated through Fourier transform spectroscopy (FT-IR), X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Scanning Electron Microscopy (SEM). Results of SEM unveiled smooth surface of drug-loaded patches. In-vitro dissolution studies were conducted by using dissolution medium phosphate buffer saline pH 7.4. Effect of natural permeation enhancers was elucidated on two optimized formulations (Z4 and Z9). Different concentrations (5%-10 %) of permeation enhancers i.e. Olive oil, Castor oil and Eucalyptus oil were evaluated on Franz diffusion cell using excised abdominal rat skin. Z4-O2 (Olive oil 10%) had enhanced sustain effect and flux value (310.72) close to the desired flux value. Z4-O2 followed Higuchi release model (R2= 0.9833) with non-fickian diffusion release mechanism (n=0.612)

Advances in the study of peptide drugs in oral drug delivery system / 药学学报

Peptide drugs exhibit an irreplaceable role in clinics due to their high specificity, efficiency and low toxicity. At present, more than 80 peptide drugs have been approved for marketing with global sales exceeding $50 billion in 2019. However, with large molecular weights, high hydrophilicity and instability in digestive tract, oral peptide drugs encounter substantial physiological barriers leading to low oral bioavailability. Therefore, peptide drugs are mostly administered by parenteral routes. Although parenteral delivery of peptide drugs achieves high bioavailability, this is associated with inconvenience and discomfort, even causing severe side effects compared with the oral route possessing a high degree of patient compliance. Therefore, numerous studies concentrate on novel strategies to improve the oral bioavailability of peptide drugs. Some delivery technologies such as Eligen™ and Axcess™ have been successfully applied to the oral dosage form of therapeutic peptides and have accelerated relevant oral formulations for Food and Drug Administration (FDA) approval and clinical treatment. In this review, we focus on the oral peptide delivery, mainly summarizing the progress of recent strategies used to overcome oral barriers and the commercialization applications of related patents, which could facilitate the research and development (R&D) of clinical applications of oral delivery techniques for peptide drugs.

Characterization of Methyl and Ethyl Esters of Amino-Acids as Corneal Permeation Enhancers

@#Introduction: Amino acids are important role-playing components in the maintenance of the normal functions of parts of eye like retina and conjunctiva. In the current study the methyl and ethyl esters of amino acids such as lysine, phenyl alanine and valine were used to enhance the corneal permeation of ketorolac tromethamine. Methods: The amino-acid esters were coupled with the drug ketorolac tromethamine to obtain the test products and were characterized by various analytical techniques. The characterized test products were used to formulate the test ophthalmic solutions of Ketorolac tromethamine such as KPD-1, KPD-1A, KPD-2, KPD-2A, KPD-3 and KPD-3A with methyl and ethyl esters of corresponding amino-acids. These test products were subjected percentage corneal hydration and to permeation studies by using Franz diffusion cell mounted with freshly isolated goat cornea. Results: All the test results were compared with those of the standard Ketorolac tromethamine ophthalmic solution and observed that all the test solutions have exhibited less percentage corneal hydration and enhanced corneal permeation of ketorolac tromethamine. Conclusion: From all the results it can be concluded that the NonsteroidalAnti-Inflammatory Ketorolac has enhanced trans-corneal permeation and reduced corneal hydration when formulated with amino acid transporters by the pro-drug approach in ophthalmic solutions as the formulated pro-drugs have revealed high vitreal drug concentration.

Studies on in vitro Transdermal Permeability of Nifedipine Nanoemulsion Containing Different Permeation Enhancers / 中国药师

Objective:To study the in vitro transdermal permeability of nifedipine nanoemulsion ( NFNE) containing different per-meation enhancers to lay foundation for the development of transdermal nifedipine preparation. Methods: Franz diffusion cells were used to study the transdermal enhancement of NFNE with different transdermal enhancers ( Azone, oleic acid, TMC20, TMC40, TMC60). Results:The in vitro transdermal effect of NFNE was better than that of nifedipine (NF). The order of in vitro transdermal permeation enhancement was as follows: azone > oleic acid > TMC60 > TMC40 > TMC20, while the water-soluble transdermal permeation enhancers had faster effect. Conclusion:For NFNE, fat-soluble transdermal permeation enhancers have better effect.

Percutaneous permeation characteristic research of dencichine / 中草药

Objective: To evaluate the percutaneous absorption properties of dencichine. Methods: Shaking flask method was used to determine the apparent solubility and oil-water partition coefficient of dencichine. The Franz diffusion cell method was adopted and skin of mice and pig was used as the model skin. The content of dencichine and optimized penetration enhancer were determined using HPLC. Results: Dencichine is water soluble with a low lg P value. Dencichine showed a better penetrability in mice skin than in pig skin. The permeation profiles of dencichine can be fitted well by Higuchi model. The significant percutaneous absorption for dencichine is 5% NMP. Conclusion: Dencichine shows the certain perctaneous absorption ability. And the skin permeation profiles are related with the diffusion rate of the drug in skin. The permeability rate could be promoted by 5% NMP.

