Current Drug Delivery - Volume 15, Issue 6, 2018

The imbalance of hydrophilicity and lipophilicity along with a large molecular size (due to a unique chemical structure) of natural compounds or plant actives poses a significant challenge for their absorption through a biological membrane and thus, alters the therapeutic efficacy. Therefore, it is desirable to have a novel approach for such formulation in order to improve the solubility and bioavailability of these phytoconstituents as a phospholipid complexation. Herbal drugs are precisely, embedded and bound by phospholipids to form vesicular structures which are amphoteric in nature. Thus, the phytolipid complex technology is unique, in the respect that it has a higher stability profile owing to its amphoteric nature or owing to its solubility in aqueous as well as oil media. It also exhibits a greater absorption and bioavailability, as the drug molecules are embedded in the pockets of the phytosomal assembly, therefore, with more drug loading capability, protection from the gastric environment, and subsequently inactivation in gastro-intestinal tract (GIT). Phytolipid complexes have a great potential in the field of medicine, pharmaceuticals and cosmetics due to improved pharmacokinetics and pharmacological attributes. The present review explores the various aspects of phytolipid complexes concerning the phospholipids, vesicles, choice of ingredients, phytolipid complexation, advantages, preparation methods and their applications.

Background: Improvisation of the nanosized vesicular systems has led to a series of useful developments including the deformable vesicles namely transfersomes, ethosomes and invasomes. The former two have been explored extensively, however, literature on invasomes is relatively scanty. Method: Invasomal formulations researched for various applications have been reviewed using search engine “Scopus”. The present review focuses on the update of the research activity on effectiveness and permeation enhancing effects of invasomes for dermal and topical delivery. Result: Many research reports could be found on invasomes in the literature but scarce patent citations were found. The present write up elaborates the mechanism of penetration, and compiles literature dental applications of the invasomes, the detection ability, use in photodynamic therapy, pilosebaceous targeting, and for delivery of macromolecules. The use of massage and microneedles for penetration enhancement is the newer element in this area. Interestingly, the majority of research has been reported on temoporfin molecule but scarce literature is available for other molecules, so the area provides ample research opportunities. The review also highlights toxicity fact sheet of commonly used terpenes for invasome formulation. Conclusion: Though invasomes present an advantageous system for enhanced topical delivery but it needs to be assessed for dermatopharmacokinetics; safety and toxicity issues on long term usage.

Diabetes is a serious and chronic problem that can be attributed to the insufficient release of the insulin or when body does not respond to the insulin which is already present. This disease has been targeted for corrective action and implementation among four non-communicable diseases by world leaders according to WHO report. The prevalence of diabetes has been estimated to be double from 4.7% of adult population in 1980 to 8.5% in the present scenario. The estimated deaths due to this epidemic disease were 1.5 million in 2012 alone. Currently, approximately 400 million people are suffering from diabetes worldwide. Although the factors leading to Type I diabetes are unknown, there are many therapies available in market for Type II disease which bags more than 90% of the total diabetes cases. But, the current treatment for this disease seems to be lacking in terms of proper management of disease, while insulin still remains the ultimate therapy to achieve comparatively effective glycemic control. In this review, an attempt has been made to summarize the patent applications filed in the field of pulmonary delivery of insulin as dry powder through an inhaler in various formulations. This review will provide an insight to the development and advancement for various formulations of insulin and the design of inhaler to improve the bioavailability of powder formulation of insulin, which would provide an alternate treatment with better acceptability or tolerability among the patients as compared to the intravenous delivery to offer better management of epidemic diabetes.

Background: In the study of lipid vesicular carriers in permeation enhancement of drug molecules across skin after the success story of liposomes, ethosomes are a recent addition. There are a number of published reviews but still, there is a lack of reviews representing various aspects in a systematic way with a detailed description of current research works. This review serves to fill this deficiency along with special emphasize on its preparation methods and applications. Methods: Information was collected from previously published literatures which were represented after analysis in terms of various aspects such as principles, composition, preparation, mechanism of penetration, modified forms, characterization, marketed preparations and its applications. Result: This review is represented in an informative and easily understandable way. Basic principles and background were covered in the introduction section. Composition section contains the basic components of formulations along with the impact of various parameters on the characterization of the ethosome. A detailed discussion of all the methods along with their own utility is elaborately provided. Various aspects of characterization studies of ethosomes are also discussed. Therapeutic and cosmetic applications of ethosomes are also outlined here. Conclusion: In spite of having a excellent permeation-enhancing and targeted drug release profile, ethosome suffers from limited commercialization. Various challenges regarding their commercialization and product development are also discussed in this review with an objective of acting as a directional route for the researchers.

