INTRODUCTION:

A vesicular drug delivery system (VDDS) is a way to deliver drugs that bridges the gap between optimal and appropriate novel drug delivery systems by enclosing active moieties in a vesicular structure. Conventional chemotherapy for the treatment of intracellular infections is not effective due to the limited permeation of drugs into cells.

To improve bioavailability at the site of diseases, reduce harmful side effects of conventional and controlled release drug delivery systems, and overcome problems of degradation and/or drug &/or drug lose^1,2. The amphiphilic molecules act as building block and are exposed to water phase. Broad range of surfactants with varying HL blocksk sue based on thtothenotched of core phase encapsulation, are used for formulating VDDS. Vesicular drug delivery has been found to improve the bioavailability of many poorly water-soluble drugs.

"Vesicles have become the vehicle of choice in a drug delivery system called Vesicular Drug Delivery system,", e.g., liposomes, niosomes, pharmacosomes, etc.^3,4.

Vesicles are divided into the following categories based on their chemical composition:

1. Lipoidal bio-carriers, including liposomes, emulsomes, pharmacosomes, virosomes, ethosomes, sphingosomes, transferosomes, and enzymosomes.

2. Aquasomes, bilosomes, and niosomes are non-lipoidalbiocarriers.

Niosomes:

Both hydrophilic and hydrophobic medications can be included in niosomes because they are a unique drug delivery system that stores hydrophilic medications in the core cavity and hydrophobic drugs in the non-polar area found inside the bilayer.⁵L'Oreal created and received a patent for the initial niosome formulations in 1975. Niosomes are ampiphillic in nature; their name derives from the fact that the drug is enclosed in a vesicle formed by a non-ionic surfactant. Surfactants and cholesterol are added to appropriate solvents to create niosomes, which are subsequently extracted to form a thin film. While increasing surfactant concentration causes noise, it also makes vesicles bigger and more charged, which improves entrapment effectiveness. Therefore, taking into consideration the cost of production, formulation stability, effectiveness of drug entrapment, and in vivo performance of the medication, they may offer more potential for the administration of drugs than liposomes^6,7,8.

The size of the niosomes determines how they are classified ^{9, 10}.

1. SUV (Small Unicellular Vesicles)

2. Large Unilamellar Vesicles

3. Multilamellar Vesicles

In terms of drug penetration, skin deposition, prolonged-controlled drug release, and a quicker rate of absorption in the skin, niosomes provide extraordinary advantages for topical formulation^11,12.

Mechanisms of Action of Niosomes as Permeation Enhancers:

Drugs administered by niosomes are believed to have enhanced transdermal penetration through a number of ways¹³.

1. Reversible disruption of lipid organisation in the outermost layer of skin.

2. Enhancing S. corneum's ability to act as a barrier.

3. Increasing S. corneum hydration and relaxing tightly bound cell structures.

4. Niosomes adhering to or fusing with skin.

Structural components:^14,15

1. Surfactants: Drugs are trapped in vesicle layers using nonionic surfactants, either alone or in combination with other substances in different ratios. Comparing nonionic surfactants to anionic, cationic, or amphoteric surfactants indicates that nonionic surfactants provide advantages in terms of improved stability, compatibility, and non-toxicity. They are non-hemolytic, non-toxic, and do not irritate cellular surfaces. By inhibiting glycoproteins, they improve medication penetration and absorption. Nanoparticles are known to increase the rate at which various medications penetrate the skin.

2. Cholesterol: In addition to nonionic surfactants, cholesterol, a waxy steroid metabolite that resembles fat, gives vesicle layers rigidity and structural stability. Bilayers cannot spontaneously develop in it. Its hydroxyl group faces the aqueous phase, while its aliphatic chain faces the surfactant's hydrocarbon chain, making it an amphiphilic moiety. Drug holding in the nucleus is enhanced, and drug leakage is minimised by cholesterol. Rigidization results from the surfactant molecules in the vesicle layers replacing the steroidal skeleton. They are

also known to stabilise the vesicular membrane.

3. Charge Inducers: They enhance niosome stability by introducing charge onto the vesicle surface. They are combined to provide the best possible zeta potential value, which prevents the accumulation of vesicles. Any fusion is prevented because vesicle surfaces with the same charge have a tendency to avoid each other.

For example, positive charge inducers include steryl amine and cetylpyridinium chloride, whereas negative charge inducers include dicetyl phosphate, dihexadecyl phosphate, and lipoamine acid.

