Utilization of nanoemulsions to enhance bioactivity of pharmaceuticals,supplements, and nutraceuticals: Nanoemulsion delivery systems and nanoemulsion excipient systems

ABSTRACT

Introduction: The efficacy of many hydrophobic bioactives (pharmaceuticals, supplements, and nutraceuticals) is limited due to their relatively low or highly variable bioavailability. Nanoemulsions consisting of small lipid droplets (r < 100 nm) dispersed in water can be designed to improve bioavailability.

Areas covered: The major factors limiting the oral bioavailability of hydrophobic bioactive agents are highlighted: bioaccessibility, absorption and transformation. Two nanoemulsion-based approaches to control these processes and improve bioavailability are discussed: nanoemulsion delivery systems (NDS) and nanoemulsion excipient systems (NES). In NDS, hydrophobic bioactives are dissolved within the lipid phase of oil-in-water nanoemulsions. In NES, the bioactives are present within a conventional drug, supplement, or food, which is consumed with an oil-in-water nanoemulsion. Examples of NDS and NES utilization to improve bioactive bioavailability are given.

Expert opinion: Considerable progress has been made in nanoemulsion design, fabrication, and testing. This knowledge facilitates the design of new formulations to improve the bioavailability of pharmaceuticals, supplements, and nutraceuticals. NDS and NES must be carefully designed based on the major factors limiting the bioavailability of specific bioactives. Research is still required to ensure these systems are commercially viable, and to demonstrate their safety and efficacy using animal and human feeding studies.     

Potential Biological Fate of Emulsion-Based Delivery Systems: Lipid Particles Nanolaminated with Lactoferrin and β-lactoglobulin Coatings

Purpose

To develop lipid particles coated by nanolaminated protein coatings as potential oral delivery systems to encapsulate, protect, and deliver lipophilic bioactives.

Methods

Nanolaminated protein coatings were formed by sequential electrostatic deposition of cationic lactoferrin (LF) and anionic β-lactoglobulin (BLG) at pH?6.5: LF, LF-BLG, LF-BLG-LF, and LF-BLG-LF-BLG. Changes in physicochemical properties were characterized after exposure to environmental stresses (pH?2 to 9; 0 to 200 mM NaCl) and simulated gastrointestinal tract (GIT) conditions (mouth, stomach, small intestine). Triglyceride digestion and β-carotene bioaccessibility were also measured.

Results

The pH and salt dependence of the electrical charge and aggregation stability of the emulsions were strongly influence by the structure of the interfacial coatings. All emulsions behaved similarly under simulated GIT conditions: extensive droplet aggregation occurred in the stomach and small intestine; triglycerides were rapidly and fully digested after exposure to intestinal fluids; the bioaccessibility of β-carotene was low (< 4%).

Conclusions

Nanolaminated protein coatings may be useful for stabilizing encapsulated lipids in functional food and pharmaceutical products during storage, but releasing them after ingestion. Protein coatings had little impact on triglyceride digestion, but they greatly reduced β-carotene bioaccessibility, possibly due to binding to lactoferrin.

     

Delivering bioactive molecules as instructive cues to engineered tissues

Introduction : Growth factors and other bioactive molecules play a crucial role in the creation of functional engineered tissues from dissociated cells.

Areas covered : This review discusses the delivery of bioactive molecules – particularly growth factors – to affect cellular function in the context of tissue engineering. We discuss the primary biological themes that are addressed by delivering bioactives, the types of molecules that are to be delivered, the major materials used in producing scaffolds and/or drug delivery systems, and the principal drug delivery strategies.

Expert opinion : Drug delivery systems have allowed the sustained release of bioactive molecules to engineered tissues, with marked effects on tissue function. Sophisticated drug delivery techniques will allow precise recapitulation of developmental milestones by providing temporally distinct patterns of release of multiple bioactives. High-resolution patterning techniques will allow tissue constructs to be designed with precisely defined areas where bioactives can act. New biological discoveries, just as the development of small molecules with potent effects on cell differentiation, will likely have a marked impact on the field.     

