Novel Strategies in Drug Delivery System: A Review

The effectiveness of a medication can be greatly impacted by how it is given. Certain drugs have an ideal concentration range where the greatest benefit is received; concentrations above or below this range may be dangerous or fail to produce any therapeutic benefit On the other hand, the very modest progress in the efficacy of treating serious diseases has shown that a multidisciplinary approach to medicine delivery to targets in tissues is becoming more and more necessary. As a result, novel ideas for controlling the pharmacokinetics, pharmacodynamics, immunogenicity, bioavailability, and efficacy of drugs were developed. These novel techniques—often referred to as drug delivery systems. Drug delivery and targeting systems are now being developed in a variety of ways to lower drug loss and degradation, avoid adverse effects, increase medication bioavailability, and increase the amount of the drug that accumulates in the required zone¹. The novel dose forms and advanced technology known as NDDS are considerably superior than traditional dosage forms. For almost two decades, scientists have acknowledged the potential benefits of nanotechnology in bringing about substantial improvements in drug delivery and targeting. Other drug delivery strategies concentrate on finding safe and effective ways to deliver protein drugs outside of the gastrointestinal tract, where they may degrade, or on overcoming particular delivery barriers, such as the blood-brain barrier (BBB), to better target the drug and increase its efficacy. The term Novel Drug Delivery System refers to a method of administering medication that differs from traditional drug delivery systems. It blends state-of-the-art methodology with novel dosage forms that outperform customary dosage forms. NDDS leads to methodologies, formulations, technologies, and systems that are used for this purpose. In any case, it might also entail supporting systematic pharmacokinetics. It usually has to do with how much and how long the medication has been present. It also contains the body's particular scientific site targeting. The efficacy of the medication may be significantly impacted by these novel methods for drug delivery. New methods for controlling a drug's pharmacokinetics, pharmacodynamics, toxicity, immunological response, biorecognition, and efficacy have therefore appeared².

There are several advantages of novel drug delivery systems over conventional drug delivery.

1. Optimum therapeutic- drug concentration in the blood or tissue maintained over a prolonged period of time.
2. Pre- determined release rates of extended period of time may be achieved.
3. Duration for short half- life drug may be increased
4. By targeting the site of action, side effects may be eliminated.
5. Frequent dosing and wastage of the drug may be reduced or excluded.
6. Better patient compliance may be ensured^.

Need of NDDS

Unlike conventional dosing forms, it does not result in fluctuations in the drug level in the blood. NDDS is a sophisticated drug delivery technology that has shown promise in terms of drug effectiveness, regulated drug release for a long-lasting effect, and targeting specific tissues in ants. To reduce unwanted effects and optimize therapeutic benefits, it keeps the drug's concentration within a therapeutic window. Some medications, like vaccines, proteins, and antibodies, may not be absorbed through the regular channels due to poor bioavailability and enzymatic breakdown. These flaws have been addressed by NDDS³.

DIFFERENT ROUTES OF DRUG ADMINISTRATION.

The route of administration of a medication directly affects the drug bioavailability, which determines both the start and the duration of the pharmacological effect. Some considerations must be taken into account when designing a drug dosage form:

1. Intended route of administration.
2. Amount or dose to be administered.
3. Anatomical and physiological characteristics (membrane permeability, blood flow) of the site of absorption
4. Physicochemical properties of the site, such as pH and osmotic pressure of physiological fluids.
5. Potential effect of the medication over the site of administration.

A medication administration route is often classified by the location at which the drug is administered, such as oral or intravenous. The choice of routes in which the medication is given depends not only on convenience and compliance but also on the drug’s pharmacokinetics and pharmacodynamic profile. Each medication administration route has unique contraindications. Therefore, it is crucial to understand the characteristics of the various routes and associated techniques. When the systemic absorption of a drug is desired, medications are usually administered by two main routes: the parental route (through skin by injection, avoiding the digestive system) and the enteral route (directly at some point of the gastrointestinal tract). To a lesser extent, the pulmonary (or respiratory) and nasal routes are employed. Other routes of administration, such as ophthalmic and vaginal, are not included here because their application is almost exclusive for local (not systemic) drug administration.

Figure 1: Different routes of drug administration

Enteral Routes of Medication

Oral

This is convenient and indicated for patients who can ingest and tolerate oral medication. Medication given orally has a slower onset, typically about 30-60 minutes. Some medications with short half-lives are administered orally as timed-release or sustained-release forms that get absorbed over several hours. If the patient has difficulty swallowing (dysphagia), tablets are typically crushed and placed in a substance like applesauce or pudding for easier swallowing (based on the patient’s prescribed diet). However, it is important to verify that a tablet may be crushed by consulting a drug reference or a pharmacist. For example, medications such as enteric-coated tablets, capsules, and sustained-release or long-acting drugs should never be crushed because doing so will affect the intended action of the medication. In this event, the provider must be contacted for a change in route.

Advantages:

• Ease of administration
• Widespread acceptance by the patients
• Absorption takes place along the whole length of GI tract.
• Economical as compared with other parenteral route.

Disadvantages:

• Variable absorption rates
• Degradation of some drugs before reaching the site of absorption into the bloodstream
• The inability of many compounds to effectively traverse the intestinal epithelial membrane cells to reach the bloodstream.
• Irritation of the mucous lining of the gastrointestinal tract.

