An Overview of Nanocochleates for Improving Oral Absorption of Antifungal Drugs Using a Phospolipid-Based Drug Delivery System

Vajir Shaikh, Dipak Bade, Anuradha Salunkhe, Pravin Patil, Omkar Bhagat, Ajinkya Nalawade, Shivanjali Shelake,

doi:10.5281/zenodo.15421913

Review Paper | Open Access
Volume 03 | Issue 05 | Article Id IJPS/250304673

An Overview of Nanocochleates for Improving Oral Absorption of Antifungal Drugs Using a Phospolipid-Based Drug Delivery System
Vajir Shaikh* Dipak Bade Anuradha Salunkhe Pravin Patil Omkar Bhagat Ajinkya Nalawade Shivanjali Shelake
Satara College of Pharmacy, Degaon, Satara.

Abstract

Nanaocochleate is a unique method of systemic and oral medication delivery. It is a novel lipid-based system that provides a unique technical platform suitable for the oral and systemic delivery of several substances with important medically therapeutic qualities, including genes, vaccine antigens, and pharmaceuticals. Hydrophobic macromolecules, tiny compounds with low oral bioavailability, and negatively or positively charged molecules are particularly well-suited for the technique of nanocochleate formulation. Clinically relevant, well-established medications that are now only provided by injection are being used in appropriate animal models to study the proof-of-principle of cochleate-mediated oral delivery of macromolecules and small molecule medicines. Phospholipids have overcome many of the challenges that have limited the therapeutic potential of conventional drug delivery methods. As formulation excipients, phospholipids have become more and more significant. This study intends to give a general review of the basic characteristics and uses of phospholipids in oral delivery systems, namely drug-phospholipid complexes and nanocochleates, in order to solve problems with the solubility and permeability of anti-fungal medications.

Keywords

Cochleate Nanocochleates, Hydrogel method, Trapping method, Anti-Fungal Drug, liposomes, Nano-Carrier System; Novel Formulations; Oral Delivery; Phospholipids.

Introduction

The nanocochleate drug delivery vehicle encapsulates drugs in a multilayered lipid crystal matrix, ensuring safe and effective distribution. Cochleates are important particles made up of massive, continuous, spirally twisted lipid bilayer sheets without an aqueous phase inside. Nanocochleates are a promising delivery system since they are more stable than liposomes. Because of its rod shape, it also has a higher encapsulation efficiency. More controlled drug storage is made possible by the bilayered structure. Despite their many advantages, they have disadvantages because they need specific storage conditions.⁽¹⁾The fundamental components of nanocochleate delivery vehicles are stable phospholipid-cation precipitates, which are mostly composed of calcium and phosphatidylserine. Even though the outer layers may be exposed to harsh conditions or enzymes, the solid layers and components that make up the nanocochleate's overall development are contained within its core and remain intact. Because of the dual hydrophobic and hydrophilic characteristics of their surfaces, nanocholeates can be used to encapsulate both hydrophobic and hydrophilic medications.⁽²⁾ Numerous features of formulated products, including simplicity of production, formulation quality, prolonged drug release, processing, shelf-life stability, and biodegradability for systemic administration, could be enhanced by encochleation nanotechnology. Nanocochleate protects physiologically important compounds from degradation caused by gastrointestinal and environmental enzymes. Phospholipid bilayer structures are retained by cochleates. These solid particles can readily extract the bridging counter ions from the interbilayer gaps and change into liposomes due to their remarkable flexibility. ⁽³⁾

Discovery of Nanocochleates

Dr. D. Papahadjoupoulos and associates made the discovery of cochleats in 1975, and in the 1980s and 1990s, they were employed to deliver peptides and antigens for vaccination. Sheet aggregates and cochleates covered by the trap method or large needles similar to the structure by the dialysis method are the results of the non-uniform cochleate structure documented in the literature. In 1999, nanocochleates were developed to create particles that were smaller but more uniform. Cochleates with tiny particle sizes between 104 and 113.5 nm have been demonstrated to develop using a binary phase system, such as two fake hydrogels.

