Current Drug Delivery (v.14, #1)

Meet Our Editorial Board Member by Nilufer Yuksel (1-1).

New Generation of Fluconazole: A Review on Existing Researches and Technologies by Afsaneh Behtash, Shohreh Nafisi, Howard I. Maibach (2-15).
Background: The frontline drug fluconazole (FLZ) has been used for treating skin fungal infections for over 35 years. FLZ has relatively large molecular size and hydrophobicity which improves its bioavailability via intravenous or oral routes but makes its use in a topical application problematic. In recent years, nano-based strategies have been examined to eliminate FLZ adverse effects and increase the drug efficiency. The present overview surveys nano-drug delivery systems used to improve FLZ efficiency; the strengths and weaknesses of the systems and the relevant achievements of pharmaceutical technology follow.
Methods: A systematic literature search study was developed based on the significant concepts being used in the review. Key search terms and a matrix-based search strategy using Boolean logic strategy were defined. Nano-formulations affecting dermal permeation of nanomaterials and experimental setups for studying skin absorbance of FLZ-nanomaterials were analysed.
Results: In recent years, nano-based strategies including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), liposomes, niosomes, ethosomes, microemulsions, nanoemulsions have been examined to increase FLZ antifungal efficiency and eliminate drug adverse effects. Significant differences was demonstrated in FLZ efficiency by different nanoparticles. Few data are available regarding a comparison of FLZ antifungal effects using various nanoparticles, but the present research suggests a positive impact on penetration.
Conclusion: Various nano-formulations have been applied to optimize fluconazole topical delivery. The present review indicated that the data related to improve fluconazole efficacy by nanoparticles are few and defining the appropriate nano-formulation is not currently possible. More research is needed to compare the capability of various nanoparticles on fluconazole skin permeation, and to translate these findings into clinical arena.

Analgesic Prodrugs for Combating their Side-Effects: Rational Approach by Ruchita Ohlan, Sucheta, Sanju Nanda, Dharampal Pathak (16-26).
Background: Analgesics are the drugs which bring insensibility to pain without loosing consciousness. Treatment strategy is generally based on the type of pain. Most of the analgesics are associated with serious side effects, such as NSAIDS can cause severe GI disturbance and opioids can cause addiction. There are various ways to reduce their side effects The analgesic prodrug approach is one of the several strategies used to attain the required pharmacological response with a considerable decrease in side effects. The aim of this paper is to introduce in depth the rational behind the use of the analgesic prodrug approach from past to present.
Methods: Data is collected from online as well as from extensive literature survey which have appeared on this subject during the last decades. This review will map the origins and development of the most important of the analgesic prodrugs to date.
Results: This review indicates that, designing analgesic prodrugs represent successful strategy to gain the required pharmacological activity with a considerable decrease in side effects. However thorough knowledge of diverse biological phenomena is needed which enables scientists to invent and design superior, nontoxic and better-targeted prodrugs.
Conclusion: The newly synthesized chemical entity or prodrugs may or may not have intrinsic pharmacological activity and also synthesizing novel molecules consume a lot of time and money than developing prodrugs of existing clinically used analgesic drugs which is surely an attractive and promising area of research now a days.

