Microneedle-mediated intradermal delivery of epigallocatechin-3-gallate.

OBJECTIVE: Epigallocatechin-3-gallate (EGCG) is the physiologically most active and abundant flavanol, accounting for 50-80% of green tea catechins. It is an anti-inflammatory, antioxidant, chemopreventive and skin photoprotective agent. However, light sensitivity and low permeability of EGCG across the stratum corneum due to its high molecular weight as well as strong binding to the lipid bilayers in the skin make it difficult to be used as a key ingredient in cosmetic products. This study aimed to formulate a photostable hydrogel of EGCG with good rheological properties for dermal application and investigate the effect of skin microporation using maltose microneedles on its permeation through dermatomed porcine skin. METHODS: Effect of l-glutathione on photodegradation of EGCG was investigated by exposing samples to ultraviolet irradiation for 1 h using a solar simulator. Hydrogels with varying concentrations of Carbopol 980 (0.5-2% w/v) as an gelling agent were prepared, and their rheological properties were evaluated using a rheometer. Skin microporation was confirmed by assessing the skin resistance, transepidermal water loss and calcein imaging of the microchannels created by the microneedles. Permeation of EGCG from aqueous solution as well as the rheologically optimized hydrogel through the dermatomed porcine skin (untreated and microneedle treated) was evaluated using static vertical Franz diffusion cells. RESULTS: l-glutathione acting as a co-antioxidant and photostabilizer significantly (P < 0.05) reduced the degradation of EGCG from 21.53 ± 2.78% to 1.0 ± 0.68% after 1 h of ultraviolet irradiation. Rotational and oscillatory rheological tests indicated that the hydrogel containing 1.5% Carbopol 980 is acceptable for topical application in terms of flow behaviour, elasticity, spreadability, structural stability and thixotropy. Microneedle-treated skin showed significant enhancement (P < 0.05) in the delivery of EGCG to viable epidermis and dermis from the aqueous solution (38.67 ± 2.96 µg cm(-2) ) as well as hydrogel (24.60 ± 2.62 µg cm(-2) ) in comparison with the untreated skin (24.16 ± 2.11 and 15.62 ± 0.24 µg cm(-2) for aqueous solution and hydrogel, respectively). CONCLUSION: Addition of glutathione in EGCG formulations significantly reduces its photodegradation. Skin microporation with maltose microneedles facilitates the penetration of EGCG across the stratum corneum into the deeper skin layers - viable epidermis and dermis.

Stable insulin-secreting ducts formed by reprogramming of cells in the liver using a three-gene cocktail and a PPAR agonist.

With the long-term aim of developing a new type of therapy for diabetes, we have investigated the reprogramming of liver cells in normal mice toward a pancreatic phenotype using the gene combination Pdx1, Ngn3, MafA. CD1 mice were rendered diabetic with streptozotocin and given a single dose of Ad-PNM, an adenoviral vector containing all three genes. Ad-PNM induced hepatocytes of the liver to produce insulin, and the blood glucose became normalized. But over several weeks, the insulin-positive cells were lost and the blood glucose rose back to diabetic levels. Simultaneous administration of a peroxisome-proliferator-activated receptor agonist, WY14643, caused remission of diabetes at a lower dose of Ad-PNM and also caused the appearance of a population of insulin-secreting ductal structures in the liver. The insulin-positive ducts were stable and were able to relieve diabetes in the long term. We show that the effect of WY14643 is associated with the promotion of cell division of the ductal cells, which may increase their susceptibility to being reprogrammed toward a beta cell fate.

Formulation of tocopherol nanocarriers and in vitro delivery into human skin.

