Primaquine-loaded transdermal patch for treating malaria: design, development, and characterization

The main aim of this study was to expand the present formulation with patch and to evaluate the transdermal patches of Flurbiprofen, NSAID (Non-Steroidal Anti-Inflammatory Drug) used in the treatment of arthritis. Flurbiprofen is required at a sustained rate of its short half- life (3-4 hours) long term percutaneous absorption is required for its gastrointestinal side effects. Hence in this study, an effort was done to develop transdermal patches of Flurbiprofen by employing a different combination of polymers were prepared by the solvent evaporation technique. Nine formulations were prepared consists of Hydroxy Propyl Methyl Cellulose (HPMC) E15 and polyvinylpyrrolidone in the ratios of 1:1, 1:2. Formulation, HPMC E15 and Ethylcellulose (EC) in 1:1, 1:2. Formulations, HPMC E15 and Eudragit RS100 in 1:1, 1:2, and Formulation HPMC E15 and Eudragit RL100 in 1:1, 1:2.Formulations (F1- F8). F9 formulations contain HPMC E15, Eudragit RS100 in 2:1 ratio with permeation enhancer DMSO 20% v/w of propylene glycol was used as a plasticizer in all the formulations. The developed patches were considered for several physicochemical parameters. In vitro drug release studies showed maximum percentage in 24 hrs for F9 formulation 94.31±1.43, showed maximum Ex-vivo skin permeation of 10,120±0.91 µg/cm2, and the obtained flux meets the required flux. The resultant data was fitted into zero; first, Higuchi and Peppas model and Formulation F9 followed zero order. Drug compatibility studies were resulted by FTIR. The results specify that Flurbiprofen transdermal patch can be designed with the required amount of flux with desire mechanical properties for the cause of better therapeutic benefits.

Transdermal drug delivery systems of indapamide have been formulated by using solvent casting method. Monolithic systems were prepared by using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC) polymers by incorporating glycerine and dibutyl phthalate as plasticizers, respectively. All the patches were uniform with respect to physicochemical and scanning electron microscopy (SEM) evaluation. Th e in vitro drug release studies indicated that HPMC containing fi lms have shown better release than that of EC containing fi lms without any permeation enhancer. A total of eight monolithic systems were prepared by using a drug polymer ratio of 1:4 and incorporated diff erent vegetable oils as permeation enhancers in diff erent concentrations. Th e prepared systems released the drug in the following order: F3 > F4 > F7 > F5 > F8 > F6 > F1 > F2. Th e various permeation parameters such as fl ux, permeability coeffi cient, enhancement ratio and diff usion rate constants were determined for all the formulations. Th e maximum fl ux of 9.08 × 102 mg/ cm2 h was observed with HPMC monolithic system containing 30% w/w olive oil. A signifi cant improvement of fl ux was observed in the following order: olive oil > linseed oil > sunfl ower oil > cottonseed oil > coconut oil > castor oil. Further improvement of fl ux was observed, when 30% w/w olive oil was applied directly onto the skin prior to the studies. Th e in vitro release studies revealed that the release was sustained up to 24 h and it follows zero-order kinetics. All the fi lms were found to be stable at 37°C and 45°C with respect to their physical parameters and drug content. Key words: EC, HPMC, linseed oil, olive oil, permeation enhancers, sunfl ower oil, transdermal