Solid lipid nanoparticles: an oral bioavailability enhancer vehicle

Introduction: The therapeutic efficacy of perorally administered drugs is often obscured by their poor oral bioavailability (BA) and low metabolic stability in the gastrointestinal tract (GIT). Solid lipid nanoparticles (SLNs) have emerged as potential BA enhancer vehicles for various Class II, III and IV drug molecules.

Area covered: This review examines the recent advancements in SLN technology, with regards to oral drug delivery. The discussion critically examines the effect of various key constituents on SLN absorption and their applications in oral drug delivery. The relationship between the complexity of absorption (and various factors involved during absorption, including particle size), stability and the self-emulsifying ability of the lipids used has been explored.

Expert opinion: The protective effect of SLNs, coupled with their sustained/controlled release properties, prevents drugs/macromolecules from premature degradation and improves their stability in the GIT. An extensive literature survey reveals that direct peroral administration of SLNs improves the BA of drugs by 2- to 25-fold. Overall, the ease of large-scale production, avoidance of organic solvents and improvement of oral BA make SLNs a potential BA enhancer vehicle for various Class II, III and IV drugs.     

Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route

Introduction: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems.

Areas covered: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems.

Expert opinion: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain.     

Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles

ABSTRACT

Objective: Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability.

Methods: Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats.

Results: Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times.

Conclusion: These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability.     

Exploiting microspheres as a therapeutic proficient doer for colon delivery: a review

Introduction: Colon-specific drug delivery systems have recently gained importance for delivering a variety of therapeutic agents via oral route. This mode offers the feasibility of treating colonic pathologies with less risk of bioburden to other organs/tissues and has been widely researched for the delivery of challenging drugs. Microspheres targeted to colon have occupied central position on drug delivery due to their small size that offers characteristic intrinsic properties attributable to the carrier.

Areas covered: The present deliberation precariously covers the capacious usage of microspheres for the treatment of local colonic pathologies like colon carcinomas, inflammatory bowel disease and parasitic diseases using natural as well as synthetic carriers. The write up also encompasses clinical application of microspheres.

Expert opinion: Microspheres have comprehensive potential to be marketed as the patient-friendly formulation, as it would provide direct treatment at the disease site and, consequently, lower dosing and reducing systemic side effects. Wherefore, the major obstacles in delivering drugs to the colon like the absorption and degradation pathways in the proximal part of GIT could be easily overcome, and also a range of pathologies from constipation and diarrhea to the exhaustive inflammatory bowel diseases and colon carcinoma could be cured.     

Advance in oral delivery systems for therapeutic protein

Abstract

Oral delivery is the most common method of drug administration with high safety and good compliance for patients. However, delivering therapeutic proteins to the target site via oral route involves tremendous challenge due to unfavourable conditions like biochemical barrier, mucus barrier and epithelial barriers. According to the functional differences of various protein drug delivery systems, the recent advances in pH responsive polymer-based drug delivery system, mucoadhesive polymer-based drug delivery system, absorption enhancers-based drug delivery system and composite polymer-based delivery system all were briefly summarised in this review, which not only clarified the clinic potential of these novel drug delivery systems, but also described the way for increasing oral bioavailability of therapeutic protein.     

Novel probiotic dissolvable carboxymethyl cellulose films as oral health biotherapeutics: in vitro preparation and characterization

Objectives: Oral health is influenced by the mouth's resident microorganisms. Dental caries and periodontitis are oral disorders caused by imbalances in the oral microbiota. Probiotics have potential for the prevention and treatment of oral disorders. Current formulations, including supplements and foods, have limitations for oral delivery including short storage time, low residence time in the mouth, effects on food consistency, and low patient compliance. Oral thin films (OTFs) may be efficient in delivering probiotics to the mouth. This research aims to develop a novel carboxymethyl cellulose (CMC)-probiotic-OTF to deliver probiotics for the treatment/prevention of oral disorders.

Methods: CMC-OTFs were developed with varying CMC concentration (1.25 – 10 mg/mL), weight (5 – 40 g), thickness (16 – 262 μm), hygroscopicity (30.8 – 78.9 mg/cm² film), and dissolving time (135 – 600 s). The 10 g 5 mg/mL CMC-OTF was selected and used to incorporate Lactobacillus fermentum NCIMB 5221 (6.75 × 10⁸ cells/film), a probiotic with anti-inflammatory potential for periodontitis treatment and capable of inhibiting microorganisms responsible for dental caries and oral candidiasis.

