Drug Permeation Rate Research Articles

Quantitative estimation of drug permeation through nasal mucosa using in vitro membrane permeability across Calu-3 cell layers for predicting in vivo bioavailability after intranasal administration to rats

For establishing a precise system for predicting in vivo bioavailability following intranasal (IN) administration, the relationships among membrane permeability of drugs across Calu-3 cells, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration were quantified. The membrane permeability coefficient (Papp) was determined for sixteen model drugs by in vitro permeation studies in Calu-3 cells. The drug permeation rate constant through the nasal mucosa (kn) was calculated from the in situ nasal perfusion of the drug solutions in rats. Bioavailability following IN administration of six model drugs with different membrane permeabilities were determined by in vivo drug absorption studies in rats. The correlations among in vitro membrane permeability properties, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration, were assessed. The significant correlation between the in vitro Calu-3 cell permeability and nasal mucosal drug permeation rate (r2 = 0.812, p < 0.001) indicated that nasal mucosal drug permeability is estimable from in vitro membrane permeability. Furthermore, bioavailability following IN administration significantly correlated with the in vitro Papp across Calu-3 cells (r2 = 0.984, p < 0.001), suggesting that in vivo drug absorption following IN administration can be predicted from in vitro Calu-3 membrane permeability.

The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: In vitro–in vivo correlation of nanocrystals

Nanocrystal formulation is a well-established approach for improving oral absorption of poorly water-soluble drugs. However, it is difficult to predict the in vivo performance of nanocrystal formulations from in vitro dissolution studies. The object of the present study was to investigate the in vitro-in vivo correlation of nanocrystal formulations of different particle sizes. A microsuspension and three nanosuspensions with different particle sizes for model drugs, fenofibrate and megestrol acetate, were prepared. In the comparison between the microsuspension and the nanosuspension having the smallest particle sizes, drug permeation rates from the nanosuspension were about 3-fold higher in the dissolution-permeation study. On the other hand, the solubility enhancement effect due to nanocrystal formation was only up by 1.4-fold, suggesting that nanocrystal formulations dramatically improved not the solubility but the apparent permeability. The oral absorption rate in rats increased with particle size reduction. There were positive and very strong correlations (R2 > 0.95) between the in vitro permeation rate and in vivo maximum absorption rate. We concluded that the enhanced permeability rate due to nanocrystal formation is the main factor for improving oral absorption, and the in vitro dissolution-permeation study could be useful for predicting oral absorption enhancement of nanocrystal formulations.

Review on Buccal Adhesive Drug Delivery System: A Promising Strategy for Poorly Soluble Drugs

Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoid of untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensive presystemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parentral route of administration is the only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly, have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the last few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging. With the right dosage form design, local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution and permeation. Advances in experimental and computational methodologies will be helpful in shortening the processing time from formulation design to clinical use.

In Vitro Assessment of Supersaturation/Precipitation and Biological Membrane Permeation of Poorly Water-Soluble Drugs: A Case Study With Albendazole and Ketoconazole

This study aimed to elucidate the relationship between supersaturation and precipitation and the effect of a supersaturated state on drug membrane permeation. Stock solutions of albendazole (ALB) and ketoconazole (KTZ) dissolved in dimethyl sulfoxide (0.1-50 mg/mL) were diluted 100-fold with buffer solution (pH 6.8, 37°C). In the case of ALB, a supersaturated state and immediate precipitation were observed at 10 μg/mL or less and 20 μg/mL or higher, respectively. When KTZ was used, at an initial concentration of 200 μg/mL or higher, precipitation was observed, although the dissolved concentration remained at approximately 120 μg/mL for at least 30 min. These dissolved concentrations of ALB and KTZ related to approximately 10-fold and 14-fold over the saturated solubility from respective bulk powder. An in vitro permeation study implied that the rate of drug permeation across a biological membrane increased with increasing supersaturation. These results suggested favorable strategies for development of a supersaturable formulation could depend on the precipitation properties of the drug. Immediate- and controlled-release forms might be suitable for supersaturable formulations for KTZ and ALB, respectively.

Role of Porous Carriers in the Biopharmaceutical Performance of Solid SMEDDS of Canagliflozin.