Background: Lymphatic route is one of the prominent routes for improving the poor bioavailability of the drugs which undergo extensive hepatic first pass metabolism. Nanocarriers (solid lipid nanoparticles) offer a new drug delivery system that could hold great promise for attaining the bioavailability enhancement along with controlled and site specific drug delivery. Objective: The aim of the present research work was to prepare and optimized the Quetiapine fumarate (an antipsychotic drug) loaded solid lipid nanoparticles for lymphatic targeting through intraduodenal administration. Method: Thirteen quetiapine fumarate loaded solid lipid nanoparticle formulations were developed using different lipids by Microemulsion technique and optimized by box behnken design. Results: Optimized formulation (Q9) had a mean particle size of 230.38 nm with 75.92% of entrapment efficiency. The percentage drug release after 24 h was found to be 95.81%. A significant difference (P<0.05) was found in the in vitro release data of optimized formulation as compared to marketed formulation. In vitro release data of optimized formulation (Q9) was subjected to zero order, first order and Higuchi model to evaluate the release kinetics. Higuchi model was found to be the best fitted model with highest value of correlation coefficient (R2= 0.999). In vivo studies for optimized solid lipid nanoparticles formulation and drug suspension were performed on male Wistar rats after intraduodenal administration and several pharmacokinetic parameters were determined. AUC (0–∞) of optimized formulation was significantly (P<0.01) more than that of drug suspension. Bioavailability of quetiapine in solid lipid nanoparticles was 2.76 fold increased after intraduodenal administration as compared with that of drug suspension. Conclusion: On the basis of results of in vitro study, Q9 formulation was selected as optimized formulation. It exhibited better bioavailability as compared to drug suspension. It can be concluded that solid lipid nanoparticles are potential carrier for improving quetiapine bioavailability through lymphatic delivery.

Background: The combination of timolol maleate (TM) and brinzolamide (BRZ) has potential therapeutic prospects for treating glaucoma. However, the conventional formulation of TM and BRZ exhibits sub optimal therapeutic effects attributable to the poor ocular bioavailability of these drugs. Objective: Therefore, the aim of the present study was to design and evaluate TM and BRZ loaded nanostructured lipid carrier (NLC) to enhance the bioavailabilities, permeation and precorneal residence time of these drugs that would result in efficacious treatment of glaucoma. Methods: In this study, combination of drugs with different characteristic properties was loaded in NLC. The dual drugs loaded NLC was prepared by melt emulsification technique and evaluated for characteristic properties such as particle size (PS), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL), in vitro drug release and ex vivo drug penetration studies. Results: The PS and PDI of optimized NLC formulation were found to be 110.36 ±0.47 nm and 0.24 ± 0.00 respectively. The EE and DL of optimized NLC formulation were found to be 77.12 ± 0.64 % and 0.360 ± 0.01 % for TM respectively; whereas, 70.73±0.64 % and 0.71 ± 0.02 %for BRZ respectively. In vitro drug release studies showed a comparable initial rapid release of around 34 ± 2.90 % for TM and 38 ± 3.10 % for BRZ in the first 5 h followed by sustained drug release around 72.29 ± 5.90 % for TM and 70.08 ± 6.40 % for BRZ until last 24 h. Ex vivo drug penetration studies showed about 33.47 ± 2.80 % of TM and 36.20 ± 2.80 % of BRZ permeated in the first 5 h followed by 72.30 ± 6.40% of TM and 67.69 ± 6.500 % of BRZ until 24 h. There was remarkable enhancement in the release pattern and permeation of both the drugs from NLC as compared to that from their suspension. Conclusion: With dextrous optimization of dose and excipients concentration, the dual drugs with different characteristic properties can be successfully loaded in NLC formulation.

Background: Nanofibers such as bacterial cellulose nanofibers (BC-NFs) have gained increasing attention for use in wound dressings. Topical application of arginine can stimulate wound healing significantly. Objective: In order to promote the wound healing process, arginine functionalized BC-NFs containing gel (Arg-BC-NFs gel) was prepared by the electrostatic attachment of arginine on the surface of BCNFs. Method: The effect of pH was evaluated on the amount of the attached arginine on the BC-NFs surface. The attachment of arginine on BC-NFs surface was investigated by FTIR spectroscopy. The morphology of Arg-BC-NFs was evaluated using FESEM. The viscosity and spreadability of Arg-BC-NFs and the release of arginine from Arg-BC-NFs were evaluated. The effectiveness of Arg-BC-NFs gel was assessed in a full thickness wound model in rats. Re-epithelization, collagen deposition and neovascularization were investigated in the wound tissues using histological and immunohistochemical analysis. Results: FTIR spectra and the zeta potential of BC-NFs confirmed the surface modification of BC-NFs by arginine. FESEM images showed the nanofibrous structure of Arg-BC-NFs. The release of arginine from Arg-BC-NFs gel was in a sustained release manner for 24 h. The appropriate viscosity and spreadability of Arg-BC-NFs gel confirmed its easy topical application. In vivo studies revealed that Arg-BCNFs gel promoted wound closure at a faster rate than BC-NFs gel and arginine solution. Moreover, faster and more organized re-epithelialization, angiogenesis and collagen deposition were achieved in Arg-BC-NFs gel treated group in comparison to other groups. Conclusion: Arg-BC-NFs gel can be introduced as an effective wound dressing for acute wounds.