Results: The CMC-OTF maintained probiotic viability and antioxidant activity following 150 days of storage with a production of 549.52 ± 26.08 μM Trolox equivalents.

Conclusion: This research shows the successful development and characterization of a novel probiotic-CMC-OTF with potential as an oral health biotherapeutic.     

Melt extrusion: process to product

Introduction: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues.

Areas covered: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems.

Expert opinion: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.     

Potentials and challenges in self-nanoemulsifying drug delivery systems

Introduction: A significant number of new chemical entities (almost 40%), that are outcome of contemporary drug discovery programs, have a potential therapeutic promise for patient, as they are highly potent but poorly water soluble resulting in reduced oral bioavailability. Self-nanoemulsifying drug delivery systems (SNEDDS) have emerged as a vital strategy to formulate these poorly soluble compounds for bioavailability enhancement.

Areas covered: The review gives an insight about potential of SNEDDS with regards to oral drug delivery. The effect of various key constituents on formulation of SNEDDS and their applications in oral drug delivery is also discussed. Various aspects of formulation, characterization and biopharmaceutical aspects of SNEDDS are also been explored. The choice and selection of excipients for development of SNEDDS is also discussed.

Expert opinion: The ability of SNEDDS to present the drug in single unit dosage form either as soft or hard gelatin capsule with enhanced solubility maintaining the uniformity of dose is unique. With the ease of large-scale production, high drug-loading capacity, improvement in release behavior of poorly water-soluble drugs and improvement of oral bioavailability, SNEDDS have emerged as preferable system for the formulation of drug compounds with bioavailability problems due to poor aqueous solubility.     

Promising complexes of acetazolamide for topical ocular administration

Importance of the field: Acetazolamide (ACZ), a carbonic anhydrase inhibitor (CAI), and other oral CAIs have been an integral part of antiglaucoma therapy for > 40 years. ACZ is used orally for the reduction of intraocular pressure in patients suffering from glaucoma. However, this treatment leads to unpleasant systemic side effects. The answer to the undesirable effects of ACZ is the topical delivery of this drug into the eye, where it could elicit its physiological action. However, the development of a topical formulation of ACZ is limited by its poor ocular bioavailability, which can be largely attributed to its poor penetration coefficient and poor biphasic solubility.

Areas covered in this review: This review offers an overview of different approaches to delivering ACZ to the eye, highlighting the potential of the ternary system ACZ:HP-β-CD:TEA as a tool for formulating aqueous ACZ eye drop solutions.

What the reader will gain: A critical analysis is provided to highlight the key issues to design formulations containing hydrophilic cyclodextrins.

Take home message: The ACZ:HP-β-CD:TEA complex is an important new approach to improve the ocular bioavailability of this drug. This approach may be applied to other CAIs in the future.     

Nanostructured lipid (NLCs) carriers as a bioavailability enhancement tool for oral administration

ABSTRACT

Context: Nanostructured lipid carrier (NLCs) is the second generation solid lipid nanoparticles (NPs) made up of physiological, biocompatible, biodegradable, non-sensitizing and non-irritating lipids.

Objective: The main objective of this review is to explore the role of NLCs system for delivering drugs by oral route and thus increasing the oral bioavailability.

Methods: The present review article highlights the definition and types of NLCs and their importance as colloidal carriers including the production techniques and their formulation. This review article also deals with the fate of lipids used in the NLCs formulation and the NLCs toxicity.

Conclusion: On the basis of the literature survey done, it was concluded that the NLCs enhances the oral bioavailability of the drug and may decrease the side effects and toxicity of the lipids used in other polymeric NPs as NLCs uses physiological and biodegradable lipids.     

Formulation approaches in enhancement of patient compliance to oral drug therapy

Introduction: Disease management of outdoor patients is mainly affected by patient compliance to the drug therapy, which in turn is governed by patient convenience. Failure to follow through with a treatment decision is one of the biggest causes of unsuccessful medical care. At present, different formulation options are available for various drugs, and hence, the decision is based on the most convenient dosage form for the patient, along with optimum therapeutic benefits.