The aim of the present investigation entails the development of solid SMEDDS for improving the oral bioavailability of canagliflozin using porous carriers. The previous patent (WO2017046730A1) was based on enhanced solubility of canagliflozin through co-crystal formation. Preconcentrates were prepared by employing Lauroglycol (80 mg), Tween 80 (300 mg) and Transcutol P (120 mg) and successfully adsorbed onto various hydrophilic and hydrophobic carriers. The prepared solid SMEDDS were characterized for various parameters to determine the optimized formulation. In vitro, ex vivo and in vivo studies were carried out to determine drug release kinetics, permeation and absorption rate, respectively. Stability of the formulation was investigated at 45°C/75% RH. The solid preconcentrates prepared with hydrophobic carriers exhibited desired attributes in a uniform range. Neusilin adsorbed solid SMEDDS (S(N)SMEDDS) portrayed enhanced amorphization in XRD and DSC studies and found to be physically compatible in FTIR studies. SEM revealed colloidal particles having spherical morphology with negligible aggregation. Ex vivo permeation rate of the drug across excised intestinal segments (duodenum, jejunum, ileum and colon) was observed to be 3.72, 5.85, 4.51 and 3.0-fold, respectively, as compared to pure drug. TEM of reconstituted SMEDDS indicated nano-sized globules with negligible coalescence. Enhanced in vitro dissolution rate of optimized solid SMEDDS manifested in bioavailability enhancement of 167.54% and 188.98%, as compared to pure drug and marketed product. These studies further substantiate the lymphatic uptake of SMEDDS through chylomicron flow blocking approach. Establishment of Level A IVIVC showed a uniform correlation between the in vitro dissolution efficiency and in vivo pharmacokinetic parameters. The present investigation reveals the immense potential of solid SMEDDS in augmenting the oral bioavailability profile of poorly water-soluble drug canagliflozin.

Electrically Triggered Transdermal Drug Delivery Utilizing Poly(Acrylamide)-graft-Guar Gum: Synthesis, Characterization and Formulation Development

Objective: The study aimed to prepare electrically-triggered transdermal drug delivery systems (ETDS) using electrically responsive polyacrylamide-graft-gaur gum (PAAm-g-GaG) copolymer. Methods: The PAAm-g-GaG copolymer was synthesized by adopting free radical polymerization grafting method. This PAAm-g-GaG copolymer hydrogel acts as a drug reservoir and blend films of Guar Gum (GaG) and Polyvinyl Alcohol (PVA) were included as Rate Controlling Membranes (RCM) in the system. The PAAm-g-GaG copolymer was characterized by FTIR, neutralization equivalent values, thermogravimetric analysis and elemental analysis. Results: On the basis of results obtained, it is implicit that the drug permeation decreased with an increase in the concentration of glutaraldehyde and RCM thickness; while drug permeation rate was increased with increasing applied electric current strength from 2 to 8 mA. A two fold increase in flux values was observed with the application of DC electric current. An increase in drug permeation was witnessed under on condition of electric stimulus and permeation was decreased when electric stimulus was "off". The skin histopathology study confirmed the changes in skin structure when electrical stimulus was applied. Conclusion: The electrically-sensitive PAAm-g-GaG copolymer is a useful biomaterial for transdermal drug delivery application.

Prediction of Skin Permeation of Flurbiprofen from Neat Ester Oils and Their O/W Emulsions.

Although many in silico models were reported to predict the skin permeation of drugs from aqueous solutions, few studies were founded on the in silico estimation models for the skin permeation of drugs from neat oil formulations and o/w emulsions. In the present study, the cumulative amount of a model lipophilic drug, flurbiprofen (FP), that permeated through skin was determined from 12 different kinds of ester oils (Qoil) and an in silico model was developed for predicting the skin permeation of FP from these ester oils. Thus, the obtained Qoil values were well predicted with the FP solubility in the oils (Soil), the amount of FP uptake into the stratum corneum (SCoil) and molecular descriptors of dipolarity/polarizability (π2H) and molecular density. This model suggests that the thermodynamic activities of FP both in the formulations and skin are the key factors for predicting the skin permeation of FP from the ester oils. In addition, a high linear relationship was observed in the double-logarithm plots between the Qoil and the cumulative amount of FP permeated through skin from 20% ester oil in water emulsion (Qemul20%). Furthermore, the skin permeations of FP from 5 and 10% ester oil in water emulsions, Qemul5% and Qemul10%, respectively, were also predicted by the horizontal translation of the y-axis intercept of the liner equation for the relation between the Qoil and Qemul20%. These prediction methods must be helpful for designing topical oily and/or o/w emulsion formulations having suitable and high skin permeation rate of lipophilic drugs.

