Influence of ion pairing on topical delivery of retinoic acid from microemulsions.

The purpose of the present study was to determinate the significance of ion pairing on the topical permeation of retinoic acid (R.A) using microemulsions as delivery vehicles. Phenylalanine methyl ester, phenylalanine ethylester, histidine methyl ester, tryptophan methyl ester and valine methyl ester were used as counter ions. Results of diffusion studies through polydimethylsiloxane membrane (PDMS) indicate that retinoic acid permeation from ethanol-pH 6.4 buffer mixture significantly increased in the presence of counter ions. A linear relationship was found between apparent partition coefficients and permeation coefficients. The highest values were with valine methyl ester and phenylalanine ethyl ester. In order to develop alternative formulations for topical administration of R.A, microemulsions were evaluated as delivery vehicles. Oil-in-water (O/W) and water-in-oil (W/O) microemulsion formulations were prepared using water, isopropyl myristate, lecithin, caprylyl-capryl glucoside and ethanol or 1,2 hexanediol. Experiments with PDMS membranes showed decreasing permeabilities of R.A from microemulsions in the presence of counter ions. This was related to the increased lipophilicity and different vehicle membrane affinity of the ion pairs The ability of the systems to deliver R.A through the skin was evaluated in vitro using pig-skin. R.A permeabilities were much lower with microemulsions than with solution, while a large increase in R.A skin deposition was observed only from O/W microemulsions in the presence of counter ions. The depth of skin accumulation was below 100 microm after 24 h application. The results suggest that O/W microemulsions containing a counter ion can be used to optimise drug targeting without a concomitant increase in systemic absorption.     

A study of microemulsion systems for transdermal delivery of triptolide.

Triptolide possesses immunosuppressive, anti-fertility and anti-cancer activities. Due to its severe toxicity, microemulsions with controlled, sustained and prolonged delivery of triptolide via a transdermal route are expected to reduce its adverse side effects. The purpose of the present study was to investigate the microemulsions for transdermal delivery of triptolide. The pseudo-ternary phase diagrams were developed and various microemulsion formulations were prepared using oleic acid as an oil, Tween 80 as a surfactant and propylene glycol as a cosurfactant. The droplet size of microemulsions was characterized by photocorrelation spectroscopy. The transdermal ability of triptolide from microemulsions was evaluated in vitro using Franz diffusion cells fitted with mouse skins and triptolide was analyzed by high-performance liquid chromatography. The effect of menthol as a permeation enhancer, and the loading dose of triptolide in microemulsions on the permeation rate were also evaluated. The triptolide-loaded microemulsions showed an enhanced in vitro permeation through mouse skins compared to an aqueous solution of 20% propylene glycol containing 0.025% triptolide. The permeation of microemulsions accorded with the Fick's first diffusion law. No obvious skin irritation was observed for the studied microemulsion ME6, but the aqueous solution of 20% propylene glycol containing 0.025% triptolide revealed the significant skin irritation. The results indicate that the studied microemulsion systems, especially ME6, may be promising vehicles for the transdermal delivery of triptolide.     

NMR characterisation and transdermal drug delivery potential of microemulsion systems.

The purpose of this study was to investigate the influence of structure and composition of microemulsions (Labrasol/Plurol Isostearique/isostearylic isostearate/water) on their transdermal delivery potential of a lipophilic (lidocaine) and a hydrophilic model drug (prilocaine hydrochloride), and to compare the drug delivery potential of microemulsions to conventional vehicles. Self-diffusion coefficients determined by pulsed-gradient spin-echo NMR spectroscopy and T(1) relaxation times were used to characterise the microemulsions. Transdermal flux of lidocaine and prilocaine hydrochloride through rat skin was determined in vitro using Franz-type diffusion cells. The formulation constituents enabled a broad variety of microemulsion compositions, which ranged from water-continuous to oil-continuous aggregates over possible bicontinuous structures, with excellent solubility properties for both lipophilic and hydrophilic compounds. The microemulsions increased transdermal flux of lidocaine up to four times compared to a conventional oil-in-water emulsion, and that of prilocaine hydrochloride almost 10 times compared to a hydrogel. A correlation between self-diffusion of the drugs in the vehicles and transdermal flux was indicated. The increased transdermal drug delivery from microemulsion formulations was found to be due mainly to the increased solubility of drugs and appeared to be dependent on the drug mobility in the individual vehicle. The microemulsions did not perturb the skin barrier, indicating a low skin irritancy.     

