Formulation and optimization of duloxetine hydrochloride buccal films: in vitro and in vivo evaluation

Duloxetine hydrochloride (DH) is a serotonin–norepinephrine reuptake inhibitor (SSNRI) indicated for the treatment of depression. Duloxetine suffers from reduced oral bioavailability (≈50%) due to hepatic metabolism. This study aims to develop DH buccoadhesive films to improve its bioavailability. DH buccoadhesive films were prepared adopting the solvent casting method using hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA). The prepared films were evaluated for weight uniformity, drug content, surface pH, swelling index, mucoadhesion strength and drug release percentages. Accelerated stability and bioavailability studies in healthy human volunteers were also performed for the selected films. Results of the evaluation tests showed that the optimum physicochemical characters were obtained by the films prepared with 2% HPMC using 10% propylene glycol (F2 films). Accelerated stability studies revealed that DH showed proved stability throughout the experiment time. DH bioavailability from F2 films was determined and compared with that of the marketed oral capsules (Cymbalta^® 30?mg). The pharmacokinetic results showed that C_max for F2 was higher than the market product. In addition, ANOVA analysis showed that a T_max of F2 film was significantly lower, while, the AUC_0–72 of F2 was significantly higher than that of Cymbalta capsules. The percentage relative bioavailability of DH from F2 was found to be 296.39%. Therefore, the prepared buccal films offer an alternative route for the administration of DH with the possibility of improving its bioavailability.     

Nanodispersion-loaded mucoadhesive polymeric inserts for prolonged treatment of post-operative ocular inflammation

Mucoadhesive polymeric films incorporated with ketorolac tromethamine-loaded nanodispersion aiming the sustained delivery of the drug to the cornea have been developed and characterised for the treatment of post-operative ocular inflammation. Nanodispersions were prepared by ionic gelation method with various concentrations of chitosan and sodium tripolyphosphate. The developed nanodispersions were analysed for morphology, particle size, dispersion homogeneity, zeta potential, entrapment efficiency and drug release. The nanodispersion that showed the smallest particle size and the highest entrapment efficiency was incorporated in optimised HPMC E15 and Eudragit RL100/HPMC K4m films. The formulation with optimum physicomechanical properties was selected to study its ex vivo transcorneal permeation through freshly excised bovine cornea in comparison with the nanodispersion and the marketed eye drops (Acular®). The polymeric ocular film showed greater permeation than aqueous eye drops. Moreover, the ocular film revealed a prolonged anti-inflammatory effect compared to eye drops when applied to inflamed rabbit’s eyes.     

Biphasic drug release: the permeability of films containing pectin, chitosan and HPMC

The permeabilities of mixed films of pectin/chitosan/HPMC have been studied to assess their value in producing a dosage form with biphasic drug release characteristics. The inclusion of chitosan enhanced the properties of the films, rendering them stable at all physiological pH values. Pectin/HPMC films were soluble at pH values above 3.0. All pectin/chitosan/HPMC films were permeable to a model drug, paracetamol. HPMC initially increased the permeability of the films and subsequently reduced it at higher concentrations. The minimum permeability was obtained at pH 3 and at an HPMC level of 5% where the potential for polyelectrolyte complex formation between pectin and chitosan exists. The permeabilities of the films increased when they were exposed to pectinolytic enzymes, a system designed to mimic conditions in the colon. The film formulation thus show the potential for biphasic delivery with an initial, controllable slow phase that can be manipulated by changes in the formulation followed by a faster phase under conditions pertaining in the colon.     

Formulation of metoclopramide HCl gastroretentive film and in vitro- in silico prediction using Gastroplus® PBPK software

The new trends in pharmaceutical studies focus on targeting drug delivery and computer software that help in the body environment simulation, such as Gastroplus® software. The interest of this study is to prepare a gastroretentive film of metoclopramide HCl (MTC) that was followed by applying the in silico approach to estimate the in vivo prepared formulations. The films were prepared from HPMC E5 and sodium alginate polymers as primary polymers with the aid of secondary polymers. The sodium alginate high proportions films showed instant and long floating duration reaching 24 h but with variable folding endurance. Moreover, sodium alginate films with their secondary polymers carbopol and HPMC E5 slowed the release of MTC. The floating and slow-release patterns assessed the gastroretentive properties of sodium alginate films and were further examined by a mucoadhesive study that guaranteed mucosal adhesion, and the film’s FESEM images showed similar top morphology, but different side view structures. Last, the pharmacokinetic profile of selected films that approached the gastroretentive properties was in silico predicted depending on in vitro release study and floating duration employing the physiological-based pharmacokinetic model in Gastroplus® software. The model determines this prediction found successfully of intravenous and immediate oral release tablets (10 and 30 mg) of MTC. The simulation showed a high amount of MTC retained for long periods in the stomach to Sod.Alginate-3, Sod.Alginate-8, and Sod.Alginate-10 films (films of secondary polymers carbopol and HPMC E5) aid in reaching the optimum site of absorption jejunum 1 due to the slow MTC release.     