Controlled delivery of rivastigmine using transdermal patch for effective management of alzheimer's disease

Alzheimer's disease is a chronic neurodegenerative disease. Preparation of transdermal patches is a useful strategy for management of the disease. The transdermal patches bearing Rivastigmine tartarate were prepared using solvent casting method to provide good drug content uniformity. Transdermal patches were characterized for various attributions viz. patch weight, patch thickness, folding endurance, surface morphology study, X-Ray diffraction study, Differential Scanning Calorimetry, tensile strength, surface pH, percent swelling, percent moisture sorption, drug content uniformity, In vitro release study, and ex-vivo study. Results of in vitro drug release studies clearly indicate that the drug release governed polymer interaction. No lag time was observed then reduction in drug release rate was observed. Extended drug release of 75.15 ± 1.43% within 24 h was observed with formulation. The results of the permeation study indicated that the rate of drug permeation was slow and it was found that 61 ± 1.43% of Rivastigmine tartrate could permeate through the skin membrane in 24 h. In the light of the above mentioned considerations, it is clear that the developed transdermal patch bearing Rivastigmine tartrate was retained in skin layer and delivers the therapeutic amount of drug in blood for longer time. This indicates the potential use of transdermal patches in the treatment of Alzheimer disease.

Colon-specific pulsatile drug release provided by electrospun shellac nanocoating on hydrophilic amorphous composites.

BackgroundColon-specific pulsatile drug release, as a combined drug controlled-release model, is a useful drug delivery manner for a series of diseases. New nanomedicines and related preparation methods are highly desired.MethodsWith diclofenac sodium (DS) as a model drug, a new type of structural nanocomposite (SC), in which composite polyvinylpyrrolidone (PVP)–DS core was coated by shellac, was fabricated via modified coaxial electrospinning. For comparison, traditional PVP–DS monolithic hydrophilic nanocomposites (HCs) were generated using a traditional blending process. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), water contact angle (WCA), and in vitro dissolution and ex vivo permeation tests were conducted to characterize the composites.ResultsSEM images demonstrated that both composites were linear nanofibers with smooth surface morphology and cross sections. TEM disclosed that the SCs had a thin shellac sheath layer of approximately 12 nm. XRD and ATR-FTIR results demonstrated that the crystalline DS was converted into amorphous composites with PVP because of favorable secondary interactions. WCA and in vitro dissolution tests demonstrated that the sheath shellac layers in SC could resist acid conditions and provide typical colon-specific pulsatile release, rather than a pulsatile release of HC under acid conditions. Ex vivo permeation results demonstrated that the SCs were able to furnish a tenfold drug permeation rate than the DS particles on the colon membrane.ConclusionA new SC with a shellac coating on hydrophilic amorphous nanocomposites could furnish a colon-specific pulsatile drug release profile. The modified coaxial process can be exploited as a useful tool to create nanocoatings.

Evaluation of drug permeation under fed state conditions using mucus-covered Caco-2 cell epithelium

The absence of a surface-lining mucus layer is a major pitfall for the Caco-2 epithelial model. However, this limitation can be alleviated by applying biosimilar mucus (BM) to the apical surface of the cell monolayer, thereby constructing a mucosa mimicking in vivo conditions. This study aims to elucidate the influence of BM as a barrier towards exogenic compounds such as permeation enhancers, and components of fed state simulated intestinal fluid (FeSSIF). Caco-2 cell monolayers surface-lined with BM were exposed to several compounds with distinct physicochemical properties, and the cell viability and permeability of the cell monolayer was compared to that of cell monolayers without BM and well-established mucus-secreting epithelial models (HT29-MTX-E12 cell monolayers and HT29-MTX-E12/Caco-2 cell co-culture monolayers). Exposure of BM-covered cells to constituents from FeSSIF revealed that it comprised a strong, hydrophilic barrier effect as 90% of BM-covered cells remained viable for >4 h, and the permeation rate of hydrophobic drugs was reduced. In contrast, the permeation rate of hydrophilic drugs was largely unaffected. Control monolayers displayed a loss of barrier function and <10% viable cells. The efficacy of fatty acid permeation enhancers were altered when investigated in BM-covered cells as compared to all the other studied epithelial models. Thus, Caco-2 cell monolayers surface-lined with BM constitute a valuable in vitro model that makes it possible to mimic intestinal fed state conditions when studying drug permeation.

Methotrexate Aspasomes Against Rheumatoid Arthritis: Optimized Hydrogel Loaded Liposomal Formulation with In Vivo Evaluation in Wistar Rats.