Sublingual and Buccal Routes

These are indicated for medications with high first-pass metabolism that need to avoid clearance by the liver.

Sublingual route :- In this route of administration the drug is placed under the tongue. And it is taken without the use of water. When it is placed under the tongue it disintegrates there and then absorption occurs in mouth. The tablets are small in size which is to be used through the sublingual route. Example of Sublingual tablet is Nitroglycerine tablets (nitroglycerin is cleared more than 90% during a single pass through the liver)

Buccal Route :- In this route of administration the drug is kept in the buccal cavity where it disintegrates and absorption occurs in the mouth⁴.

Advantages:

• Rapid absorption is due to the abundant mucosal network of systemic veins and lymphatics, thereby leading to a rapid onset of action.
• If there is any untoward event, the tablet can be removed.
• Avoids first-pass hepatic metabolism.
• This route is useful in patients having swallowing difficulties.
• Convenience

Disadvantages:

• The tablet must be kept in the buccal cavity and neither chewed nor swallowed.
• Excessive salivation may cause quick dissolution and absorption of the tablet.
• Patients may find it difficult to accept an unpalatable tablet. Hence some drugs are applied as a patch or a spray⁵.

Rectal Route

This route is useful for patients with gastrointestinal motility problems such as dysphagia or ileus that can interfere with delivering the drug to the intestinal tract. The rectal route is also often utilized in patients near the end of life undergoing hospice care.

Advantages:

• A relatively large amount of the drug can be administered.
• Those drugs destroyed by the acidic medium in the stomach and those metabolized by pancreatic enzymes can be administered effectively.
• Safe and convenient for infants and the elderly.
• It can be used in emergency situations, such as in infants having seizures when the intravenous route is unavailable.
• The rate of absorption is uninfluenced by the ingestion of food or the rate of gastric emptying.
• Bypasses hepatic metabolism
• Less degradation of drugs compared to that in the upper gastrointestinal tract.

Disadvantages:

• Some hydrophilic drugs like antibiotics and peptide drugs are unsuitable for rectal administration as they are not readily absorbed.
• Some drugs can cause rectal irritation and proctitis, leading to ulceration and bleeding.

Parenteral Routes of Medication

Intravenous Route

This directly administers the medications to the systemic circulation. It is indicated when a rapid drug effect is desired, a precise serum drug level is needed, or when drugs are unstable or poorly absorbed in the gastrointestinal tract. It is also the route utilized in patients with altered mental status or severe nausea or vomiting, unable to tolerate oral medications⁵.

Advantages:

• Rapid onset of action
• Predictable way of action and almost complete bioavailability
• The problems of oral drug administration can be eliminated by avoiding the gastrointestinal tract
• The best way of administration in very ill and comatose patients who cannot ingest anything orally

Disadvantages:

• Causes pain
• Chance of infection
• The delivery of protein products that require sustained levels can be difficult.

Intramuscular Route

This can be utilized when oral drug absorption occurs in an erratic or incomplete pattern, the drug has high first-pass metabolism, or the patient is not compliant^. A depot preparation of the drug can be given intramuscularly, and the medication dissolves slowly into the circulation to provide a sustained dose over a more extended time. An example includes haloperidol decanoate. Vaccines are also administered via the intramuscular route⁶.

Disadvantages:

• Injection site pain
• The amount of drug administered has to be adjusted according to the mass of the muscle available.
• Peptides get degraded locally.
• Complications - hematoma, abscess, peripheral nerve injury, puncture of a blood vessel leading to inadvertent intravascular administration.

Subcutaneous Route

In this route of administration the drug is given into the subcutaneous layer with the help of injection. Drug once reaches to the subcutaneous layer crosses the membrane and absorbs into the blood. This is used when the drug's molecular size is too large to be effectively absorbed in the intestinal tract or when better bioavailability or a faster absorption rate is needed than the oral route. It is easy to administer and requires minimal skills, so patients can often self-administer the medication. Common medications administered subcutaneously include insulin, heparin, and monoclonal antibodies. The rate of absorption of drugs through this route can be enhanced by infiltration with the enzyme hyaluronidase. The major factors that affect the rate of absorption by this route include the size of the molecules (large molecules having slow penetration), viscosity, and the anatomical characteristics of the site of injection (vascularity and amount of fatty tissue).

Disadvantages:

• The rate of absorption is difficult to control.
• Local complications - irritation and pain.
• Injection sites must be changed frequently to prevent the build-up of unabsorbed medication, which could lead to tissue injury⁷.

Other Routes of Medication

Intranasal Route

This can be utilized in administering nasal decongestants for cold or allergy treatment. Other uses include desmopressin for the treatment of diabetes insipidus or intranasal calcitonin for the treatment of osteoporosis⁵

Factors that affect the rate of absorption of drugs via the nasal route are:

• The rate of nasal secretion - The rate of secretion is inversely proportional to bioavailability of  drug.
• Ciliary movement - The speed of ciliary movement is inversely proportional to the bioavailability of the drug.
• Vascularity of the nose - The volume of blood flow is directly proportional to the rate of drug absorption.
• Metabolism of drugs in the nasal cavity - The enzymes present in the nasal tissues alter the absorption of some compounds, especially peptides that are disintegrated by aminopeptidases.
• Diseases affecting nasal mucous membrane. Common colds can affect nasal drug absorption.