Structure and composition of nanocochleates

The stable, negatively charged phospholipid cations precipitates known as nanocochleates are made of naturally occurring substances like calcium and phosphatidylserine. Nanocochleares are structures made of a continuous lipid bilayer that resemble cigars.Small unilamellar anionic liposomes condense to produce a structure like a cigar. With the exception of water, the divalent cations, such as calcium, arrange the negatively charged lipids into a solid sheet that rolls up on itself to produce cochleates that resemble cigars. Cochleate and nanocochleate, two negatively charged phospholipid bilayers, interact with multivalent counter ions such as Zn2+ or Ca2+ to produce bridging agents that enable the bilayers to form cigar-like spiral rolls.⁽⁴) Cochleates, as a particulate structure, have unique properties above liposomes because of their solid matrix, including improved protection for medications and increased mechanical stability. To minimize water interactions, the large multilayer sheets with hydrophobic surfaces tend to wrap up into a cigar-like shape. The molecular mechanism is dehydration of the phosphatidyl head group, which is necessary for bilayers to become close together and for the cochleate cylinders to begin developing (Figure 1). The orientation of the lipid bilayer repeats at a close to 54 Å. ⁽⁵⁾

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Fig. 1: Structure of Nanocochleates

Components Of Nanocochleates

Lipids, cations, and active pharmaceutical ingridients (API) are the three primary ingredients utilized to make nanocochleates.

1. Lipids: Phosphatidyl serine (PS), phosphatidylinositol (PI), di-oleyl PS, phosphatidyl glycerol (PG), phosphatidyl choline (PC), di-myristoyl PS, phosphatidyl ethanolamine (PE), di-phosphatidyl glycerol (DPG), diolyl phosphatidic acid, di-stearoyl phosphatidyl serine, and dipalmitoyl PG.

2. Cation: Zn+2 or Ca+2 or Mg+2 or Ba+2.5

3.Possible drugs: - polynucleotides, proteins, peptides, antiviral drugs, anesthetics, immunosuppressants, anticancer drugs, steroid anti-infective drugs, sedatives, vitamins, herbal items, dietary supplements, and/or vascular drugs. As a result, it shows promise as a carrier for a number of medicinal medications.⁽⁶⁾

Routes of administration for nanocochleate drug delivery

Effective oral drug delivery is made possible by nanocochleates as drug delivery devices. Parenteral, rectal, topical, sublingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intestinal, arterial, bronchial, lymphatic, and intrauterine administration, as well as other mucosal surfaces, are possible alternate routes of administration.⁽⁷⁾

Dosage forms available for nanocochleate drug delivery

· For oral administration: Capsules, cachets, pills, tablets, lozenges, powders, granules, or suspensions, emulsions, or solutions for oral administration.

· For topical or transdermal administration: Inhalants, pastes, creams, lotions, gels, sprays, ointments, patches, and powders.

· For parenteral administration: Sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use, as well as sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions. ⁽⁸⁾

Merits of nanocochleates

They are more stable than the liposome, because of less oxidation of lipid.
The lipids utilized to prepare the nanocochleates are non-toxic, non-immunogenic, and non-inflammatory because they are present in the membranes of both plant and animal cells.
The nanocochleates maintain their structure even after lyopilization, whereas liposomes structures get destroyed after lyophilization.
They improve oral bioavailability of broad spectrum compound, such as those drugs which are hydrophobic and hydrophilic in nature, also useful for the delivery of dedicated drugs like protein and peptides, genes, vaccine, antigen.
Nanocochleate exhibit the sufficient encapsulation of hydrophobic drugs in to lipid bilayer of nanocochleate structure. ⁽⁹⁾

Demerits of nanocochleates

Nanocochleates is require specific storage condition. Sometime aggregation may occur in nanocochleate formulation during storage, this can be avoid by the use of aggregation inhibitor such as polyethylene glycol and also use surfactant to avoid the aggregation of nanocochleates. The manufacturing cost of nanocochleates formulation is high.^(9,10)

