The technique of delivering a pharmaceutical substance to produce a therapeutic effect in either humans or animals is known as drug delivery. The most popular non-invasive administration techniques include topical (skin), transmucosal (nasal, buccal, sublingual, vaginal, ophthalmic, and rectal), inhalation, and peroral (via the mouth).

NDDS: The term "novel drug delivery system" (NDDS) describes methods, compositions, apparatus, and systems for delivering a medicinal substance throughout the body as required to safely produce the intended therapeutic effects. It usually involves addressing the quantity and duration of drug presence, and it may entail scientific site-targeting within the body or systemic pharmacokinetics facilitation.

Needs of NDDS:

• Targeted Delivery:

NDDS aims to deliver medications precisely to the targeted site of action in order to reduce side effects and improve therapeutic efficacy. This is important because localized delivery can lessen damage to healthy tissues in the treatment of disorders like cancer.

• Controlled Release:

By lowering the frequency of administration and increasing patient compliance, NDDS can offer controlled or sustained release of pharmaceuticals. This is advantageous for short-half-life medications as well as chronic illness management.

• Enhanced Bioavailability:

Because of problems like instability or poor solubility, several medications have low bioavailability. By improving these medications' solubility and stability, NDDS can make sure that a larger percentage of them enters the bloodstream and is effective.

• Minimized Toxicity:

NDDS might lessen the possibility of toxicity and unfavorable consequences related to systemic medication administration by focusing on particular cells or tissues. This is especially crucial for medications with limited therapeutic windows.

• Non-invasive Administration:

By offering oral, transdermal, or inhalation methods as alternatives to injections, NDDS can help patients get drugs more conveniently and with less discomfort.

• Personalized medicine:

To maximize therapeutic efficacy and safety, advanced NDDS can be customized to each patient's needs, taking into account genetic, metabolic, and other unique characteristics.

• Overcoming Biological Barriers:

NDDS can assist medications in getting past biological barriers, such as the blood-brain barrier, which presents a special difficulty for medications targeting the central nervous system.

• Cost-effectiveness:

NDDS can potentially reduce overall healthcare expenditures by lowering the need for subsequent treatments and hospitalizations by improving pharmacological efficacy and reducing adverse effects.

• Flexibility and Adaptability:

 NDDS should be able to accommodate various medication regimens and medical conditions, enabling a range of treatment options.

• Enhanced Patient Compliance:

Patients' adherence to recommended treatments can be improved by systems that make medication regimens simpler or easier to administer.

II. HISTORICAL BACKGROUND;

Novel Drug Delivery Systems is what NDDS stands for. Compared to conventional drug administration techniques, these systems offer a sophisticated means of administering medication that increases efficacy, safety, and patient compliance. This is a chronological synopsis of NDDS's creation and progression.

Initial Thoughts and Basis

Traditional Methods:

Early medication delivery methods have been around since antiquity. For example, herbal treatments were used topically as ointments, infusions, and powders.

19th century:

The development of tablets and capsules laid the groundwork for contemporary drug delivery. Comparing these approaches to earlier types, a more standardized dosage was offered.

Developments of the 20th Century

1960s–1970s:

A major advancement was the introduction of controlled-release formulations. Scientists started working on methods to gradually deliver medications at a regulated pace. Enteric-coated formulations and extended-release tablets were introduced during this period.

1980s:

Targeted medication administration became popular. The goal of research was to precisely target the site of action of medications to reduce side effects and enhance therapeutic results. During this time, lipid-based vesicles containing pharmaceuticals were developed as liposomal drug delivery methods.

1990s:

The development of nanotechnology and polymers resulted in the development of sophisticated drug delivery methods, including carriers based on nanoparticles and biodegradable polymeric systems. These developments made it possible to target and release drugs with increased accuracy.                                

The Advances of the 21st Century:

In the 2000s: Smart medication delivery systems- which react to changes in the body or outside stimuli saw significant breakthroughs. Examples include drug delivery systems that release medication in reaction to changes in the environment and insulin pumps that modify insulin delivery based on blood glucose levels.