Enhancement of nasal drug delivery:

Rapid mucociliary clearance can lead to poor bioavailability of the drug. This can be overcome by in situ gelling drug delivery. Chitosan is a natural bioadhesive polysaccharide obtained from crustacean shells that can be used as an absorption enhancer. Chitosan binds to the nasal mucosal membrane and facilitates drug absorption through paracellular transport and other mechanisms.

Advantages:

• Increased permeability of the nasal mucosa compared to the gastrointestinal mucosa.
• Highly vascularized sub epithelial tissue.
• Quick absorption, usually within thirty minutes
• Avoids the first-pass effect.
• Ease of administration.
• Higher bioavailability of the drugs than in the case of the enteral route or inhalational route.

Disadvantages:

• Nasal cavity diseases and conditions may result in impaired absorption.
• The dose is limited due to the small area available for absorption.
• The time available for absorption is limited.
• This route does not apply to all drugs.

Inhalational Route

The structure of the airways, with rich capillary bed of the alveoli, allows air to come in close contact with the blood. This makes drug administration through the airways, in the form of inhalation or aerosol, a useful route. Inhalation therapies have been used successfully for years, providing rapid relief for respiratory illnesses such as asthma and chronic obstructive pulmonary disease (COPD)

Advantages:

• Large surface area
• Proximity to blood flow
• Avoids first-pass hepatic metabolism
• Only smaller doses are enough to achieve equivalent therapeutic effects as the oral route
• There is greater protection against drug degradation by oxygen and moisture, so stability is increased.

Disadvantages:

• The transport of drug to the site of action is not guaranteed.
• There may be drug irritation and toxicity.
•  Drug retention and drug clearance may be a problem.
• Only 10–40% of the drug from a conventional inhalation device is actually deposited in the lungs.
• Targeting specificity is questionable⁸.

Transdermal Route

Transdermal therapeutic systems are defined as a type of dosage form which when applied to the intact skin; deliver the drug through the skin at a controlled rate to the systemic circulation. The drug enters the systemic circulation through a process known as Percutaneous Absorption which involves the passive diffusion of substances across the skin. This permeation of drug can take place through:

1. Passage through epidermis itself (Trans epidermal)
2. Diffusion through widely distributed hair follicles and sweat glands (Trans follicular)^9,10

Advantages

• Provides smooth plasma concentrations of the drug without fluctuations, for a long period.
• Minimizes inter-individual variations as drug is subjected to little first pass metabolism
• Fewer side effects thereby increasing the therapeutic value of many drugs.
• Equivalent therapeutic effect can be elicited with less amount of dose if given as a transdermal patch.
• Drug intake can be stopped at any point by simply removing the transdermal patch.
• Self- administration is possible.
• Patient compliance is better as many patients prefer transdermal patches to oral tablets of same drug¹¹

Disadvantages

• Only lipophilic drugs can effectively cross the stratum corneum and hence the drugs must have some desirable physicochemical properties for penetration. Hydrophilic drugs will not be able to reach the systemic circulation unless modified to some suitable form.
• Doses of only 5mg or less can be administered in a day.
• Large numbers of excipients used may cause rashes, local irritation, erythema or contact dermatitis. E.g.: Scopolamine patches used to treat motion sickness or to prevent nausea and vomiting. However, excessive uptakes through the skin and rubbing of the patch on the eye have resulted in mydriasis
• The patch may be uncomfortable to wear as adhesives may not adhere well to all types of skin.
• High cost of product.

DRUG DELIVERY CARRIERS

Colloidal drug carrier systems such as micellar solutions, vesicle and liquid crystal dispersions, as well as nanoparticle dispersions consisting of small particles of 10–400 nm diameter show great promise as drug delivery systems. When developing these formulations, the goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties.

5. Carrier based Drug Delivery System:
5. Liposomes
5. Dendrimers
5. Nanoparticles
5. Microspheres
5. Niosomes
5. Phytosomes
5. Ethosomes

A) Carrier based Drug Delivery System:

LIPOSOMES

Liposomes are spherical artificial vesicles that can be synthesized from natural harmless phospholipids and cholesterol. Because of their size and unique hydrophobic and hydrophilic properties, liposomes hold great promise as drug delivery vehicles. The manufacturing process, size, surface charge, and lipid composition all have a significant impact on liposome capabilities. Phospholipids have been shown to spontaneously form closed structures upon hydration in aqueous solutions. These vesicles with one or more phospholipid bilayer membranes can carry either lipid or aqueous medications. Lipids' thermodynamic phase qualities and self-assembling traits affect the entropically focused arrangement of their hydro-phobic sections into spherical bilayers because they are amphipathic in watery conditions. Lamellae are the names for those layers. Generally, liposomes are definite as spherical vesicles with particle sizes ranging from 30 nm to several micrometers. They consist of one or more lipid bilayers surrounding aqueous units, where the polar head groups are oriented in the pathway of the interior and exterior aqueous phases. On the other hand, self-aggregation of polar lipids is not limited to conventional bilayer structures which rely on molecular shape, temperature, and environmental and preparation conditions but may self-assemble into various types of colloidal particles¹²

Figure 2: Structure of Liposomes⁶⁴.