Stability of nanocochleate

The attached molecules are stabilized and protected via encochleation. Even though the inner portion of the cochleate structure may be exposed to external environmental factors or enzymes, the outer portion of the structure stays intact since the entire structure is a lipid bilayer complex. This structure's inside is practically watertight and impervious to oxygen, extending the formula's shelf life. The nanocochleates can be lyophilized into powder and kept at room temperature or at 4 °C. Lyophilized cochleates can be reconstituted with liquid prior to in vitro or in vivo usage. No negative impact on the structure, morphology, or lyophilization function of cochleates. Delivery vehicles for nanocochleates: safety and biocompatibility. PS and calcium are the two primary constituents of nanocochleate. All cellular membranes naturally contain PS, which is mostly found in the brain. In nanocochleate formulations, phospholipids can be synthesized from anionic lipids, which are non-biodegradable and non-swelling, or they can come from natural sources. Soy PS is safe for human consumption and comes in big, affordable amounts. Nanocochleates are a safe and biocompatible delivery system because they are made of natural, straightforward elements. According to clinical research, PS is a very safe way to support cognitive function in the aging brain. ⁽¹¹⁾

Methods for Preparation

The following techniques are often used to prepare nanocochleates.

Hydrogel technique,
Trapping technique,
Liposome before cochleates dialysis technique.
Direct calcium dialysis technique
Binary aqueous- aqueous emulsion technique.

Hydrogel method

The hydrogel method is used to create tiny unilamellar drug-loaded liposomes, which are then added to polymer-A. After that, two dispersions are added to polymer-B. Because of their immiscibility, the two polymers combine to form an aqueous two-phase system. In a two-phase system, a cation salt solution diffuses into the second polymer and subsequently into the particles that contain the polymer. Consequently, the polymer forms small-sized cochleate and cationic cross-linkage (Figure 2). Washing removes the polymer from the produced cochleates, which can then be resuspended in physiological buffer. ⁽¹²⁾

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Fig. 2: Hydrogel isolation method

Trapping method

The trapping approach consists of a few essential steps: the medication of interest is dissolved in a suitable solvent and a phospholipid solution is made. In order to encourage the production of lipid bilayers that eventually transform into cochleate structures, the lipid solution is subsequently combined with an aqueous buffer and mechanically stirred. The medication is incorporated inside the cochleates during this process. Following production, unbound components are eliminated from the nanocochleates by centrifugation or dialysis (Figure 3). In order to determine whether the nanocochleates are appropriate for drug delivery applications, characterization methods such as dynamic light scattering and transmission electron microscopy are utilized to evaluate size, morphology, and drug loading effectiveness.⁽¹³⁾

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Fig. 3: Trapping method

Liposome before cochleates dialysis method:

Using this method, the liposomes are first produced with the addition of lipid and detergent. Liposomes are made in two steps. The first phase involves employing dialysis to remove the detergent. Nanocochleates are then produced when the produced liposomes are employed for dialysis against a calcium chloride (CaCl2) solution. The produced nanocochleates are small because the intermediate liposomes are small. Membrane proteins and other hydrophobic materials are commonly treated with this technique. This method may yield nanocochleates with a size of 50–100 nm.⁽¹⁴⁾

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Fig. 4: Liposome before cochleates dialysis method

Direct calcium dialysis method

The cochleates will be the same size, and unlike the liposome utilized in the previous cochleate dialysis procedure, this method does not involve the creation of transitional liposomes. The calcium chloride arrangement dialyzes against the lipid instantly, making it a more effective combination. This creates a thin, highly layered structure due to the tension between the release of the cleanser from the cleanser/lipid/drug micelles and the production of calcium. In a non-ionic cleaner and extraction cushion, phosphatidylserine, cholesterol, and a predetermined concentration of polynucleotide are combined, and the mixture is vortexed for five minutes. The resulting clear solution is then dialyzed against three distinct buffer modifications at room temperature. The final dialysis is performed in a solution containing 6 mM Ca2+, even though 3 mM Ca2+ is sufficient. The resultant whitish calcium phospholipid is called DC cochleate.⁽¹⁵⁾

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Fig. 5: Direct Calcium Dialysis Method

Binary aqueous-aqueous emulsion system

Tiny liposomes are encased in this way using a film process or a high pH, and they are subsequently combined with a polymer, like dextran. The dextran/liposome step is subsequently injected with a second, non-miscible polymer (such as Stake). The calcium was then gradually administered and distributed, first to one stage and then to the framing nanocochleates that followed. The molecules in the cochleates framed with this technique are less than 1000 nm. ⁽¹⁴⁾

Applications of Nanocochleates

Drug delivery

Drug delivery is one of the main applications for nanocochleates. These nanostructures can encapsulate a variety of drugs, such as small molecules, peptides, proteins, and nucleic acids. Better therapeutic results are achieved because nanocochleates prevent the encapsulated drug from degrading, increase its stability, and offer controlled release.