Advances and Potential Applications of Chitosan Nanoparticles as a Delivery Carrier for the Mucosal Immunity of Vaccine by Dan Li, Dongwei Fu, Hong Kang, Guangyu Rong, Zheng Jin, Xiaohua Wang, Kai Zhao (27-35).
Background: Drug research and development has entered into the new epoch of innovation formulation, and the drug delivery system has been in the forefront of pharmaceutical innovation. Chitosan, a natural polysaccharide derived from chitin, due to its well-known biocompatibility and biodegradability, it has been widely used in drug delivery, immunostimulation, tissue regeneration, blood coagulation, wound healing, drug delivery and tissue engineering. Chitosan has become a valuable vaccine adjuvant and delivery carrier, which have attracted increasing attention for its applications. In this paper, we reviewed chitosan nanoparticles, which is a promising biomaterial as vaccine adjuvant and delivery carrier, including characteristics, preparation methods and applications, or even its limitations. We also investigated the mucosal immune delivery route for drug loaded chitosan nanoparticles, such as the routes of oral and nasal. Due to the low toxicity, better biodegradability and adhesivity of chitosan nanoparticles, it can be used as the delivery carrier of vaccine antigens and drugs. These promising studies laid a foundation for the applications of chitosan nanoparticles as a delivery carrier in the vaccine or drug.
Methods: We undertook a structured research of biodegradable polymeric nanoparticles of chitosan used as a delivery carrier for the mucosal immunity of vaccine. We have searched the bibliographic databases for peer-reviewed research literature. The outstanding characteristics of the screened papers were described respectively, and a systematic content analysis methodology was used to analyse the findings.
Results: Sixty-three papers were included in the review, the majority defined leadership and governance approaches that had impacted upon the polymeric nanoparticles as the delivery carrier for the mucosal immunity of vaccine in therapeutic applications and developments. Thirty-five papers outlined the superiority characteristics of chitosan nanoparticles that applied in the field of vaccine. Twenty-eight papers overviewed the application prospects of chitosan derivatives used as drug delivery systerm. These included current advances in research and clinical applications of chitosan derivatives. This review identified the drug delivery systerm of chitosan or its derivatives, and we described the synthesis methods, applications and challenges of chitosan.
Conclusion: The findings of this review identified that the chitosan derivatives were used as delivery carrier for vaccines. It also indicates that the chitosan or its derivatives play a vital role in the drug and vaccine delivery systerm.

Overcoming the Challenges of siRNA Delivery: Nanoparticle Strategies by Neda Shajari, Behzad Mansoori, Sadaf Davudian, Ali Mohammadi, Behzad Baradaran (36-46).
Background: Despite therapeutics based on siRNA have an immense potential for the treatment of incurable diseases such as cancers. However, the in vivo utilization of siRNA and also the delivery of this agent to the target site is one of the most controversial challenges. The helpful assistance by nanoparticles can improve stable delivery and also enhance efficacy. More nanoparticle-based siRNA therapeutics is expected to become available in the near future.
Methods: The search strategy followed the guidelines of the Centre of Reviews and Dissemination. The studies were identified from seven databases (Scopus, Web of Science, Academic Search Premiere, CINAHL, Medline Ovid, Eric and Cochrane Library). Studies was selected based on titles, abstracts and full texts.
Results: One hundred twenty nine papers were included in the review. These papers defined hurdles in RNAi delivery and also strategies to overcome these hurdles. This review discussed the existing hurdles for systemic administration of siRNA as therapeutic agents and highlights the various strategies to overcome these hurdles, including lipid-based nanoparticles and polymeric nanoparticles, and we also briefly reviewed chemical modification.
Conclusion: Delivery of siRNA to the target site is the biggest challenge for its application in the clinic. The findings of this review confirmed by encapsulation siRNA in the nanoparticles can overcome these challenges. The rapid progress in nanotechnology has enabled the development of effective nanoparticles as the carrier for siRNA delivery. However, our data about siRNA-based therapeutics and also nanomedicine are still limited. More clinical data needs to be completely understood in the benefits and drawbacks of siRNA-based therapeutics. Prospective studies must pay attention to the in vivo safety profiles of the different delivery systems, including uninvited immune system stimulation and cytotoxicity. In essence, the development of nontoxic, biocompatible, and biodegradable delivery systems for medical application of RNAi-based therapeutics is needed.