Various methods are used to Prepare Niosomes: ^16,17

1. Thin film hydration (TFH) or hand shaking method: The rotary evaporator is connected to this solution in the RBF, and at a temperature of around 200 C, the organic solvent is evaporated, leaving a thin coating of mixture on the RBF wall. The medication is then hydrated into this thin film using an aqueous solution in PBS while gently shaking it at the appropriate temperature. Multilamellar vesicles frequently arise as a result of the TFH technique.

2. Micro fluidization: Unilamellar vesicles are prepared using this modern technique. By using this method, vesicle size and distribution may be managed. It operates on the two streams of fluidized colloids flowing extremely quickly in the submerged jet concept. The interaction chamber's microchannels allow for fine process control. Microfluidizedniosomes are incredibly homogenous, consistently sized, and reproducible.

3. Bubble method: Niosomes may be made using an entirely novel, one-step process without the use of organic solvents. Niosomes are made using a unique bubbling apparatus. Using a high-speed homogenizer, nonionic surfactant and cholesterol are dispersed in a buffer of pH 7.4 at 700 °C. Nitrogen gas is used to bubble the dispersion at 700 °C. Niosomes are safer since there are fewer risks of residual contamination due to the absence of organic solvents.

4. Ether injection method: Water is slowly mixed with a non-ionic surfactant solution in diethyl ether while being kept at 600 °C. A 14-gauge needle is used to inject the ether-surfactant mixture into the material's aqueous solution. Ether vaporisation causes the development of single-layered vesicles. The diameter of the vesicle varies depending on the parameters used, from 50 to 1000 nm.

5. Reverse-phase evaporation (REV) method: The chloroform-ether mixture contains a 1:1 molar mixture of cholesterol and non-ionic surfactant. The lipid phase is then combined with the drug that has been dissolved in the aqueous phase, and the final dispersion is then sonicated at 450 C. A little quantity of PBS is then added to the clear gel that is created as a result of this. The organic phase of the gel is carefully removed at low pressure to create a viscous suspension of niosomes. To create niosomes, the suspension is heated for 10 minutes at 600 °C after being diluted with PBS.

6. Tran’s membrane pH gradient (inside acidic) Drug Uptake Process (Remote Loading): The solubilization of cholesterol in chloroform By evaporating the chloroform at low pressure, the substance is retrieved, leaving a thin film on the container's wall. Then, using a vortex combination, citric acid is used to hydrate the film. MLVs that have thus been generated are then frozen and thawed three times before being sonicated to obtain a suspension of niosomes. It is combined with and added to the drug suspension in the aqueous phase. The pH gradually increases to 7 to 7.5 values with the addition of 1M disodium phosphate, and the mixture is then heated for 10 min at 60°C in order to generate niosomes.

7. Sonication: The cholesterol-surfactant mixture is combined with the drug solution in buffer before it is sonicated for three minutes at 60⁰C using a titanium probe sonicator. This is the most common and simple method for creating niosomes.

Permeation Enhancers:

Permeation enhancers are compounds that promote skin permeability. They play an important part in a VDDS that is utilised for improving flux (J). The amount of material moving through a unit cross-section area at a specific time (t) is known as flux ^{18, 19, 20}.

Optimal characteristics of penetration enhancers: ^21,
22

1. It should be physically and chemically stable.

2. It should be tasteless, colourless, and odourless.

3. They must be nontoxic, nonallergenic, and pharmacologically inactive.

4. It should be compatible with medications and excipients.

5. It must be an appropriate solvent.

Natural Permeation Enhancers:

Natural permeation enhancers in the pharmaceutical field are a relatively new type of penetration enhancer. Additional research in the field is needed to produce stable transdermal formulations incorporating natural permeation enhancers that can be scaled up for commercial transdermal medication products due to their advantages, such as lower cost and a better safety profile^23,24,25.

Table 1: Natural chemical penetration enhancers used in topical medication delivery systems.

