Metoclopramide loaded buccal films for potential treatment of migraine symptoms: in vitro and in vivo study.

OBJECTIVE: Developing mucoadhesive buccal films loaded with metoclopramide for the treatment of migraine-associated vomiting. METHODS: Buccal films were prepared using the solvent casting method. Several tests were conducted, including measurement of film weight, thickness, drug content, moisture uptake, swelling index, and DSC analysis. The bioadhesion properties were also assessed. Furthermore, in vitro release profiles and in human bioavailability were studied. RESULTS: The developed films were transparent, homogeneous, and easy to remove. Film weight and thickness increased with higher drug content. The drug entrapment exceeded 90%. Film weight increased with moisture uptake, and DSC analysis indicated the absence of drug crystallinity. Bioadhesion properties and swelling index decreased with increasing drug content. In vitro release demonstrated that drug release depended on the drug-polymer ratio. The in vivo study showed significant improvements in Tmax (from 1.21 ± 0.33 to 0.50 ± 0.0) and Cmax (from 45.29 ± 14.66 to 63.27 ± 24.85) compared to conventional tablets. CONCLUSION: The prepared mucoadhesive buccal films exhibited the desired characteristics and demonstrated enhanced drug absorption, evidenced by the significantly reduced Tmax and increased Cmax compared to conventional tablets. The results indicate the successful achievement of the study objectives in selecting and designing an effective pharmaceutical dosage form. as cm2.

Bioadhesive behaviors of HPMC E5: comparative analysis of various techniques, histological and human radiological evidence.

Enhancing drug residence duration within the stomach offers distinct advantages for both localized and systemic effects. Numerous strategies have been proposed to extend drug residence time, with mucoadhesive polymers being a notable avenue. In this context, hydroxypropyl methylcellulose E5 has been employed as both a binding agent for granulating contrast metal powder and a mucoadhesive polymer, spanning various concentrations. The in vitro bioadhesion strength of the formulated tablets was gauged against the stomach lining of rabbits, for the quantification of bioadhesive forces. The temporal aspect of bioadhesion was evaluated through two approaches: one centered on gastric fluid dynamics and another proffered by the researchers, focusing on gastric wall kinetics. The results divulged a decline in bioadhesion force concomitant with high polymer concentrations. Histological examination of stained stomach sections revealed mucosal perturbations within the rabbit stomach. These disruptions exhibited an escalating trend in conjunction with elevated polymer concentrations, culminating in extensive disturbance at a 7.5% polymer concentration. The outcomes unveiled a direct relationship between polymer concentration increments and extended contact time. Subsequent radiological tracking of contrast metal behavior within a mature human stomach indicated a residence time of 6 h due to the entrapment of displaced components at disparate locations.

Engineering Thermo/pH-Responsive Lactoferrin Nanostructured Microbeads for Oral Targeting of Colorectal Cancer.

AIM: Colorectal cancer is an extremely aggressive form of cancer that often leads to death. Lactoferrin shows potential for targeting and treating colorectal cancer; however, oral delivery faces hurdles hampering clinical applications. We engineered dual-responsive lactoferrin nanostructured microbeads to overcome delivery hurdles and enhance drug targeting. METHODS: The hydrophobic drug mesalazine (MSZ) was coupled to lactoferrin to form amphiphilic conjugate nanoparticles, dispersed in water. The lipid-soluble polyphenolic drug resveratrol (RSV) was then encapsulated into the hydrophobic core of LF-MSZ nanoparticles. To impart thermoresponsive properties, the dual-payload NPs were coupled with a PNIPAAm shell; finally, to further endow the nanoparticles with gastrointestinal resistance and pH responsiveness, the nanoparticles were microencapsulated into ionically cross-linked pectin-alginate beads. RESULTS: The nanoparticles showed enhanced internalization and cytotoxicity against HCT colon cancer cells via LF-receptor-mediated endocytosis. Thermal triggering and tuned release were conferred by the temperature-sensitive polymer. The coatings protected the drugs from degradation. Orally delivered microbeads significantly reduced tumor burden in a mouse colon cancer model, lowering carcinoembryonic antigen and elevating antioxidant enzymes. Apoptotic pathways were stimulated, indicated by heightened Bax/Bcl2 ratio and caspase-3/9 expression. CONCLUSION: Overall, we propose the innovative lactoferrin nanostructured microbeads as a paradigm shift in oral colorectal cancer therapeutics.

An industrial procedure for the intestinal permeability enhancement of acyclovir: in-vitro and histological evidence.