2010s–Present:

The integration of nanotechnology, gene therapy, and personalized medicine has further revolutionized NDDS. Nanoparticles are utilized to deliver medications with high precision, whereas tailored techniques adjust drug delivery depending on individual genetic profiles. Additionally, breakthroughs in biotechnology have permitted the development of systems that can transport biologics and big molecules effectively.

Advantage of NDDS:

• Enhance the bioavailability of drug substances.
• Enhance the solubility of drug.
• Enhancement of pharmacological activity.
• Improve stability of drug.
• Protect physical and chemical degradation of drug.
• Avoid GIT irritation and other complicated side effect of drugs.
• Provide sustain release for longer time periods.

Disadvantage of NDDS:

• Repeated dose is necessary.
• Inactivation by gastric juice of some drug carrier.
• High expensive for production.
• Short half-life.
• Sometime oxidised or hydrolysed.

III. DRUG CARRIER IN NDDS:

Materials or systems known as drug carriers in NDDS are intended to deliver a medication to its intended site of action, release it under regulated conditions, and maximize therapeutic impact while reducing side effects. Different materials, including proteins, polymers, lipids, and even inorganic compounds, can make up these carriers. Enhancing drug solubility, stability, bioavailability, and controlled release are the goals.

       
           
       
   Figure 1: Drug Carrier for NDDS

1. Liposome:

Liposomes are small, spherical vesicles composed of phospholipids and a substance resembling cell membranes. The process of emulsifying synthetic or natural lipids in an aqueous solution yields liposomes, which can range in diameter from 50 to 500 nanometers. The hydrophobic and hydrophilic qualities, as well as their size and biocompatibility, make liposomes an excellent choice for targeted drug delivery systems. They can transport both hydrophilic and hydrophobic molecules, and they can enclose an area of aqueous solution inside a hydrophobic membrane.  Via methods like sonication, biological membranes can be broken to prepare liposomes. Phosphatidylcholine-enriched phospholipids make up the majority of liposomes, but they can also include mixed lipid chains with surfactant characteristics like phosphatidylethanolamine or egg.

       
           
       
    Figure 2: Structure of Liposome

Liposomes range in size from tiny vesicles (0.025 µm) to huge ones (2.5 µm). Furthermore, the membranes of liposomes might be single or bilayer. The amount of medicine encapsulated in the liposomes is influenced by the size and number of bilayers, and vesicle size is an important determinant in determining the circulation half-life of liposomes.

Advantage of Liposome:

• Selective passive targeting to tumor tissues (Liposomal doxorubicin)
• Enhanced efficacy and therapeutic index.
• Enhanced stability through encapsulation.
• Decreased toxicity of the encapsulated agents.
• Site avoidance effect.
• Improved pharmacokinetic effects (minimized elimination, longer circulation life times).
• Flexibility to couple with site specific ligands to achieve active targeting.

Disadvantage of Liposomes:

• Half-life is short.
• Minimal solubility.
• Drug/molecule encapsulation leakage and fusing.
• The expense of production is substantial.
• Decreased stable numbers.
• Phospholipids can occasionally experience reactions akin to hydrolysis and oxidation.
• Application of Liposomes:
• Drugs are delivered to specific areas via liposomes. For instance, liposomes have been utilized to treat a variety of illnesses, including fungal infections and cancer.
• In vaccinations, liposomes function as antigen transporters and adjuvants. For instance, hepatitis and influenza vaccinations have been developed using liposomes.
• Liposomes are employed in analytical biochemistry and medical diagnostics as signal enhancers and carriers.
• In cosmetics, liposomes are employed as penetration enhancers.
• In scientific fields like chemistry, theoretical physics, biology, and mathematics, liposomes are employed as instruments, reagents, and models.

2. Nanoparticles:

The basic elements of nanotechnology are nanoparticles. Nanoparticles are made of metal, metal oxides, organic materials, and carbon and range in size from 1 to 100 nm. Nanoparticles vary in size, shape, and dimension depending on the material they are made of. A surface may be uniform or uneven, with surface differences. Certain nanoparticles consist of single or many crystal solids that are either loose or aggregated, while some are crystalline or amorphous.When developing new medications, the majority of drug candidates are either poorly or completely soluble in water, which is extremely detrimental to the pharmaceutical industry. The complex and massive molecular structure of a medicine is one of the key causes of its insolubility. More than 65 percent of newly developed active pharmaceutical ingredients (APIs) are either insoluble or only weakly soluble in water, according to reports. They fall under class II of the Biopharmaceutics Classification System (BCS), where the dissolving step is the rate-limiting element in drug absorption, because of their low water solubility and high permeability. The pharmaceutical industries are currently confronted with the difficulty of improving the dissolving property of medications that are not very water soluble, which is essential to increasing the bioavailability of drugs.