Advantages:-

• Provides selective passive targeting to tumor tissues (Liposomal doxorubicin).
• Increased efficacy and therapeutic index.
• Increased stability via encapsulation.
• Reduction in toxicity of the encapsulated agents.
• Site avoidance effect
• Improved pharmacokinetic effects (reduced elimination, increased circulation life times).
• Flexibility to couple with site specific ligands to achieve active targeting¹²

General method of Liposomes preparation.

Reverse phase evaporation technique-

Inverted micelles or water-in-oil emulsions, in which the organic phase is made up of lipids to form liposomal bilayers and the aqueous phase contains the pharmaceuticals of interest, are the basis of the reverse phase evaporation technique. (To obtain lipid films, we add this lipid mixture to a flask and evaporate the solvents. The lipid films are then dissolved once more using an organic phase that is primarily made of isopropyl ether and/or diethyl ether. A two-phase system is created by the addition of the water phase, and a homogenous dispersion is the outcome of the next sonication. As the organic solvent gradually evaporated, the mixture changed into a thick gel that created an aqueous suspension containing liposomes. Higher internal aqueous loading is one advantage of the reverse phase evaporation technique over the thin-film hydration method. While some organic solvent may remain and be able to interact further with the lipids or the drugs, techniques like centrifugation and dialysis can be used to remove the remaining solvent.)¹³.

Figure 3: Flow Chart of Reverse Phase Evaporation⁶⁵.

DENDRIMERS

Dendrimers are symmetrical macromolecules with nanometer-sized, highly branching, monodisperse structures. A central core, branching units, and terminal functional groupings make them up. The environment of the Nano cavities and, subsequently, their solubilizing capabilities are determined by the core together with the internal units, whilst the solubility and chemical behavior of these polymers are determined by the exterior groups. Attaching targeting ligands to the dendrimers' exterior surfaces influences the efficiency of targeting, and functionalizing the dendrimers with polyethylene glycol chains increases their stability and protects them from the Mononuclear Phagocyte System. The characteristics of both the liquid and solid states are combined in liquid crystals. They are capable of taking on various geometries and can incorporate aqueous medicinal solutions in alternative polar and non-polar layers¹⁴.

NANOPARTICLES

Nanoparticles are in the solid form and can be either amorphous or crystalline, with sizes ranging from 10 to 200 nm for Nano spheres and Nano capsules. They have the capacity to adsorb and/or encapsulate a medication, shielding it from enzymatic and chemical deterioration. Given their uses in the controlled release of drugs, the ability to target specific organs or tissues, the ability to carry DNA in gene therapy, and the ability to deliver proteins, peptides, and genes orally, biodegradable polymeric nanoparticles have received a lot of attention recently as potential drug delivery devices¹⁵.

Method of Preparation

The preparation techniques for nanoparticles can be broadly divided into two groups i.e, dispersion of preformed polymers and polymerization of monomers. Among the techniques for dispersing preformed polymers are:

1. Solvent evaporation method
2. Spontaneous emulsification method
3. Salting out/emulsion diffusion method
4. Non aqueous phase separation method

Solvent evaporation method

Using an organic solvent like chloroform, acetone, or ethyl acetate, preformed polymers like polylactic acid or poly (d,l-lactic co-glycolic acid) are dissolved. In order to create an oil-in-water emulsion, the payload medication is typically dissolved in the polymer solution and then transferred to an aqueous phase containing a surfactant, such as polyvinyl alcohol. If the homogenization process is carried out for a long enough duration, it can help the organic solvent evaporate. Ultracentrifugation is used to gather the nanoparticles at the conclusion of the homogenization process. To obtain the required particle size, process variables can be changed, including the ratio of polymer to organic solvent, the kind of organic solvent, and the speed and duration of homogenization¹⁶

Figure 4: Flow Chart of Solvent Evaporation Method⁶⁶

NIOSOMES

A unique vesicular drug delivery technology called niosomes makes it possible to distribute medications in a focused, regulated, and long-lasting way. Liposomes were the first vesicular drug delivery technology, but they have a lot of disadvantages, such as toxicity, cheap cost, and pH stability issues. The disadvantages of liposomes have raised interest in niosome research. It is feasible to form unilamellar, oligolamellar, and multilamellar niosomes. The reason niosomes are non-toxic is that they are made of non-ionic surfactants, which is how they got their name. In addition to non-ionic surfactants, they might also comprise charged molecules and cholesterol or its derivatives. The charged molecule in the cholesterol, which gives the structure stiffness, keeps the preparation stable. Niosomes are created when non-ionic surface-active substances self-assemble. They can be used to load and deliver both hydrophilic and hydrophobic drugs due to their structure¹⁷

Method of preparation

To prepare niosomes, a lipid mixture and surfactant are hydrated at high temperatures. Niosome size reduction is then optionally performed to produce a colloidal suspension. Niosome preparation can be done using a number of well-researched conventional techniques. Examples include sonication, hand shaking, ether injection, and micro fluidization technique. Then, by centrifugation, gel filtration, or dialysis, the unentrapped drug is separated from the entrapped drug

Reverse-phase evaporation method

In addition to ether and chloroform, the reverse-phase evaporation method employs a combination that includes cholesterol and surfactant in a 1:1 ratio. The target drug-containing aqueous phase is added to the mixture, and it is then sonicated at a temperature of 4-5°C. A tiny quantity of phosphate-buffered saline is added to the mixture, and then the sonication process is resumed. Phosphate-buffered saline is used to dilute the residual suspension after the organic solvent is extracted at 40°C while operating at low pressure. The final product, niosomes, is formed by heating the mixture at 60°C for 10 minutes¹⁸.