Acyclovir, an antiviral drug, has low bioavailability due to its low permeability. Consequently, high drug doses and frequent administration are required. This study investigates the use of span 60, at different concentrations, as a granulating agent to enhance drug permeability using an industrial procedure on a pilot scale. The micromeritics, drug content, drug crystallinity, drug partition coefficient, and drug release of the produced formulations were examined. The findings revealed an enhanced drug partition coefficient, suggesting drug entrapment in the polar portion of span 60. The drug release profiles exhibited rapid and complete drug release. The improvement of the drug permeability was evaluated using a modified non-everted sac technique. Notably, drug permeability through the rabbit intestine significantly improved, as evidenced by various calculated permeation parameters, providing insights into the drug absorption mechanism. The widening of the paracellular pathway was observed through histological examination of the rabbit intestinal segment, which aligns with the drug absorption mechanism. The utilization of a paracellular pathway enhancer as a granulating agent holds promise as a strategy to enhance the oral bioavailability of class III drugs. Overall, this study presents a novel drug delivery approach to enhance drug permeation and bioavailability, with potential implications for other medications.

A Procedure for Tablet Production by Using the 3D Molding Technology and Powder Micromeritics Properties.

The importance of personalized medicine cannot be denied. In order to meet the needs of patients requiring modified drug dosing and drug combinations, customization is integral. Among the dosage forms of importance is personalized tablets, and it is essential for compounding pharmacies to be able to provide the scientific and technological production of specific tablets. The objective of this article is to provide a general procedure for the production of personalized tablets by using 3D Mold. The drug mixing homogeneity with the filler could be achieved by using the ascending-order procedure. The 3D Mold technology is based on the micromeritics properties of powder and paste formation, an easy procedure that is reproducible and time saving.

pH-sensitive nanoparticles containing 5-fluorouracil and leucovorin as an improved anti-cancer option for colon cancer.

Background: Parenteral administration of chemotherapeutic drugs, 5-fluorouracil (5-FU) and leucovorin (LV), is commonly used to treat large bowel carcinomas such as colon cancer (CC) and colorectal carcinoma (CRC). Aim: Our study aims to design a novel nanoparticulate drug-delivery vehicle for oral use capable of colon-specific release. Methods: A modified double-emulsion solvent evaporation method was used in the preparation of pH-responsive Eudargit® S100 polymeric nanoparticles, loaded with 5-FU/LV combination (5-FU/LV-loaded Eudargit S100 NPs). Results: Our optimized drug-loaded NP showed a pH-responsive drug release and exhibited significantly more cytotoxic actions in cancer-cell lines than free drugs. Conclusion: These findings open the way for conducting clinical trials for colon malignancies treated with nanoparticles.

Molding as Innovative Technology for Personalized Tablet Production.

The future of dosage form design is expected to move towards the production of personalized dosage forms tailored to each patient. The 3D printer was introduced to solve that problem but is not easy to use in a pharmacy. Herein, a new 3D mold technology is adopted for tablet manufacturing. Preparation of amlodipine tablets was used as a Biopharmaceutics Classification System Class 1 drug model to study this technology. Different concentrations of either starch or Avicel-based formulations and different concentrations of hydroxypropyl methylcellulose as a binder for mass formation were used. The mass formed for each formula was cast into the mold for tablet preparation. Different non-pharmacopeial and pharmacopeial quality-control tests of the prepared tablets by using the 3D mold were compared to a marketed tablet product of amlodipine. 3D-molded tablets showed compliance properties with the tablet pharmacopeial quality standard. Studying the equivalence of the 3D mold tablets to the brand marketed product under biowaiver conditions was carried out. The difference and similarity factors studies of molded tablets prepared using starch or Avicel as a filler and 2.5% of hydroxypropyl methylcellulose showed acceptable characters to the drug brand name. It is predicted that by using this simple technique, it would be possible to produce tablets with designed disintegration and release profiles, which could potentially allow the tailoring of the drug release and hence personalize the medicine for each patient.

An Industrial Procedure for Pharmacodynamic Improvement of Metformin HCl via Granulation with Its Paracellular Pathway Enhancer Using Factorial Experimental Design.