       
           
       
     Figure 3: Structure of Nanoparticle

Organic nanoparticles:

These include ferritin, liposomes, dendrimers, micelles, and other widely recognized polymers. These nanoparticles are biodegradable and non-toxic. Certain particles, including liposomes and micelles, have hollow cores that are also referred to as nano capsules, and they are sensitive to electromagnetic and thermal radiation, including light and heat. Because they are effective and may be injected into particular bodily areas, a process known as targeted medication delivery, organic nanoparticles are most frequently utilized in the biomedical industry. One such application is in drug delivery systems.

Inorganic Nanoparticle:

Non-carbon-based particles are known as inorganic nanoparticles. Inorganic nanoparticles are typically defined as those based on metal and/or metal oxide.

Carbon-based Nanoparticle:

Fullerenes and carbon nanotubes (CNTs) are the two primary constituents of carbon-based nanoparticles. All that carbon nanotubes (CNTs) are is rolled graphene sheets. Because these materials are 100 times stronger than steel, they are mostly employed for structural reinforcement. Single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) are the two types of carbon nanotubes. Because they are non-conductive across the tube and thermally conductive along their length, carbon nanotubes are special in this regard. Allotropes of carbon with a hollow cage structure made up of sixty or more carbon atoms are called fullerenes.

Advantage of Nanoparticles:

• Nanoparticles frequently have special qualities like greater strength, conductivity, or catalytic activity.
• Nanoparticles can be engineered to carry medications straight to particular cells or tissues in the body, minimizing adverse effects and enhancing the effectiveness of treatment.
• Materials with improved qualities, like those that are conductive, lightweight, and strong, can be made using nanoparticles.
• Water filtration, pollution removal, and energy storage are all possible with nanoparticles.
• By using nanoparticles, electronic equipment can be made faster, smaller, and more effective.

Disadvantage of Nanoparticles:

• Certain nanoparticles, based on their size, shape, and composition, may be hazardous to the environment and human health.
• Nanoparticles have the ability to injure wildlife and interfere with natural processes when they get into the environment and build up in ecosystems.
• Nanoparticles' special qualities and possible hazards have made it difficult for regulators to ensure their safe usage.
• Concerns regarding fair distribution of risks and rewards as well as possible unforeseen effects are raised by the creation and application of nanoparticles.

3. Microspheres:

Microspheres are tiny spherical particles that are used in many different industries, but especially in the pharmaceutical and medical domains. A therapy strategy for malignant tumors called chemoembolization is one encouraging use for microspheres. Through the use of microspheres, which distribute cytostatic medications straight into the tumor site to inhibit its growth, this treatment entails locally blocking blood flow.  Microspheres can be referred as small spherical particles, with diameters in the micrometer range (typically 1 µm to 1000 µm). Microspheres can also be called as microparticles. Microspheres had been explored significantly for their use in the subject of drug transport and various polymers had been utilized for the formulation of the microspheres, which in turn have been assessed for distinctive purposes. Eventually the whole dose and few adverse reactions can be decreased due to the fact that a steady plasma concentration is maintained.

Microspheres with bioadhesion:

Adhesion is the process by which a medication sticks to a membrane using the water-soluble property of water-soluble polymers. Bioadhesion is the word used to describe the adhesion or sticking of a drug delivery system to a mucosal membrane, such as the buccal, nasal, ophthalmic, or rectal membranes. Longer residence times at the target site and improved therapeutic activity are provided by this kind of microsphere.

Magnetic spheres:

The medicine is localized to the intended place using this kind of delivery mechanism. This kind of delivery system involves injecting a medication or therapeutic radioisotope that is attached to a magnetic component into the systemic circulation. A strong magnetic field is then used to stop the circulation at the disease or target site.