Designing for topical delivery: prodrugs can make the difference

It has been shown for homologous series of prodrugs that those members who were the more water soluble ones gave the greatest enhancement in topical delivery of the parent drug and not the more lipophilic ones. However, until recently models for topical delivery and equations to predict topical delivery focused only on lipid solubility (S(LIPID)) or partition coefficient (K(OCT:AQ)) and molecular volume (or molecular weight, MW) as parameters. Now several equations (transformed Potts-Guy or Series/Parallel) have been developed which include aqueous solubility (SAQ) as a parameter for predicting flux through skin. Experimental fluxes, solubilities, and MW from seven series of prodrugs have been fit to the transformed Potts-Guy equation to give coefficients for log solubility in isopropyl myristate (log SIPM) and log solubility in water (log SAQ) (0.53 and 0.47, respectively) which show, for parent drugs delivered by prodrugs from IPM in vitro through hairless mouse skin, that water solubility is almost as important as lipid solubility. When the transformed Potts-Guy equation was fit to data for the delivery of NSAID from mineral oil (MO) in vivo through human skin, the coefficients were 0.72 log SMO and 0.28 log SAQ. When the transformed Potts-Guy equation was fit to data for the delivery of their parent drugs by three series of prodrugs from water in vitro through hairless mouse skin the coefficients were 0.66 log S(IPM) and 0.34 log SAQ. Numerous recent examples are also given where more water-soluble members of homologous series of prodrugs give higher flux values from water vehicles in vitro through human skin than the more lipid soluble ones.     

Lipid cubic phases for improved topical drug delivery in photodynamic therapy.

We have evaluated the efficacy of lipid cubic phases, highly ordered self-assembly systems on the nanometer level, as drug delivery vehicles for in vivo topical administration of delta-aminolevulinic acid (ALA) and its methyl ester (m-ALA) on nude mice skin. ALA, a precursor of heme, induces the production of the photosensitizer protoporphyrin IX (PpIX) in living tissue. Measuring the PpIX fluorescence at the skin surface, after topical administration, makes indirect quantification of the penetration of ALA into the tissue possible. Cubic phases were formed of lipid (monoolein or phytantriol), water and drug. In some cases, propylene glycol was included in the cubic phase as well. The drug concentration was 3% (w/w, based on the total sample weight) in all investigated vehicles. When the formulations were applied for 1 h, the monoolein cubic systems and the three-component phytantriol sample showed higher fluorescence compared to the standard ointment during the 10 h of measurement. Both ALA and m-ALA yielded similar results, although the differences between the investigated vehicles were more pronounced when using m-ALA. For the 24-h applications, the monoolein cubic systems with m-ALA showed faster PpIX formation than the standard ointment, implying higher PpIX levels at short application times (less than 4 h). The systemic PpIX fluorescence of ALA was elevated by using the lipid cubic formulations. Notably, a small systemic effect was also observed for the monoolein cubic sample with m-ALA. These results imply improved PpIX formation when using the lipid cubic systems, most probably due to enhanced drug penetration.     

New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo.

Microemulsion systems possessing a potentially improved skin bioavailability of lidocaine were designed and explored for some characteristics. The existence of microemulsion regions was investigated in quaternary systems composed of glyceryl oleate+polyoxyl 40 fatty acid derivatives (surfactants)/tetraglycol (co-surfactant)/isopropyl palmitate/water by constructing pseudo-ternary phase diagrams at fixed co-surfactant/surfactants (CoS/S) ratios. Light scattering measurements used to determine the diameter of the internal phase revealed that lidocaine in the microemulsions increased the droplet size, implying a drug tendency to accumulate in the interfacial layers. Percutaneous penetration studies using rat skin in vitro showed that the transdermal flux of lidocaine was significantly improved by microemulsion composed of the glyceryl oleate-PEG-40 stearate combination rather than glyceryl oleate-PEG-40 hydroxylated castor oil. Two principal factors were found to govern the transdermal penetration of lidocaine from the microemulsion: water content and the CoS/S ratio. By analyzing skin layers (epidermis and dermis) for lidocaine content, significantly higher concentrations were found after rats were treated in vivo with liquid microemulsions (CoS/S=1.8, 30 wt.% water) or patches compared to those measured after application of EMLA cream. It has been suggested, therefore, that these microemulsions loaded with lidocaine would provide adequate analgesia in relatively shorter periods of time.     