OBJECTIVE: Tocopherol is stronger antioxidant than tocopherol acetate but due to its viscous form, poor water solubility, instability to light and skin irritation issues it is not used in the current marketed formulations. To overcome the drawbacks, tocopherol was formulated as nanostructured lipid carriers and nanoemulsion. The objective of the study was to formulate tocopherol as nanocarriers. METHOD: Nanostructured lipid carriers (NLCs) and nanoemulsion (NE) were prepared by homogenization technique. They were characterized for particle size and zeta potential. In vitro release study was performed using dialysis method, and skin permeation was carried out using human cadaver skin. Further, antioxidant activity was tested by ferric reducing antioxidant potential (FRAP) assay and skin irritation testing was performed on Epiderm skin model. Effect of UV degradation was studied using solar simulator. RESULTS: The size and zeta potential of NLC was 67.0 nm ± 1.2 and -32.0 mV ± 1.2, whereas for NE, it was 586.5 nm ± 209.6 and -10 mV ± 0.6. In vitro release study showed that 30% of tocopherol was released from NLC in the first 2 h of the study as compared to only 4% from NE. Permeation study from human skin showed that 762.3 ng mL(-1) ± 184.6 of tocopherol was delivered into the epidermis when formulated as NLCs as compared to 182.3 ng mL(-1) ± 52.7 from NE. FRAP assay was performed to test the antioxidant activity of formulated tocopherol, and it was seen that both formulations were able to retain the antioxidant activity. Skin irritation testing showed that NLC was non-irritant to the skin. NLC and NE were also able to protect tocopherol from UV degradation. CONCLUSION: Based on the studies conducted, it can be concluded that formulating tocopherol as NLCs is beneficial to produce a stable, non-irritant and aqueous formulation.

Quantification of skin penetration of antioxidants of varying lipophilicity.

Antioxidants play a vital role in protecting the skin from environmental distress. As the skin is constantly exposed to harmful UV radiation, endogenous antioxidants present in the superficial layers of the skin neutralize reactive oxygen species. Over time, antioxidants become depleted and loss their protective effect on the skin. Therefore, supplementing skin with topical antioxidant can help replenish this loss and fight the oxidative stress. The objective of this study was to deliver antioxidants topically and quantify the amount permeated in the stratum corneum and underlying skin. Polyphenols (catechin, resveratrol and curcumin) and vitamin (retinol) with various lipophilic properties were delivered via porcine ear skin, using propylene glycol as a vehicle. The amount in the stratum corneum and underlying skin was quantified using tape stripping and skin extraction methods, respectively, and samples were analysed via HPLC. All four antioxidants permeated into the skin from the propylene glycol vehicle. The order of the amount of antioxidant in the stratum corneum was catechin > resveratrol~ retinol> curcumin, whereas that in the underlying skin was retinol > catechin~ resveratrol~ curcumin. Of the total amount of polyphenols in the skin, approximately 90% was retained in the stratum corneum whereas 10% was quantified in the underlying skin. In contrast, 10% of retinol was retained in the stratum corneum whereas 90% permeated in the underlying skin. Polyphenols (catechin, resveratrol and curcumin) showed high concentration in the stratum corneum whereas retinol showed high accumulation in the underlying layers of the skin.

Evaluating the Use of CT-Derived Lung Volumes in Donor-Recipient Lung Size Matching for Lung Transplantation in Patients With Interstitial Lung Disease and/or Idiopathic Pulmonary Fibrosis.

