Fabrication of Nanosuspension Directly Loaded Fast-Dissolving Films for Enhanced Oral Bioavailability of Olmesartan Medoxomil: In Vitro Characterization and Pharmacokinetic Evaluation in Healthy Human Volunteers.

Olmesartan medoxomil (OM) is an antihypertensive drug with poor water solubility and low oral bioavailability (28.6%). Accordingly, this study aimed to formulate and evaluate OM nanosuspension incorporated into oral fast-dissolving films (FDFs) for bioavailability enhancement. OM nanosuspension was prepared by antisolvent-precipitation-ultrasonication method and characterized regarding particle size (122.67 ± 5.03 nm), span value (1.40 ± 0.51), and zeta potential (- 46.56 ± 1.20 mV). Transmission electron microscopy (TEM) of the nanosuspension showed spherical non-aggregating nanoparticles. The nanosuspension was then directly loaded into FDFs by solvent casting technique. A full factorial design (22 × 31) was implemented for optimization of the FDFs using Design-Expert® software. Physical and mechanical characteristics in addition to dissolution profiles of the FDFs were investigated. The optimum formula (FDF1) showed 0.43 ± 0.02 kg/mm2 tensile strength, 20.50 ± 2.12 s disintegration time, and 87.53 ± 2.50 and 95.99 ± 0.25% OM dissolved after 6 and 10 min, respectively. Accelerated and long-term shelf stability studies confirmed the stability of FDF1. More than 75% OM was dissolved within 10 min from FDF1 compared with 9.80 and 47.80% for films prepared using coarse drug powder and market tablet, respectively. Relative bioavailability of FDF1 compared to market tablet was assessed in healthy human volunteers. The Cmax value increased significantly from 66.62 ± 14.95 to 179.28 ± 23.96 ng/mL for market tablet and FDF1, respectively. Similarly, the AUC0-72 value significantly increased from 498.36 ± 217.46 to 1083.67 ± 246.32 ng h/mL for market tablet and FDF1, respectively. Relative bioavailability of FDF1 was 209.28%. The highlighted results verified the effectiveness of OM nanosuspension-loaded FDFs in improving OM bioavailability.

Oral fast-dissolving films containing lutein nanocrystals for improved bioavailability: formulation development, in vitro and in vivo evaluation.

Lutein is widely used as diet supplement for prevention of age-related macular degeneration. However, the application and efficacy of lutein in food and nutritional products has been hampered due to its poor solubility and low oral bioavailability. This study aimed to develop and evaluate the formulation of oral fast-dissolving film (OFDF) containing lutein nanocrystals for enhanced bioavailability and compliance. Lutein nanocrystals were prepared by anti-solvent precipitation method and then encapsulated into the films by solvent casting method. The formulation of OFDF was optimized by Box-Behnken Design (BBD) as follows: HPMC 2.05% (w/v), PEG 400 1.03% (w/v), Cremophor EL 0.43% (w/v). The obtained films exhibited uniform thickness of 35.64 ± 1.64 µm and drug content of 0.230 ± 0.003 mg/cm2 and disintegrated rapidly in 29 ± 8 s. The nanocrystal-loaded films with reconstituted particle size of 377.9 nm showed better folding endurance and faster release rate in vitro than the conventional OFDFs with raw lutein. The microscope images, thermograms, and diffractograms indicated that lutein nanocrystals were highly dispersed into the films. After administrated to SD rats, t max was decreased from 3 h for oral solution formulation to less than 0.8 h for OFDF formulations, and C max increased from 150 ng/mL for solution to 350 ng/mL for conventional OFDF or 830 ng/mL for nanocrystal OFDF. The AUC 0-24h of conventional or nanocrystal OFDF was 1.37 or 2.08-fold higher than that of the oral solution, respectively. These results suggested that drug nanocrystal-loaded OFDF can be applied as a promising approach for enhanced bioavailability of poor soluble drugs like lutein.