Scintigraphic evaluation in rabbits of nasal drug delivery systems based on carbopol 971p((R)) and carboxymethylcellulose.

The residence time of apomorphine mucoadhesive preparations incorporating 99mTc labeled colloidal albumin in rabbit nasal cavity was evaluated by gamma scintigraphy. This technique was used to compare the nasal clearance of preparations based either on Carbopol 971P((R)) or lactose (control), each with and without apomorphine, or carboxymethylcellulose with apomorphine. The planar 1-min images showed an excipient-dependent progressive migration of radioactivity with time from the nasal cavity to the stomach and intestine. Thirty minutes post insufflation, the percentages of the formulations cleared from the nasal cavity were 47% for lactose, 26% for lactose/apomorphine, 10% for Carbopol 971P((R)), and 3% for both Carbopol 971P((R))/apomorphine and carboxymethylcellulose/apomorphine. Three hours post insufflation, the percentages of the formulations cleared from the nasal cavity were 70% for lactose, 58% for lactose/apomorphine, 24% for Carbopol 971P((R)), 12% for Carbopol 971P((R))/apomorphine, and 27% for carboxymethylcellulose/apomorphine. Apomorphine inhibited nasal mucociliary clearance since migration of the radioactivity administered with apomorphine containing preparations was in all cases slower than that of the corresponding powder without apomorphine. The peak plasma concentration of apomorphine was attained while all the formulations were still within the nasal cavity. The use of mucoadhesive polymers such as Carbopol 971P((R)) or carboxymethylcellulose in nasal dosage forms increases their residence time within the nasal cavity and provides the opportunity for sustained nasal drug delivery.     

Preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery.

To improve the solubility and bioavailability of poorly water-soluble biphenyl dimethyl dicarboxylate (BDD), a drug used in treating liver diseases, a premicroemulsion concentrate composed of oil, surfactant, and cosurfactant for oral administration of BDD was prepared, and its physicochemical properties and the pharmacokinetic parameters of BDD were evaluated. Among the non-ionic surfactants and oils studied, Tween 80, which led to the highest solubility of BDD (109.7 microg/ml), and Neobee M-5((R)) were chosen for preparing a premicroemulsion concentrate. At the 2:1 ratio of Tween 80 to Neobee M-5((R)), the solubility of BDD increased 7-fold compared with that at the ratio of 1:4. The solubility of BDD was further improved by the addition of triacetin used as a cosurfactant. Droplet size of BDD microemulsion comprising Tween 80 and Neobee M-5((R)) at the ratio of 2:1, and 35% of triacetin, was kept constant both in distilled water and artificial gastric fluid without pepsin (pH 1.2) throughout 120-min incubation period. BDD in premicroemulsion concentrate rapidly dissolved whereas the mixture of BDD and calcium-carboxymethylcellulose (Ca-CMC) (2:1) and BDD powder hardly dissolved during 120-min incubation. About 50% of BDD in premicroemulsion concentrate dissolved within 10 min. AUC(0-->24 h) and the mean maximum plasma level (C(max)) of BDD after oral administration of premicroemulsion concentrate in rats were 5- and 9.8-fold higher, respectively, than those of BDD with Ca-CMC. These results demonstrate that premicroemulsion concentrate of BDD composed of Tween 80 and Neobee M-5((R)) at the ratio of 2:1, and 35% of triacetin, greatly enhances the bioavailability of BDD after the dose, possibly due to the increase in solubility and immediate dispersion of drug in the gastrointestinal tract. Thus, this system may provide a useful dosage form for oral intake of a water-insoluble drug, BDD.     