Role of chitosan on controlling the characteristics and antifungal activity of bioadhesive fluconazole vaginal tablets

Vaginal fluconazole (FLZ) prolonged release tablets containing chitosan in physical blends with other bioadhesive polymers were designed. Chitosan was mixed with hydroxypropyl methylcellulose (HPMC), guar gum or sodium carboxymethyl cellulose (NaCMC) at different ratios and directly compressed into tablets. In-vitro release profiles of FLZ were monitored at pH 4.8. Compressing chitosan with HPMC at different ratios slowed FLZ release, however, time for 80% drug release (T₈₀) did not exceed 4.3?h for the slowest formulation (F11). Adding of chitosan to guar gum at 1:2 ratio (F3) showed delayed release with T₈₀ 17.4?h while, in presence of PVP at 1:2:1 ratio (F5), T₈₀ was 8.8?h. A blend of chitosan and NaCMC at 1:2 ratio (F15) showed prolonged drug release with T₈₀ 11.16?h. Formulations F5 and F15 showed fair physical characteristics for the powder and tablets and were subjected to further studies. Fast swelling was observed for F15 that reached 1160.53?±?13.02% in 4?h with 2?h bioadhesion time to mouse peritoneum membrane compared with 458.83?±?7.09% swelling with bioadhesion time exceeding 24?h for F5. Extensive swelling of F15 could indicate possible dehydration effect on vaginal mucosa. Meanwhile, antifungal activity against C. albicans was significantly high for F5.     

Optimization and evaluation of venlafaxine hydrochloride fast dissolving oral films

Three factors, three levels (3³) full factorial design was used to develop venlafaxine HCl fast dissolving oral films (FDOFs) to optimize the concentrations of the film forming polymer; hydroxypropyl methylcellulose HPMC (X1), superdisintegrant; sodium starch glycolate SSG, (X2) and glycerol as the film plasticizer (X3). Effects of the three factors on the disintegration time (Y1), swelling index (Y2), and dissolution efficiency at 15 min; DE%15 (Y3) of the prepared FDOFs were evaluated by using statistical models. The optimized film formula was characterized in term of x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and morphological characteristics.Disintegration time was found to increase with the increase in HPMC (X1) concentration, and the shortest disintegration time (21.67 ± 2.08 s) was observed in case of F2 formula (lowest HPMC level and highest glycerol level in absence of SSG). The highest swelling index (3.64 ± 0.59) was observed in case of film formula F1 (medium concentrations of both HPMC and glycerol and highest SSG concentration. The results also indicated that as the concentration of HPMC increased the DE%15 decreased. SSG (X2), with highest value (72.33 ± 1.71%) was recorded for in case of F12 (using 2% HPMC, 5%SSG and 1.5% glycerol). The optimized FDOF formula derived by the statistical models suggested 2% HPMC, 5% SSG, and 1% glycerol.The data obtained from DSC and XRPD revealed no interaction between drug and FDOT excipients. In addition, XRPD studies proved that the venlafaxine HCl was homogeneously dispersed in the film matrix.     

Permeation enhancement of ketoprofen using a supersaturated system with antinucleant polymers

Permeation enhancement of ketoprofen (KP) from supersaturated systems and the effects of antinucleant polymers on both stability and permeation of supersaturated KP were investigated using silicone membrane as a skin model. The supersaturation was prepared by the cosolvent technique with water and propylene glycol (PG). Saturated solubility of KP in water/PG cosolvent increased markedly with an increase in PG percentage. The time-profiles of the cumulative amount of released KP from supersaturated solutions through the membrane increased linearly, and this KP flux had a significant correlation with the degree of saturation (DS) in 80 : 20, 60 : 40, 50 : 50, and 40 : 60 (v/v) water/PG cosolvent systems. The influence of 1% solutions of antinucleant polymers, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and sodium carboxymethylcellulose (SCMC) on the DS and the stability of supersaturated KP was examined in 60 : 40 (v/v) water/PG cosolvent. The remaining DS for 24 h after mixing the solvents increased in the presence of HPMC and SCMC but not PVP. In the presence of SCMC, the physical stability of supersaturated KP was higher, however, the KP flux was lower than that in the control and in the presence of the other polymers. In conclusion, the supersaturation system can be applied to achieve higher transmembrane permeation of KP, and appropriate antinucleant polymers such as HPMC can optimize the physical stability and permeability of KP.     

