Evaluation of diclofenac prodrugs for enhancing transdermal delivery

Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery.

Methods: Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions.

Results: The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line.

Conclusion: Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.     

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

Abstract

The present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm²) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also investigated. Steady state flux values of MT did not vary significantly with storage time (p-value = 0.14). The steady state flux was 1.88 ± 0.6 μg/hr/cm²(n = 9). However, storage time did affect the burst effect of MT. Total amount of MT released in the first hour was 137.4 ± 25.7 μg after 3 days, 61.5 ± 8.9 μg after 2 days, and 43.8 ± 20.9 μg after 1 day.     

Formulation study of a patch containing propranolol by design of experiments

Objective: To evaluate the feasibility of a transdermal patch containing propranolol (PR).

Method: Skin penetration enhancers (SPEs) able to improve the skin permeability of PR were selected and a quality by design approach was applied to the development of the patch by a 2⁴ full factorial design. The permeation profile of PR from the formulations was assessed in in vitro permeation studies performed by using Franz diffusion cells and human epidermis as membrane. Finally, skin irritation was evaluated by the Draize test.

Results: N-methyl pyrrolidone (NMP) resulted as the best SPE: in addition, the critical factors influencing the PR diffusion through the human epidermis when loaded in the patch resulted in the matrix thickness (X₁, p?=?0.0957) and PR content (X₃, p?=?0.0004) which improved the flux; conversely, NMP lacked its enhancement effect when loaded in the patch and the increase in its concentration (X₄, p?=?0.006) affected the drug permeation through human epidermis. The flux of optimal formulation was 12.7?μg/cm²/h. On the basis of the steady-state concentration and clearance of PR, the estimated patch surface was 100–120 cm², since the activity of PR is related to its Senantiomer and no in vivo bioconversion occurs.

Conclusion: A patch containing (S)-PR was prepared and the (S)-PR flux (13.3?μg/cm²/h) permitted to confirm the suitability of a transdermal administration of PR. In particular, the use of a 50?μm thick methacrylic matrix containing 8% (S)-PR and 15% NMP can allow to develop a patch non-irritating to the skin, in order to ensure a constant permeation flux of PR over 48?h.     

Effect of Nerodilol and Carvone on in vitro Permeation of Nicorandil Across Rat Epidermal Membrane

ABSTRACT

The objective of the study was to investigate the effect of nerodilol and carvone on the in vitro transdermal delivery of nicorandil so as to fabricate a membrane-moderated transdermal therapeutic system. The in vitro permeation studies were carried across the rat epidermal membrane from the hydroxypropyl methylcellulose (HPMC) gels (prepared with 70:30 v/v ethanol–water) containing selected concentrations of a terpene such as nerodilol (0% w/w, 4% w/w, 8% w/w, 10% w/w, or 12% w/w) or carvone (0% w/w, 4% w/w, 8% w/w, 12% w/w, or 16% w/w). The amount of nicorandil permeated (Q₂₄) from HPMC gel drug reservoir without a terpene was 3424.6 ± 51.4 μg/cm², and the corresponding flux of the drug was 145.5 ± 2.2 μg/cm²· h. The flux of nicorandil increased with an increase in terpene concentration in HPMC gel. It was increased ranging from 254.9 ± 3.1 to 375.7 ± 3.2 μg/cm²·h or 207.6 ± 4.7 to 356.7 ± 15.3 μg/cm²· h from HPMC gels containing nerodilol (4% w/w to 12% w/w) or carvone (4% w/w to 16% w/w), respectively. Nerodilol increased the flux of nicorandil by about 2.62-folds whereas carvone increased the flux of the drug by about 2.49-folds across the rat epidermal membrane. The results of the Fourier Transform Infrared (FT-IR) study indicated that the enhanced in vitro transdermal delivery of nicorandil might be due to the partial extraction of stratum corneum lipids by nerodilol or carvone. It was concluded that the terpenes, nerodilol and carvone, produced a marked penetration enhancing effect on the transdermal delivery of nicorandil that could be used in the fabrication of membrane-moderated transdermal therapeutic systems.     