Aspasomes of methotrexate with antioxidant, ascorbyl palmitate, were developed and optimized using factorial design by varying parameters such as lipid molar ratio, drug to lipid molar ratio, and type of hydration buffer for transdermal delivery for disease modifying activity in rheumatoid arthritis (RA). Aspasomes were characterized by drug-excipients interaction, particle size analysis, determination of zeta potential, entrapment efficiency, and surface properties. The best formulation was loaded into hydrogel for evaluation of in vitro drug release and tested in vivo against adjuvant induced arthritis model in wistar rats, by assessing various physiological, biochemical, hematological, and histopathological parameters. Optimized aspasome formulation exhibited smooth surface with particle size 386.8nm, high drug loading (19.41%), negative surface potential, and controlled drug release in vitro over 24h with a steady permeation rate. Transdermal application of methotrexate-loaded aspasome hydrogel for 12days reduced rat paw diameter (21.25%), SGOT (40.43%), SGPT (54.75%), TNFα (33.99%), IL β (34.79%), cartilage damage (84.41%), inflammation (82.37%), panus formation (84.38%), and bone resorption (80.52%) as compared to arthritic control rats. Free methotrexate-treated group showed intermediate effects. However, drug-free aspasome treatment did not show any effect. The experimental results indicate a positive outcome in development of drug-loaded therapeutically active carrier system which presents a non-invasive controlled release transdermal formulation with good drug loading, drug permeation rate, and having better disease modifications against RA than the free drug, thereby providing a more attractive therapeutic strategy for rheumatoid disease management.

The Development and Validation of an In Vitro Airway Model to Assess Realistic Airway Deposition and Drug Permeation Behavior of Orally Inhaled Products Across Synthetic Membranes.

Current in vitro approaches to assess lung deposition, dissolution, and cellular transport behavior of orally inhaled products (OIPs) have relied on compendial impactors to collect drug particles that are likely to deposit in the airway; however, the main drawback with this approach is that these impactors do not reflect the airway and may not necessarily represent drug deposition behavior in vivo. The aim of this article is to describe the development and method validation of a novel hybrid in vitro approach to assess drug deposition and permeation behavior in a more representative airway model. The medium-sized Virginia Commonwealth University (VCU) mouth-throat (MT) and tracheal-bronchial (TB) realistic upper airway models were used in this study as representative models of the upper airway. The TB model was modified to accommodate two Snapwell® inserts above the first TB airway bifurcation region to collect deposited nebulized ciprofloxacin-hydrochloride (CIP-HCL) droplets as a model drug aerosol system. Permeation characteristics of deposited nebulized CIP-HCL droplets were assessed across different synthetic membranes using the Snapwell test system. The Snapwell test system demonstrated reproducible and discriminatory drug permeation profiles for already dissolved and nebulized CIP-HCL droplets through a range of synthetic permeable membranes under different test conditions. The rate and extent of drug permeation depended on the permeable membrane material used, presence of a stirrer in the receptor compartment, and, most importantly, the drug collection method. This novel hybrid in vitro approach, which incorporates a modified version of a realistic upper airway model, coupled with the Snapwell test system holds great potential to evaluate postairway deposition characteristics, such as drug permeation and particle dissolution behavior of OIPs. Future studies will expand this approach using a cell culture-based setup instead of synthetic membranes, within a humidified chamber, to assess airway epithelia transport behavior in a more representative manner.

Development and Evaluation of pH-Responsive Cyclodextrin-Based in situ Gel of Paliperidone for Intranasal Delivery.

Paliperidone (PLPD) is approved for treatment and management of schizophrenia. The current study demonstrates the potential of in situ gel of PLPD for nasal delivery. The permeation of drug through sheep nasal mucosa was analyzed since the nose-to-brain pathway has been indicated for delivering drugs to the brain. The carbopol 934 (CP)- and hydroxypropyl methyl cellulose K4M (HPMC)-based in situ gels containing 0.2% CP and 0.4% w/v HPMC were optimized using experimental design software. The use of hydroxypropyl-β-cyclodextrin (HP-β-CD) in nasal permeation of drug was investigated. Transmucosal permeation of PLPD was examined using sheep nasal mucosa. The in situ gels of PLPD exhibited satisfactory mucoadhesion and showed sustained drug release. The mucocilliary toxicity and histopathological examination confirmed that the nasal mucosa architecture remains unaffected after treatment with PLPD in situ gel. The formulation containing HP-β-CD complex of PLPD exhibited higher rate of drug permeation through sheep nasal mucosa revealing the role of HP-β-CD as nasal absorption enhancer. Thus, CP- and HPMC-based pH-triggered in situ gel containing HP-β-CD-drug inclusion complex demonstrates a novel nasal delivery of PLPD.