Areas covered: This paper reviews various available formulation approaches, in the hope of improving patient convenience, compliance and the overall outcome of oral drug therapy.

Expert opinion: While parenterals are valued for their speed and efficiency of delivery, these systems generally score low on patient satisfaction surveys. The oral route is the preferred route for drug delivery, although it renders multiple obstacles to formulate a patient-convenient platform, such as unfavorable taste and swallowing difficulties. Transdermal drug delivery also provides high patient satisfaction, but is effective only for the delivery of smaller, lipophilic molecules. The increasing development of biopharmaceutical therapies renders an increasing number of challenges for formulation scientists to develop a more patient-convenient means of drug delivery.     

Nanovesicular carriers as alternative drug delivery systems: ethosomes in focus

Introduction: The application of vesicular carrier formulations has generated promise of overcoming some problems associated with drug delivery arising from not only the physicochemical properties of the drug but also those of the biological barriers, such as the membrane linings of various body tissues and the skin. This review article discusses the importance of various vesicular carriers, namely liposomes, niosomes, transfersomes and ethosomes in drug delivery with greater emphasis on ethosomes.

Areas covered: The nature, mechanism of drug delivery, methods of preparation as well as characterization of vesicular carriers was discussed with a focus on ethosomes. An overview of their potential applications was provided with discussions on the future prospects and challenges of achieving enhanced drug delivery using ethosomes.

Expert opinion: Vesicular carriers offer controlled and sustained drug release, improved permeability and protection of the encapsulated bioactives. Ethosomes offer more efficient and enhanced bioavailability better than the older dosage forms owing to the high ethanol content. Ethosomes have potential applications in the development of nanomedicines, including phytomedicines, for the treatment of challenging diseases ravaging the world today. The future holds great prospects in the utilization of vesicular carriers, especially ethosomes, in overcoming peculiar problems of drug delivery.     

Methanol extracts from Cystoseira tamariscifolia and Cystoseira nodicaulis are able to inhibit cholinesterases and protect a human dopaminergic cell line from hydrogen peroxide-induced cytotoxicity

Context Marine macroalgae contain several bioactive molecules that may be developed as functional foods, but information about their neuroprotective potential is scarce.

Objective The objective of this study is to determine the in vitro antioxidant and neuroprotective features of marine algae from the southern coast of Portugal and to assess the total content of different types of bioactives.

Materials and methods Methanol extracts from 21 macroalgal species from the southern Portugal were evaluated for in vitro antioxidant and acetylcholinesterase (AChE) inhibition. Active extracts were further evaluated for inhibitory activity against butyrylcholinesterase (BuChE) and tyrosinase (TYRO), and for their ability to attenuate hydrogen peroxide (H₂O₂)-induced toxicity in SH-SY5Y cells. The total contents of different phenolic groups were determined for the most active extracts.

Results Cystoseira tamariscifolia (Hudson) Papenfuss (Sargassaceae) had the highest antiradical activity (92%, 1?mg/mL). Cystoseira nodicaulis (Withering) M. Roberts (Sargassaceae) (75%) and Cystoseira humilis Schousboe ex Kützing (Sargassaceae) (70%) had the highest iron-chelating activity at 10?mg/mL. Cystoseira baccata (S.G. Gmelin) P.C. Silva (Sargassaceae) was more active towards copper (66%, 10?mg/mL). Cystoseira tamariscifolia had the highest AChE inhibitory capacity (85%, 10?mg/mL). Cystoseira tamariscifolia and C. nodicaulis were also active against BuChE and TYRO, and were able to protect SH-SY5Y cells against oxidative stress induced by H₂O₂. Cystoseira tamariscifolia had the highest content of all the groups of phenolics, and was particularly enriched in hydroxycinnamic acids (106?mg CAE/g DW).

Discussion and conclusion Results indicate that C. tamariscifolia and C. nodicaulis are important sources of nutraceutical compounds and may be considered functional foods that could improve cognitive functions.     

Chitosan: a potential polymer for colon-specific drug delivery system

Introduction: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.

Areas covered: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.

Expert opinion: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).