Release Characteristics In Vitro and In Vivo of In Situ Gels for a Novel Peptide Compared with Low-Molecular-Weight Hydrophilic Drug by Guiying Zhang, Jie Hu, Qingbin Meng, Tao Wang, Xi Yang, Lijun Gao, Dongqin Quan (47-53).
Background: The thermo-sensitive in situ gels based on copolymers are attractive as an injectable drug delivery carriers for sustained releasing of hydrophilic drugs. The purposes of this work are to investigate the release behavior in vitro and pharmacokinetic profiles in vivo of peptide and lowmolecular- weight hydrophilic drug loaded in the in situ gels.
Methods: A triblock copolymer PLGA-PEG-PLGA (1402-1000-1402) 1115A (1115A) was synthesized and its rheological and gelatin properties were evaluated. The temperature-sensitive in situ gels based on 1115A of LXT-101, a polypeptide drug, were prepared and the release characteristics in vitro and pharmacokinetic behavior in vivo were investigated. Meanwhile, naltrexone hydrochloride (NTX), a water-soluble low-molecular-weight drug was chosen as the model drug and the in situ gels were also prepared and studied comparatively.
Results: Slow-release characteristics were observed in vitro with in situ gels of LXT-101 and NTX. The release profiles and the mechanisms were different manifested by that NTX was released from in situ gels faster and more completely than LXT-101. Otherwise, the release pattern of LXT-101 showed a biphasic mechanism, an initial Fickian diffusion followed by a combination of degradation and diffusion at a later stage. The results of pharmacokinetic study indicated that a sustained release behavior could be obtained with MRT0-t (30.34 ± 12.47) h for LXT-101 and MRT0-t (2.37 ± 0.876) h for NTX, about 10 and 4 times longer than those of aqueous solution respectively. The pharmacodynamics studies in vivo further showed that in situ gel formulations of LXT-101 could sustain efficacy 6 days compared with only 1 day for aqueous solutions.
Conclusion: The results of release behavior in vitro and in vivo indicated that in situ gels with copolymer 1115A could be served as carriers for delay-released drug delivery systems and might be more suitable for polypeptide drugs compared to low-molecular-weight hydrophilic drugs.

Formulation and Characterization of Anthocyanins-Loaded Nanoparticles by Danay Dupeyrón, Monique Kawakami, Jacques Rieumont, José Carlos Carvalho (54-64).
Background: Acaí berry, from the Euterpe oleracea Mart. Palm, has been described as the most important fruit in the Brazilian Amazon. Several studies have reported that anthocyanins (ACNs), one of the components of the acaí, have enormous potential for pharmaceuticals applications. However, the bioavailability of anthocyanins is relatively low compared to that of other flavonoids. Then, in the present work, anthocyanins-loaded nanoparticles have been developed to overcome their poor bioavailability.
Methods: A two-level factorial design with three factors was considered to evaluate the effect of EUDRAGIT ® L100, polyethylene glycol 2000 (PEG 2000) and polysorbate 80 on encapsulation efficiency (EE) of anthocyanins. Also, major parameters of nanoparticles were assessed by using mainly SEM microscopy and Dynamic light scattering.
Results: PEG 2000 was the only individual factor that has statistical significance (95% confidence level). The process yields (PY) were found in between 67% and 92%; the particle size and morphology analysis showed two distribution size, one for NPs and another for the agglomerates.
Conclusion: The pH-sensitive polymer together with the hydrophilic polymer showed to be suitable as ACNs delivery system. The delayed release profile of ACNs, observed for all formulations, can enhance their poor bioavailability. Nevertheless, ACNs bioavailability in vivo remains to be studied.

Drug Release from Inert Spherical Matrix Systems Using Monte Carlo Simulations by Rafael Villalobos, Erika V. Garcia, David Quintanar, Paul M. Young (65-72).
Background: Computational approaches for predicting release properties from matrix devices have recently been purposed as an approach to better understand and predict such systems. The objective of this research is to study the behavior of drug delivery from inert spherical matrix systems of different size by means of computer simulation.
Methods: To simulate the matrix medium, a simple cubic lattice was used, which was sectioned to make a spherical macroscopic system. The sites within the system were randomly occupied by drug-particles or excipient-particles in accordance with chosen drug/excipient ratios. Then, the drug was released from the matrix system simulating a diffusion process.
Results: When the released fraction was processed until 90% release, the Weibull equation suitably expressed the release profiles. On the basis of the analysis of release equations, it was found that close to the percolation threshold an anomalous released occurs, while in the systems with an initial drug load greater than 0.45, the released was Fickian type. It was also possible to determine the amount of drug trapped in the matrix, which was found to be a function of the initial drug load. The relationship between the two mentioned variables was adequately described by a model that involves the error function. Based on the these results and by means of a non-linear regression to the previous model, it was possible to determine the drug percolation threshold in these matrix devices.
Conclusion: It was found that the percolation threshold is consistent with the value predicted by the percolation theory.