Effect of Tocopheryl Polyethylene Glycol Succinate on the Percutaneous Penetration of Minoxidil from Water/Ethanol/Polyethylene Glycol 400 Solutions

ABSTRACT

We described to achieve the local retention of minoxidil which has penetrated the skin with minimization of its absorption into the general circulation and elimination of local irritation induced by propylene glycol. The effect of tocopheryl polyethylene glycol succinate (TPGS) on the penetration flux of minoxidil and its retention in the skin from topical minoxidil formulations consisting of water, alcohol, and polyethylene glycol 400 was characterized by an experimental design of ten solvent formulations in this study. Results show that the addition of TPGS was only able to improve the solubility of minoxidil in those solvent systems containing higher proportions of water and PEG 400, and the extent of improvement was also more profound with the addition of TPGS at concentrations higher than 5%. For those solvent systems containing a higher fraction of alcohol, an insignificant change in minoxidil solubility with increasing added amounts of TPGS was noted even with the tendency to decrease the solubility of minoxidil with higher amounts of TPGS. Increasing the amount of TPGS added gradually increased the flux and the corrected flux from solvent formulations with a lower solubility parameter, but decreased those from solvent systems with a higher solubility parameter. With the addition of TPGS, solvent formulation F6 (alcohol:PEG 400 of 50:50) was demonstrated to be the optimal choice by having an improved local effect and a reduced systemic effect compared to the reference of 2% Regaine®. Tocopheryl polyethylene glycol succinate (TPGS) was mainly retained locally in the stratum corneum, and the amount was proportional to the increase in the amount of TPGS added to these ten solvent formulations.     

Development and optimization of a novel drug free nanolipid vesicular system for treatment of osteoarthritis

Objective: The goal of this study is to improve the transdermal delivery of phosphatidylcholine (PC) via constructing a novel nanolipid vesicular system (NLVS) with high level of permeability through the stratum corneum (SC).

Significance: In our study, a novel drug free NLVS was developed. The system depends on PC boundary cartilage lubrication to relieve osteoarthritic pain without developing gastrointestinal problems associated with anti-inflammatory drug.

Materials and methods: A full two-level (2³) factorial design is applied to optimize the quality of the prepared NLVS. The selected independent variables are the concentration of PC, the concentration of edge activator (EA), and EA type. The developed NLVS was evaluated for in-vitro, ex-vivo as well as in-vivo efficacy in rat animal model.

Results: Based on the factorial design, the selected formulation variables significantly affect the tested responses. The prepared NLV formulations have a particle size (PS)in the range of 10.34 to 496.3?nm, polydispersity index (PdI) values less than one, and negative zeta potential (ZP) range of ?1.42 to ?32.01?mV. In-vitro and ex-vivo study results reveal that the designed NLVS is effective in sustaining PC release and enhancing its transdermal permeation over 24?h. The optimal permeation flux through ex-vivo study is 0.415?mg/cm²/h following zero-order kinetics. Moreover, in-vivo study of the optimized formulations demonstrated remarkable reduction in inflammatory mediators associated with osteoarthritis (OA).

Conclusion: The results indicate that the optimized drug free NLVS significantly augment transdermal delivery of PC and have a potential role in treatment of OA without the risk of systemic side effects.     