MICROSPHERES

Another name for the microspheres is micro-particles. They are made to improve a drug's therapeutic efficacy and address some of the issues with traditional therapy. To achieve the intended effect, the drug must deliver the maximum therapeutic effect and the least amount of side effects to the target tissue at the right time. The prolonged release of the anticancer drugs and their ability to target the tumor with the microspheres attracted a lot of attention. The spherical micro particles known as microspheres are utilized in applications where a consistent and predictable particle surface area is crucial. The medication is contained in the center of the microspheres, where it is protected by a special polymeric membrane¹⁹.

Method of  Preparation

Wax coating and hot melt

Wax used to encapsulate the main components, by dissolving or dispersing the product in melted wax. The waxy paste or mixture, such as frozen liquid paraffin, is released by high intensity blending with cold water. The water is heated up for at least an hour. The substance is stirred up for at least 1 hour. Then the external layer (liquid paraffin) is decanted and the microspheres are immersed in a non-miscible solvent and dry air is required to dry. For the surface ingredients, carnauba wax and beeswax can be used and both should be combined to obtain desirable characteristics.

Spray drying technique

This was used to prepare polymer microsphere mixed charged with drug. This requires dispersing the raw substance into liquefied coating liquid, and then spraying the mixture into the air for surface solidification accompanied by rapid solvent evaporation. Organic solvent and polymer solution are formulated and sprayed in various weight ratios and drug in specific laboratory conditions producing microspheres filled with medications. This is fast but may lose crystalinity due to rapid drying.

Coacervation

This method is a straight forward separation of macromolecular fluid into two immiscible types of material, a thick coacervate layer, comparatively condensed in macromolecules, and a distilled layer of equilibria. This method is referred to as basic coacervation, in the presence of just one macromolecule. If two or more opposite-charge macromolecules are involved, they are considered complex coacervation. The former is caused by specific factors including temperature shift,Using non-solvent or micro-ions contributing to dehydration in macromolecules, since they facilitate interactions between polymer and polymer through polymer solvent interactions. This can be engineered to generate different properties on microsphere

Freeze Drying

Freeze-drying is effectively used in protein API microspheres praparation. The method is freezing, sublimation, main drying, and secondary drying. At the freezing step, account is taken of the eutectic point of the components. During the process, lyoprotectants or cryoprotectants will stabilise API molecules by removing water, creating a glass matrix, lowering intermolecular interaction by forming hydrogen bonds between the molecules or dipole - dipole interactions. It's a beneficial cycle for heat tolerant molecules, given its high expense. Freeze-drying produces solidification and then enables the reconstitution of particles in an aqueous media.

Ionic gelation method

Ionotropic gelation is depend on the tendency of polyelectrolytes to cross connect to develop hydrogel beads often called gelispheres in the existence of counter ions. Gelispheres are Circular cross linked polymeric hydrophilic agent capable of substantial gelation and thickening in model biological fluids and drug release regulated by polymer relaxation via it. The hydrogel beads are formed by dumping a drug-laden polymeric solution into the polyvalent cations aqueous solution. The cations migrate through the drug-laden hydrophilic compounds, creating a three-dimensional lattice the moiety is ionically crosslinked. Biomolecules may also be placed into these gelispheres to maintain their three-dimensional form under moderate conditions.

Emulsion Solvent Evaporation Technique

This method involves dissolving the medication in a polymer that has already been dissolved in chloroform, and then adding the resultant solution to an aqueous phase that contains 0.2 percent sodium PVP as an emulsifying agent. After 500 rpm of agitation, the drug and polymer (eudragit) were separated into fine droplets, which were then collected by filtration, cleaned with demineralized water, and dried at room temperature for a full day. The solidified microspheres were formed by solvent evaporation²⁰.

PHYTOSOMES

Phytosomes means herbal drug loaded in vesicles, which is available in the Nano form. The phytosome provide an envelope, like coating around the active constituent of drug and due to this the chief constituent of herbal extract remains safe from degradation by digestive secretion and bacteria. Phytosome is effectively able to absorb from a water loving environment into lipid loving environment of the cell membrane and finally reaching to blood circulation. The current review highlights the future scope and emerging technologies in the field of NDDS for the benefit of herbal and traditional medicines prepared from plant origins^. The term “Phyto” means plant and “some” means cell like. It is also mentioned as herbosomes. This is a new patented technology, where standardized plant extracts or water soluble phytoconstituents are complexed with phospholipids to produce lipid compatible molecular complexes, there by greatly increasing absorption and bioavailability. Phospholipids are complex molecules which are used in the formation of cell membranes Phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol are the phospholipids used, but phosphatidylcholine obtained from soya bean are widely used because of their certain therapeutic value in case of liver diseases, alcoholic steatosis, drug induced liver damage and hepatitis. Phospholipids are also employed as natural digestive aids and as carriers for both fat miscible and water miscible nutrients. Phytosomes can easily traverse the lipophilic path of the enterohepatic cell membranes and also stratum corneum layer of the skin^21.