Background: There are conflicting reports regarding the effect of polymer viscosity grade on microcapsule properties. The aim of the present study was to investigate the effect of just viscosity grade of ethylcellulose (EC) (not polymeric solution) on properties of theophylline microcapsules prepared by emulsion solvent evaporation.
Methods: The effect of EC viscosity grade and drug:polymer ratio was investigated on microcapsule properties (yield, particle size, morphology, surface characteristics and drug release). Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) were implemented to study the interaction and solid state of drug. The microcapsules were compressed in the presence of excipients and drug release was evaluated.
Results: The yield of microencapsulation and encapsulation efficiency at 1:1 drug:polymer ratio was dependent on EC viscosity. Microcapsules were spherical with some pores on their surfaces. The number of pores was more and their size was bigger for EC 100 cP microcapsules. Theophylline remained in crystalline form after encapsulation. DSC studies confirmed lack of interaction between drug and polymer. The drug release was rapid at 2:1 drug:polymer whilst it was slowed down at 1:1 drug:polymer ratio. Microcapsules obtained from EC 100 cP showed slightly faster drug release at latter ratio. Marginal changes in release rate were observed after compression of microcapsules.
Conclusions: All viscosity grades of EC were able to sustain the release of the drug from microcapsules. Considering the similar release profiles for microcapsules prepared from different viscosities of EC, the use of lower viscosity grade of EC is recommended due to the ease of production and also less processing time.

Background: In recent years, gastroretentive, hydrodynamically balanced system (HBS) for stomach-specific floating sustained drug release has gained a lot of importance in improving absorption of drugs especially those absorbed from stomach and small intestine.
Objective: The objective of the current investigation is to evaluate chitosan-hydroxypropyl methylcellulose (HPMC) based on polymeric matrices as a carrier for single-unit capsules based on HBS for stomach- specific floating sustained drug release using moxifloxacin HCl (MX) as a model drug.
Method: Various HBS capsules of MX were prepared by physical blending of MX with chitosan (low or medium molecular mass) or HPMC (K4M or K15M) or chitosan-HPMC combinations in varying proportions followed by encapsulation into size 0 capsules made of hard gelatin. The in vitro buoyancy and drug release in 0.1 N HCl (pH 1.2) were evaluated.
Results: HBS capsules based on chitosan (low and medium molecular weight and their combination) as polymer matrix failed to float on 0.1 N HCl (pH 1.2). Whereas, formulations containing HPMC (K4M or K15M) or their mixture with chitosan, remained buoyant and released MX over 9 h in the acidic dissolution medium following zero-order kinetics.
Conclusion: HPMC (K4M, K15M, blend of K4M and K15M) or their mixture with low/medium molecular mass chitosan may constitute excellent carrier systems for the stomach-specific sustained delivery of MX over a longer period.

Dipolar Reorientations in Amorphous Nimesulide: A TSDC and DSC Study by Joaquim J. Moura Ramos, Hermínio P. Diogo (91-98).
Background: The preparation of APIs in the amorphous solid form can be a means of circumventing problems arising from poor solubility and low dissolution rate of the crystalline drugs. However, molecular mobility can be responsible for the glass instability, so that the kinetic characterization of the different relaxations that subsist in the amorphous solid is useful to allow define the conditions for greater stability of the glassy pharmaceutical. Our purpose is to use the experimental techniques of differential scanning calorimetry (DSC) and thermally stimulated depolarization currents (TSDC) to study the thermal behavior of the pharmaceutical drug nimesulide and its slow molecular mobility in the amorphous solid state.
Methods: DSC provides us a general view of the thermal behaviour of nimesulide and allows a general kinetic characterization of its glass transition relaxation. TSDC allows isolating the individual modes of motion present in nimesulide (in the temperature range between -150°C and +15°C). From the experimental output of the TSDC experiments, the kinetic parameters associated with the different mobility modes of motion were obtained, which allowed a detailed characterisation of the distribution of relaxation times of the complex relaxations.
Results: No molecular mobility was detected below ? -30°C. A sub-Tg relaxation, or secondary process, was found by TSDC in the temperature region between ? -15°C and ? +7°C; this is a local mobility that is affected by physical aging, and was attributed to a slow ?-relaxation (Johari-Goldstein). The analysis by DSC and TSDC of the ?-relaxation showed that nimesulide is a moderately fragile glass former. The dynamic fragility obtained by DSC was mDSC = 52 while that obtained by TSDC was mTSDC = 70.
Conclusions: From the DSC study of the thermal behaviour we concluded that nimesulide has a moderate glass forming ability and a week glass stability. The fact that the cold crystallization occurs only some few tens of degrees above the glass transition temperature, and shows a slow kinetics, allowed the study of the mobility by TSDC. TSDC thus proved to be an adequate technique to study the molecular mobility in the amorphous nimesulide. However, the study by spectroscopic dielectric relaxation is probably impossible under these conditions.