Permeation enhancer	model drugs/permeant	model type/skintype	Ref
Fatty acids
Linoleic acid	Bupivacaine, Insulin, Arginine Vasopressin, glimepiride	In vitro permeation, ex vivo study, rat skin, modified Franz diffusion cell.	26,27,28
Lauric acid	Ondansetron, phenmetrazine, Alprazolam	Human cadaver skin.	29,30
Palmitic acid, oleic acid	Diclofenac	Rat skin.	31.32
Oleic Acid	Zinc phthalocyanine, Lamotrigine, Caffeine	Suine ear skin, Human skin.	33,34
Caprylic acid	Pranoprofen	Rat skin.	35
Essential oils
Eucalyptus oil	Chlorhexidinedigluconate	Full-thickness human skin.	36, 37
Turpentine oil	Ibuprofen	Cellulose membrane, excised rabbit abdominal skin.	38
Black cumin, tulsi, clove, eucalyptus oils.	Carvedilol	Excised rat abdominal skin.	39
Basil oil	Labetolol hydrochloride	Rat abdominal skin.	35, 40,41
Peppermint, tea tree, eucalyptus oils	Benzoic acid	Human breast or abdominal skin.	41
Eryngium bungee essential oil	Piroxicam	Rat skin.	42, 43
Tulsi, Turpentine oils	Flurbiprofen	Rat skin.	44, 45
Turpentine, eucalyptus, peppermint oils	Ketoconazole	Pig skin.	46
Cardamom oil	Indomethacin, diclofenac, piroxicam	Rabbit abdominal skin.	47
Terpenes
Menthol	ligustrazine, Osthole, paeonol, Risperidone,5-fluorouracil	Modified Franz diffusion cell experiment, porcine skin, in vitro permeation studies And coarse grained molecular dynamics.	48
Alpha-terpinol	Lidocaine	Porcine	49, 50
Eugenol	Valsartan, glibenclamide and glipizide, tamoxifen	Rat skin, in-vitro permeation study, Porcine epidermis.	51, 52
Verbenone	Genistein, valsartan, propranolol hydrochloride	In vitro human skin, rat skin and humancadaverskin, ratandhuman cadaver skin.	53
Saponins and Herbal extracts
Asparagus racemosus	Carvedilol	Rat epidermis.	54, 55
Senkyu (Ligustici Chuanxiong Rhizome)	Herbal extracts	Hairless mouse skin.	56, 57

Ellagic acid as therapeutic agent:

1. El-Shitany NA et al, showed in the research study that Ellagic acid protects against carrageenan-induced acute inflammation through inhibition of nuclear factor kappa B, inducible cyclooxygenase and proinflammatory cytokines and ensshancement of interleukin-10 via an antioxidant mechanism. There are several hypotheses that explain the process of acute inflammation, including free radical overproduction, pro-inflammatory enzyme activation, and release of pro-inflammatory cytokines. In this study, the protective role of ellagic acid against carrageenan-induced acute inflammation was assessed. In addition, the immunomodulatory action, the antioxidant effects, and the role of COX-2 and NF-κB were also investigated. Inflammation was induced by the injection of 100μl of 1.5% carrageenan solution. Ellagic acid (10, 25, 50, 100 and 200mg/kg), indomethacin (10 mg/kg), meloxicam (4mg/kg), and saline, were injected 2h before carrageenan injection. The percentage inhibition in the paw weight was calculated. Paws, MDA, NO, GSH, IL-1β, TNF-α, IL-10 and NF-κB mRNA expression were estimated. Formalin fixed hind paws were used for histopathological examination and immunohistochemical staining for COX-2 expression. Ellagic acid, meloxicam and indomethacin reduced paws, edema, MDA and NO formation. In addition, all of them restored the depleted GSH contents in the paws. Ellagic acid, meloxicam and indomethacin reduced NF-κB mRNA expression. Ellagic acid ameliorated COX-2 expression; meloxicam inhibited while indomethacin failed. Both ellagic acid and meloxicam increased IL-10 while indomethacin did not. The docking study revealed a high affinity of ellagic acid towards COX-2. Ellagic acid exhibited a potent anti-inflammatory effect against carrageenan-induced inflammation. The mechanisms of ellagic acid induced protection were proved to be due to reduction of NO, MDA, IL-1β, TNF-α, COX-2 and NF-κB expression and induction of GSH and IL-10 production⁵⁸.