PURPOSE: This study aims to assess the efficacy of current measurement strategies for lung sizing and the feasibility of future use of computed tomography (CT)-derived lung volumes to predict a donor-recipient lung size match during bilateral lung transplants. METHODS: We reviewed the data of 62 patients who underwent bilateral lung transplantation for interstitial lung disease and/or idiopathic pulmonary fibrosis from 2018 to 2019. Data for recipients was retrieved from the department's transplant database and medical records, and the donor's data was retrieved from the DonorNet. The data included demographic data, lung heights, measured total lung capacity (TLC) from plethysmography for recipients and estimated TLC for donors, clinical data, and CT-derived lung volumes in both pre- and post-transplant recipients. The post-transplant CT-derived lung volume in recipients was used as a surrogate for donor lung CT volumes due to inadequate or poor donor CT data. Computed tomography-derived lung volumes were calculated using thresholding, region growing, and cutting techniques on Computer-Aided Design and Mimics (Materialise NV, Leuven, Belgium) programs. Preoperative CT-derived lung volumes in recipients were compared with the plethysmography TLC, Frustum Model, and donor-predicted TLC. The ratio of the recipient's pre-and postoperative CT-derived volumes, the ratio of preoperative CT-derived lung volume, and donor-estimated TLC were studied to detect a correlation with 1-year outcomes. RESULTS: The recipient preoperative CT-derived volume correlated with the recipient preoperative plethysmography TLC (Pearson correlation coefficient [PCC] of 0.688) and with the recipient Frustum model volume (PCC of 0.593). The recipient postoperative CT-derived volume correlated with the recipient's postoperative plethysmography TLC (PCC of 0.651). There was no statistically significant correlation between recipients' CT-derived pre- or postoperative volume with donor-estimated TLC. The ratio of preoperative CT-derived volume to donor-estimated TLC correlated inversely with the length of ventilation (P value = .0031). The ratio of postoperative CT-derived volume to preoperative CT-derived volume correlated inversely with delayed sternal closure (P = .0039). No statistically significant correlations were found in evaluating outcomes related to lung oversizing in the recipient (defined as a postoperative to preoperative CT-derived lung volume ratio of >1.2). CONCLUSIONS: Generating CT-derived lung volumes is a valid and convenient method for evaluating lung volumes for transplantation in patients with ILD and/or IPF. Donor-estimated TLC should be interpreted carefully. Further studies should derive donor lung volumes from CT scans for a more accurate evaluation of lung size matching.

Characteristics and Outcomes Among Patients With Early Venous Thromboembolic Events After Lung Transplant.

BACKGROUND: Despite several previous studies reporting a high frequency of venous thromboembolism (VTE) after lung transplant (LT), few actionable risk factors have been identified. There are limited data regarding the practice patterns of anticoagulation use among patients with LT. METHODS: All adult patients with single or bilateral LT between 2012 and 2016 were included (n = 324; mean age, 56.3 ± 13.3 years; male, 61.1%). Demographic, clinical, and laboratory variables before and after LT were recorded. Follow-up data included survival up to 3 years post-transplant. Development of VTE during the first 30 days after LT was the primary outcome variable. RESULTS: The overall incidence of VTE during the first 30 days after LT was 29.9% (n = 97), among which the majority were upper extremity thromboses. Female sex, personal history of VTE, hospitalization at the time of transplant, and use of 3 or more central venous catheters during index hospitalization were independently associated with VTE. The use of anticoagulants was independently associated with a reduced risk of VTE. Despite increased morbidity, the development of VTE was not associated with worse post-transplant survival. CONCLUSIONS: A significant proportion of patients develop early VTE after LT. Limiting the number of central catheters to < 3 during the post-transplant period, along with the early institution of thromboprophylaxis, may lower the risk of VTE.

Iontophoretic skin delivery systems: Success and failures.

Iontophoretic transdermal delivery uses a small electric current to push charged molecules into the skin under an electrode of same polarity and offers an attractive option to facilitate the delivery of macromolecules or hydrophilic molecules and to improve patient compliance. This technique has been used in physical therapy clinics for several decades, though the science was not always there to support claims of clinical effectiveness. Recently, this modality of treatment has undergone more systematic and rigorous investigations to withstand the scrutiny of regulatory authorities. In recent years various drugs have gained FDA approval for iontophoretic patches. This technique is gaining recognition due to better compliance rates, non-invasive drug delivery leading to fewer side effects, and sustained release of the drug. Furthermore, programmed delivery and bolus delivery systems have helped with customizing the drug dosage and frequency of dosage based on the patient's need.

Enhanced transdermal delivery of low molecular weight heparin by barrier perturbation.