Pharmacokinetics of Ciclopirox Olamine after Buccal Administration in Rabbits by Ivana LukáŠová, Jan Muselík, David Vetch (99-108).
Background: Prevalence of oral mucosal fungal infections increases with the frequent administration of antibiotics, corticosteroids and immunosuppressive drugs. Therapeutically used antifungals are usually associated with a variety of drug interactions. Furthermore, there has been a noticeable increase in microorganisms resistant to these preparations. Mucoadhesive buccal films represent a modern therapeutic system for the treatment of oral mucosal fungal infection paired with a high degree of patient compliance. Ciclopirox olamine applied directly onto the oral mucosa offers an attractive alternative to treatment with systemic antifungals thanks to its low incidence of resistance and side effects.
Objective: The aim of this work was to evaluate the pharmacokinetic parameters of ciclopirox olamine after the buccal application of mucoadhesive film prepared by the solvent casting method.
Method: A chromatographic method using an internal standard was developed and validated for evaluation of ciclopirox olamine plasma concentrations. Method accuracy was 88.5-104.6% and 89.5-99.7% for interday and intraday assays, respectively.
Results: The pharmacokinetic properties of ciclopirox olamine were studied in New Zealand White rabbits. The mucoadhesive films containing ciclopirox olamine in a total dose of 34.4 (33.0; 35.9) mg kg-1 were applied to all the rabbits. Plasma ciclopirox olamine concentrations were determined during the 12 h following application. The time taken to reach maximum plasma concentration was 1.7 (1.1; 2.2) h after the drug administration with cmax 5.73 (4.18; 7.28) ?g mL-1. Overall elimination half-life was 3.8 (1.9; 10.8) h.
Conclusion: The experiment suggests that oral mucoadhesive film may be a valuable alternative ciclopirox olamine administration.

Novel Salted Anionic-Cationic Polymethacrylate Polymer Blends for Sustained Release of Acidic and Basic Drugs by Wasfy M. Obeidat, Duaa Qasim, Ali Nokhodchi, Ahmad Al-Jabery, AL-Sayed Sallam (109-122).
Background: Since a unique matrix tablet formulation that independently controls the release of various drug types is in a great demand, the objective of this research was to develop a sustained release matrix tablet as a universal dosage form using a binary mixture of the salt forms of Eudragit polymers rather than their interpolyelectrolyte complexes.
Methods: Tablets were prepared by wet granulation and compressed at different compression forces, depending on drug type. Dissolution tests were conducted using USP XXII rotating paddle apparatus at 50 rpm at 37°C in consecutive pH stages.
Results: Tablets containing Ibuprofen (IB) as a model acidic drug and Metronidazole (MD) as a model basic drug showed controlled/sustained release behavior. For IB tablets containing 80% Ibuprofen and 5% (w/w) polymeric combination; the time for 50% of the drug release was about 24 hours compared to 8.5 hours for plain tablets containing 80% IB. In case of MD, the drug release extended to about 7 hours for tablets containing 80% MD and 5% (w/w) polymeric combination, compared to about 1 hour for plain tablets containing 80% MD. In terms of extending the release of medications, the dissolution profiles of the tablets containing polymeric salts forms were found to be statistically superior to tablets prepared by direct compression of the polymers in their powdered base forms, and superior to tablets containing the same polymers granulated using isopropyl alcohol.
Conclusion: The findings indicated the significance of combining the polymers in their salt forms in controlling the release of various drug types from matrices.