2. Rios JL et al reviewed the therapeutic and pharmacological activities of the Ellagic acid. Ellagic acid is a common metabolite present in many medicinal plants and vegetables. It is present either in free form or as part of more complex molecules (ellagitannins), which can be metabolized to liberate ellagic acid and several of its metabolites, including urolithins. While ellagic acid's antioxidant properties are doubtless responsible for many of its pharmacological activities, other mechanisms have also been implicated in its various effects, including its ability to reduce the lipidemic profile and lipid metabolism, alter pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β, interleukin-6), and decrease the activity of nuclear factor-κB while increasing nuclear factor erythroid 2-related factor 2 expression. These events play an important role in ellagic acid's anti-atherogenic, anti-inflammatory, and neuroprotective effects. Several of these activities, together with the effect of ellagic acid on insulin, glycogen, phosphatases, aldose reductase, sorbitol accumulation, advanced glycation end-product formation, and resistin secretion, may explain its effects on metabolic syndrome and diabetes. In addition, results from recent research have increased the interest in ellagic acid, both as a potential protective agent of the liver and skin and as a potential anticancer agent, due to the specific mechanisms affecting cell proliferation, apoptosis, DNA damage, and angiogenesis and its aforementioned anti-inflammatory properties.The authors concluded that the pharmacological effects make ellagic acid a highly interesting compound that may contribute to different aspects of health; however, more studies are needed, especially on the compound's pharmacokinetic profile⁵⁹.

3. Javaad SR et al, reviewed Ellagic acid (EA) as a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA is Known as a naturally occurring bioactive and pharmacologically active polyphenolic compound, EA possesses a remarkable broad spectrum of therapeutic activities in addition to pharmacological potentials to treat numerous diseases and ailments. Findings from this review indicate EA may be involved in regulating a spectrum of cellular signaling pathways to prevent, mitigate, or slow down the progression of chronic disorders, including cardiovascular and neurodegenerative diseases, diabetes, and cancer. In addition, there is also evidence of a positive therapeutic effect of the combination of EA with other antioxidants, known for their multiple bioactivities and therapeutic potential. Due to a wide range of biological effects of EA, edible plants containing this phytochemical and its hydrolyzable derivatives, mainly ellagitannins, are a valuable source of EA for humans and belong to functional foods that promote health and may reduce the risk of disease. EA is also currently used in the pharmaceutical and cosmetics industries; consequently, various plant species are now being studied for EA content in order to find novel sources of EA in human nutrition, as well as sources of raw materials for the preparation of functional nutritional supplements and nutraceuticals. In modern medicine, natural substances represent an unlimited source of active molecules whose medical applications may increase in the near future. For this reason, it is very important to clarify the molecular mechanisms underlying the observed beneficial activities. Currently for EA, as for many other natural compounds, it is not completely clear whether for some observed beneficial effects, such as antineoplastic activity, a transcriptional action is necessary or whether they are mainly related to epigenetic action. Therefore, a large number of nutraceutical and therapeutic interventions can be designed, considering the possible mechanisms of this active agent and its precursors⁶⁰.

Formulation aspect of Ellagic acid:

1. Varaporn Buraphacheep et al, Investigated the influence of chemical penetration enhancers on the physicochemical properties of ellagic acid loaded niosomes. The reverse phase evaporation technique was employed to prepare niosomes of ellagic acid with Cholesterol, Span 60, Tween 60 and Solulan C24 (steric stabilizing agent). Skin penetration enhancing agents as DMSO/N-methyl 2 Pyrrolidone and solubilizing agent as PEG were used in the formulating niosomes. The vesicles obtained were spherical in shape and were found stable over 4 months of storing at 4⁰C. The niosomes prepared with DMSO as penetration enhancer showed greater proportion of ellagic acid in layer of epidermis. While nisomes with NMP possessed greater amount of ellagic acid in acceptor medium. By the conclusions made in the study, Niosomes prepared with DMSO could be promising way for epidermal delivery of ellagic acid and niosomes prepared with NMP for dermal delivery⁶¹.