The purpose of this work was to investigate the in vitro transdermal delivery of low molecular weight heparin (LMWH). Hairless rat skin was mounted on Franz diffusion cells and treated with various enhancement strategies. Passive flux was essentially zero and remained low even after iontophoresis (0.065 U cm(-2) h(-1)) or application of ultrasound (0.058 U cm(-2) h(-1)). A significant increase in flux across tape stripped skin (4.0 U cm(-2) h(-1)) suggests the interaction of stratum corneum (SC) with LMWH which was confirmed using Differential Scanning Calorimetry and Fourier Transform-Infrared spectrophotometry. Maltose microneedles were then employed as a means to locally disrupt and bypass the SC. Transepidermal water loss (TEWL) and transcutaneous electrical resistance (TER) were measured to confirm the barrier disruption. Microneedles breached the SC resulting in increased TEWL, decreased TER and enhanced LMWH permeability (0.175 U cm(-2) h(-1)). Microneedles when used in conjunction with iontophoresis had a synergistic effect on LMWH delivery resulting in enhancement of flux by 14.7-fold as compared to iontophoresis used alone. Confocal laser scanning microscopy substantiated the evidence about LMWH interaction with SC. In conclusion, LMWH was shown to interact with SC and therefore tape stripping or microneedles dramatically increased its delivery due to disruption of the SC skin barrier.

Thermal and non-thermal methods to evaluate compatibility of granisetron hydrochloride with tablet excipients.

Compatibility of granisetron hydrochloride with selected excipients was assessed using Differential Scanning Calorimetry (DSC) as a thermal screening technique. Non-thermal methods like Fourier Transform Infrared spectroscopy and Thin Layer Chromatography were used as complementary techniques to adequately support and assist in interpretation of DSC results. Some drug-excipient interaction was observed with beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, mannitol, and magnesium stearate in DSC studies. However, further evaluation of these incompatible excipients with non-thermal methods showed that these excipients were compatible with granisetron hydrochloride. Non-thermal methods were, thus, of help in interpreting DSC results and excluding all relevant pharmaceutical incompatibilities.

Predictors of development and outcome in patients with acute respiratory distress syndrome due to tuberculosis.

OBJECTIVE: To study the predictors of development and determinants of outcome in patients with acute respiratory distress syndrome (ARDS) due to tuberculosis (TB). METHODS: Retrospective case-control study of demographic, clinical and laboratory data of hospitalised adult patients with active TB. RESULTS: Of 2733 TB patients treated during 1980-2003, 29 (1.06%; 1.21 patients/year; mean age 31.6 +/- 10.9 years; 16 males) developed ARDS (cases). Seven had pulmonary TB and 22 had miliary TB (MTB); 298 (mean age 32.0 +/- 14.2 years; 110 males) who did not develop ARDS constituted controls. Presence of MTB (OR 4.6, 95%CI 1.2-17.8; P = 0.02), duration of illness beyond 30 days at presentation (OR 177.9, 95%CI 39-811.7; P < 0.001), absolute lymphocyte count < 1625/ mm3 (OR 4.5, 95%CI 1.1-19.3; P = 0.04) and serum ALT > 100 IU (OR 15.7, 95%CI 3.0-81.1, P < 0.001) were independent predictors of ARDS development. Twelve cases died (41.4%). Patients with APACHE II score >18; those with APACHE II score <18 in the presence of hyponatraemia and PaO2/FIO2 ratio <108.5 were likely to die. CONCLUSIONS: In patients with TB, prolonged illness, MTB, absolute lymphocytopaenia and elevated ALT are independently associated with ARDS development. APACHE II score, serum sodium and PaO2/FIO2 ratio are determinants of outcome.

Validation of the modified Berlin questionnaire to identify patients at risk for the obstructive sleep apnoea syndrome.