Preparation and Evaluation of Hydrogel Film Containing Tramadol for Reduction of Peripheral Neuropathic Pain

To develop and assess new dosage forms for the alternative to existing oral medication for peripheral neuropathy, a hydrogel film in the skin patch formation containing tramadol hydrochloride (TRA), a water-soluble drug used as an analgesic, was prepared and evaluated. A hydrogel film composed of 20%(w/w) hydroxypropyl methylcellulose (HPMC) irradiated with electron beams had high transparency and elasticity similar to commercially available wound dressings and soft tissues, suggesting that it is a suitable substrate for TRA. The inclusion of TRA was enabled by immersing the HPMC hydrogel film in TRA aqueous solution. The release and skin permeation of TRA from TRA-containing hydrogel films differed depending on the electron beam dose. Moreover, the analgesic effects in mice were confirmed in a dose-dependent manner. This study demonstrated the usefulness of a hydrogel film containing TRA as a new dosage form alternative to the existing oral medication for peripheral neuropathy.     

Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release

The gastrointestinal transit and in vivo drug release behaviour of a film-coated tablet formulation was investigated in five healthy human subjects using the technique of gamma scintigraphy. The film coating system consisted of a mixture of pectin, chitosan and HPMC in a ratio of 6:1:0.37 applied to 750 mg cores at a coat weight gain of 9%. The estimated mean values of the gastric emptying time (62±17 min), small intestinal transit time (219±53 min), ileocaecal junction lag time (79±30 min) and the colon arrival time (345±33 min), were similar to published values for the transit of similar sized tablets in humans. The amount of radioactive tracer released from the labelled tablets was minimal when the tablets were in the stomach and the small intestine. There was increased release of radioactivity when the tablets were in the colon due to increased degradation of the film coatings by pectinolytic enzymes resident in the colon. The pectin/chitosan/HPMC film coating system thus acts as a colonic delivery system.     

Mucoadhesive buccal film containing ornidazole and dexamethasone for oral ulcers: in vitro and in vivo studies

A bilayered mucoadhesive buccal film containing a combination of ornidazole (OD) and dexamethasone sodium phosphate (DEX) was prepared using solvent casting to treat oral ulcers. Films were systematically evaluated in vitro to obtain the optimum formulation. The therapeutic effects of these films were investigated in the rabbit oral ulcer model and the in vivo release of OD and DEX in the human oral cavity was also evaluated. The backing layer contained ethyl cellulose and an optimal mucoadhesive layer containing both OD and DEX was produced. Films from the optimum formulation were 0.427?±?0.015?mm thick, weighed 55.89?±?0.79?mg, and had a surface pH of 6.34?±?0.01. The drug content of the optimum formulation approximated the theoretical value with good uniformity (2.959?±?0.106?mg/cm² for OD and 0.877?±?0.031?mg/cm² for DEX). The formulation showed favorable swelling characteristics and both drugs were released at >95% after 4?h. Moreover, the compound film had a statistically significant effect on mucosal repair and reduced ulcer inflammation without stimulating the human oral mucosa. C_max of OD in saliva was 37.04?μg/ml and that of DEX was 9.737?μg/ml. Given promising therapeutic effects, the compound film developed here could become a local drug delivery device for treating oral ulcers.     

Preparation and in vitro evaluation of sustained release tablet formulations of diclofenac sodium

The effects of formulation variables on the release profile of diclofenac sodium (DS) from hydroxypropylmethyl cellulose (HPMC) and chitosan matrix tablets were studied. DS tablets were prepared by wet granulation and direct compression methods and different ratios of HPMC and chitosan were used. Physical properties of the prepared tablets and targeted commercial sustained release (SR) tablet and the drug release were studied in tablets that were placed in 0.1 M HCl for 1 h and phosphate buffer solution was added to reach pH value of 7.5. In vitro studies showed that 20% HPMC contained SR formulation with direct (dry) compression method is the optimum formulation due to its better targeting profile in terms of release. This formulation also exhibited the best-fitted formulation into the zero order kinetics. The precision and accuracy of the analytical method were also checked. The repeatability and reproducibility of the method were also determined.     