Percutaneous absorption kinetics of topical metronidazole formulations in vitro in the human cadaver skin model

Topical formulations containing identical active agents are available in various vehicles and concentrations, which may affect percutaneous absorption. This study was undertaken to evaluate the in vitro percutaneous absorption pharmacokinetics of metronidazole in different vehicles and concentrations as the active agent in 6 topical formulations. Formulations were applied to sections from 3 cadaver skin donors, and percutaneous absorption of metronidazole was measured over a 48-h test period through the finite dose technique and the use of Franz diffusion cells. Metronidazole penetrates into and through human cadaver skin. Data show the general ranking of delivery of similar concentrations of metronidazole according to vehicle as cream > lotion > gel. The 48-h penetration of metronidazole in the human cadaver skin model was greatest with cream formulations and lowest with gel formulations. These results reveal the importance of the vehicle selected for penetration of metronidazole into the skin. The relevant target zone in rosacea is the dermis because this is the area where inflammation takes place. Additional studies are warranted to examine absorption of metronidazole into the relevant target zone and the correlation of absorption with efficacy.     

Identification of penetration enhancers for testosterone transdermal delivery from spray formulations.

The goal of this study was to identify a suitable penetration enhancer-containing formulation for the transdermal delivery of testosterone from a spray. The first step involved in vitro measurement of drug flux from a 1:1 ethanol/water saturated solution across hairless rat skin, which had been pre-treated with a series of penetration enhancers. Isopropyl myristate (IPM) was found to be the most efficient excipient, increasing testosterone transport by more than a factor of 5. The enhancing ability of IPM was also apparent when the drug was formulated in 3:1 ethanol/propylene glycol, a more compatible vehicle for use in a spray. IPM was then incorporated into this formulation directly (as opposed to being used to pre-treat the skin) over a range of concentrations from 10-25% v/v, and testosterone transport was evaluated when delivered from either a solution, or from a mechanical spray, or from an aerosol (which also contained 50% v/v propellant). At the highest level of enhancer, the flux was improved 2.5-fold from both the spray and the aerosol, relative to a control. However, these formulations were far from optimally conceived, in that the amount of drug which eventually contacted the skin represented only approximately 10% of the pulverized quantity from the spray, and approximately 40% of that from the aerosol. Repeated application, especially from the aerosol, improved matters somewhat, but further work is clearly required before the concept can be developed for practical application.     

Failure of topical acyclovir in ointment to penetrate human skin.

Topical acyclovir (ACV) in polyethylene glycol (PEG) ointment has been disappointing in the treatment of recurrent herpes simplex virus infections in immunocompetent patients. To investigate the possible role of poor drug delivery from this formulation, we studied the penetration of ACV through excised human skin from three vehicles; PEG ointment, modified aqueous cream, and dimethyl sulfoxide. A second antiviral agent, idoxuridine, was studied in the same formulations, and drug delivery through excised guinea pig skin was also assessed for comparison. The delivery of ACV from PEG ointment was very slow for both human and guinea pig skin (drug flux, 0.055 and 0.047 microgram/cm2 per h, respectively). Formulation of ACV in modified aqueous cream and in dimethyl sulfoxide resulted in an 8- and 60-fold increase, respectively, in the flux of ACV through human skin. Idoxuridine behaved similarly to ACV in the three vehicles. The poor clinical results seen with topical use of ACV ointment may be due in part to retarded drug delivery from this formulation.     

Influence of carrageenan on the rheology and skin permeation of microemulsion formulations.

Three different microemulsions (A-C) and one semisolid preparation D were investigated in terms of viscoelastic properties and skin permeation of the model compound sodium fluorescein. The influence of the polysaccharide carrageenan on these parameters was investigated. Carrageenan is frequently used as food additive and has very interesting properties like good adhesiveness on skin which can be a benefit for topical application. The viscoelastic properties of the preparations (A-D) and of mixtures with carrageenan (A'-D') were characterized by oscillatory measurements. It was possible to adjust the rheologic properties of the formulations and to increase the sodium fluorescein permeation through porcine skin by mixing them with carrageenan gels. Therefore, the presented formulations as well as mixtures with carrageenan might be promising alternative drug carrier systems for topical pharmaceutical as well as cosmetics.     