Molecular particles known as magnetic microspheres are so small that they can pass through capillaries without obstructing the esophagus (less than 4 ?m). However, because they are ferromagnetic, they are very susceptible to being caught in micro-vessels and pulled through adjacent tissues by a magnetic field. Here, a smaller quantity of a medicine that is magnetically targeted can substitute a larger quantity of a drug that is freely circulating.

Floating Microsphere:

Because the bulk density of the floating type is lower than that of the gastric fluid, it floats in the stomach without slowing down the rate of gastric emptying. The system is discovered to be floating on gastric contents, decreasing gastric residency, and increasing fluctuations in plasma concentration as the drug is released gradually and at the desired rate. Additionally, it lessens the possibility of dosage dumping. As a result of its extended effects, dose frequencies are decreased.

Radioactive microspheres:

When they are encountered, radio embolization therapy microspheres, which range in size from 10 to 30 nm, are larger than the capillary bed's diameter. Radiation-active microspheres are injected into the arteries that lead to the tumor of interest, thereby treating all of these problems while delivering a high dosage of radiation to the targeted locations without endangering the healthy tissues nearby. In this instance, radioactivity works within a radioisotope at a normal distance rather than being expelled from the microsphere. There are three distinct kinds of radioactive microspheres: those that emit ?, ?, and ? radiation.

Advantage:

• A smaller microsphere increases the surface area, which boosts the efficacy of the poorly soluble substance.
• It is possible to lower dosage frequency and side effects.
• A rise in patient adherence.
• Polymer-packed drugs shield the medication from enzymatic cleavage, allowing the medication to be shielded from different enzymes.
• Promotes better bioavailability.
• Reduced gastric irritation is possible.
• The biological half-life is improvable.
• It is possible to lower first pass metabolism.
• The drug's unpleasant taste and odor can be concealed.

Disadvantage:

• There is less reproducibility.
• When compared to traditional preparations, the cost of ingredients and processing is substantial.
• The stability of core particles may be impacted by changes in process factors such as temperature, pH, solvent addition, and agitation/evaporation.
• What happens to the additives and polymer matrix?

4. Hydrogel:

Hydrogels are soft, wet materials that have attracted a lot of attention because of their versatility and potential applications in biomedical engineering. Because they can be tailored to achieve specific mechanical and chemical properties and retain a lot of water, they can be used for a variety of purposes, such as drug delivery and tissue engineering. Polymeric networks known as hydrogels have the ability to absorb and retain large amounts of water. The polymeric network contains hydrophilic groups that hydrate in watery conditions to produce hydrogel structures.1. It can also be defined as a polymeric substance that, although not dissolving in water, has the potential to swell and hold a sizable portion of water within its structure. Because of their high-water content, they have a degree of flexibility that is extremely close to that of natural tissue. Hydrophilic functional groups connected to the polymeric backbone provide hydrogels their capacity to absorb water, whereas crosslinks between network chains give them resistance to disintegration.

Classification based on source:

1. Natural hydrogels:

These hydrogels have good cell adhesion properties, are biodegradable, and are biocompatible. Two major types of natural polymers are used to produce natural hydrogels: proteins like collagen, gelatin, and lysozyme, and polysaccharides like hyaluronic acid, alginate, and chitosan.

2. Synthetic hydrogels:

These hydrogels are more useful than natural hydrogels because they can be engineered to have a much wider range of mechanical and chemical properties than their natural counterparts. One class of these materials is polyethylene glycol-based hydrogels, which are used extensively in biomedical applications due to their non-toxicity, biocompatibility, and low immunogenicity.

3. Hybrid hydrogels:

These hydrogels are a combination of natural and synthetic polymer hydrogels. To combine the advantages of both synthetic and natural hydrogels many naturally occurring biopolymers such as dextran, collagen, Chitosan, have been combined with synthetic polymers such as poly (N-isopropylacrylamide) and polyvinyl alcohol.

Advantage of Hydrogel:

• Hydrogel has greater strength and elasticity.
• Hydrogel is easily modifiable and has good transparency qualities.
• They are quite flexible, much like genuine tissue, because of their high water content.
• They can be injected and are both biocompatible and biodegradable.
• Hydrogels can detect changes in pH, temperature, or metabolite concentration and release their load in response to such changes.
• Timely release of nutrients or medications.