Development of 3D Printed Multi-Layered Orodispersible Films with Porous Structure Applicable as a Substrate for Inkjet Printing.

The direct tailoring of the size, composition, or number of layers belongs to the advantages of 3D printing employment in producing orodispersible films (ODFs) compared to the frequently utilized solvent casting method. This study aimed to produce porous ODFs as a substrate for medicated ink deposited by a 2D printer. The innovative semi-solid extrusion 3D printing method was employed to produce multilayered ODFs, where the bottom layer assures the mechanical properties. In contrast, the top layer provides a porous structure for ink entrapment. Hydroxypropyl methylcellulose and polyvinyl alcohol were utilized as film-forming polymers, glycerol as a plasticizer, and sodium starch glycolate as a disintegrant in the bottom matrix. Several porogen agents (Aeroperl® 300, Fujisil®, Syloid® 244 FP, Syloid® XDP 3050, Neusilin® S2, Neusilin® US2, and Neusilin® UFL2) acted as porosity enhancers in the two types of top layer. ODFs with satisfactory disintegration time were prepared. The correlation between the porogen content and the mechanical properties was proved. A porous ODF structure was detected in most samples and linked to the porogen content. SSE 3D printing represents a promising preparation method for the production of porous ODFs as substrates for subsequent drug deposition by 2D printing, avoiding the difficulties arising in casting or printing medicated ODFs directly.

Formulation of Fast Dissolving ß-Glucan/Bilberry Juice Films for Packaging Dry Powdered Pharmaceuticals for Diabetes.

The aim of this study was to develop fast dissolving films based on ß-glucan and bilberry juice due to the bioactive potential of ß-glucan and antidiabetic effect of bilberry juice. The benefit of incorporation of bioactive compounds into the films is due to the removal of unnecessary excipients and to confer protection as well as increase stability and shelf life to the packaged product. Due to the fast dissolving requirements of the European Pharmacopeia, which reduced the dissolution time from 180 to 60 s, indicating less than a minute, hygroscopic materials, such as sodium alginate and a suitable plasticizer, such as glycerin were incorporated. Moreover, the influence of ingredients and surfactants, such as soybean oil was studied in the design of fast dissolving films. Additionally, the steady state rate water vapor transmission rate (WVTR), water vapor permeability (WVP), and FT-IR spectroscopy tests were performed at high resolution to ensure the reliability of the films and composition as well as to validate the results. Our data suggest that the addition of surfactants contributed to the development of fast dissolving films without influencing the diffusion of water vapor. Low levels of WVTR and short dissolution time made from ß-glucan and bilberry juice are a convenient candidate for packaging dry powdered pharmaceuticals for diabetes.

Fabrication and Characterization of Fast-Dissolving Films Containing Escitalopram/Quetiapine for the Treatment of Major Depressive Disorder.

Major depressive disorder (MMD) is a leading cause of disability worldwide. Approximately one-third of patients with MDD fail to achieve response or remission leading to treatment-resistant depression (TRD). One of the psychopharmacological strategies to overcome TRD is using a combination of an antipsychotic as an augmenting agent with selective serotonin reuptake inhibitors (SSRIs). Among which, an atypical antipsychotic, quetiapine (QUE), and an SSRI, escitalopram (ESC), were formulated as a fixed-dose combination as a fast-dissolving film by coaxial electrospinning. The resultant fiber's morphology was studied. SEM images showed that the drug-loaded fibers were smooth, un-beaded, and non-porous with a fiber diameter of 0.9 ± 0.1 µm, while the TEM images illustrated the distinctive layers of the core and shell, confirming the successful preparation of these fibers. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies confirmed that both drugs were amorphously distributed within the drug-loaded fibers. The drug-loaded fibers exhibited a disintegration time of 2 s, which accelerated the release of both drugs (50% after 5 min) making it an attractive formulation for oral mucosal delivery. The ex vivo permeability study demonstrated that QUE was permeated through the buccal membrane, but not ESC that might be hindered by the buccal epithelium and the intercellular lipids. Overall, the developed coaxial fibers could be a potential buccal dosage form that could be attributed to higher acceptability and adherence among vulnerable patients, particularly mentally ill patients.

Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis.

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B's high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.

Self-microemulsifying oral fast dissolving films of vitamin D3 for infants: Preparation and characterization.

Combining the advantages of self-microemulsifying technology and oral fast dissolving technology, a self-microemulsifying oral fast dissolving films (SMEOFDF) of vitamin D3 was developed in this study. The pseudoternary phase diagram of microemulsion was constructed using water titration method, and the formulation of films was optimized by orthogonal experimental design. The prepared SMEOFDF of vitamin D3 was a thin film, in which the liquid drops of self-microemulsion were embedded. It had good mechanical properties (thickness 166.7 ± 3.30 µm, tensile strength 38.45 ± 3.72 MPa, elongation 23.38 ± 4.23%, and folding endurance >200 times), and its disintegration time was about 18 ± 1.23 s. After being redissolved in water, microemulsion could form spontaneously, with particle size of 181.2 nm and zeta potential of 16.1 mV. The release profile of vitamin D from SMEOFDF could be well described by first-order equation.

Electrospun fixed dose formulations of amlodipine besylate and valsartan.

Increasing numbers of elderly people require multi-drug therapies. One route to improve adherence rates is to prepare fixed dose combinations (FDCs), in which multiple active ingredients are loaded into a single formulation. Here, we report the use of electrospinning to prepare fast-dissolving oral FDCs containing amlodipine besylate and valsartan, two drugs prescribed as FDCs for the treatment of hypertension. Electrospun fibers were prepared loaded with one or both drugs, using polyvinylpyrrolidone as the polymer matrix. The fibers were largely cylindrical in morphology and comprise amorphous solid dispersions except with the highest loadings of amlodipine besylate. HPLC demonstrated drug entrapment efficiencies of >85% of the theoretical dose. The mats have folding endurances and thicknesses suitable for use as oral films. The amlodipine besylate-loaded systems are fast-dissolving, with >90% release obtained within 120 s. In contrast, valsartan release from its single-drug formulations took longer, ranging from 360 s to 24 min. With the FDC formulations, rapid release within 360 s was achieved when the loading was 5% w/w of each drug, but again the release time increased with drug loading. Electrospun fibers therefore have significant promise as FDCs, but the target drug and its loading need to be carefully considered.

Maltodextrin fast dissolving films for quercetin nanocrystal delivery. A feasibility study.

The objective of this study was to evaluate the feasibility to prepare fast dissolving films as quercetin nanocrystal delivery systems, using maltodextrins as film forming material and glycerin as plasticizer, with the goal of enhancing quercetin oral bioavailability. Quercetin nanosuspensions were prepared using a high-pressure homogenizer, and then directly used to prepare the films by a casting method. Spectroscopic and calorimetric analysis evidenced that reduction of quercetin size at nanoscale and incorporation in maltodextrin films do not affect the solid state of the active ingredient. The loading of quercetin nanocrystals into the film determined a slight variation of film elasticity and ductility. Indeed, the elastic modulus of the loaded films resulted about a half of the placebo ones, while the elongation at break increased four folds. Free and film loaded quercetin nanocrystals showed a comparable dissolution rate, much higher than that of bulk quercetin.

Aminoacids as non-traditional plasticizers of maltodextrins fast-dissolving films.