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles.

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.

Preparation and Characterization of Rivastigmine Transdermal Patch Based on Chitosan Microparticles.

Here we report a novel approach for preparation of a 6-day transdermal drug delivery system (TDDS) as treatment for mild to moderate Alzheimer's disease. The spray drying method was used to prepare microparticles containing the anti-Alzheimer drug, Rivastigmine, in combination with the natural polymer, chitosan, for transdermal drug delivery applications. The content of the drug was determined by High Performance Liquid Chromatography (HPLC) method which was validated as per FDA guidelines. The morphology and size range of the microparticles were determined; and the effect of drug concentration in the solution injected into the spray dryer on the particles characterizations was studied. The stability of Rivastigmine at high temperature was confirmed using FTIR analysis as well as a validate HPLC assay. The obtained results show that the drug was stable at high temperatures with 7 to 42% loading in the microparticles, and the higher drug concentrations of the solution injected into the spray dryer resulted in increase of the drug loading, surface drug and microparticles distortion. The TDDS containing the microparticles was also prepared with microparticle to dry adhesive ratios of 5, 10 and 15% using acrylic adhesive. Based on adhesion properties of the patches, gained from the probe tack and the peel adhesion 180° tests, and the 15% patch by having more drug content per unit area of the patch, and still having similar adhesion properties was compared to the microparticles-free patch of 5.1% Rivastigmine salt (equivalent to the drug content of the 15% patch) from the permeation point of view by using Franz cell diffusion over 6 days. The drug permeation rate from the microparticle-free patch was slower than the 15% microparticles patch, which is the result of crystallization of Rivastigmine salt in the acrylic adhesive. The 6-day-prepared TDDS can be considered as an alternative for one-week application of 6 Exelon patches.

Nanosized Drug Delivery Systems for Direct Nose to Brain Targeting: A Review.

Drug targeting to brain has always been problematic due to Blood-Brain Barrier (BBB), which, does not allow most of the drugs to pass through it as they are hydrophilic and macromolecular drugs. So, in order to bypass the BBB, alternative modes of administration were searched and nasal to brain delivery route was tried by many workers. Such studies yielded patented nano-formulations with the ability to cross blood brain barrier. Nanoparticles being smaller in size and large surface area help in increasing the rate of drug permeation to the brain. In this review work, emphasis has been laid on discussion on various works done in the field of nasal delivery of drugs to brain over the last decade. The works that are discussed in this paper show better drug targeting of brain when given through nasal route as nanoparticles. Experiments performed in animal models have clearly exhibited that nano-sized formulations are able to facilitate the delivery of drugs to brain through nose in comparison to tantamount drug solutions. However, it is not yet confirmed whether the drug is freed from the formulation in the nasal cavity and then absorbed or the nanoparticles themselves are absorbed and then the drug is released in the CNS. Furthermore, the toxicity studies were not carried out extensively in suitably designed model, which should be considered before going for further studies and application.

ETHOSOME: A NEW TECHNOLOGY USED AS TOPICAL &amp; TRANSDERMAL DELIVERY SYSTEM

Transdermal drug delivery system was first introduced more than 20 years ago. Transdermal drug delivery system is a type of convenient drug delivery system where drug goes to the systemic circulation through the protective barrier i.e. Skin is the main target of topical and transdermal preparations. Major aim of transdermal drug delivery system is to cross the stratum corneum. Various methods have been tried to increase the permeation rate of drugs temporarily. Vesicular system is one of the most controversial methods for transdermal delivery of active substances in that ethosome are the ethanolic phospholipids vesicles which are used mainly for transdermal delivery of drugs. Ethosomes are soft, malleable vesicles tailored for enhanced delivery of active agents. Ethosomes have higher penetration rate through the skin. The increased permeation of ethosomes is probably due to its ethanolic content. Ethanol increases the cell membrane lipid fluidity which results in increased skin penetrability of the ethosomes. These ethosomes permeates inside the skin and fuse with cell membrane lipids and release the drug. Hot and cold methods are used for formulation of ethosomes. Evaluation parameters include size, shape, drug content, zeta potential etc. Ethosomes have been successfully evaluated for the delivery of many drugs for e.g. Cyclosporine A, insulin, salbutmol, trihexyphenidil, etc. Ethosomes provides a number of important benefits including improving the drug’s efficacy, enhancing patient compliance and comfort and reducing the total cost of treatment. Ethosomes can be important drug delivery tool in the future. KEYWORDS: Ethosomes, Transdermal, Vesicular carriers, Ethanol, Phospholipid.