Leaching of pectin from mixed films containing pectin,chitosan and HPMC intended for biphasic drug delivery

Mixed films containing pectin, chitosan and HPMC, prepared by solvent casting from 0.1 M HCl (pH 1.5) and 0.1 M acetic acid (pH 2.9) were evaluated for their morphological and leaching properties. Films cast at pH 1.5 were uniform with smooth surfaces while films cast at pH 2.9 showed particle aggregation and had rough surfaces due to polyelectrolyte complex (PEC) formation between pectin and chitosan in the medium. The leaching of pectin was higher from films at cast pH 1.5 due to the absence of PEC formation. Pectin leaching was controlled in simulated upper gastrointestinal conditions but was accelerated in the presence of pectinolytic enzymes. The leaching of pectin from the mixed films was a function of the pH of the film casting solvent, pH of the incubation medium, PEC formation and HPMC content.     

Multiunit Controlled-Release Diclofenac Sodium Capsules Using Complex of Chitosan with Sodium Alginate or Pectin

This study explored the application of chitosan–alginate (CA) and chitosan–pectin (CP) complex films as drug release regulator for the preparation of multiunit controlled-release diclofenac sodium capsules. Pellets containing drug and microcrystalline cellulose, in a ratio of 3:5, were prepared in a fluidized rotary granulator. The pellets were coated with CA, CP, sodium alginate, pectin, and chitosan solutions. The pellets, equivalent to 75 mg drug, were filled into capsules. After 2 h of dissolution test in acidic medium, the amount of the drug released from any preparation was negligible. The pellets were further subject to pH 6.8 phosphate buffer. More than 80% drug release at 12 h was observed with the uncoated pellets and those coated with sodium alginate, pectin or chitosan. Both 1% CA and 3% CP coated pellets exhibited drug release profiles similar to that of Voltaren SR75. It was found that approximately 60% and 85% of the drug were released at 12 and 24 h, respectively. Both Differential thermal analysis (DTA) and Fourier transform infrared spectroscopy (FTIR) analyses revealed complex formation between chitosan and these anionic polymers. It could be concluded that CA and CP complex film could be easily applied to diclofenac sodium pellets to control the release of the drug.     

Formulation and characterization of the microencapsulated entomopathogenic fungus Metarhizium anisopliae MA126

Abstract

Bioinsecticides are expected to be used for controlling major species of aphids. The present study explored a liquid phase coating technique for the formulation of microencapsulated conidia of the entomopathogenic fungus Metarhizium anisopliae MA126. Various parameters for microencapsulation were investigated. The biopolymers sodium alginate, hydroxypropyl methyl cellulose (HPMC) and chitosan were tested as coating materials. Calcium chloride was used as the cross-linking agent for converting soluble sodium alginate into an insoluble form. To improve the efficiency of microencapsulation, the additives of HPMC, dextrin, chitosan or HPMC/chitosan in various ratios (1 : 1, 1 : 3 and 3 : 1) were used as the coating materials. The particle size of a bare microcapsule was less than 30 µm. Larger size microcapsules were produced using vortex method by comparison with that using homogenization method. The latter method, however, was easy to scale up. The effect of coating materials on the morphology and encapsulation efficiency of the microcapsules was also studied. The best encapsulation efficiency (78%) was using HPMC as the additive of the coating material. The next was dextrin (70%). By measuring the germination rate, the results showed that the activity was ～80% of the initial after 6 months of storage at 4°C, while that of the bare conidia was less than 50% stored in identical conditions.     

鱼腥草素钠缓释片的制备及体外释放特性研究

目的制备鱼腥草素钠缓释片,并考察其体外释放特性。方法分别采用羟丙基甲基纤维素（HPMC）、联合应用HPMC与乙基纤维素（EC）作为骨架材料制备鱼腥草素钠缓释片,以累积释放度为指标,评价其体外释放特性。结果HPMC黏度及用量、EC用量对药物的释放有较大影响,填充剂对药物的释放几乎无影响。缓释片释药结果符合Higuchi方程。结论所制备的鱼腥草素钠缓释片缓释性能良好,其释放机制为非Fick’s扩散。     

Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation

Abstract

Objective: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films.

Methods: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters.

Results: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher C_max and almost doubled AUC compared with raw SMV-loaded films.

Conclusion: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS-transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters.     