The purpose of this study was to evaluate the most appropriate conditions to generate silver nanoparticles (AgNPs) loaded with a potent antimycotic drug like amphotericin B (AmB), characterize the physicochemical properties, and to evaluate the cytotoxic effect and biological activity of these new nanostructures as a potential nanocarrier for hydrophobic drugs. It was determined that the optimal molar ratio between Ag and AmB is 1/1 given the uniformity of size around 170 nm of the nanoparticles generated as well as their strongly negative ζ potential of -35 mV, a condition that favors repulsions between AgNPs and inhibiting their aggregation. In this condition, only 0.8 mg.mL-1 of Ag is needed to solubilize 5 mg.mL-1 of AmB, a concentration currently used in commercial formulations. It is important to emphasize that the loading capacity (w/w) of this nanostructure is much higher than that of micellar and liposomal formulations. These AgNP-AmB nanoparticles retain both the bactericidal effect of silver and the cytotoxic and antifungal effect of AmB. However, it was shown that these nanoparticles are spontaneously associated with plasma lipoproteins (LDL and HDL), inhibiting their cytotoxic effects on red blood cells and on at least two cell lines, Vero and H1299 and slightly reducing its bactericidal effect on P. aeruginosa. In contrast, the antifungal effect of the formulation is maintained and is even higher than that when the nanoparticle is not associated with lipoproteins, indicating that this association is of the reversible type. The characterization of these nanoparticles is discussed as a potential new model formulation able to improve the antifungal therapeutic efficiency of AmB.

Background: Eugenol, as the major phenolic component of clove essential oil due to its desired properties in medical field, was loaded into polyacrylonitrile (PAN) nanofibers with various percentages. Objective: Our main purpose in this study was to determine the in vitro antifungal activity of eugenol loaded on PAN nanofibers against Candida albicans as the most common causative agent for candidiasis. Method: Also, the surface morphology and the mechanical properties of nanofibers were studied by scanning electron microscope (SEM) and a tensile tester, respectively. The average diameters of nanofibers in pure PAN nanofibers were found to be 127 nm. Results: The results showed that the average diameter of nanofibers after increasing the eugenol ratio (from 127 to 179-218 nm) was increased. Drug release profile of the samples was gradual and was completed after 150 hours. Conclusion: According to the results, these nanofiber mats loaded with eugenol can be used for treating cutaneous mucocutaneous candidiasis in high risk patients as a coating on a fabric substrate or temporary wound dressing.

Background: Gene therapy is an expanding field and it can treat genetic and acquired diseases. Objective: It was found that formulations with DNA: CM-β–CD (Carboxymethyl-beta-cyclodextrin): Pluronic-F127 1:3:3 and 1:3 DNA: CM-β–CD are the most stable formulations indicating high incorporation of DNA within CM-β –CD. Method: Gel electrophoresis revealed DNA with low CM-β –CD concentration has formed a more stable complex. Samples 1:3 DNA: CM-β–CD and 1:3:3 DNA: CM-β–CD: Pluronic-127 show no DNA fragment, suggesting good condensation of DNA inside cyclodextrin cavity. Results: This was confirmed by fluorescence data where fluorescence intensity was reduced for samples DNA: CM-β–CD 1:3. Overall, the findings showed that Carboxymethyl-beta-cyclodextrin (as a novel non-viral gene vector) was able to provide condensation and protection to the DNA, with and without Pluronic-F127, at low concentration. Conclusion: pDNA/CM-β–CD complex has not only shown to be able to transfect COS 7 and SHSY5Y cell lines, but it gives a higher transfection efficiency than that produced by the TransIT-LT1 commercial transfection reagent.

Background: Hydroxyapatite (HA) was emerging as the most promising biomaterial owing to its excellent bioactivity, biocompatibility, and high compressive strength for segmental bone defects. However, due to the lack of synergistic signals of osteogenic cells or growth factors, attempts concerning HA have not achieved an ideal therapeutical effect. Objective: This work was intended to combine HA particles with nerve growth factor (NGF) to coaccelerate the bone repair. Method: To deal with the strong absorption on HA particles and short half-life of exogenous NGF, bovine serum albumin (BSA) and silk fibroin (SF) were introduced. Result: Protected with SF, maximum release rate was 49.8% at 48 h for 2 mg/ml SF used group while the release rate was less than 5% without SF. PC-12 cells cultured in the NGF release fluid quit proliferation and differentiated to neural phenotype, and approximately 9.5% of NGF loading released from the particles within 48 h. Conclusion: Protected with BSA, in vitro release showed no obvious effect on strong absorption for the surface of HA particles, however, the drug loading of model protein decreased. Fortunately, SF demonstrated the capacity of adjusting the release profile of protein by varying the amount of SF embedded with no influence on drug loading and maintaining the bioactivity of NGF absorbed on HA particles.