BACKGROUND & OBJECTIVES: Awareness regarding obstructive sleep apnoea (OSA) among general public as well as practicing physicians is low in India. The present study was undertaken to test the utility of modified Berlin questionnaire for risk categorization of OSA in Indian setting. METHODS: The modified Berlin questionnaire was administered in 180 middle aged adults (of 320 screened), of whom, 104 underwent overnight polysomnograhy, in a cross-sectional study at a tertiary care, referral center in north India. Questionnaire addressed the presence of frequency of snoring, wake time sleepiness, fatigue, obesity and hypertension. Subjects with persistent and frequent symptoms in any two of these three domains were considered in high risk category for obstructive sleep apnoea. Overnight polysomnograhy was performed to measure apnoea and hypopnoea index (AHI). RESULTS: Questions about the symptoms demonstrated internal consistency (Cronbach alpha correlations 0.92-0.96). Of the 180 respondents to the screening questions, 80 were in the high risk and the rest were in low risk group. For 104 subjects who underwent polysomnograhy, risk grouping was useful in prediction of AHI. High risk category predicted an AHI >5 with a sensitivity of 86 per cent, specificity of 95 per cent, positive and negative predictive values of 96 and 82 per cent respectively. These results were comparable to Berlin questionnaire study done in the western population for validation. INTERPRETATION & CONCLUSION: On the basis of the findings of present study it is concluded that administration of modified Berlin questionnaire prior to a polysomnography study can identify high risk subjects and can thus avoid unnecessary polysomnography studies especially in resource-limited settings. To identify subjects at risk for OSA syndrome in general population, this questionnaire can be applied. However, the findings of the present study need to be confirmed further in a large number of subjects in a community-based setting.

Assessing the potential of skin electroporation for the delivery of protein- and gene-based drugs.

Although transdermal drug delivery has many potential advantages, the permeability of skin to macromolecules is extremely low. However, the application of short, high-voltage pulses to electroporate skin has recently been shown to make it reversibly permeable. A number of studies have demonstrated that electroporation-mediated transdermal delivery of peptides, polysaccharides, oligonucleotides and genes may be possible at clinically relevant rates, leading to the current commercial development of electroporation techniques.

Use of intravaginal microbicides to prevent acquisition of Trichomonas vaginalis infection in Lactobacillus-pretreated, estrogenized young mice.

D2A21, a novel peptide antibiotic has in vitro activity against a wide spectrum of sexually transmitted diseases (STD). In this study we tested the hypothesis that intravaginal D2A21 would interfere with acquisition of Trichomonas vaginalis infection in a modified mouse model. T. vaginalis infections of estrogenized young mice pretreated with Lactobacillus vaginalis or Lactobacillus rhamnosus were more frequent and persistent than those in mice pre-treated with Lactobacillus gasseri or Lactobacillus acidophilus. One hundred percent T. vaginalis infection was achieved for 2-4 days post-challenge when intravaginal L. rhamnosus pre-treatments were given to estrogenized mice 48 hr prior to a single T. vaginalis challenge. Estrogenized mice pre-treated with L. rhamnosus were pre-medicated with intravaginal placebo gel, 0.5% or 2% D2A21 gel, or 500 microg/mL metronidazole gel prior to T. vaginalis challenge. Both 2% D2A21 and metronidazole gels were significantly more efficacious (10% or none infected) than placebo gel (53% infected) in preventing vaginal T. vaginalis infections in mice.

A stepped approach for prediction of obstructive sleep apnea in overtly asymptomatic obese subjects: a hospital based study.