Figure 5: Structure of phytosomes⁶⁷.

ADVANTAGES OF PHYTOSOMES:

1. Phytosomes have better stability due to formation of chemical bonds between phytoconstituents and the phosphatidylcholine molecules.
2. Phytosomes produces a little cell where the active components of herbal extracts are protected from destruction by gut and digestive secretions.
3. Small dose can produce desired results, as the absorption of active component is improved.
4. Formulation of phytosomes is easy and it shows better drug entrapment efficiency.
5. Phytosomes increases the solubility of bile to herbal constituents.
6. Duration of action of phytosomes is increased.
7. Phosphatidylcholine is not only a carrier, also having hepatoprotective activity and nutritional value.
8. Cosmetic and other topical use of herbal constituents can be done by phytosome  formulations

PREPRATION OF PHYTOSOMES:-

Solvent evaporation method

The solvent evaporation methods involves integration of the phytoconstituents and PC during a flask containing organic solvent. This reaction mixture is kept at an optimum temperature usually 40°C for specific interval of 1 hr to achieve maximum drug entrapment within the phytosomes formed. Thin film phytosomes are seprated by 100 mesh sieves and stored in desiccators for overnight²².

Mechanical Dispersion method

In the experiments, the lipids dissolved in organic solvent are brought be in contact with aqueous phase containing the drug (Sikarwar MS et al., 2008). the next removal of the organic solvent under reduced pressure results in the formation of phyto-phospholipid complex. Recently methods for the phospholipid involute preparation includes super critical fluids (SCF), which include gas anti-solvent technique (GAS) compressed anti-solvent process (PCA), supercritical anti-solvent method (SAS)²³.

Lyophilization method

The lyophilization technique DSN was plenarily dissolved in DMSO. The resulting DSN solution (2.5% weight/volume) was added to the answer of SPC dissolved in t-butylalcohal (1.5% weight/volume) followed by stirring for 3 hours on a magnetic stirrer until complex formation. The complex was then isolated by lyophilization. After abstracting the samples from the freeze drier, the resultant DSN:SPC involute (yield 90.4%, weight/weight) was placed during a desiccator over P2O5 at 4°C until testing. For the culled developing technique the influence of variable formulation factors was assessed including SPC type (Lipoid® S100, Lipoid® S75 and Lipoid® S PC-3), drug phospholipid ratio (1:1, 1:2, and 1:4) and co-solvent type of chemical (methanol, ethanol, chloroform, acetone, and TBA). Non-conventional methods are customarily employed in construction of phytosome complexes. Modernistic herbal complexes are composed by reaction between equilar amalgamation of natural or synthetic phospholipid and active constituents or herbal extract in acrostic organic solvents

Figure 6: General method of phytosomes preparation⁶⁸

ETHOSOMES

Ethosomes were developed by Touitou et al.,1997, as additional novel lipid carriers composed of ethanol, phospholipids, and water. They are reported to improve the skin delivery of various drugs^. Ethanol is an efficient permeation enhancer that is believed to act by affecting the intercellular region of the stratum corneum. Ethosomes are soft malleable vesicles composed mainly of phospholipids, ethanol (relatively high concentration), and water. These soft vesicles represent novel vesicles carriers for enhanced delivery through the skin. The size of the ethosomes vesicles can be modulated from tens of nanometers to microns. Ethosomes are non-invasive delivery carriers that enable drugs to reach the deep skin layers and / or the systemic circulation. The high concentration of ethanol makes the ethosomes unique, as ethanol is known for its disturbance of skin lipid bilayer organization. Therefore, when integrated into a vesicles membrane; it gives the vesicle the ability to penetrate the stratum corneum. Also, because of their high ethanol concentration, the lipid membrane is packed less tightly than the conventional vesicles, although it has equivalent stability, allowing a more malleable structure and improves the drug distribution ability in the stratum corneum lipids²⁴.

Methods of Preparation of Ethosomes ^25,26,27

1. Hot method

The drug is dissolved in a mixture of ethanol and propyleneglycol and the mixture is added to the phospholipid dispersion in water at 40°C. After mixing for five minutes the preparation is sonicated at 4°C for three cycles of five minutes, with a rest of five minutes between each cycle, using the Probe Sonicator. The formulation is then homogenized at 15,000 psi pressure, in three cycles, using a high-pressure homogenizer to get nano-sized ethosomes

2. Cold method

This is one of the most widely used techniques for preparation of ethosomes, which consists of two basic and simple setups. In the first setup, phospholipid and other lipid material is dissolved in ethanol at room temperature by vigorous stirring with the use of mixer such as Heidolph mixer with continuous addition of polyols such as propylene glycol etc. with constant stirring followed by heating at 30 °C in water bath. In the second setup, water is to be heated at 30 °C in a separate vessel, both mixtures (obtained from first and second setup) are to be blended together following 5 min stirring in a covered vessel. The vesicle size of ethosomal formulation can be decreased to desire extend using sonication or extrusion method. Finally, the formulation is stored under refrigeration