BACKGROUND: Sorbitan monostearate is a surfactant used in the food industry. It was proved as a penetration enhancer to metformin HCl via a paracellular pathway. It is solid at room temperature and has a low melting point. Therefore, it was selected, as a granulating agent for metformin HCl. METHODS: Multi-level factorial design was applied to determine the optimized formula for industrial processing. The selected formulations were scanned using an electron microscope. Differential scanning calorimetry was used to ascertain the crystalline state of a drug. A modified non-everted sac technique, suggested by the authors, was used to evaluate the in vitro permeation enhancement of the drug. To simulate the emulsification effect of the bile salt, a tween 80 was added to the perfusion solution. As a pharmacodynamic marker, blood glucose levels were measured in diabetic rats. RESULTS: The results showed that drug permeability increases in the presence of tween 80. Drug permeability from granules increased than that of the pure drug or pure drug with tween 80. The prepared granules decreased blood glucose levels of diabetic rats than the pure drug and drug plus tween 80. There was an excellent correlation between the results of the drug permeation percent in vitro and the dropping of blood glucose level percent in vivo. CONCLUSION: Improving the drug permeation and consequently, the drug pharmacodynamic effect in addition to an excellent micromeritics property of the prepared drug granules showed the dual enhancement effect of the suggested industrial procedure. Therefore, we suggest the same industrial procedure for other class III drugs.

Metformin hydrochloride entrapment in sorbitan monostearate for intestinal permeability enhancement and pharmacodynamics.

Penetration enhancement of metformin hydrochloride via its molecular dispersion in sorbitan monostearate microparticles is reported. This represents basic philosophy to maximize its entrapment for maximum penetration effect. Drug dispersion in sorbitan monostearate with different theoretical drug contents (TDC) were prepared. Products showed excellent micromeritics and actual drug content (ADC) increased by increasing TDC. The partition coefficient of the drug products showed huge improvement. This indicates the drug entrapped in the polar part of sorbitan monostearate as a special image which effects on the drug release. The drug permeation profiles from the different products are overlapped with nearly equal permeation parameters. The permeation results suggested the main driving force for improving the drug paracellular pathway is its dispersion in sorbitan monostearate and is independent of ADC. Pharmacodynamic of the products showed a significant improvement than the drug alone at p ˂ 0.05. ANOVA test indicated the insignificant pharmacodynamic difference between the low, middle, and high ADC of the products. An excellent correlation founded between the drug permeation and pharmacodynamic precents. Drug permeation driving force via the paracellular pathway is its entrapment in sorbitan monostearate and independent on ADC. The technique is simple and the products had excellent micromeritics.

Recent advances in polymer shell oily-core nanocapsules for drug-delivery applications.

Polymeric nanocapsules are vesicular drug-delivery systems composed of an inner oily reservoir surrounded by polymeric membranes. Nanocapsules have various advantages over other nanovesicular systems such as providing controlled drug release properties. We discuss the recent advances in polymeric shell oily-core nanocapsules, illustrating the different types of polymers used and their implementation. Nanocapsules can be utilized for many purposes, especially encapsulation of highly lipophilic drugs. They have been shown to have variable applications, especially in cancer therapy, due to the ability of the polymeric shell to direct the loaded drugs to their target sites, as well as their high internalization efficacy. Those productive applications guaranteed their high potential as drug-delivery systems. However, their clinical development is still in an early stage.

Formulation and Bioavailability of Novel Mucoadhesive Buccal Films for Candesartan Cilexetil in Rats.

Candesartan cilexetil (CC) is an antihypertensive drug. It has low solubility and faces hepatic first-pass metabolism after oral ingestion. We formulated bioadhesive buccal films and studied the respective drug pharmacokinetics. Different bioadhesive films were prepared (40, 80, 120, 160, 200, and 240 mg CC per film) by using the solvent casting method. The drug concentrations used affect the drug entrapment mechanism, which was reflected in the film physicochemical properties like thickness, weight, drug content, bioadhesion, and drug release. Low drug concentration (F2, 40 mg per film) led to minute drug crystal dispersion while increasing the drug concentration (F7, 240 mg per film) showed drug crystal encapsulation, which affects the drug release. The drug pharmacokinetic from the prepared films was studied compared to the oral form by serial blood sampling via an inserted catheter in the carotid of rats. High-Performance Liquid Chromatography assay was used to measure the plasma concentration of CC in different forms. Compared to other films, the F2 showed the highest maximal concentration (Cmax) and the lowest elimination half-life (t1/2). Bioadhesion buccal film of CC has better bioavailability, especially at low concentrations. The ease, robustness, and ruggedness of the preparation suggests the same procedure for drugs like CC.

Preparation, and Assessment of Antidermatophyte Activity of Miconazole-Urea Water-Soluble Film.