BACKGROUND AND PURPOSE: Prevalence of obstructive sleep apnea (OSA) is high in obese subjects, many of whom may not be overtly symptomatic. Polysomnography (PSG) is a costly and time-consuming investigation. Since it is not feasible to subject all obese individuals to PSG, it is useful to define predictors of OSA among these subjects. PATIENTS AND METHODS: One hundred and eighteen obese subjects [body mass index (BMI)> or =25 kg/m(2)] presenting to the hospital with non-sleep related complaints were included, of which 53 subjects with PSG evidence of OSA [apnea-hypopnea index (AHI)> or =15/h] were defined as cases and 65 subjects without any evidence of OSA (AHI<15/h) were defined as controls. Anthropometry, biochemical investigations, blood gas analysis, pulmonary function tests, and PSG were performed for all subjects. RESULTS: Waist hip ratio (WHR) (as percentage of a standard) [odds ratio (95% CI): 1.07 (1.00-1.14); P = 0.049] male gender [odds ratio (95% CI): 3.97 (0.99-15.81); P = 0.046] and neck circumference (NC) [odds ratio (95% CI): 1.23 (1.03-1.47); P = 0.023] were found to be independent predictors of OSA. Overnight oxygen desaturation data were evaluated in patients selected as having OSA on the basis of these clinical markers, and the best cut-off for level of desaturation (10%) was defined. The stepped approach had a specificity, sensitivity, positive and negative predictive value of 89.2, 88.5, 86.8 and 90.6%, respectively, for the diagnosis of OSA. CONCLUSIONS: Male gender, WHR and NC are independent predictors of OSA in overtly asymptomatic obese subjects. A stepped approach to diagnose OSA should be used, as it is accurate and cost-effective.

The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones.

Electrically-assisted delivery by iontophoresis and/or electroporation was used in vitro to deliver the calcium regulating hormones, salmon calcitonin (sCT) and parathyroid hormone (1-34) (PTH) through human epidermis. Such delivery could be useful for chronic treatment of post-menopausal osteoporosis and other clinical indications as a superior alternative to parenteral delivery. sCT (50 microg/ml) or PTH (1-34) (100 microg/ml) formulation was prepared in citrate buffer (pH 4.0 or 5.0, respectively). Epidermis separated from human cadaver skin was used. Iontophoresis was applied using a constant current power source and electroporation with an exponential pulse generator. Silver/silver chloride electrodes were used. A combination of electroporation and iontophoresis resulted in higher transdermal permeation than either one technique alone. Electroporation also shortened the lag time of iontophoretic transdermal delivery of salmon calcitonin. Pulsing at lower voltages followed by iontophoresis did not result in increased transport (over iontophoresis alone), perhaps because the transdermal voltage was very low. The transdermal transport of salmon calcitonin by pulsing with 15 pulses (1 ppm) of 500 V (200 ms) followed by iontophoresis led to a quick input and high flux. The average transdermal voltage was only about 50 V for a 500 V study.

Electrically-assisted transdermal delivery of buprenorphine.

The objective of this study was to explore the electrically assisted transdermal delivery of buprenorphine. Oral delivery of buprenorphine, a synthetic opiate analgesic, is less efficient due to low absorption and large first-pass metabolism. While transdermal delivery of buprenorphine is expected to avoid the first-pass effect and thereby be more bioavailable, use of electrical enhancement techniques (iontophoresis and/or electroporation) could provide better programmability. Another use of buprenorphine is for opiate addiction therapy. However, a patch type device is subject to potential abuse as it could be removed by the addict. This abuse can be prevented if drug particles are embedded in the skin. The feasibility of doing so was investigated by electro-incorporation. Buprenorphine HCl (1 mg/ml) in citrate buffer (pH 4.0) was delivered in vitro across human epidermis via iontophoresis using a current density of 0.5 mA/cm(2) and silver-silver chloride electrodes. Electroporation pulses were also applied in some experiments. For electro-incorporation, drug microspheres or particles were driven into full thickness human skin by electroporation. It was observed that the passive transdermal flux of buprenorphine HCl was significantly enhanced by iontophoresis under anodic polarity. The effectiveness of electro-incorporation seemed inconclusive, with pressure also playing a potential role. Delivery was observed with electro-incorporation, but the results were statistically not different from the corresponding controls.

Minimization of shaking-induced formation of insoluble aggregates of insulin by cyclodextrins.