Nifedipine transdermal patches were developed by using various types and concentrations of surfactants as permeation enhancers. The preparation composed of 1% W/ W nifedipine, 50% W/W Pluronic F-127, 10% W/W glycerin and 6% W/W Aerosil A 200 was used as control formulation. The good physical appearance formulations were assessed the in vitro skin permeation. The nifedipine transdermal patch with the highest skin permeation amount and rate was selected for in vivo study, using rabbits as animal model comparing with single oral dose administration (Adalat ® 10 mg) . Kinetic parameters included tMAX , CMAX and normalized AUC |0 24 were evaluated. The results from in vitro study indicated that 2% cetyltrimethyl ammonium bromide was a suitable surfactant with providing the highest skin permeation amount whereas 1% cetyltrimethylammonium bromide evidently exhibited the lowest value. Other surfactants showed the difference enhancing effect due to themselves properties. Various concentration of cetylpyridinium chloride were similar to control formulation. For anionic surfactant, preparation composed of 0.5% sodium lauryl sulfate exhibited greater skin permeation amount than other formulations in this group. Increasing concentration of Cremophor A25 decreased nifedipine permeation amount. All nifedipine transdermal systems in this study exhibited, the first phase (0-10 hr), showing the lower nifedipine permeation rate from each formulation involved the process of drug releasing and the effect of skin uptake on the permeation of drug through pig's skin. After that, the permeation rate of the second phase (10-24/28 hours) was higher than the first phase. The selected nifedipine transdermal patch was put on back area of rabbit. It was clearly shown that nifedipine can be released from the transdermal patch into systemic circulation. The nifedipine plasma concentration time profiles of two out from five rabbits showed sustained release pattern of drug from dosage form up to 24 hours. The normalized maximum nifedipine plasma concentration from transdermal patch were relatively less than oral single dose. The significant higher AUC |0 24 of oral nifedipine administration than of transdermal patch was observed. The release pattern of nifedipine from transdermal patch into diffusion cell was highly significant than that release into rabbit circulation. Therefore, It is suggested that transdermal patches have to be improved to get the better released drug in systemic circulation for once a day medication.

Felodipine, an effective calcium channel blocker, widely used for the treatment of chronic stable angina and hypertension seems to be potential therapeutic transdermal system candidate, mainly due to its low oral bioavailability, short half life and high first-pass metabolism. Hence an attempt was made to develop transdermal therapeutic systems for felodipine using the polymer blend of eudragit RL100 (ERL) and hydroxypropyl methylcellulose (HPMC) by casting method and to study the effect of polymer composition, plasticizer and permeation enhancer on the physico-mechanical and in vitro drug release characteristics of the film. Polyethylene glycol 400 (PEG 400) and span 60 were used as plasticizer and permeation enhancer respectively. Incorporation of HPMC and PEG 400 improved the flexibility, folding endurance and handling properties and in vitro drug release of the films. The patches were also evaluated for ex vivo skin permeation using human cadaver skin. The presence of span 60 produced significant increase in the flux and permeability. The formulation with ERLHPMC ratio 2:3,4% w/w span 60 as permeation enhancer and 7.5% w/w PEG 400 as plasticizer showed the best results which exhibited the cumulative percentage of drug release of 84.96% and the cumulative amount of drug permeation across skin of 4861.4ng/cm 2 in 24 hrs. In vivo studies of this transdermal system in rabbits demonstrated a four fold enhancement of bioavailability of felodipine relative to oral administration. It may be concluded that the fabricated transdermal delivery system have the potential to provide controlled and extended drug release, better bioavailability and thus, they may improve the patient compliance.

Transdermal drug delivery is important to maintain plasma drug concentrations for therapeutic efficacy. The current study reports the design, formulation, and evaluation of tizanidine transdermal patches formulated using chitosan and thiolated chitosan, ethyl cellulose (EC), polyvinylpyrrolidone (PVP), and Eudragit RL100 in different ratios. The tizanidine patches were formulated using flaxseed oil and coriander oil in the concentrations of 1% v/w, 2% v/w, 3% v/w, 4% v/w, 5% v/w, and 10% v/w. The patches were subjected to characterization of physicochemical property (thickness, weight uniformity, drug content, efficiency, percentage moisture uptake/loss), in vitro drug release and drug permeation, skin irritation, in vivo application, pharmacokinetics analysis, and stability studies. The results indicate that the interaction of thiolated chitosan with the negative charges of the skin opens the tight junctions of the skin, whereas flaxseed and coriander oils change the conformational domain of the skin. The novelty of this study is in the use of flaxseed and coriander oils as skin permeation enhancers for the formulation of tizanidine transdermal patches. The formulations follow non-Fickian drug release kinetics. The FTZNE23, FTZNE36 and FTZNE54, with 5% v/w flaxseed oil loaded formulations, exhibited higher flux through rabbit skin compared with FTZNE30, FTZNE35, FTZNE42, and FTZNE47, formulations loaded with 10% v/w coriander oil. The study concludes that flaxseed oil is a better choice for formulating tizanidine patches, offering optimal plasma concentration and therapeutic efficacy, and recommends the use of flaxseed and coriander oil based patches as a novel transdermal delivery system for tizanidine and related classes of drugs.

