Microemulsions for topical delivery of 8-methoxsalen.

8-Methoxsalen (8-MOP) and related furocumarins have been extensively used for the treatment of hyperproliferative skin diseases in association with long-wavelength UVA light. In order to develop alternative formulations for the topical administration of 8-MOP, microemulsions were evaluated as delivery vehicles. Six microemulsion formulations were prepared using water, isopropyl myristate (IPM) and Tween((R)) 80: Span((R)) 80: 1,2-Octanediol (3:1:1.2 w/w). The microemulsions were characterized using conductimetric and dynamic light scattering analyses. The ability of the systems to deliver 8-MOP into and through the skin was evaluated in vitro using newborn pig-skin. The in vitro permeation data showed that the novel microemulsions increased the 8-MOP total penetration through the skin by order of 1.9-4.5, as compared with IPM. In general, the accumulation of 8-MOP into the skin was increased by a factor of 1.5-4.5 by the microemulsion systems with respect to their total amount of drug delivered across the skin. These results suggest that the studied microemulsion systems may be appropriate vehicles for the topical delivery of 8-MOP.     

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.     

In vivo evaluation of 3-O-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.

Naltrexone (NTX) is a potent competitive antagonist with high affinity for the mu-opioid receptor. Therapeutically, NTX is used for the treatment of alcohol dependence and opioid addiction; however, it does not have the ideal physicochemical properties necessary to achieve therapeutic plasma concentrations via the transdermal route. The aim of the present investigation was to evaluate the in vivo transdermal delivery of three 3-O-alkyl ester prodrugs of NTX, including NTX-3-O-acetate (ACE-NTX), NTX-3-O-propionate (PROP-NTX), and NTX-3-O-hexanoate (HEX-NTX) in hairless guinea pigs. The pharmacokinetic parameters for NTX and the 3-O-alkyl ester prodrugs of NTX were determined after intravenous drug administration and topical drug application of transdermal therapeutic systems (TTS) in guinea pigs. The results of the in vivo studies showed mean steady-state plasma concentrations of NTX from NTX, ACE-NTX, PROP-NTX and HEX-NTX at 4.2, 25.2, 16.0, and 8.3 ng/mL, respectively. These NTX plasma concentrations were maintained for 48 h. The results of these in vivo studies demonstrated that ACE-NTX and PROP-NTX prodrugs of NTX were the most promising drug candidates for transdermal delivery.     

Electroporation-mediated delivery of 3'-protected phosphodiester oligodeoxynucleotides to the skin.

The feasibility of topical delivery in the skin of 3' end modified phosphodiester oligonucleotides using electroporation was investigated. Experiments were performed in vitro, using hairless rat skin. Five pulses of (200 V, 450 ms) were applied. The 3' end modifications of the 15 mer oligonucleotide were: (1) 3'-aminohexyl, (2) biotin, with a triethyleneglycol arm, (3) methylphosphonate links between nucleotides 13, 14 and 15, and (4) 2-O-methyl nucleotides at 13, 14 and 15 positions. All the modifications were efficient to protect the oligonucleotides against degradation in the skin. Electroporation increased the topical delivery of the 3' end-modified phosphodiesters by two orders of magnitude compared to passive diffusion, without significant differences between the derivatives. Oligonucleotide concentrations in the range of 1 microm could be achieved in the viable skin. The delivery of a phosphorothioate congener was lower than phosphodiester delivery due to the interaction of phosphorothioate with the stratum corneum. Consequently, 3' end-protected phosphodiesters could be an interesting alternative to phosphorothioate oligonucleotides for topical treatment of cutaneous diseases.     

Potential usefulness of solubility index for prediction of the skin permeation rate of 5-ISMN from pressure-sensitive adhesive tape.

Skin permeation of 5-ISMN from pressure sensitive adhesive (PSA) tape was evaluated using thermodynamic activity of the drug in PSA. Three acrylic adhesives (Gelva 737, Gelva 1430 and Gelva 1753) were used as PSA. Since the drug activity in PSA is difficult to determine, however, a solubility index was defined. Several PSA tapes containing different amounts of 5-ISMN were prepared, and heat of fusion at the dissolution of 5-ISMN in each PSA was determined by DSC. No exothermic peak was found when the drug concentration was less than the solubility in PSA, whereas the heat of fusion increased proportionally with amount of solid drug in the PSA when the drug concentration was above the solubility. The bending point in the profile of heat of fusion versus 5-ISMN content in PSA was defined as the solubility index. In vitro skin permeation was determined using excised hairless rat skin from 5-ISMN-saturated PSA tapes. The obtained skin permeation of the drug decreased with increases in the solubility index. These profiles were confirmed by a theoretical approach using the differential equation corresponding to Fick's second law of diffusion. These results suggested that the solubility index can be utilized for prediction of the skin permeability of drugs from PSA tape.     