Background: Recurrent aphthous ulcer (RAU) is one of the most common ulcerative diseases of the oral mucosa which is recurrent, painful and slow to heal. Treatment is primarily for pain relief and promotion of healing to shorten the disease duration or reduce the rate of recurrence.
Objective: Development of a new design of topical buccal bilayer mucoadhesive films containing sodium alginate and gellan gum loaded with low dose of 1 mg prednisolone sodium phosphate to reduce the treatment period and decrease side effects of systemic treatment.
Methods: Films were prepared by solvent casting technique and evaluated to ensure optimum film characteristics, and in vivo efficiency.
Results: The bilayer films were thin, flexible with good water uptake, mucoadhesive and mechanical properties. In vitro drug release was sustained and showed anomalous non-Fickian kinetics. SEM confirmed the development of bilayer formation. Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetery indicated no chemical interaction between the layers. In vivo study in rabbits with induced oral ulceration showed complete ulcer healing within 4-5 days by once daily treatment of the studied film. Histological examination indicated no inflammation on treatment sites compared to inflamed tissue on the control sites.
Conclusion: The results suggested that buccal application of the developed bilayer mucoadhesive films loaded with only 1mg of prednisolone provided mucoadhesive and convenient application and was able to promote RAU healing with shorter treatment duration.

Zero-Order Controlled Delivery of Gliclazide from Polyethylene Oxides Matrix Tables: In vitro and In vivo Evaluation by Lijie Wang, Xinggang Yang, Yan Di, Kai Chen, Haoyang Wen, Weisan Pan (136-144).
Background: In recent years, controlled and sustained release drug delivery system has become the focus of pharmaceutical researchers. Some technologies aimed to develop the controlled and sustained release of the drug, which used to be administered several times a day and generate plasma concentration fluctuation. As all, a controlled drug release rate has always been a goal pursued by researchers. This paper introduced a controlled delivery hydrophilic matrix system, and evaluated their relevance between in vitro and in vivo behaviors.
Methods: The matrix tablets were fabricated by direct powder compression method. Single-factor test and the orthogonal experimental design were used to find out the optimal formulation. And the in vivo pharmacokinetics study was also evaluated in this paper.
Results: The amount of WSR N301 and low viscosity materials significantly affect the drug release. Compared with commercially available sustained-release tablets Diamicron®, the pharmacokinetics parameters of these matrix tablets exhibited similar blood profiles, and other parameters such as prolonged Tmax, Cmax, MRT and similar bioavailability. However, this matrix system showed unstable blood profiles in comparison with two-layer-core osmotic pump tablet. The IVIVC study suggested that there was a good correlation between absorption in vivo and drug release in vitro.
Conclusion: Zero-order controlled drug release of hydrophilic matrix system has the simpler manufacture process. And it will be a promising system to control drug release. Due to the disadvantage of hydrophilic matrix tablets in vivo release, for further research the zero-order delivery of PEO matrix tablets system, some pharmaceutical technology are needed to decrease the influence of gastrointestinal peristalsis. Therefore, the study of polyethylene oxide hydrophilic matrix tablets provides a promising formulation for promoting the development of a drug delivery system.

Controlled Release Oral Delivery of Apigenin Containing Pellets with Antioxidant Activity by Zsófia Edit Pápay, Nikolett Kállai-Szabó, Emese Balogh, Krisztina Ludányi, Imre Klebovich, István Antal (145-154).
Background: Drug delivery of phytochemicals has gained interest recently due to their remarkable health effects. Apigenin, a plant flavonoid, has antioxidant, anti-inflammatory and anticancer activities but its delivery is challenging. It could be absorbed through the whole intestine, however, it has poor bioavailability due to its low aqueous solubility. In Europe, the daily intake was estimated to be as low as 3 ± 1 mg. Pellets offer several advantages such as improved bioavailability and various resultant drug release profiles can be obtained by simply mixing pellets with different coatings.
Objective: The objective of our study was to develop a carrier system containing 20 mg apigenin thus enhancing intake and to offer reduction of oxidative stress which can cause inflammation in the intestine.
Method: The apigenin powder was dispersed in aqueous solution of binding material and layered onto the inert cores in a fluidized bed apparatus. The layered cores were further coated with enteric polymers and the process parameters were optimized.
Results: The prepared pellets met with the requirements and have good physical characteristic. 10% (w/w) Eudragit® L was suitable for enteric coating with a complete release at pH 6.8 within 1 hour. 15% (w/w) Eudragit® FS coating ensured acid resistance ability and colonic delivery. The therapeutic efficiency was confirmed with antioxidant activity measurement by using DPPH* assay.
Conclusion: Enteric coated spheres allow targeted delivery into the intestine and colon thus reaching the main absorption site. Pellets were proved to be an optimal delivery system for apigenin thus providing enhanced apigenin intake.