Cutaneous mycoses, particularly tinea pedis caused by Trichophyton rubrum, are commonly known infections in humans. They are still considered as a major public health problem worldwide affecting the quality of life due to prolonged period of treatment and development of drug resistance, which leads to recurrence of infections. The objective of our study was to assess the effectiveness of miconazole in the presence and absence of urea, as a penetration enhancer, against T. rubrum and to formulate both of them in a water-soluble film to be applied topically for the purpose of treating tinea pedis caused by this fungus. Drug combination revealed synergism where miconazole minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) (0.5 and 1 mg/L) were considerably declined to 0.001 and 0.004 mg/L, respectively, when combined with 20% urea. This enhanced drug interaction activity against the test strain was explained by the alterations raised on the morphology and ultrastructures observed microscopically. Minimal fungicidal dose of miconazole/urea combination displayed plasmolysis and shrink cytoplasm; however, necrotic cells with punctured walls and degraded cytoplasmic content were observed at high fungicidal dose. Water-soluble films, prepared using increasing values of miconazole MFC and urea, were transparent, smooth, uniform, and flexible. Their physicochemical characters showed homogeneity in weight, thickness, drug content, and folding endurances with normal surface pH values, indicating the reproducibility of the preparation method. The novel simulation model for the film mechanism of action supported the idea and the suggested application method of the new dosage form. Evaluation of these films was carried in vitro using disk diffusion assay as well as in vivo using guinea pig dermatophytosis model. The in vitro assessment revealed an increase in the inhibition zone diameters in a concentration-dependent manner upon using 10 or 20% of urea combined with miconazole. In vivo test showed that combination of 0.004 mg/L miconazole with 20% urea (M + U20) showed the highest efficacy percentage (95.83%), which was statistically superior to the infected untreated control (p < 0.001) in fungal burden reduction as well as improvement in clinical scores (p < 0.001). This work supports the hypothesis and suggests a new promising dosage form for the treatment of T. rubrum infections.

Paracellular Pathway Enhancement of Metformin Hydrochloride via Molecular Dispersion in Span 60 Microparticles.

Surfactants are well known as permeation enhancers. Span 60 microparticles encapsulating different concentrations of metformin HCl were prepared by using rapid congeal melting technique. Electro-scanning microscope showed smooth surface but less round microparticles. The actual drug content was nearly equal in the different particle sizes of the microparticles. Differential scanning calorimetry results indicated the molecular distribution of the drug molecules with no evidence of drug thermal degradation. The drug release profile from the microparticles has, in each case, burst and there was incomplete drug release. The drug partition coefficient is markedly enhanced as a result of its molecular dispersion in Span 60, indicating the increasing of the drug lipophilicity as a result of its encapsulation in the polar part of the surfactant. Non-everted sac was used to study the drug permeability after solving its critical points. Compared to pure drug, the permeability profile of the drug increased from the Span 60-encapsulated drug, with a total permeation of 68% and drug absorption enhancement of 253%. The drug permeation enhancement mechanism was suggested to be molecular dispersion in the matrix, which is emulsified by Tween 80, and this leads to increasing the hydrophilic paracellular pathway of the drug. Considering the emulsification system of the GIT, which emulsifies the Span 60 instead of Tween 80, a huge improvement of the biopharmaceutics classification system class III permeability and consequently bioavailability could be expected. In addition, this study will open the door to the use of the same technique for enhancing the drug absorption mechanisms by the paracellular pathway for rapid and complete pharmacological effect.

Miconazole-Urea in a Buccal Film as a New Trend for Treatment of Resistant Mouth Fungal White Patches.

A growing concern about Candida albicans is the emergence of high incidence of resistance against antifungal agents, which requires searching for new medications or improving the response to the existing members. The objective of this work was to evaluate the effectiveness of the miconazole in the absence and presence of urea, as a penetration enhancer, against C. albicans. In addition to, formulating both of them in a polymer film to be used topically for treatment of mouth fungal white patches caused by C. albicans. A synergistic effect was recorded between this imidazole and urea against the test strain. Miconazole MIC (32 mg/L) was dramatically reduced to 0.0625 mg/L following combination with urea. Transmission electron microscopy explained the mechanisms of action mediated by the test agents. Minimal fungicidal dose of miconazole combined with urea showed early apoptotic cells with condensed chromatin and small blebs. Cytoplasmic leakage and necrosis in some cells was observed at high fungicidal dose. Buccal bioadhesive films were prepared using increasing values of the drug MIC and urea. The physicochemical characters of the prepared films including; film weight, thickness, swelling index, drug content, folding endurance, surface pH, bioadhesion force and time and drug release kinetics, were studied. Microbiological evaluation of all prepared films showed an increase in the inhibition zone diameters for films containing increasing concentrations of both miconazole and urea in a concentration-dependent manner (30-40 mm) compared to miconazole alone (18 mm). Based on our results, the prepared films are promising for buccal administration of miconazole/urea showing synergistic effect for treatment of C. albicans infection.