Approaches for breaking the barriers of drug permeation through transdermal drug delivery

In past years, various studies have considered transdermal drug delivery system for improving patient compliance. One approach to deliver drug via transdermal route is transdermal patch. These patches include single-layer drug in adhesive patches and micro reservoir transdermal patch & matrix system. Acrylic-acid, hydroxypropyl methylcellulose (HPMC) and polyethylene glycol are commonly used polymers for manufacturing of transdermal patches. Characterization of patches includes patch thickness, weight uniformity, irritation studies, in-vitro drug release and permeation studies. This review summarizes various polymers, types of transdermal patches and evaluation of transdermal patches based on up-to-date data extracted from reputed journals and official websites.

The topical route for local anaesthesia including ointments and creams can be easily washed off by wetting agents or with contact or movement. The goal and objective of the present study was to develop and formulate a transdermal patch for local anaesthesia. These patches were formulated by solvent casting method by the use of Hydroxypropyl Methylcellulose (HPMC) polymer, different enhancers, and vasoconstrictor which is the key ingredient for enhancing aesthetic activity. Formulated patches were evaluated for the physical and physicochemical parameters like moisture content, moisture uptake, folding endurance, water vapour permeability, drug content, and drug release, and in vivo study was done on rats. Amongst all the formulations, F7 was considered the ideal formulation which is the combination of HPMC polymer, polyoxyethylene 2-oleyl ether as an enhancer, and vasoconstrictor Tetrahydrozoline. For in vivo testing Tail flick method was applied and the effect of anaesthesia was maximum as compared to other formulations. In comparison to the control formulation, there was a 2.34-fold increase in aesthetic activity. When compared to the control formulation, the F7 formulation exhibited improved and longer efficacy. A transdermal bupivacaine patch incorporating a penetration enhancer and a vasoconstrictor could be created to improve the local cosmetic effects of bupivacaine.

Vehicles and permeation enhancers (PEs) used in transdermal drug delivery (TDD) of a drug can affect skin hydration, integrity and permeation of the solute administered. This investigation was designed to study the effect of the most commonly used vehicles and PEs on rat skin hydration, barrier function and permeation of an amphiphilic drug, imipramine hydrochloride (IMH). An array of well-established techniques were used to confirm the findings of the study. Thermogravimetric analysis (TGA) and Fourier transform infrared (FTIR) spectroscopy were used to determine changes in skin hydration. Alteration of the stratum corneum (SC) structure was investigated using FTIR studies. To monitor the barrier function alteration, transepidermal water loss (TEWL) measurement and permeation studies were performed. Our findings indicate that with hydration, there was an increase in the bound water content of the skin, and pseudoequilibrium of hydration (a drastic decrease in hydration rate) was achieved at around 12 h. Hydration increased the ratio between amide-I and amide-II peaks in FTIR and reduced the C-H stretching peak area. Both propylene glycol (PG) and ethanol (EtOH) dehydrated skin, with the latter showing a predominant effect. Furthermore, it was confirmed that PG and EtOH decreased the bound water content due to alteration in the protein domains and extraction of SC lipids, respectively. The effect of hydration on the SC was found to be similar to that reported for temperature. Permeation studies revealed that the dehydration caused by vehicles decreased IMH flux, whereas the flux was enhanced by PEs. The role of partition was predominant for the permeation of IMH through dehydrated skin. A synergistic effect was observed for PG and menthol in the enhancement of IMH. Further findings provided strong evidence that PG affects protein domains and EtOH extracts lipids from the bilayer. Both PG and EtOH, with or without PEs, increased TEWL. Initial TEWL was well correlated with the flux of IMH through the same skin. It was found that both PG and EtOH affect the permeation of solute and TEWL by dehydration. The experiments also proved that the initial TEWL value has a strong potential as a predictive tool for the permeation of the solute.