Mechanism of Action

The stratum corneum and pilosebaceous pathways are involved in a number of related processes that occur when the ethosomal system is applied to the skin. These processes involve the disruption of the stratum corneum lipid bilayer's organization by ethanol, followed by an increase in the lipid bilayer's fluidity. Due to their particle nature, stretchable ethosomes vesicles can even mimic a passage through the skin by penetrating disrupted stratum corneum bilayers. The fusion of ethosomes with skin lipids and drug release at different locations along the penetration pathway may also result in the release of the medication into the deep layers of the skin and its transdermal absorption. Skin lipids, ethanol, and vesicles work together to support ethosome function. Ethamomes increase the dispersion of active substances over liposomes because they interact better with skin lipids. The transition temperature of the lipids in the stratum corneum is lowered when ethanol interacts with the lipid molecules in the polar head group region. They reduce the density of the lipid multilayer and increase fluidity, which allows the medicine to be absorbed into theskin's deeper layers. Moreover, ethanol gives vesicles a smoother, more flexible texture, which promotes deeper penetration into the epidermal layer²⁸.

Figure 7: Projected model presenting mechanism of action of ethosomes for skin delivery⁶⁹.

AQUASOMES

Aquasomes are  nanoparticulate  carrier  system  but  instead  of being  simple  nanoparticle these are three layered self-assembled structures, comprised of a solid phase nanocrystalline core coated  with  oligomeric  film  on  which  biochemically  active  molecules  are  adsorbed  with  or without modification Aquasomes are like “bodies of water" and their water like properties protect  and  preserve  fragile biological  molecules, and this  property  of  maintaining  conformational  integrity  as  well as high degree  of  surface exposure  is exploited in targeting  of bio-active  molecules  like  peptide  and  protein  hormones,  enzymes, antigens and genes to specific sites. These three-layered structures are  self-assembled  by  non-covalent  and  ionic  bonds.  These carbohydrates  stabilize  nanoparticles  of  ceramic  are  known  as “aquasomes”. The pharmacologically active molecule incorporated by  co-polymerization,  diffusion  or  adsorption  to  carbohydrate surface  of  pre  formed  nanoparticles.  Aquasomes  discovery comprises  a  principle  from  microbiology,  food  chemistry, biophysics and many discoveries including solid phase synthesis, supramolecular  chemistry,  molecular  shape  change  and  self assembly²⁹.

METHOD OF PREPARATION OF AQUASOMES

By using the principle of self assembly, the aquasomes are prepared in three steps i.e., preparation of core, coating of core, and immobilization of drug molecule.

Preparation of the core:

The first step of aquasome preparation is the fabrication of the ceramic core. The process of ceramic core preparation depends on the selection of the materials for core. These ceramic cores can be fabricated by colloidal precipitation and sonication, inverted magnetron sputtering, plasma condensation and other processes. The precipitated cores are centrifuged and then washed with enough distilled water to remove sodium chloride formed during the action. The precipitates are resuspended in distilled water and passed through a fine membrane, filter to collect the particles of desired size. Two ceramic cores that are most often used are diamond and calcium phosphate.

Carbohydrate coatings:

The second step involves coating carbohydrate on the surface of ceramic cores. There are number of processes to enable the carbohydrate (polyhydroxy oligomers) coating to adsorb epitaxially on to the surface of the nano-crystalline ceramic cores. The processes generally entail the addition of polyhydroxy oligomer to a dispersion of meticulously cleaned ceramics in ultra pure water, sonication and then lyophilization to promote the largely irreversible adsorption of carbohydrates on to the surfaces. Excess and readily desorbing carbohydrate is removed by by stir cell ultra-filtration17. The commonly used coating materials are cellobiose, citrate, pyridoxal-5-phosphate, sucrose and trehalose.

Immobilization of drugs: The surface modified nano-crystalline cores provide the solid phase for the subsequent non-denaturing self assembly for broad range of biochemically active molecules. The drug can be loaded by partial adsorption^30,31.

Figure 8: Preparation of Aquasomes⁷⁰

Table 1: Comparative evaluation of Phytosome, Liposomes, Niosomes, and Ethosomes⁷¹

MICROENCAPSULATION

Through the process of microencapsulation, thin wall material coatings are formed around solids, liquids, or even gases, enclosing them in microscopic particles. A variety of microencapsulated materials, including medications, were developed as a result of the breakthrough invention of replication paper and ribbons in the 1950s that contained dyes in microscopic gelatine capsules that were released upon hit by a typewriter key or the pressure of a pen or pencil. And the technique is also known as "microencapsulation “which involves coating or encircling minuscule liquid or solid droplets with a continuous polymeric layer. Bioencapsulation, which is more limited to enclosing a biologically active material (such as DNA or a complete cell or group of cells) in order to increase its performance and/or prolong its shelf life, is a subset of microencapsulation. Through microencapsulation, liquids may be turned into solids, surface and colloidal properties can be changed, the environment can be protected, and the release characteristics or availability of coated materials can be managed³². Three processes are typically involved in coacervation-phase separation microencapsulation, which is done under continuous agitation: (a) production of three immiscible chemical phases; (b) coating deposition; and (c) coating rigidization. There are two types of coacervation-phase separation: simple coacervation and complicated coacervation. The former suggests incorporating a very hydrophilic material into a colloid solution. Two phases are created as a result of this additional material. The process of complicated corrosion is primarily pH dependent. Microcapsules are created by manipulating the system's basic or acidic composition. Depending on how basic or acidic the system is, it may form microcapsules over a particular threshold pH value. They won't develop at pH values lower than that. Complex coacervation typically addresses the system containing more than one colloid³³.