Lipid cubic phases in topical drug delivery: Visualization of skin distribution using two-photon microscopy

The distribution of sulphorhodamine B (SRB), a fluorescent hydrophilic model drug, was investigated in human skin after passive diffusion using four different topical delivery systems. The delivery vehicles applied were two bicontinuous lipid cubic systems, a commercial ointment and water. The lipid cubic systems consisted of either monoolein (MO) or phytantriol (PT) and water. The formulations were applied on full-thickness human skin during 24 h. Thereafter the samples were investigated using two-photon microscopy (TPM). The TPM system consisted of an inverted microscope with a 40× water-immersion objective, laser scan-box, and a pulsed femtosecond titanium:sapphire laser operating at 780 nm. The fluorescence was detected using a 560 nm long-pass filter. Sequential optical sectioning was performed, resulting in images obtained at different tissue depths. TPM revealed that SRB mainly penetrates the skin via the intercellular lipid matrix. Samples exposed to the cubic phases showed a higher accumulation of SRB in micro-fissures, from which a fluorescent network of threadlike structures spread laterally in the tissue. These structures were also detected in some of the ointment samples, but not as frequent. The penetration of SRB into the stratum granulosum was deduced from the fluorescence of SRB present inside polygonal keratinocytes with cell nuclei. Higher SRB fluorescence was obtained in the outermost layer of the epidermis using the bicontinuous cubic phases, compared to when using the reference formulations. Thus, our results suggest that the dominating delivery route using the cubic phases is via micro-fissures caused by microscopic clustering of the keratinocytes in the skin. From these micro--fissures hydrophilic compounds, here modeled by SRB, can diffuse into the surrounding intercellular lipid matrix acting like a source for sustained release.     

Effect of hydrophobically modified PEO polymers (PEO-dodecyl) on oil/water microemulsion properties: in vitro and in silico investigations

Microemulsions are excellent systems for transdermal delivery of multifunctional drugs because they have the potential to improve drug absorption/permeation and handling limitations. Biocompatible polymers are used as a coating of microemulsions to avoid the interactions that can occur between the microemulsions and the skin. Thus, they protect and lubricate these transporter nanovesicles. In this paper, we studied decane/water microemulsions covered with hydrophobically modified PEO polymer (PEO-m). To reveal the effect of hydrophobically modified PEO (PEO-m) polymer on the shape, the micro-arrangement and the dynamics of the microemulsions, we used an integrated strategy combining Molecular Dynamics simulation (MD), Small-Angle Neutron Scattering experiments (SANS), and the Ornstein–Zernike integral equations with the Hypernetted Chain (HNC) closure relation. We determined the microemulsion shape in vitro using the renormalized intensities spectra from SANS experiments. We discussed the micro arrangements of microemulsions, in vitro and in silico, employing the pair correlation function g(r) and the structure factor S(q), obtained from the three approaches with good agreement. Thus, we used the validated MD simulations to calculate the microemulsion''s dynamics properties that we discussed using the mean-squared displacement (MSD) and the diffusion coefficients. We found that the presence of moderate quantities of PEO-m, from 4 to 12 PEO-m per microemulsion, does not influence the microemulsion shape, increases the stability of the microemulsion, and slightly decrease the dynamics. Our in vitro and in silico results suggest that polymer incorporation, which has interesting in vivo implications, has no disadvantageous effects on the microemulsion properties.

In this work, we study the effect of grafted PEO-dodecyl co-polymers on the decane/water microemulsions properties. For this purpose, we combined the MD simulations, the OZ integral equations resolved using the HNC closure, and SANS experiments.     

Characterization of the Percutaneous Absorption of Ketoprofen Using the Franz Skin Finite Dose Model

Objectives: Ketoprofen is an analgesic, anti-inflammatory agent commonly used in the management of chronic musculoskeletal pain. The aim of this study is to characterize the percutaneous absorption of 2 ketoprofen formulations (ketoprofen 10% in Pluronic Lecithin Organogel (PLO) and ketoprofen 10% in Lipoderm, referred to as phospholipid base), when applied to the human cadaver trunk skin, in vitro, using the Franz skin finite dose model. PLO and phospholipid base are vehicles used to facilitate the delivery of drugs into and through the skin following topical applications.

Methods: The percutaneous absorption of ketoprofen was evaluated using human cadaver trunk skin from 3 donors. The skin was cut into small sections and cultured within Franz diffusion cells. A variable finite dose of each formulation was then applied to 3 replicate skin sections per donor and receptor solutions were collected at predetermined time points (0, 4, 8, 12, 24, 32, and 48 hr). After the last receptor sample was collected, skin surfaces were washed and split into epidermis and dermis. Collected samples were analyzed using HPLC.