Effect of O-acylmenthol and salt formation on the skin permeation of diclofenac acid

Purpose: To enhance the transdermal delivery of diclofenac acid (DA) by using O-acylmenthol as a penetration enhancer and complexing with amines, or by a combination of the two methods. Methods: The skin permeability of diclofenac was tested in vitro across rat skin with each of the evaluated permeants in a saturated isopropyl myristate (IPM) donor solution. Results: A 4.5-fold increase in the flux of diclofenac was observed by ion-pair formation with diethylamine; however, the cations with hydroxyl groups had negative effects on the transdermal delivery of diclofenac. 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate and 2-isopropyl-5-methylcyclohexyl heptanoate produced significant increase in the permeation of diclofenac potassium (D-K); however, both of them were ineffective for the other diclofenac salts, including diclofenac diethylamine (D-DETA), diclofenac ethanolamine (D-EA), diclofenac diethanolamine (D-DEA), diclofenac triethanolamine, and diclofenac N-(hydroxylethyl) piperidine. 2-isopropyl-5-methylcyclohexyl tetradecanoate was effective on the penetration of D-K, D-DETA, D-EA, and D-DEA. Also, it is exciting to note that the combined use of diethylamine with 2-isopropyl-5-methylcyclohexyl tetradecanoate produced a 9.74-fold increase in accumulation amount of diclofenac compared with DA in IPM. Conclusions: The use of ion pair in combination with O-acylmenthol is necessary to further increase the diclofenac flux to provide better compliance for the patients undergoing clinical therapy.     

Evaluation of Verapamil Hydrochloride Permeation Through Human Cadaver Skin

Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of verapamil hydrochloride (VPHC1). The apparent partition coefficient (octanol/water or buffer) of VPHC1 in buffers of different Ph values was determined. The saturation solubility of VPHC1 in different buffers and propylene glycol was determined. The target drug flux through the human skin to attain therapeutic concentrations in blood was determined. The maximum flux attainable through the human skin was determined. An attempt was made to increase the flux of the drug using azone as a penetration enhancer. The rate limiting barrier for the permeation of VPHC1 through the skin was determined.     

Microneedle-assisted transdermal delivery of Zolmitriptan: effect of microneedle geometry,in vitro permeation experiments,scaling analyses and numerical simulations

Objective: The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of Zolmitriptan (ZMT).

Methods: Two types of MN devices viz. AdminPatch^® arrays (ADM) (0.6, 0.9, 1.2 and 1.5?mm lengths) and laboratory fabricated polymeric MNs (PM) of 0.6?mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77?cm² skin area (PM-3) to maintain the MN density closer to 0.6?mm ADM. Scaling analyses was done using dimensionless parameters like concentration of ZMT (C_t/C_s), thickness (h/L) and surface area of the skin (Sa/L²).

Results: Micro-injection molding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 3.17- and 3.65-fold increase in ZMT flux values were observed with 1.5?mm ADM and PM-3 applications when compared to the passive studies. Good correlations were observed between different dimensionless parameters with scaling analyses. Numerical simulations, using MATLAB and COMSOL software, based on experimental data and histological images provided information regarding the ZMT skin distribution after MN application.

Discussion: Both from experimental studies and simulations, it was inferred that PM were more effective in enhancing the transdermal delivery of ZMT when compared to ADM.

Conclusions: The study suggests that MN application enhances the ZMT transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.     

A modern approach for controlled transdermal delivery of diflunisal: optimization and in vivo evaluation

The purpose of the present work was to elaborate an optimized transdermal therapeutic system for diflunisal. Selection of suitable ingredients was done via solubility and phase behavior studies. Composition of microemulsion (ME) systems consisting of butyl lactate, Brij^® 97, Transcutol^® and water was optimized using augmented simplex lattice mixture design. The independent variables selected were the percentages of butyl lactate, surfactant mixture and water. The dependent variables were refractive index, pH, conductivity, viscosity, drug solubility in the ME formulation and the ex vivo skin permeation flux. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of the polynomials was established. Optimized formulation factors were selected by desirability approach. The optimized ME formulation was converted into gel using Carbomer^® 934. The microemulsion based gel (MBG) showed better spreadability and 5.07-fold increase in the transdermal flux than Carbomer^® 934 gel. The in vivo antihyperalgesia assay performed on mice showed significant reduction of the licking time in the treated group compared to the control group. This demonstrated the reliability of the simplex lattice statistical design for predicting optimum ME formulation. The developed MBG proved its in vivo efficiency for transdermal delivery of diflunisal.     