2. Li B et al, have evaluated structurally varied, carboxyl-containing cellulose derivatives for their ability to form amorphous solid dispersions (ASD) with ellagic acid (EA), in order to improve the solubility of this high-melting, poorly bioavailable, but highly bioactive natural flavonoid compound. ASDs of EA with carboxymethylcellulose acetate butyrate (CMCAB), cellulose acetate adipate propionate (CAAdP), and hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) were prepared, and EA dissolution from these ASDs was compared with that from pure crystalline EA and from EA/poly(vinylpyrrolidinone) (PVP) solid dispersions (SD). Polymer/drug mixtures were characterized by powder X-ray diffraction (XRPD), modulated differential scanning calorimetry (MDSC), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR). The XRPD and FT-IR results indicated that EA was amorphous in solid dispersions with EA concentration up to 25wt%. The stability against crystallization and solution concentrations of EA from these solid dispersions were significantly higher than those observed for physical mixtures and pure crystalline EA. HPMCAS stabilized EA most effectively, among the polymers tested, against both chemical degradation and recrystallization. The relative ability to solubilize EA from ASDs at pH 6.8 was PVP/HPMCAS/CMCAB. EA dissolves from ASD in PVP quickly and completely (maximum 92%) at pH 6.8, but EA is also released from PVP at pH 1.2, and then crystallizes rapidly. Therefore PVP is not a practical candidate for EA ASD. In contrast, the cellulose derivative ASDs show very slow EA release at pH 1.2 (<4%) and faster but still incomplete drug release at pH 6.8 (maximum 35% for HPMCAS SD). In was concluded in the study that the pH-triggered drug release from HPMCAS ASD makes HPMCAS a practical choice for EA solubility enhancement⁶².

3. Zuccari G et al, reviewed formulation strategies to improve oral bioavailability of ellagic acid. It was stated in the review that EA exerts various health-promoting activities, suggesting that it may play an important role in dietary supplements. The review article concludes that EA is endowed with a wide spectrum of therapeutic effects against oxidation-linked chronic illnesses such as, above all, diabetes, cancer, neurodegenerative disorders and cardiovascular diseases. But EA presents unsuitable biopharmaceutical features, including poor bioavailability and interindividual variability, that hamper its successful employment in prophylaxis and disease treatment. On this background, in order to address the many drawbacks associated to EA in vivo absorption, several strategies mainly consisted in micro/nano-technology approaches have been designed and performed. The obtained EA formulations demonstrated to modify its release and to improve its solubility, stability during storage and bioavailability in animal models. The attempt of reducing the size of EA powder through anti-solvent precipitation could be a recommended preliminary step as reported by different authors. Regarding micro/nano-systems preparative methods, encapsulation in biodegradable PLGA or PCL micronanospheres represents a valid route when effective EA protection, long circulation and controlled release are required, as these systems provided a sustained release over one week. Concerning lipid carriers, self-emulsifying systems are the most investigated ones, since they were usually endowed with high EA loading capacity and gastrointestinal release within 1 h. It is of great importance to develop formulations with residual organic solvents or surfactants below the recommended maximum levels indicated by regulatory agencies. With many promising advances, novel and more effective strategies could be applied for allowing extensive investigations on EA in vivo beneficial effects. In one pharmacokinetic study in humans, it has been reported that after pomegranate extracts consumption, the key factors hampering EA effectiveness are: its low solubility at the gastric pH, its bounded to intestinal epithelium, the saturable transcellular transport and the interindividual variability to produce urolithins. All these drawbacks may be overcome at least to a large extent by applying micro/nano-carrier based approaches⁶³.

4. Sharma K et al, evaluated solubility, photostability and antioxidant activity of ellagic acid cyclodextrinnanosponges fabricated by melt method and microwave assisted synthesis. The research was aimed to encapsulate EA in cyclodextrinnanosponges (CDNS). The melt method and microwave-assisted technique have been employed for crafting CDNS. EA was loaded in CDNS via freeze-drying, followed by appropriate characterization. EA-CDNS were also assessed for encapsulation, particle size, zeta potential, and polydispersity index, which presented satisfactory results. In vitro, antioxidant activity was conducted using the DPPH (2, 2-diphenyl-1-picrylhydrazyl) assay. The solubilization efficacy of EA was analyzed in distilled water and compared with CDNS, which demonstrated ten folds augmentation for the selected batch. Study reports remarkable improvement in the photostability of EA as was observed after its inclusion. The results demonstrated the superiority of the melt method in terms of solubility, entrapment, photostability, and antioxidant potential⁶⁴.

CONCLUSION:

Despite of having wide array of therapeutic, prophylactic and neutritional uses of ellagic acid, its use is limited because ofpoor solubility, stability, bioavailability, first pass effect and inter subject variability in gut metabolism. Formulating neosomes of ellagic acid in transdermal drug delivery system can address these problems of ellagic acid and improve its utility for future use.

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Received on 28.06.2023 Modified on 14.08.2023

Res. J. Pharma. Dosage Forms and Tech.2024; 16(1):60-66.

DOI: 10.52711/0975-4377.2024.00011