Results: Both PLO and phospholipid base were capable of facilitating the absorption of ketoprofen across human cadaver trunk skin. However, ketoprofen, when in phospholipid base, showed higher mean total absorption (p = 0.022) and faster rate of absorption (p < 0.05 at 2, 6, 10, and 18 hr) than when in PLO.

Conclusion: Chronic musculoskeletal pain can be a major burden for most patients, affecting their lifestyle and reducing overall quality of life. When compared to PLO, phospholipid base has the ability to potentially deliver higher concentrations of ketoprofen to underlying soft tissues and at a more rapid rate. With more ketoprofen at the site of injury, the analgesic and anti-inflammatory effects will likely be enhanced, potentially reducing pain and improving quality of life.     

Sustained ex vivo skin antiseptic activity of chlorhexidine in poly(epsilon-caprolactone) nanocapsule encapsulated form and as a digluconate.

In this work, the sustained bactericidal activity of chlorhexidine base loaded poly(epsilon-caprolactone), PCL, nanocapsules against Staphylococcus epidermidis inoculated onto porcine ear skin was investigated. Drug loaded nanocapsules were prepared by the interfacial polymer deposition following solvent displacement method, then characterized by photon correlation spectroscopy, electrophoretic measurements, transmission and scanning electron microscopy. Antimicrobial activity of these colloidal carriers was evaluated (i) in vitro against eight strains of bacteria, and (ii) ex vivo against Staphylococcus epidermidis inoculated for 12 h onto porcine ear skin surface treated for 3 min either with 0.6% chlorhexidine base loaded or unloaded nanocapsules suspended in hydrogel, or 1% chlorhexidine digluconate aqueous solution. Chlorhexidine absorption into the stratum corneum (SC) was evaluated by the tape-stripping method. The results showed that chlorhexidine nanocapsules in aqueous suspension having a 200-300 nm size and a positive charge exhibited similar minimum inhibitory concentrations against several bacteria with chlorhexidine digluconate aqueous solution. Ex vivo, there was a significant reduction in the number of colony forming units (CFUs) from 3-min treated skin with chlorhexidine nanocapsule suspension (5 to <1 log(10)) compared to chlorhexidine digluconate solution (5 to 2.02 log(10)) after a 8-h artificial contamination. After a 12-h artificial contamination, both formulations failed to achieve a 5 log(10) reduction. Furthermore, from a 3-min treatment with an identical applied dose and a subsequent 12-h artificial contamination, a residual chlorhexidine concentration in the SC was found to be three-fold higher with chlorhexidine nanocapsule suspension than with chlorhexidine digluconate solution. Interestingly, nanocapsules were shown in porcine skin follicles. Consequently, a topical application of chlorhexidine base-loaded positively charged nanocapsules in an aqueous gel achieved a sustained release of bactericide against Staphylococcus epidermidis for at least 8 h. Enhancement of drug delivery by mediating a more direct and prolonged contact between the carrier and (i) bacteria, (ii) skin surface, and (iii) skin follicles was assumed.     

Transdermal delivery from a lipid sponge phase--iontophoretic and passive transport in vitro of 5-aminolevulinic acid and its methyl ester.

The hydrochloride salts of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA), respectively, were dissolved in a lipid sponge phase comprising monoolein, propylene glycol and aqueous buffer at concentrations of approximately 0.25% and 16% w/w m-ALA. The iontophoretic and passive delivery of ALA and m-ALA from this formulation through porcine skin in vitro were measured and compared to formulations used in clinical practice, 20% w/w ALA in Unguentum M and Metvix (a cream containing 16% w/w m-ALA). A sponge phase with 16% w/w m-ALA showed a higher passive flux (approximately 140 nmol cm(-2) h(-1) at 5 h) but a lower iontophoretic flux (approximately 800 nmol cm(-2) h(-1) at 5 h) compared to the clinically used products but the differences are hardly significant due to large standard deviations. ALA and m-ALA in sponge phase formulation showed iontophoretic fluxes in the range 80-100 nmol cm(-2) h(-1) at 3 h, i.e. values comparable to the passive fluxes from the more concentrated vehicles. The results demonstrate that the lipid sponge phase, a thermodynamically stable liquid with amphiphilic character, may have potential as a transdermal drug delivery vehicle.     

Topical delivery of liposomally encapsulated interferon evaluated by in vitro diffusion studies.