Figure 10: Microencapsulation⁶⁶.

MICROSPONGES

Microsponges are patented polymeric delivery systems consisting of porous microspheres that can entrap a wide range of active ingredients such as emollients, fragrances, essential oils, sunscreens, and anti-infective, anti-fungal, and anti-inflammatory agents Like a true sponge, each microsphere consists of a myriad of interconnecting voids within a non-collapsible structure, with a large porous surface. The size of the microsponges can be varied, usually from 5 – 300 μm in diameter, depending upon the degree of smoothness or after-feel required for the end formula. Although the microsponge size may vary, a typical 25 μm sphere can have up to 250000 pores and an internal pore structure equivalent to 10 ft in length, providing a total pore volume of about 1 ml/g. This results in a large reservoir within each microsponge, which can be loaded with up to its own weight of active agent. The microsponge particles themselves are too large to be absorbed into the skin and this adds a measure of safety to these microsponge materials. Another safety concern is the potential bacterial contamination of the materials entrapped in the microsponge. As the size of the pore diameter is smaller, the bacteria ranging from 0.007 to 0.2 μm cannot penetrate into the tunnel structure of the microsponges^34,35.

Characteristics of microsponges ^36,37

1. Microsponge formulations are stable over range of pH 1 to 11 and temperature upto 130⁰C.
2. Compatible with most vehicles and ingredients.
3. Self- sterilizing as their average pore size is about 0.25μm where the bacteria cannot penetrate the pores. 
4. Formulations have high entrapment upto 50 to 60%.
5. Microsponge formulations are free flowing and can be cost effective. 
6. Microsponge particles themselves are too large so they are difficult to be absorbed into the skin and this adds a measure of safety to these microsponge materials by avoiding the side effects of the microsponge adjutants.
7. Microsponges can absorb oil up to 6 times its weight without drying.
8. It provides continuous action up to 12 hours i.e. extended release.
9. They have superior formulation flexibility.

METHODS OF PREPARATION

Quasi-emulsion solvent diffusion method

Quasi-emulsion solvent diffusion method is a two-step process and increases the sensitivity of the drug release. This method uses different amounts of polymer. This consists of two phases i.e., internal phase and external phase.The internal phase consists of polymer such as Eudragit RS-100 (low permeability). This polymer is cationic and non-biodegradable and entrapment efficiency was found to increase with increased amount of Eudragit RS-100. The external phase consists of polyvinyl alcohol (PVA) with distilled waterInternal phase containing Eudragit RS-100 is dissolved in a solvent like ethyl alcohol at 35 °C under ultrasonication so that the internal phase is dispersed in the external phase containing PVA solution in water. The solution is stirred and 1 hour andis filtered to obtain the solid microsponges. This solid microsponge is dried in an oven at 35 °C- 40 °C for 12 hours before use^38,39.

Figure 11: Quasi-emulsion solvent diffusion method⁷².

Hypothetical mechanism of action

The active ingredient is added to the vehicle in an entrapped form. As the microsponge particles have an open structure (i.e., they do not have a continuous membrane surrounding them), the active  ingredient is free to move in and out from the particles and into the vehicle until equilibrium is reached, when the vehicle becomes saturated. Once the finished product is applied to the skin, the active ingredient that is already in the vehicle will be absorbed into the skin, depleting the vehicle, which will become unsaturated, therefore, disturbing the equilibrium. This will start a flow of the active from the microsponge particle into the vehicle, and from it to the skin, until the vehicle is either dried or absorbed. Even after that the microsponge particles retained on the surface of the stratum corneum will continue to gradually release the active to the skin, providing prolonged release over time. If the active is too soluble in the desired vehicle during compounding of the finished products, the products will not provide the desired benefits of gradual release³⁹.

B.) Other Approaches of Novel drug delivery

SONOPHORESIS

It is a method that uses ultrasonic radiation to dramatically accelerate the absorption of topical chemicals (transdermal administration) into the skin's dermis, epidermis, and appendages. One quick, easy, non-invasive, targeted way to transfer macromolecules and low molecular weight medications to the skin are using sonophoresis.Sonophoresis is thought to improve medication delivery mechanistically by altering skin tissue through a mix of chemical, mechanical, and thermal changes. Sonophoresis has been achieved using ultrasound at different frequencies between 20 kHz and 16 MHz, with intensities up to 3 W/cm. Percutaneous absorption is known to be impacted by ultrasound parameters, with frequency, intensity, and length of treatment being the most significant. Sonophoresis happens when ultrasonic waves raise the total kinetic energy of the molecules that make up topical medicines and induce micro-vibrations beneath the skin's epidermis. Drug distribution is likely improved by ultrasound by cavitation, microstreaming, and heating.^40,41,42.

Figure 9: Mechanism of sonophoresis⁷³