Formulation and physicochemical characterisation of buccoadhesive films containing ketorolac

Ketorolac tromethamine, the non-steroidal anti-inflammatory drug, was formulated onto buccoadhesive films to overcome the limitations in the currently available dosage and routes of administration which in sequence will increase patients’ compliance. Films were cast from organic and aqueous solvents using various bioadhesive polymers namely: sodium carboxymethyl cellulose (Na-CMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) and Carbopol 934. The prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, in vitro bioadhesion, drug permeation via bovine buccal mucosa and in vitro drug release. These properties were found to vary significantly depending on the preparation methods, the type of the polymers and the ratio of addition of both plasticizer (i.e. polyethylene glycol) and film forming agent (ethyl cellulose and polyvinylpyrolidene). Formula number K10 containing carbopol 0.5% and HPMC 0.5% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable ketrolac release (about 85-90% at 6 h). In addition, this film was subjected to in vitro and in vivo release. The obtained results indicate that the concentration of ketorolac in the oral cavity was maintained above 4.0 μg/mL for a period of at least 6 h. This film shows promising results for using the ketrolac buccoadhesive route of administration topically and systemically, and thus it will be subjected to clinical evaluation in future work.     

Orodispersible films: Product transfer from lab-scale to continuous manufacturing

Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was qualified in regards of the process conditions for film compositions and their effects on the formed films. To investigate differences between both manufacturing processes, various film formulations of hydrochlorothiazide and hydroxypropylcellulose (HPC) or hydroxypropylmethycellulose (HPMC) as film formers were produced and the resulting films were characterized.The qualification of the continuously operating coating machine reveals no uniform heat distribution during drying. Coating solutions for continuous manufacturing should provide at least a dynamic viscosity of 1?Pa*s (wet film thickness of 500?μm, velocity of 15.9?cm/min). HPC films contain higher residuals of ethanol or acetone in bench-scale than in continuous production mode. Continuous production lead to lower drug content of the films. All continuously produced films disintegrate within less than 30?s. There are observed significant effects of the production process on the film characteristics. When transferring film manufacturing from lab-scale to continuous mode, film compositions, processing conditions and suitable characterization methods have to be carefully selected and adopted.     

Transdermal absorption enhancing effect of the essential oil of Rosmarinus officinalis on percutaneous absorption of Na diclofenac from topical gel

Abstract

Context: Rosemary essential oil has been used topically for several purposes (analgesic, anti acne, and anti-inflammatory) in Iranian traditional medicine.

Objectives: This investigation aimed to study the effect of essential oil of Rosmarinus officinalis L. (Lamiaceae) on the transdermal absorption of Na diclofenac from topical gel.

Material and methods: Diclofenac sodium topical gel was prepared with HPMC K4M and Carbopol 934P as a gelling agent, and several vehicles. The most stable gel was chosen and enhancing effects of the essential oil with different concentrations (0.1, 0.5, and 1.0% w/w) on the permeation of diclofenac were evaluated. The anti-nociceptive effect of preparations was evaluated based on the formalin and tail flick tests in mice.

Results: The major constituents of the essential oil were 1,8-cineol (15.96%), α-pinene (13.38%), camphor (7.87%), bornyl acetate (6.54%), verbenone (5.82%), borneol (5.23%), camphene (4.96%), and (E)-caryophyllene (3.8%). Topical diclofenac containing 0.5% essential oil showed more analgesic effect after 25, 30, and 35?min (p?<?0.001) than the reference drug in the tail flick test. The analgesic effect of preparation containing 1% essential oil was more than reference gel after 15?min (p?<?0.05). This difference was observed after 20, 25, 30, 35, and 40?min (p?<?0.001) too. Rosemary essential oil 1% promoted analgesic effect of drug in comparison with diclofenac gel in the formalin early phase (p?<?0.05). The enhancing effect of rosemary was observed in 0.5 and 1% concentration (p?<?0.05 and p?<?0.001, respectively) in the late phase.

Conclusion: This study proved the enhancing effect of 0.5 and 1% of rosemary essential oil on diclofenac percutaneous absorption.     

The morphology of blends of ethylcellulose with hydroxypropyl methylcellulose as used in film coating

Near-equilibrium morphologies of thin films (< 0.2μm) of ethylcellulose-rich incompatible blends of ethylcellulose (EC) with hydroxypropyl methylcellulose (HPMC) consist of HPMC-rich macroscopic polydisperse domains (3-approx. 20 μm) dispersed in an EC-rich matrix implying complete leaching of the water soluble phase. However, for thick films (> 100 μm) complete leaching was observed only for systems with above 60% w/w HPMC, whereas all other systems showed some HPMC retention. The observed HPMC leaching behaviour is attributed to deviations of the phase decomposition from equilibrium during film formation arising from the rate of viscosity increase and changes in the solvent system composition.