Aggregation is known to complicate insulin delivery and the processing and formulation of biotechnology-derived peptide/protein drugs. Shaking-induced formation of insoluble aggregates in bovine insulin and the potential role of cyclodextrins in preventing such aggregation were investigated. Insulin, dissolved in phosphate buffer, pH 7.2, and preserved with 2 mg/ml of phenol was aggregated, in triplicate, by shaking at 450 rpm for 2.5 days on a gyratory shaker. Visible aggregation was quantitated by measuring optical density in the visible range on a spectrophotometer. Solutions were then filtered through a 0.22 mu filter and the amount of insulin remaining in filtrate was determined by HPLC. Aggregation increased at lower concentrations, with solutions turning milky at 0.5 mg/ml; HPLC assay of filtrate indicated a complete loss of insulin. Under the same conditions, except for shaking, control solutions exhibited no insulin loss, excluding absorption as a cause of the insulin loss. The use of cyclodextrins (0.5 mg/ml) to stabilize insulin was investigated. alpha-, beta-, gamma- and hydroxypropyl-beta-cyclodextrin, each at 1.5% level, were used to prevent aggregation. The efficacy of cyclodextrins in preventing aggregation (% insulin aggregated in parentheses), was: hydroxypropyl-beta- (15) approximately beta- (18) > alpha- (54). No protection was observed with gamma-cyclodextrin.

Effect of surfactants on the physical stability of recombinant human growth hormone.

The physical stability of a human growth hormone (hGH) formulation upon exposure to air/water interfaces (with vortex mixing) and to nonisothermal stress [determined by differential scanning calorimetry (DSC)] was investigated. The effect of these stresses on the formation of soluble and insoluble aggregates was studied. The aggregates were characterized and quantified by size exclusion-HPLC and UV spectrophotometry. Vortex mixing of hGH solutions (0.5 mg/mL) in phosphate buffer, pH 7.4, for just 1 min caused 67% of the drug to precipitate as insoluble aggregates. These aggregates were noncovalent in nature. Non-ionic surfactants prevented the interfacially induced aggregation at their critical micelle concentration (cmc) for Pluronic F-68 (polyoxyethylene polyoxypropylene block polymer) and Brij 35 (polyoxyethylene alkyl ether) and above the cmc for Tween 80 (polyoxyethylene sorbitan monooleate). However, the same surfactants failed to stabilize hGH against thermal stress in DSC studies. Higher concentrations of surfactants actually destabilized hGH as evidenced by the decrease in the onset temperature for the denaturation endotherm.

Transdermal iontophoretic delivery of enkephalin formulated in liposomes.

Transdermal iontophoretic transport of a liposomal formulation of [Leu5]enkephalin, across human cadaver skin, was investigated. Franz (vertical) cells were supplied with 0.5 mA/cm2 current density via silver/silver chloride electrodes from a Scepter power supply. Enkephalin spiked with [3H]enkephalin was transported across skin from anode or cathode, depending on the charge on the molecule. Liposomes or their constituents were shown to penetrate into the skin. Enkephalin, when delivered iontophoretically at its isoelectric point, from liposomes carrying positive or negative charge on their surface, resulted in permeation of radioactivity which was same or less than that of the controls when analyzed by liquid scintillation counting. When analyzed by radiochromatography detector on HPLC, degradation of enkephalin during transport was observed, with several degradation peaks in the chromatogram. The degradation was less in liposome formulations, as compared to controls. This is the first report of the combined use of liposomes and iontophoresis for transdermal delivery.

Iontophoresis and electroporation: comparisons and contrasts.

The techniques of iontophoresis and electroporation can be used to enhance topical and transdermal drug delivery. Iontophoresis applies a small low voltage (typically 10 V or less) continuous constant current (typically 0.5 mA/cm2 or less) to push a charged drug into skin or other tissue. In contrast, electroporation applies a high voltage (typically, ?100 V) pulse for a very short (micros-ms) duration to permeabilize the skin. This electric assistance of drug delivery across skin will expand the scope of transdermal delivery to hydrophilic macromolecules such as the drugs of biotechnology. These two techniques differ in several aspects such as the mode of application and pathways of transport but can be used together for effective drug delivery. Iontophoresis is already used clinically in physical therapy clinics and is close to commercialization for development of a systemic delivery patch with miniaturized circuits and similar in overall size to a passive patch. The use of electroporation for drug delivery is relatively new and is being actively researched.