Stimulating effect of essential oils from Ligusticum chuanxiong hort on HaCaT cells and skin / 第二军医大学学报

Objective To investigate the skin stimulation effect of essential oils from Ligusticum chuanxiong Hort. Methods HaCaT cells were cultured in vitro. Using MTT and ELISA methods, we examined the effect of the essential oil (different concentrations) on HaCaT cell proliferation and prostaglandin E2 (PGE2) levels in culture supernatants of HaCaT cells, and the resultswere compared with those of oleic acid, a classic permeation enhancer. The cumulative skin stimulation effect was determined by visual scoring in guinea pigs and the histological changes were determined by light microscopy. Results The HaCaT cell viabilities of the 0. 005%, 0.015%, and 0. 025% essential oil groups were 1. 79-, 1. 65-, and 1. 48-fold that of the 0. 005% oleic acid group, respectively, and there was no significant difference between the 0. 05% essential oil group and 0.005% oleic acid group. The 0. 005 %, 0.015%, 0.025%, and 0.05% essential oil influenced the supernatant PGE2 levels by (0.99±0.08)%, (1.63±0. 09) %, (0. 98±0. 09) %, and (0. 04±0. 01) %, respectively, which were all significantly lower than the influence of 0.005% oleic acid ([4. 23 + 0. 68] %, P<0. 05). Only slight erythema was observed after continuous administration the essential oil (different concentrations) for 7 days, with no edema or skin uplift, and the erythema caused by 15% essential oil was lower than that causedby5% oleic acid. Only 15% essential oil exhibited the mechanical injury of the stratum corneum. And 5 % oleic acid group showed stripped and lost stratum corneum over large areas. Conclusion Chuanxiong oil is less cytotoxic and less stimulating to the skin compared with oleic acid, and may become an excellent skin permeation enhancer.

Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol(R), sodium cholate, sodium caprate, hydroxypropyl beta-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and Papp of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC0-24 h of ZMR in the lungs following oral administration of PO-SC was 125.22 +/- 27.25 ng hr ml(-1) with a Cmax of 156.00 +/- 24.00 ng/ml reached at 0.50+/-0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC50 concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.

Preparation of aminophylline patches and their pharmacokinetics in rabbits after navel adminstration / 中国药学杂志

OBJECTIVE: To prepare aminophylline patches and study the pharmacokinetic characteristics in rabbits after application on navel. METHODS: Aminophylline patches were prepared by hot-envelop method. Modified Franz diffusion cells were employed to screen permeation enhancers with excised rat abdomen skins as diffusion barrier. The concentration of aminophylline in rabbit plasma was determined by HPLC after aminophylline solution was irrigated intragastrically and the aminophylline patches were applied on notum and navel, respectively. Pharmacokinetic parameters were calculated and the pharmacokinetic profiles were characterized by comparing the above three groups with statistical analysis. RESULTS: Based on the excised rat skin permeation test, 3% menthol-propanediol (1: 1) mixture was the optimal permeation enhancer with a steady state permeation rate of (9.08 ± 0.21) μg · cm-2 · h-1. The main pharmacokinetic parameters of, notum application group and navel application group were as follows: ρmax were (13.42 ± 1.10), (4.53 ± 0.39) and (5.77 ± 0.44) μg · mL-1 and tmax(1.83 ± 0.29), (5.67 ± 0.58) and (4.33 ± 0.58) h, AUC0→t, (47.65 ± 3.46), (31.65 ± 4.11) and (39.97 ± 3.14) μg · h · mL-1, t1/2 (1. 90 ± 0.30), (2.45 ± 0.07) and (1.90 ± 0.06) h, Ka(2.01 ± 0.55), (0.33 ± 0.02) and (0.55 ± 0.04) h-1, tlag were (0.19 ± 0.04), (0.59 ± 0.03) and (0.32 ± 0.19) h, respectively. The relative bioavailabilities of aminophylline after notum and navel application were (67.41 ± 19.11)% and (84.81 ± 18.03)% respectively compared with intragastrical irrigation group. CONCLUSION: The preparation process of aminophylline patches with desirable skin permeation property is practicable. Aminophylline patches are able to realize sustained-drug release and have higher bioavailability after navel application compared with notum application.

Preliminary screening of different permeation enhancers in transcutaneous immunization with inactivated human highly pathogenic avian influenza vaccine / 中华微生物学和免疫学杂志

Objective To screen the potent permeation enhancers used in transcutaneous immunization with inactivated highly pathogenic avian influenza vaccine. Methods Five different permeation enhancers, ethanol, propylene glycol, dimethyl sulfoxide, ratinoic acid, oleic acid, were used to treat the skin of BALB/c mice before transcutaneous immunization. Sera were collected before the flist transcutaneous immunization and every two weeks post immunization. The titers of influenza virus-specific humoral IgG and IgA were assayed in serum, lung and nasal lavages by ELISA. The titers of hemagglutination inhibition ( HAI), IFN-γand IL-4 produced by splenic lymphocytes were also detected. Except that, clinical symptom of the skin in different time points and skin pathological changes were observed. Results The serum IgG titers, HAI titers and the influenza virus-specific lgA and IgG in lung and nasal lavages in the groups of HA +CT + DMSO, HA + CT + RA and HA + CT + OA were significantly higher than those of HA and HA + CT groups( P ＜0.05). Moreover, the numbers of splenic lymphocytes producing IFN-γ and IL-4 were increased in the above three groups than those in control groups. In addition, no evident clinical symptoms were observed, but stratum corneum of the skin in different groups showed different changes. Conclusion DMSO,RA and OA are potent permeation enhancers in mouse model inoculated with inactivated high pathogenic avian influenza vaccine transcutaneously.