A vehicle for photodynamic therapy of skin cancer: influence of dimethylsulphoxide on 5-aminolevulinic acid in vitro cutaneous permeation and in vivo protoporphyrin IX accumulation determined by confocal microscopy.

Topical application of 5-aminolevulinic acid (5-ALA) followed by light irradiation is a new concept of photodynamic therapy (PDT) of skin cancers. 5-ALA is a prodrug that can be converted by the heme biosynthetic pathway into protoporphyrin IX, an effective photosensitizer. In the present work we propose the enhancement of 5-ALA-induced protoporphyrin IX accumulation by dimethylsulphoxide (DMSO) and ethylenediamine-tetraacetic acid disodium salt (EDTA). The presence of 20% DMSO (w/w) in oil-in-water emulsions increased the in vitro permeation of 5-ALA through hairless mouse skin. In vivo studies demonstrated a significant increase in the amount of protoporphyrin IX extracted from healthy hairless mouse skin after 3 h treatment with an oil-in-water emulsion containing 10% 5-ALA (w/w), 3% EDTA (w/w) and 20% DMSO (w/w). By confocal scanning laser microscopy imaging, an observed increase in red fluorescence, at 476 nm excitation and emission detected longer than 590 nm, in skin that had received this treatment, was attributed to protoporphyrin IX accumulation. Although no effect of EDTA on short-term protoporphyrin IX accumulation in skin was detected, this chelator could protect 5-ALA from decomposition during prolonged topical administration. The results obtained indicate that association of 5-ALA, EDTA and 20% DMSO may enhance the delivery of 5-ALA to the skin in the topical PDT.     

Elasticity of vesicles affects hairless mouse skin structure and permeability.

One of the possibilities for increasing the penetration rate of drugs through the skin is the use of vesicular systems. Currently, special attention is paid to the elastic properties of liquid-state vesicles, which are supposed to have superior properties compared to gel-state vesicles with respect to skin interactions. In this study, the effects of vesicles on hairless mouse skin, both in vivo and in vitro, were studied in relation to the composition of vesicles. The interactions of elastic vesicles containing the single chain surfactant octaoxyethylene laurate-ester (PEG-8-L) and sucrose laurate-ester (L-595) with hairless mouse skin were studied, in vivo, after non-occlusive application for 1, 3 and 6 h. The skin ultrastructure was examined by ruthenium tetroxide electron microscopy (TEM) and histology. The extent, to which vesicle constituents penetrated into the stratum corneum, was quantified by thin layer chromatography (TLC). The interactions of the elastic vesicles containing PEG-8-L and L-595 surfactants were compared with those observed after treatment with rigid vesicles containing the surfactant sucrose stearate-ester (Wasag-7). Furthermore, skin permeability experiments were carried out to investigate the effect of treatment with PEG-8-L micelles, elastic vesicles (containing PEG-8-L and L-595 surfactants) or rigid Wasag-7 vesicles on the 3H(2)O transport through hairless mouse skin, in vitro, after non-occlusive application. Treatment of hairless mouse skin with the elastic vesicles affected the ultrastructure of the stratum corneum: distinct regions with lamellar stacks derived from the vesicles were observed in intercellular spaces of the stratum corneum. These stacks disrupted the organization of skin bilayers leading to an increased skin permeability, whereas no changes in the ultrastructure of the underlying viable epidermis were observed. Treatment with rigid Wasag-7 vesicles did not affect the skin ultrastructure or skin permeability. TLC measurements showed that after 1 h of non-occlusive application of elastic or rigid vesicles, a six-fold increased amount of elastic vesicle material was present within the stratum corneum compared to rigid vesicle material. After 3 and 6 h of application the amount of PEG-8-L vesicle material in SC decreased to approximately three- and two-fold, respectively, compared to Wasag-7 vesicle material. Pretreatment of the hairless mouse skin with the elastic vesicles containing 70 mol% PEG-8-L increased the diffusion of 3H(2)O with an optimum application dose of 2.5 mg lipids/cm(2) compared to PBS pretreatment. No significant difference in the enhancement of the 3H(2)O-diffusion was observed between PEG-8-L micelles or elastic vesicles containing 30 or 70 mol% PEG-8-L. Pretreatment with the rigid Wasag-7 vesicles decreased the diffusion rate of 3H(2)O, most probably by the formation of a lipid layer on the skin surface. The effect of the elastic vesicles on the skin permeability is supported by the ultrastructural changes observed by TEM in the intercellular lipid domains. The elastic vesicles containing 70 mol% PEG-8-L disorganize the lipid bilayers thereby creating or modifying pathways for possible drug penetration.     