Deformability properties of timolol-loaded transfersomes based on the extrusion mechanism. Statistical optimization of the process

The purpose of this work was to analyze the deformability properties of different timolol maleate (TM)-loaded transfersomes by extrusion. This was performed because elastic liposomes may contribute to the elevation of amount and rate of drug permeation through the corneal membrane. This paper describes the optimization of a transfersome formulation by use of Taguchi orthogonal experimental design and two different statistical analysis approaches were utilized. The amount of cholesterol (F1), the amount of edge-activator (F2), the distribution of the drug into the vesicle (F3), the addition of stearylamine (F4) and the type of edge-activator (F5) were selected as causal factors. The deformability index, the phosphorous recovery, the vesicle size, the polydispersity index, the zeta potential and percentage of drug entrapped were fixed as the dependent variables and these responses were evaluated for each formulation. Two different statistical analysis approaches were applied. The better statistical approach was determined by comparing their prediction errors, where regression analysis provided better optimized responses than marginal means. From the study, an optimized formulation of TM-loaded transfersomes was prepared and obtained for the proposed ophthalmic delivery for the treatment of open angle glaucoma. It was found that the lipid to surfactant ratio and type of surfactant are the main key factors for determining the flexibility of the bilayer of transfersomes. From in vitro permeation studies, we can conclude that TM-loaded transfersomes may enhance the corneal transmittance and improve the bioavailability of conventional TM delivery.

A novel application of electrospinning technique in sublingual membrane: characterization, permeation and in vivo study

Isosorbide dinitrate–polyvinylpyrrolidone (ISDN–PVP) electrospinning fibers were formulated and explored as potentially sublingual membrane. The addition of polyethylene glycol (PEG) to the formulation improved flexibility and reduced fluffiness of the fiber mat. The scanning electron microscopy (SEM) demonstrated that the fibers tended to be cross-linking, and the crosslinking degree increased with the increase of PEG amount. The differential scanning calorimetry (DSC) indicated that ISDN existed in non-crystalline state in the fibers (except at the highest drug content). The infrared spectroscopy suggested that ISDN had better compatibility with the ingredients owing to the hydrogen bonding (or hydrophobic interactions). The fibers were highly favorable for the fabrication of sublingual membrane due to neutral pH, large folding endurance and rapid drug release (complete dissolution within 120 s). The permeation study of ISDN through both dialysis membrane (DM) and porcine sublingual mucosa (SM) were carried out. A significant relationship of drug permeation rate through DM and SM was built up, which indicated that DM could be used to partly simulate SM and assess formulation. The pharmacokinetic study in rats demonstrated that the electrospinning fiber membrane had a higher Cmax and lower Tmax compared to the reference preparation, and the relative bioavailability of the fiber membrane was 151.6%.

Needle-free buccal anesthesia using iontophoresis and amino amide salts combined in a mucoadhesive formulation

Iontophoresis is a strategy to increase the penetration of drugs through biological membranes; however, its use has been underexplored in mucosa. The aim of this work was to investigate the influence of iontophoresis in the mucosal penetration of prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL), which are largely used in dentistry as local anesthetics, when combined in the same formulation. Semisolid hydrogels containing these drugs either alone or in combination were developed at two different pHs (7.0 and 5.8) and presented adequate mechanical and mucoadhesive properties for buccal administration. The distribution coefficients between the mucosa and the formulations (Dm/f) and the in vitro mucosa permeation and retention rates were evaluated for both PCL and LCL. At pH 7.0, the combination of the drugs decreased the Dm/f of PCL by approximately 3-fold but did not change the Dm/f of LCL; iontophoresis increased the permeation rate of PCL by 12-fold and did not significantly change LCL flux compared with the passive permeation rate of the combined drugs. Combining the drugs also resulted in an increase in both PCL (86-fold) and LCL (12-fold) accumulation in the mucosa after iontophoresis at pH 7.0 compared with iontophoresis of the isolated drugs. Therefore, applying iontophoresis to a semisolid formulation of this drug combination at pH 7.0 can serve as a needle-free strategy to speed the onset and prolong the duration of buccal anesthesia.