The topical delivery of several liposomal interferon formulations was evaluated by in vitro diffusion experiments in an effort to understand the effects of liposomal composition and method of preparation on the deposition of interferon into the stratum corneum and deeper strata of the skin. Application of liposomes prepared from lipids with a composition similar to that of the stratum corneum resulted in almost twice the amount of interferon being deposited in the deeper skin layers than did application of liposomes prepared from phospholipids. Topical application of "skin lipid" liposomes prepared by the dehydration-rehydration method was twice as effective as was topical application of liposomes prepared by the reverse-phase evaporation method with respect to their ability to deposit interferon into the skin strata where the basal cell layers reside. These results are consistent with the effects of liposomal composition and method of preparation on the ability of the formulation to reduce lesion scores in the cutaneous herpes simplex virus type 1 guinea pig model.     

A comparison of the skin permeation of three topical 0.5% fluorouracil formulations with that of a 5% formulation.

BACKGROUND: Topical fluorouracil has proven efficacy in the treatment of actinic keratosis. The systemic absorption of various topical formulations of fluorouracil varies, however, and may be affected by the concentration and delivery system used. OBJECTIVE: This study compared the flux and percutaneous absorption of 3H-labeled fluorouracil from three 0.5% fluorouracil formulations incorporated into a porous microsphere delivery system with those from a commercially available 5% fluorouracil formulation. METHODS: Penetration of all formulations through the skin was sampled every 3 hours for 24 hours using full-thickness human cadaver skin samples mounted in a Bronaugh flow-through diffusion cell apparatus. Total absorption was defined as the sum of the amount of cumulative flux through the skin over 24 hours and the amount retained in the skin at 24 hours. RESULTS: The flux through the skin of the 5% fluorouracil formulation was 20 to 40 times greater (normalized, 2-4 times greater) than that of the 0.5% fluorouracil formulations. A higher percentage of absorbed fluorouracil was retained in the skin after 24 hours with the 0.5% formulations (86%-92%) than with the 5% formulation (54%). CONCLUSION: These findings suggest that the 0.5% formulations are associated with less flux through the skin than the 5% formulation and, therefore, potentially less systemic exposure.     

A delivery system to avoid self-aggregation and to improve in vitro and in vivo skin delivery of a phthalocyanine derivative used in the photodynamic therapy

The hydrophilic character and aggregation phenomena exhibited by the photosensitizer zinc phthalocyanine tetrasulfonate (ZnPcSO₄) make it difficult for this compound to penetrate the skin, and reduce the compound's photodynamic efficacy. A microemulsion (ME) was developed to increase the skin penetration of ZnPcSO₄ while avoiding its aggregation. Ternary phase diagrams composed of surfactants (Span® 80/Tween® 80), canola oil and a propylene glycol (PG)/water mixture (3:1) were constructed as a basis for choosing an adequate ME preparation. Rheological, electrical conductivity, dynamic light scattering and zeta potential studies were carried out to characterize the ME formulations. Monomerization of ZnPcSO₄ in the ME was determined photometrically and fluorometrically. In vitro skin penetration and retention of the compound in the skin were measured using porcine ear skin mounted on a diffusion cell apparatus. The in vivo accumulation 6 h after ZnPcSO₄ application was determined fluorometrically in hairless mice skin. Confocal laser scanning microscopy was used to visualize ZnPcSO₄ distribution in the skin. A ME composed of canola oil:surfactant:PG-water at 38:47:15 (w/w/w) was chosen for ZnPcSO_4. This was oil-in-water with internal phase diameter of 15.7 ± 0.15 nm. Spectroscopic techniques confirmed that the ME was able to keep ZnPcSO₄ in its monomeric form. In the in vitro penetration of ZnPcSO₄ in the stratum corneum (SC) and in epidermis (without stratum corneum) with dermis ([E + D]) was 33.0- and 28.0-fold higher, respectively compared to the control solution of the drug. In vivo studies, confirmed that when the ME was used as carrier, ZnPcSO₄ concentrations in the SC and [E + D] were about 1.6- and 5.6-fold higher, respectively, than controls. Visualization of ZnPcSO₄ skin penetration by confocal laser scanning microscopy confirmed that the ME increased both penetration and biodistribution of this photosensitizer in the skin.