Lipidic prodrug approach for improved oral drug delivery and therapy

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.     

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.     

Enhancement of skin permeation of docetaxel: A novel approach combining microneedle and elastic liposomes

A combination method of using microneedle pretreatment and elastic liposomes was developed to increase skin permeation of drugs with high molecular weight and poor water solubility. Docetaxel (DTX, MW = 807.9) was chosen as a model drug. DTX liposomal systems with and without elastic properties were prepared and characterized. The effect of the developed formulations on the permeation of DTX across both rat and porcine skin was investigated in vitro. The combination effect of microneedle pretreatment and elastic liposomes on the permeability of DTX was evaluated using porcine skin in vitro. The following results were obtained: (1) Elastic liposomes loaded with DTX can enhance transdermal delivery of DTX without microneedle treatment. (2) An enhanced transdermal flux (1.3–1.4 μg/cm²/h) for DTX from all liposomal formulations was observed after microneedle treatment. Importantly, the lag time obtained following the application of elastic liposomes through microneedle-treated skin was decreased by nearly 70% compared with that obtained from conventional liposomes. These results suggest that the combination of elastic liposomes with microneedle pretreatment can be a useful method to increase skin permeation of drugs with high molecular weight and poor water solubility.     

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.     

ATR-FTIR and Raman spectroscopic investigation of the electroporation-mediated transdermal delivery of a nanocarrier system containing an antitumour drug

The aim of the present work was the optimization of the transdermal delivery of a lyotropic liquid crystal genistein-based formulation (LLC-GEN). LLC was chosen as medium in view of the poor solubility of GEN in water. Membrane diffusion and penetration studies were carried out with a Franz diffusion cell, through a synthetic membrane in vitro, a chick chorioallantoic membrane ex ovo, and ex vivo excised human epidermis. Thereafter, LLC-GEN was combined with electroporation (EP) to enhance the transdermal drug delivery. The synergistic effect of EP was verified by in vivo ATR-FTIR and ex vivo Raman spectroscopy on hairless mouse skin.OCIS codes: (170.3880) Medical and biological imaging, (300.6540) Spectroscopy, ultraviolet, (120.7280) Vibration analysis, (300.6340) Spectroscopy, infrared, (300.6300) Spectroscopy, Fourier transforms, (170.5660) Raman spectroscopy     

Ocular pharmacology of methazolamide analogs: distribution in the eye and effects on pressure after topical application

The authors studied the relation between physicochemical properties and lowering of intraocular pressure (IOP) after topical application to rabbit in a series of 5-acylimino- and related imino-substituted analogs of methazolamide (Compound 4). All had Ki vs. carbonic anhydrase C of about 10(-8) M. The parent, methazolamide (5-acetyl) does not lower IOP, in contrast to the 5-CF3 acetyl compound (Compound 28). The 5-propionyl compound (6) unexpectedly was 3 times more water soluble than methazolamide and had 10 times greater CHCl3-buffer partition. The in vivo transcorneal permeability constant was 6 times greater than methazolamide. One hour after 1 drop of a 2% suspension of Compound 6, anterior aqueous concentration (in micromolar) was 69 (for methazolamide, 8), posterior aqueous was 19 and ciliary process was 17. IOP dropped 2.2 mm Hg and returned to normal in 4 hr. Other compounds in the series showed varying degrees of activity, ranging from Compound 28, which elicited an IOP fall of 3.5 mm Hg, to Compound 7, (n-pentyryl), for which the fall was 1.3 mm Hg. Also studied are substitutions for CH3 on the ring N at position 4. There are multiple criteria for in vivo activity; a major factor is the balance between water and lipid solubility. The methazolamide analogs are compared with benzothiazole-2-sulfonamides, another class under investigation as topical carbonic anhydrase inhibitors designed to treat glaucoma.     

Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole enhance metabolic stability in vitro and in vivo

2-Bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) is a potent and selective inhibitor of human cytomegalovirus (HCMV), but it lacks clinical utility due to rapid in vivo metabolism. We hypothesized that amino acid ester prodrugs of BDCRB may enhance both in vitro potency and systemic exposure of BDCRB through evasion of BDCRB-metabolizing enzymes. To this end, eight different amino acid prodrugs of BDCRB were tested for N-glycosidic bond stability, ester bond stability, Caco-2 cell uptake, antiviral activity, and cytotoxicity. The prodrugs were resistant to metabolism by BDCRB-metabolizing enzymes, and ester bond cleavage was rate-limiting in metabolite formation from prodrug. Thus, BDCRB metabolism could be controlled by the selection of promoiety. In HCMV plaque-formation assays, l-Asp-BDCRB exhibited 3-fold greater selectivity than BDCRB for inhibition of HCMV replication. This potent and selective antiviral activity in addition to favorable stability profile made l-Asp-BDCRB an excellent candidate for in vivo assessment and pharmacokinetic comparison with BDCRB. In addition to rapid absorption and sufficient prodrug activation after oral administration to mice, l-Asp-BDCRB exhibited a 5-fold greater half-life than BDCRB. Furthermore, the sum of area under the concentration-time profile (AUC)(BDCRB) and AUC(prodrug) after l-Asp-BDCRB administration was roughly 3-fold greater than AUC(BDCRB) after BDCRB administration, suggesting that a reservoir of prodrug was delivered in addition to parent drug. Overall, these findings demonstrate that amino acid prodrugs of BDCRB exhibit evasion of metabolizing enzymes (i.e., bioevasion) in vitro and provide a modular approach for translating this in vitro stability into enhanced in vivo delivery of BDCRB.     

Rapid determination of partition coefficients between n-octanol/water for cardiovascular therapies.

The lipid solubility of a pharmaceutical may greatly influence its tissue activity. To evaluate lipid solubility of a group of cardiovascular agents a procedure to determine partition coefficients in n-octanol/water for a series of cardiovascular compounds was described. Ultraviolet absorbance measurements were used to assess partitioning between the two liquid phases of these compounds. In this study, sotalol was found to be the most hydrophilic (n-octanol/water ratio of 0.33) and fosinopril-sodium was the most lipophilic (ratio of 6.19). This is a versatile method permitting the evaluation of lipophilicity and, thus, parameters governing the events leading to pharmacologic actions such as gastrointestinal dissolution, absorption, and bioavailability. These observations can be related to a drug series, composed of several compounds having structural similarities or minor variations. The lipid solubility of a compound can markedly alter its side-effects profile, especially because lipophilic drugs enter the central nervous system with facility. Additionally, lipophilic agents may enter target tissue with greater ease than nonlipophilic compounds and thus possess local intracellular effects in addition to a macro systemic action.     

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines.     

Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis.

The in vitro transport of nalbuphine (NA) and its prodrugs across various skins was investigated in order to assess the effects of prodrug lipophilicity on passive as well as iontophoretic permeation. The passive diffusion of NA and its prodrugs increased with the drug lipophilicity. Iontophoresis significantly increased the transport of NA and its prodrugs; the enhancement ratio was highest for NA and decreased as the drug lipophilicity increased. Measurements using intact and stratum corneum (SC)-stripped skins showed that the SC was the major skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate (NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped skins indicated that the SC layer was not rate-limiting for the permeation of NA, but remained the rate-limiting barrier for transdermal permeation of NAP. Permeation studies using SC-stripped and delipidized skins suggested that the intercellular pathway was the predominant route for the passive permeation of NA and NAP as well as the iontophoretic permeation of NAP across the SC. The relative rates of passive and iontophoretic permeation across Wistar rat skins demonstrated that a significant amount of NA may permeate skin via the appendageal routes, whereas NAP permeated predominantly through the lipid matrix.     

Submicron lipid emulsion as a drug delivery system for nalbuphine and its prodrugs.