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling,characterization, and ex vivo skin permeation

Objective: The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience.

Methods: TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3?×?2²-level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y₁), vesicle size (Y₂), polydispersity index (Y₃), and zeta potential (Y₄) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug–excipient interactions, and vesicle stability were also investigated.

Results: The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p?Conclusion: The study suggests the applicability of statistical modeling as a promising tool for prediction of ethosomal characteristics. The ethanolic vesicles were considered as novel potential nanocarriers for accentuated transdermal TRO delivery.     

In Vitro Evaluation of the Release of Albuterol Sulfate from Polymer Gels: Effect of Fatty Acids on Drug Transport Across Biological Membranes

ABSTRACT

In this investigation, the diffusion of the beta₂ agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37°C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel® (hydroxypropylcellulose) and Methocel® (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel®. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of ?0.09 mg/hr cm² was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6–14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.     

Synthesis and properties of <Emphasis Type="Italic">O</Emphasis>-carboxymethyl chitosan/methoxy poly(ethylene glycol) graft copolymers

O-carboxymethyl chitosan/methoxy poly(ethylene glycol) graft copolymers (OCMCS-g-MPEGs) with different degrees of substitution (DS) were synthesized by reductive N-alkylation of chitosan with poly(ethylene glycol) aldehyde. The properties of OCMCS-g-MPEGs, including the solubility, structure, hydrodynamic behaviors, isoelectric point (IEP) and interaction with water-soluble chitosan, were investigated. As a PEGylated polyampholyte, OCMCS-g-MPEGs can resolve in water over all pH range and the pH value at IEP (pH_IEP) decreases when DS increases. The hydrodynamic behaviors of OCMCS-g-MPEGs in deionized H₂O are markedly affected by DS and pH_IEP in the experiment concentration range. The particle size of the complexes of OCMCS-g-MPEGs with water-soluble chitosan is strongly affected by the concentration of water-soluble chitosan and the pH value.     

Enhanced transdermal delivery of carvedilol using nanoemulsion as a vehicle

The aim of the present study was to develop nanoemulsion as a possible vehicle for enhanced transdermal penetration of carvedilol (CVD). For screening of nanoemulsion components, solubility of CVD in oils, surfactants and co-surfactants was determined. Various surfactants and co-surfactants were screened for their ability to nanoemulsify the selected oily phases. The obtained results indicated that Acconon CC6® had shown good nanoemulsification efficiency (minimum surfactant required S _min?=?46.52%?w/w) among the selected surfactants and further improved in presence of CO-20® (S _min?=?37.11%?w/w). The ranges of nanoemulsion existence were delineated through the construction of the pseudo-ternary phase diagram at different ratio of surfactant mixture (S/CoS), and various nanoemulsions were selected from phase diagram of S/CoS ratio 1?:?1. The effect of content of oil and S/CoS (1?:?1) on the skin permeation of CVD was evaluated through an excised wistar rat skin using Franz diffusion cell. All the nanoemulsions showed a high skin permeation rate (92.251–161.53?µg/cm²/h), good enhancement ratio (3.5–6.2) and high permeability coefficient in comparison to control groups. The optimised nanoemulsion formulation with the highest skin permeation rate (161.53?µg/cm²/h) consisted of 0.25%?w/w CVD, 12.5%?w/w Miglyol 810®, 50%?w/w Acconon CC6®/CO-20® (1?:?1) and water. The above formulation had the smallest mean globules size (9.28?nm). The superior transdermal flux of CVD may be due to nanorange size of oil globules that lead to intimate contact with the skin layer. These studies suggest that the nanoemulsion system is a promising vehicle for the transdermal delivery of CVD.     