Objective : The compatibility of four binary active substances combinations adapalene – levofloxacin (ADP-LFX), adapalene – miconazole nitrate (ADP-MCZ), levofloxacin – meloxicam (LFX-MLX) and levofloxacin – miconazole nitrate (LFX-MCZ) was analysed to be comprised in new transdermal therapeutic systems. Also, the compatibility of selected active substances and four polymeric excipients (hydroxypropyl methyl-cellulose - HPMC 15000, hydroxypropyl methylcellulose - HPMC E5, ethyl cellulose - EC 10, and hydroxyethyl cellulose – HEC) was studied. Methods : Thin layer chromatographic method (TLC) and four selected mobile phases were used. On the plate ( in situ ) were obtained the binary combinations (active substances and active substance-polymer). Results : A good compatibility of ADP-LFX was found using ammonia : methanol : acetonitrile : methylene chloride 2:4:1:4 mobile phase. Using chloroform : acetone : glacial acetic acid 34:4:3 on the chromatogram of ADP-MCZ, only ADP spots appeared but without changes in the shape of the spots and R f values. Any modifications of LFX and MLX spots (from LFX-MLX mixture) had been observed using toluene : glacial acetic acid : methanol 11:1:0.5 mobile phase, although LFX spots have remained on the baseline. Only LFX spots were visible from LFX-MLX and LFX-MCZ mixtures (ammonia : methanol : acetonitrile : methylene chloride 2:4:1:4 mobile phase). Distinctive spots were observed for ADP, LFX and MLX with variable results from no chemical interactions to limited chemical interactions when the compatibility with polymers was verified. Conclusions : ADP-LFX and LFX-MLX mixtures were found to be compatible. ADP with HPMC polymers and LFX with HPMC E5 and HEC had presented excellent compatibility; for the other binary combinations, different analytical methods will be necessary.

The skin irritating, sensitizing, and acute dermal toxicity potential of a novel combinational prophylactic transdermal patch, mainly composed of eserine and pralidoxime chloride as active pharmaceutical ingredients, against (±) anatoxin-a poisoning were investigated in rabbits, guinea pigs, and rats in compliance with the Organisation for Economic Cooperation and Development guidelines. In primary skin irritation test, rabbits were dermally attached with the therapeutically active transdermal patch or with a placebo patch for 72 hours. The transdermal patches did not induce any adverse reactions such as erythema and edema on intact skin sites. The active patch was classified as a practically nonirritating material based on the score in the primary irritation index. In the Buehler test, guinea pigs were sensitized by the active or placebo transdermal patches attached for 24 hours. The patches did not induce any sensitization reactions in contrast to a severe sensitization reaction that occurred in the positive control. Therefore, the active patch and placebo patch were both graded as weak in sensitization score and rate. Acute dermal toxicity test in rats did not produce any overt signs of toxicity following a 14-day treatment period. Taken together, these findings suggest that the transdermal patch does not cause skin irritation, skin sensitization, or dermal toxic effects following dermal application.

Since two decades or so transdermal route established itself as better alternative to traditional oral route. This is possible due to continuous innovations in transdermal drug delivery (TDD), which not only enables researchers from academia and industry to successfully develop and launch many new pharmaceuticals but also allow to include new classes of drugs that can be developed into transdermal formulations. These successes are achieved due to the use of novel techniques based on either physical or chemical approaches. However, both of these techniques suffer due to their own disadvantages. Comparatively, a simple method of supersaturation to enhance drug permeation across skin has created a new wave of interest. Even though the application supersaturated principle in topical and TDD has been used from 1960s, but proper control of drug release and formation of stable supersaturated states has been the core of intense research in the last decade. Out of various methods used to get supersaturated system, evaporation method is considered as most efficient and practically feasible for TDD. Therefore, in this review concept of supersaturation, selection of solvent system and the mechanism of inhibition of crystallization are discussed. Application of evaporation systems in the development of transdermal formulations such as solutions, semisolids and metered dose therapeutic systems (MDTS) and the commercial evaporative systems are also discussed in this review.