This study investigates the submicron lipid emulsion as a potential parenteral drug delivery system for nalbuphine and its ester prodrugs. Submicron emulsions were prepared using egg phospholipid as the main emulsifier, various co-emulsifiers were also incorporated, including Brij 30, Brij 98, and stearylamine. Squalene as the oil phase formed stable emulsions with small particles. Drug release was affected by incorporating various co-emulsifiers and drugs with various lipophilicity. The loading of nalbuphine into lipid emulsions resulted in the slower and sustained release of nalbuphine. Lipid emulsions containing Brij 98 could further enhance the release of prodrugs as compared to the aqueous solution (control) especially for nalbuphine enanthate (NAE). Hemolysis caused by the interaction between erythrocytes and lipid emulsions was investigated. Brij 30 and Brij 98 could shield the hemolytic activity of phospholipids in the oil/water interface, decreasing the acute toxicological potential of the emulsions. The in vivo analgesic activity of various emulsions was examined by a cold ethanol tail-flick test. The analgesic duration and potency were significantly increased by incorporating nalbuphine and NAE into Brij 98-containing emulsions. There was no need for nalbuphine benzoate (NAB) to show a controlled delivery manner by encapsulating into emulsions, since NAB itself could prolong the analgesic duration of nalbuphine due to the slow enzyme degradation. The in vivo analgesic activity correlated well to the profiles of in vivo pharmacokinetic profiles. The study demonstrates the feasibility of using submicron lipid emulsion as the parenteral drug delivery system for nalbuphine and its prodrugs.     

Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media.

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a target for increasing intestinal transport of low permeability compounds by creating prodrugs designed for the transporter. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to have affinity for hPepT1. Furthermore, in aqueous solution at pH 5.5 to 10, the release of the model drug seems to be controlled by a specific base-catalyzed hydrolysis, indicating that the compounds may remain relatively stable in the upper small intestinal lumen with a pH of approximately 6.0, but still release the model drug at the intercellular and blood pH of approximately 7.4. Even though benzyl alcohol is not a low molecular weight drug molecule, these results indicate that the dipeptide prodrug principle is a promising drug delivery concept. However, the physico-chemical properties such as electronegativity, solubility, and log P of the drug molecule may also have an influence on the potential of these kinds of prodrugs. The purpose of the present study is to investigate whether the model drug electronegativity, estimated as Taft substitution parameter (sigma*) may influence the acid, water or base catalyzed model drug release rates, when released from series of D-Glu-Ala and D-Asp-Ala pro-moieties. Release rates were investigated in both aqueous solutions with varying pH, ionic strength, and buffer concentrations as well as in in vitro biological media. The release rates of all the investigated model drug molecules followed first-order kinetics and were dependent on buffer concentration, pH, ionic strength, and model drug electronegativity. The electronegativity of the model drug influenced acid, water and base catalyzed release from D-Asp-Ala and D-Glu-Ala pro-moieties. The model drug was generally released faster from D-Asp-Ala- than from the D-Glu-Ala pro-moieties. In biological media the release rate was also dependent on the electronegativity of the model drug. These results demonstrate that the model drug electronegativity, estimated as Taft (sigma*) values, has a significant influence on the release rate of the model drug.     

Lipid-based nanoparticles for psoriasis treatment: a review on conventional treatments,recent works,and future prospects

Psoriasis is a lingering inflammatory skin disease that attacks the immune system. The abnormal interactions between T cells, immune cells, and inflammatory cytokines causing the epidermal thickening. International guidelines have recommended topical treatments for mild to moderate psoriasis whilst systemic and phototherapy treatments for moderate to severe psoriasis. However, current therapeutic approaches have a wider extent to treat moderate to severe type of psoriasis especially since the emergence of diverse biologic agents. In the meantime, topical delivery of conventional treatments has prompted many unsatisfactory effects to penetrate through the skin (stratum corneum). By understanding the physiology of stratum corneum barrier functions, scientists have developed different types of lipid-based nanoparticles like solid lipid nanoparticles, nanostructured lipid carriers, nanovesicles, and nanoemulsions. These novel drug delivery systems help the poorly solubilised active pharmaceutical ingredient reaches the targeted site seamlessly because of the bioavailability feature of the nanosized molecules. Lipid-based nanoparticles for psoriasis treatments create a paradigm for topical drug delivery due to their lipids'' amphiphilic feature to efficiently encapsulate both lipophilic and hydrophilic drugs. This review highlights different types of lipid-based nanoparticles and their recent works of nano formulated psoriasis treatments. The encapsulation of psoriasis drugs through lipid nanocarriers unfold numerous research opportunities in pharmaceutical applications but also draw challenges for the future development of nano drugs.

Lipid-based nanoparticles are lipidic nanocarriers that can encapsulate different antipsoriatic agents for topical uses, which enhance the alleviation process compared to conventional topical agents (without nanocarriers).