Cancer therapy

By encapsulating chemotherapeutic chemicals and directing them toward tumor cells, nanocochleates have demonstrated promise in cancer treatment. Chemotherapy's effectiveness can be increased while systemic toxicity and adverse effects are reduced with this focused delivery method.

Vaccine delivery

The use of nanocochleates to deliver adjuvants and antigens in vaccines has been investigated. They are intriguing candidates for vaccine development because they can increase vaccine stability, encourage antigen absorption by antigen-presenting cells, and elicit strong immune responses.

Gene delivery

Nanocochleates can be used to deliver nucleic acid-based treatments for gene therapy applications, such as mRNA, siRNA, and plasmid DNA. They facilitate cellular uptake, prevent nucleic acids from degrading, and improve targeted distribution to particular tissues or cells.

Diagnostics

Potential uses for nanocochleates in diagnostics include biosensing and imaging. Because they can be functionalized with imaging agents or targeting ligands to allow for the viewing of specific tissues or biomolecules, nanoparticles are helpful tools for disease monitoring and diagnostic imaging.

Antimicrobial therapy

Antibiotics, antifungal medicines, and antiviral medications can be encapsulated in nanocochleates to treat a variety of infections. Cochleates' special structure makes it possible to distribute antimicrobial drugs to infected cells or tissues efficiently, which enhances the effectiveness of treatment.

Nutraceuticals and cosmeceuticals

Bioactive substances including vitamins, antioxidants, and phytochemicals can be encapsulated in nanocochleates and used in cosmeceuticals and nutraceuticals. They increase these compounds' stability and bioavailability, which boosts their effectiveness in cosmetics and dietary supplement

Regenerative medicine

In regenerative medicine, nanocochleates can be used to distribute growth factors, cytokines, and other bioactive substances to promote wound healing and tissue regeneration. They can be utilized in regeneration and tissue engineering treatments and customized for particular tissue types.⁽¹⁶⁾

Charecterization Study of Nanocochleates

Particle Size and Size Distribution

The Malvern 2000SM (Malvern, UK) is used in the laser diffraction technique to assess the average particle size of distributed cochleates. It is analyzed at a temperature of 30±2°C and a detection angle of 90°. The average diameter of a sphere with the same volume as the particle being measured, or volume mean diameter D, is used to express the mean vesicle size.⁽¹⁷⁾

Polydispersity Index ⁽¹⁸⁾

PDI (Polydispersity Index) reflects the uniformity of the nanoparticle diameter and measures the particle homogeneity. The Polydispersity Index was computed using the below mentioned formula: -

???????????????????????????????????????????????????????? ???????????????????? = ????????/????????*100

Here,

Mw= average molecular weight &

Mn= No of average Molecular weight.

Entrapment Efficiency ⁽¹⁹⁾

Nanocochleates are transferred into centrifugation tubes in an aliquot of 100 μl. 60 μl of pH 9.5 EDTA and 1 ml of ethanol are added to each tube while being vortexed. The end product is colorless and transparent. In order to determine entrapment efficiency using equations, the samples were appropriately diluted, and absorbance was measured.

Entrapment efficiency = Amount of API present in cochleates / Total amount of API× 100

Fourier transform infrared spectroscopy study:

Fourier transform infrared spectroscopy study determines the functional groups as well as the purity of the compound. Samples are formulated by mixing with KBr. Then samples are located in the holder. The spectra are scanned at ambient temperature over the particular range of wave numbers. ⁽²⁶⁾

Differential scanning calorimetry study:

Differential examining calorimetry study determines the lipid status. The samples are stored hermetically in perforated aluminum pans and heated over the temperature range of-10 to 180 °C at a constant Degree of 10 °C/min. The system is eliminated at a speed of a 100 ml/min with nitrogen energy to protect the atmosphere inert. ⁽²⁷⁾

Specific Surface Area ⁽²⁰⁾

A sorptometer is typically employed to measure the specific surface area of frozen Nanocochleates. The specific surface area can be computed using the following formula.