This study explored the effect of aminoacids as non-traditional plasticizers of maltodextrins fast dissolving films. 5% w/w glycine and proline decreased the glass transition temperature (Tg) of maltodextrins from 102.6±2.0°C to 73.1±1.4°C and 76.1±0.7°C, respectively; meanwhile the binary mixture made with lysine had a Tg value of 83.6±2.2°C. At the same time, all aminoacids increased the ΔCp values. The shift of the thermal data were due to profound effect on the hydrogen bonding as evidenced by ATR-FTIR spectra since the OH stretching and scissoring bands decreased of about 15-26 cm(-1). A linear relationship was found (R(2)=0.9334) between HOH scissoring wavenumbers and Tg values. The addition of glycine and proline resulted effective in reducing the elastic modulus (about 50%) and tensile strength (about three times) and, therefore, can be used to increase the film ductility.

Formulation of rizatriptan benzoate fast dissolving buccal films by emulsion evaporation technique.

AIM: The present study deals with the formulation of fast dissolving films of Rizatriptan benzoate that is used for the treatment of Migraine. The concept of fast-dissolving drug delivery emerged from the desire to provide patient with more conventional means of taking their medication. MATERIALS AND METHODS: In the present research work, various trials were carried out using film forming agents such as maltodextrin, gum karaya and xanthan gum to prepare an ideal film. Emulsion evaporation method was used for the preparation of films. The prepared films were evaluated for weight uniformity, drug content, film thickness, folding endurance, dispersion test and curling. The in vitro dissolution studies were carried out using simulated salivary fluid (pH 6.8 phosphate buffer). RESULTS: About 97% of the drug was found to be released from the film within 10 min that is a desirable character for fast absorption. The drug excipient interaction studies carried out by differential scanning calorimetry analysis and Fourier transform infrared studies revealed that there were no major interactions between the drugs and excipients used for the preparation of films. CONCLUSION: Fast dissolving films of Rizatriptan benzoate prepared by emulsion evaporation technique were found to be suitable for eliciting better therapeutic effect in the treatment of migraine.

Orally dissolving strips: A new approach to oral drug delivery system.

Recently, fast dissolving films are gaining interest as an alternative of fast dissolving tablets. The films are designed to dissolve upon contact with a wet surface, such as the tongue, within a few seconds, meaning the consumer can take the product without need for additional liquid. This convenience provides both a marketing advantage and increased patient compliance. As the drug is directly absorbed into systemic circulation, degradation in gastrointestinal tract and first pass effect can be avoided. These points make this formulation most popular and acceptable among pediatric and geriatric patients and patients with fear of choking. Over-the-counter films for pain management and motion sickness are commercialized in the US markets. Many companies are utilizing transdermal drug delivery technology to develop thin film formats. In the present review, recent advancements regarding fast dissolving buccal film formulation and their evaluation parameters are compiled.

Fast Dissolving Sublingual Films of Ondansetron Hydrochloride: Effect of Additives on in vitro Drug Release and Mucosal Permeation.

Ondansetron hydrochloride, a 5 HT3 antagonist is a powerful antiemetic drug which has oral bioavailability of 60% due to hepatic first pass metabolism and has a short half-life of 5 h. To overcome the above draw back, the present study was carried out to formulate and evaluate fast dissolving films of ondansetron hydrochloride for sublingual administration. The films were prepared from polymers such as polyvinylalcohol, polyvinyl pyrrolidone, Carbopol 934P in different ratios by solvent casting method. Propylene glycol or PEG 400 as plasticizers and mannitol or sodium saccharin as sweeteners were also included. The IR spectral studies showed no interaction between drug and polymer or with other additives. Satisfactory results were obtained when subjected to physico-chemical tests such as uniformity of weight, thickness, surface pH, folding endurance, uniformity of drug content, swelling index, bioadhesive strength, and tensile strength. Films were also subjected to in vitro drug release studies by using USP dissolution apparatus. Ex vivo drug permeation studies were carried out using porcine membrane model. In vitro release studies indicated 81-96% release within 7 min and 66-80% within 7 min during ex vivo studies. Drug permeation of 66-77% was observed through porcine mucosa within 40 min. Higher percentage of drug release was observed from films containing the sweeteners. The stability studies conducted for a period of 8 weeks showed no appreciable change in drug content, surface pH, and in vitro drug release.