Hydrogen permeation through mild steel in temperature range 20–500°C measured by hydrogen collection method

Abstract

Hydrogen permeation through steel plate maintained at various constant temperatures between 20 and 500°C was investigated using the hydrogen collection method. Fused salts were employed at elevated temperatures. Hydrogen entry was induced by step changes in cathodic charging current density. Emanating flux transients obtained at the hydrogen exit face corresponded closely to a model for permeation determined exclusively by bulk hydrogen diffusion through steel, induced by stepped changes in hydrogen concentration at the steel entry face subsurface, and zero hydogen at the exit face subsurface. An Arrhenius plot of log (D) v. 1/T, using diffusion coefficients D derived from permeation transients was approximately linear in the range 20–310°C. The values derived for activation energy E _a of 17 kJ mol ^-1 and for the pre-exponential factor D ₀ of 2·6 × 10^-3 cm2 s^-1, according to D = D ₀ exp (-E _a/RT) were similar to literature values. Between 310 and 500°C, stable permeation conditions were difficult to obtain, but flux measurements were repeatable and unaffected by moisture in air.     

The utility of rat jejunal permeability for biopharmaceutics classification system

Purpose: The biopharmaceutical classification system has been developed to provide a scientific approach for classifying drug compounds based on their dose/solubility ratio and human intestinal permeability. Therefore in this study a new classification is presented, which is based on a correlation between rat and human intestinal permeability values. Methods: In situ technique in rat jejunum was used to determine the effective intestinal permeability of tested drugs. Then three dimensionless parameters—dose number, absorption number, and dissolution number (D_o, A_n, and D_n)—were calculated for each drug. Results: Four classes of drugs were defined, that is, class I, D₀ < 0.5, P_eff(rat) > 5.09 × 10^?5 cm/s; class II, D_o > 1, P_eff(rat) > 5.09 × 10^??5 cm/s; class III, D₀ < 0.5, P_eff(rat) < 4.2 × 10^?5 cm/s; and class IV, D_o > 1, P_eff(rat) < 4.2 × 10^?5 cm/s. A region of borderline drugs (0.5 < D_o < 1, 4.2 × 10^?5 < P_eff(rat) < 5.09 × 10^?5 cm/s) was also defined. Conclusion: According to obtained results and proposed classification for drugs, it is concluded that drugs could be categorized correctly based on dose number and their intestinal permeability values in rat model using single-pass intestinal perfusion technique. This classification enables us to remark defined characteristics for intestinal absorption of all four classes using suitable cutoff points for both dose number and rat effective intestinal permeability values.     

Formulation and evaluation of ubidecarenone transdermal delivery systems

Purpose: This study is aimed to examine the feasibility of developing ubidecarenone (coenzyme Q₁₀, CoQ₁₀) transdermal delivery systems (TDS). Method: In vitro permeation study using solution formulation and pressure-sensitive adhesive (PSA) TDS and in vivo pharmacokinetic study were conducted. Results: When using solution formulations, isopropyl alcohol (103.39 ± 1.61), ethyl alcohol (81.55 ± 7.27), and the mixture of diethylene glycol monoethyl ether (DGME)/propylene glycol monolaurate (PGML) at the ratio of 60:40 (91.08 ± 26.07) showed high flux (μg/cm²/hour). The addition of fatty acids to DGME-PGML failed to show profound enhancing effects; only unsaturated fatty acids such as linoleic acid and oleic acid at 3% and caprylic acid at 3% and 10% slightly increased permeation flux. CoQ₁₀ from the acrylic PSA TDS showed biphasic permeation profile that was permeated very rapidly up to the first 12 hours, and after that, permeation rate became slower. Overall, 6% fatty acids showed high permeation rates and the highest maximum flux of 9.3 μg/cm²/hour was obtained with a formulation containing 6% lauric acid in DGME-PGML (60:40). The in vivo pharmacokinetic study using TDS with 6% fatty acids in DGME-PGML (60:40) showed that the absorption of CoQ₁₀ decreased in the following order: TDS containing linoleic acid > oral dosage form > TDS with oleic acid > TDS with lauric acid > TDS with caprylic acid > TDS with capric acid. TDS containing oleic acid showed preferable pharmacokinetic profile with respect to lower C_max, comparable AUC, and prolonged t_1/2 and T_max compared to oral administration of drug. Conclusions: For effective transdermal delivery system of CoQ₁₀, 6% linoleic acid or oleic acid in DGME-PGML (60:40) could be employed.     