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<img alt="6.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250515124854-0.png" width="150">
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Where d is the cochleate's diameter, ρ is its density, and its specific surface area is denoted by A. The measured and computed specific surface areas generally agree fairly, although occasionally there may be a discrepancy in the measured values due to residual surfactant.⁽²⁰⁾

Scanning Electron Microscopy

Using a SEM (S-3400 N type II model) of an optimized batch of nanocochleates, the surface morphology and structure were investigated. Dual ion beam sputtering (DIBS) was used to deposit gold onto a few droplets of a liquid nanocochleate dispersion. This is set up for SEM at a temperature of 252 ?C, a voltage of 5.0 kV, and magnification levels ranging from 10 to 20 kX.⁽²¹⁾

Density

Using a gas pycnometer and either air or helium, one can find the density of nanocochleates. Because of the porosity and specific surface area of the structure, the value obtained combining helium and air is far more noticeable. ⁽²²⁾

Molecular weight measurements

Gel permeation chromatography (GPC) can be used to find the molecular weight and distribution of polymers within a matrix by using a refractive index detector. It was demonstrated using GPC that the formation of poly-alkyl-cyano-acrylate (PACA) nanocochleates occurs not from one or longer polymer strands rolled up, but rather from the connection of several tiny oligomeric monomers. ⁽²⁵⁾

Drug content

The redispersed suspension of nanocochleates undergoes centrifugation at a rate of 15,000 revolutions per minute for 40 minutes at a temperature of 25°. The aim of this procedure is to extract the unbound medication from the leftovers. Subsequently, after an appropriate dilution, the amount of drug in the supernatant can be detected using UV-visible spectrophotometry. ⁽²²⁾

Stability study:

For the stability study the nanocochleates dispersion can be kept at 2-8⁰C and 25±2⁰C/60%RH for 3-month to check the stability of nanocochleates dispersion. The stability of nanocochleates is determined. Check the particle size and percent entrapment efficiency, drug release through nanocochleate formulation after their stability study ⁽²⁴⁾

In-vitro Release

One can use diffusion cell, modified ultra-filtration, or normal dialysis to assess the profile of in vitro release of nanocochleates. These techniques make use of dual chamber diffusion cells on a shake stands and phosphate buffers. The upper chamber i.e. donor is loaded with nanocochleates suspension, and a Millipore membrane is positioned between the two chambers. Using a modified ultra-filtration approach, aliquots are filtered across the membrane at various intervals after adding Nanocochleates directly into a stirred ultra- filtration cell. ⁽²³⁾

CONCLUSION

Nanocococleates have been widely used to deliver many active therapeutic agents, as this system can deliver hydrophilic and hydrophobic drugs due to the bilayer lipid structure. Encocleation can be helpful by improving shelf life, stability, bioavailability, reducing toxicity to improve the quality of formulation. This drug delivery system can therefore be used in the future as an alternative to delivering biological or therapeutic agents. This review article focuses on the therapeutic potential of the new class of drug carriers, i.e. nanocococleates, which can definitely lead the pharmaceutical world to the new era of highly challenging drug delivery. The evolution of nanocochleate drug delivery systems represents a significant leap in drug technology. These structures offer unparalleled advantages in delivering a variety of drugs, including hydrophilic and hydrophobic compounds, proteins, peptides, and DNA. With promising applications for vaccine delivery, gene therapy, antifungal agents, and more, nanocochleates show potential in various therapeutic areas. Despite its great advantages, challenges remain, especially in terms of storage and production costs. However, ongoing research and advances in preparation methods and characterization methods promise to overcome these challenges, leading to wider use and commercial viability. The comprehensive understanding presented in this review serves as a valuable resource for researchers, the pharmaceutical industry, and healthcare providers, demonstrating the tremendous potential of nanocochleate drug delivery systems in drug administration and changing therapeutic outcomes

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