Background: Periodontitis is a chronic inflammatory disease, which affects the supporting tissues of the teeth, and without proper treatment it may lead to tooth loss. Antibiotics - administered orally - have been widely used in the treatment of periodontitis. With the conventional administration routes, adequate drug levels cannot be reached in the periodontal pockets and oral application of antimicrobials could lead to side effects. Drug delivery systems containing antibiotics, administered at the site of infection, could possibly help eliminate pathogen bacteria and treat periodontitis. Objective: The aim of the recent study was to create a locally swellable, biodegradable, biocompatible, mucoadhesive, lipophilic drug delivery system containing antimicrobial drugs which softens at body temperature, accommodate to the shape of the periodontal pocket and can provide extended drug release for at least one week. Methods: During the formulation, thermoanalytical, consistency, wettability, swelling, degradation and drug release studies were applied to determine the ideal ratios of lipid bases, structure-building components and surface active agent concentrations. Results and Discussion: The structure-building component cetostearyl alcohol appeared to be the most convenient, thanks to its wettability and mechanical properties, which led to controlled drug release. With the use of ideal concentrations of components (10% surfactant, 40% structure-building component, 32 % lipid base, 15% antimicrobial agent and 3% polymer), sustained drug release can be provided up to nearly 3 weeks.

Background: Zaleplon is a pyrazolopyrimidin derivative hypnotic drug indicated for the short-term management of insomnia. Zaleplon belongs to Class II drugs, according to the biopharmaceutical classification system (BCS), showing poor solubility and high permeability. It undergoes extensive first-pass hepatic metabolism after oral absorption, with only 30% of Zaleplon being systemically available. It is available in tablet form which is unable to overcome the previous problems. Objective: The aim of this study is to enhance solubility and bioavailability via utilizing nanotechnology in the formulation of intranasal Zaleplon nano-emulsion (ZP-NE) to bypass the barriers and deliver an effective therapy to the brain. Method: Screening studies were carried out wherein the solubility of zaleplon in various oils, surfactants( S) and co-surfactants(CoS) were estimated. Pseudo-ternary phase diagrams were constructed and various nano-emulsion formulations were prepared. These formulations were subjected to thermodynamic stability, in-vitro characterization, histopathological studies and assessment of the gamma aminobutyric acid (GABA) level in plasma and brain in rabbits compared to the market product (Sleep aid®). Results: Stable NEs were successfully developed with a particle size range of 44.6±3.4 to 136.9±1.6 nm. Conclusion: A NE composed of 10% Miglyol® 812, 40% Cremophor® RH40 40%Transcutol® HP and 10% water successfully enhanced the bioavailability and brain targeting in the rabbits, showing a three to four folds increase than the marketed product.

Background: Liposomes are promising systems for the delivery of macromolecules and poorly absorbed drugs, owing to their ability to compartmentalize drugs, their biodegradability and biocompatibility. Objective: The aim of the present study was to formulate and evaluate conventional and modified glucosamine sulphate (GluS) and chondroitin sulphate (CS) liposomal formulations, to enhance their oral permeation for the treatment of osteoarthritis (OA). Method: Liposomal formulations were prepared by the thin-film hydration method using two types of phospholipids; Epikuron 200© and Epikuron 200© SH, and three permeation enhancers; poloxamer 407, cetylpyridinium chloride, and sodium deoxycholate. In-vitro characterization of liposomal formulations was conducted in terms of entrapment efficiency, particle size, zeta potential, viscosity, physical stability and mucoadhesive strength. Surface morphology and vesicle shape, ex-vivo intestinal permeation, and histopathological studies were further carried out on the selected formulation. Results: Results showed that the liposomal formulation containing sodium deoxycholate was the most optimum formula, showing high entrapment efficiency (60.11% for GluS and 64.10% for CS) with a particle size of 4.40 μm, zeta potential of -17.2 mV and viscosity of 2.50 cP. Conclusion: The aforementioned formula displayed the highest cumulative % permeated of GluS and CS through rabbit intestinal mucosa compared to the solution of drugs and other liposomal formulations (64.20% for GluS and 78.21% for CS) after 2 hours. There were no histopathological alterations in the intestinal tissue, suggesting the safety of the utilized liposomal formulation. In light of the above, liposomes can be considered promising oral permeation-enhancer system for GluS and CS, which is worthy of future bioavailability experimentation.