Speeds of Sound and Isentropic Compressibilities of n-Alkoxyethanols and Polyethers with Propylamine at 298.15 K

The speeds of sound (u) have been measured at 298.15 K and atmospheric pressure, as a function of composition for seven binary liquid mixtures of propylamine (CH₃CH₂CH₂NH₂, PA) + ethylene glycol monomethyl ether (2-methoxyethenol, CH₃(OC₂H₄)OH, EGMME); + diethylene glycol monomethyl ether [{2-(2-methoxyethoxy)ethanol}, CH₃(OC₂H₄)₂OH, Di-EGMME]; + triethylene glycol monomethyl ether [{2-(2-(2-methoxyethoxy)ethoxy) ethanol}, CH₃(OC₂H₄)₃OH, Tri-EGMME]; + diethylene glycol monoethyl ether [{2-(2-ethoxyethoxy)ethanol}, C₂H₅(OC₂H₄)₂OH, Di-EGMEE]; + diethylene glycol monobutyl ether [{2-(2-butoxyethoxy) ethanol}, C₄H₉(OC₂H₄)₂OH, Di-EGMBE]; + diethylene glycol diethyl ether [bis(2-ethoxyethyl)ether, C₂H₅ (OC₂H₄)₂ OC₂H₅, DEGDEE]; and + diethylene glycol dibutyl ether [bis(2-butoxyethyl) ether, C₄H₉(OC₂H₄)₂OC₄ H₉; DEGDBE] using a Nusonic velocimeter based on the sing–around technique. These values have been combined with densities derived from excess molar volumes to obtain estimates of the molar isentropic compressibility K _S,m, and their excess values . The values are shown to be negative for all mixtures over the entire composition range. The deviations u ^D of the speeds of sound from the values calculated for ideal mixtures have been obtained for all estimated values of mole fraction x₁. The change of and u ^D with composition and the number of –OC₂H₄ – units in the alkoxyethanol are discussed with a view to understand some of the molecular interactions present in alkoxyethanol – propylamine mixtures.Also, theoretical values of the molar isentropic compressibility of K _S,m and of the speed of sound u ^D have been calculated using the Prigogine-Flory-Patterson (PFP) theory with the van der Waals (vdW) potential energy model, and the results have been compared with experimental values.     

Formulation optimization of a drug in adhesive transdermal analgesic patch

Abstract

Context: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch.

Objective: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children.

Materials and methods: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24?h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife.

Results and discussion: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21?µg/cm²), and shortest lag time (4.35?±?0.01?h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48?µg/cm² of CDB, while the CDB–APAP combination patch with 5% w/w OA delivered 151.40?µg/cm² CDB and 58.12?µg/cm² APAP in 24?h.

Conclusion: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.     

Application of the three-valence model of photorefraction to rhodium-doped barium titanate

Abstract

Small signal and light induced absorption data taken at 633 nm and 1.06 μm for different samples of rhodium-doped barium titanate (Rh : BaTiO₃) have been analysed. These data have been used in conjunction with the three-valence model theory of photorefraction to determine N _D, the total amount of rhodium in each sample. It is shown that the values of N _D calculated at the two wavelengths for individual samples are inconsistent with each other, although no evidence for other impurities in the samples has been observed. This indicates that a more complex theory than the three-valence model is necessary to explain the photorefractive processes in Rh : BaTiO₃, and that an additional photorefractive centre may not be sufficient to account for the observed discrepancies in N _D.