ABSTRACTIntroduction: Transdermal drug delivery has several clinical benefits over conventional routes of drug administration. To open the transdermal route for a wider range of drugs, including macromolecules, numerous physical and chemical techniques to overcome the natural low skin permeability have been developed.Areas covered: This review focuses on permeation enhancers (penetration enhancers, percutaneous absorption promoters or accelerants), which are chemicals that increase drug flux through the skin barrier. First, skin components, drug permeation pathways, and drug properties are introduced. Next, we discuss properties of enhancers, their various classifications, structure-activity relationships, mechanisms of action, reversibility and toxicity, biodegradable enhancers, and synergistic enhancer combinations.Expert opinion: Overcoming the remarkable skin barrier properties in an efficient, temporary and safe manner remains a challenge. High permeation-enhancing potency has long been perceived to be associated with toxicity and irritation potential of such compounds, which has limited their further development. In addition, the complexity of enhancer interactions with skin, formulation and drug, along with their vast chemical diversity hampered understanding of their mechanisms of action. The recent development in the field revealed highly potent yet safe enhancers or enhancer combinations, which suggest that enhancer-aided transdermal drug delivery has yet to reach its full potential.

Aim and Background:Domperidone is a dopamine antagonist with antiemetic properties having a plasma half life of 7-9 h with 15% oral bioavailability. In the present work transdermal patches of domperidone were prepared with the objective to improve its therapeutic efficacy, patient compliance and to reduce the frequency of dosing and side effects, as well as to avoid its extensive first pass metabolism of the drug.Materials and Methods:The patches were prepared using ethyl cellulose (EC): Poly vinyl pyrrolidone (PVP), poly vinyl alcohol (PVA): Poly vinyl pyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC): Sodium (carboxy methyl cellulose) CMC as polymers in combination. The physicochemical parameters like thickness, drug content, weight variation, moisture absorption and drug permeation studies were evaluated for the prepared patches. No significant difference in thickness, average weight and in the drug content among the patches.Results:It was observed that from hydrophilic polymers the drug release was found to be faster compared to (F5 and F6 & F3 and F4) combination of hydrophilic and lipophilic polymers used in the study. Patches containing HPMC and Sodium CMC (F5 and F6) showed faster release as the patches showed maximum percentage amount moisture absorption. The in vitro release data was treated with kinetic equations and it followed Higuchi's diffusion mechanism. The in vivo bioavailability study was performed in rats and observed that, drug reached to the peak in approximately 60 min (16%) after oral route of administration. However, approximately same amount of drug was found in the serum from transdermal formulation in 6 h and further increase in the amount of drug in the serum, indicated that the drug 5 bioavailability could be better and hence the hepatic metabolism can be avoided, as it is evident from the data. Further, the decrease in the amount of drug present in the serum 45 min after oral administration also indicated that major amount of drug might have got metabolized and the bioavailability is reduced. However, the transdermal patch released further amount of drug (33%) at the end of 24 h.Conclusion:The present study can be concluded that transdermal patch can extend the release of drug for many hours with better bioavailability and also can avoid the first pass effect.

Nebivolol HCl is a unique third-generation beta blocker that has less oral bioavailability and exhibits various adverse effects like gastrointestinal disturbance and abdominal pain. This study aimed to formulate and evaluate nebivolol HCl transferosomal transdermal patches to reduce the problems associated with oral delivery of the drug and enhancement of drug permeation through the skin. Nebivolol HCl loaded transferosomes were prepared by thin film hydration method. Eight formulations were prepared based on the two independent variables, type of surfactant (Tween 80 and Span 80) and Phospholipid: Edge activator ratio and were evaluated for their vesicle size, PDI, and entrapment efficiency. The optimized formulations were incorporated into transdermal patches, which were evaluated for physicochemical properties, in-vitro and ex-vivo permeation, skin irritancy, and stability studies. The vesicle size of the transferosomes ranged from 49nm to 93nm, and EE% varied from 39% to 79%. Vesicles formed with Span 80 as an edge activator showed smaller vesicle size and greater EE% as compared to Tween 80. Based on the results, TW4 and SP4 were selected as the optimized formulations for further incorporation into the transdermal patches. In-vitro and ex-vivo permeation studies showed permeation in the order F2 > F3 > F1, indicating that transferosomal formulations showed superior permeation of the drug compared to plain Nebivolol HCl patches. Span 80 transferosomes showed a slightly better permeation than Tween 80. Stability studies showed that transferosomes and the transdermal patches demonstrated good stability under proper storage conditions. The study concluded that transferosomal patches of Nebivolol HCl could be used as a potential approach with effective transdermal delivery for the management of hypertension.