Disadvantage of Hydrogel:

• Expensive.
• Non-adherent; it might require a second dressing to keep it in place. The movement of the maggot might also make it feel uncomfortable.
• Difficult to clean.
• In hypoxia, dehydration, and red eye reactions in contact lens less deposition.

5. Micelles:

Surfactant molecules aggregate to form spherical structures known as micelles in water settings. These structures can dissolve both hydrophilic and hydrophobic substances because they have a hydrophilic shell surrounding a hydrophobic core. The amphiphilic character of surfactants, which have both hydrophilic and hydrophobic qualities, promotes the creation of micelles.When it comes to stability, polymeric micelles outperform surfactant micelles.It has the ability to solubilize a significant amount of hydrophobic molecules in their center. Their hydrophilic shell and large size allow them to have prolonged circulation periods in vivo and the ability to concentrate in tumor tissues.

Micelle Types:

Depending on which surfactants are employed, several kinds of micelles can form. For example, polymeric micelles—which are usually made of block copolymers—have drawn a lot of interest due to their durability and capacity to encapsulate medicinal substances. Furthermore, new formulations to improve drug delivery systems have been researched, including worm-like and reverse worm-like micelles.

Advantage:

• Small particle size.
• High stability structure for drug.
• High drug loading
• Low toxicity

Disadvantage:

• Lack of suitable method for large scale production.
• Long processing time.
• High time consuming for preparation.

6. Nano-capsule:

Nano capsules are vesicular systems where the medication is contained within a cavity with a polymeric membrane enclosing an inner liquid core. The study of tiny particles is known as nanotechnology. A nano capsule is a spherical, hollow nanoparticle with a diameter of less than 200 nm that can contain any desired material. They may be filled with a non-polar or polar solvent. As opposed to other nanoparticles, which lack a clearly defined core and shell, nanocapsules have these features. One term for hollow polymer nanostructures, which are composed of polymers, is nanocapsules. Three materials microencapsulation technologies have been available for a number of years, with the main uses being the reduction of hygroscopic and chemical interactions, the removal of oxidation, and the regulated release of nutraceuticals. Two different types of polymers can be employed in the creation of nanocapsules:

1. Natural polymer:

A range of pharmaceutical products are successfully formulated using natural polymers, including proteins, enzymes, muscle fibers, polysaccharides, and gummy exudates. The well-known natural polymers that are employed in medicine and other sectors include shellac, guar gum, gum karaya, chitosan5, carrageenan6, ispaghula7, acacia8, agar9, and gelatin 10.11 These natural polymers are frequently utilized in the pharmaceutical sector as adhesives, adjuvants, and emulsifiers in packaging. They are also ideally suited for the creation of pharmaceutical and cosmetic products. Seaweeds are treated with alkali to produce alginic acid 6, a naturally occurring polymer made up of beta-1, 4-linked D-Mannuronic acid and alpha-1, 4-linked Lguluronic acid molecules. When added prior to compression, it functions as a superb extra-granular disintegrant.

2. Synthetic Polymer:

Human-made polymers are known as synthetic polymers. They can be separated into four primary groups based on their utility: thermoplastics, thermosets, elastomers, and synthetic fibers. They are frequently present in a wide range of consumer goods, including cash and super glue. There is a large range of synthetic polymers with different main and side chains. The lumbar vertebrae of typical man-made polymers like polythene, Carbon-carbon bonds make up polystyrene and poly acrylates, whereas hetero chain polymers like polysulfides, polyamides, polyesters, and polyurethanes. Other components found in polycarbonates include oxygen, sulfur, nitrogen) injected posteriorly.

       
           
       
    Figure 7: Structure of Nano capsule

• Extended release, improving medication efficacy and selectivity
• Among their main benefits are decreased medication toxicity and enhanced drug absorption.
• Submicron-sized nanocapsules are injected intravenously, where they reach the target and release the medication therein.
• Submicron-sized nanocapsules are administered intravenously to release the encapsulated medication at the target.

Disadvantage:

• An expensive formula with a large yield Achieving productivity is more difficult.
• Therefore, industrial use, technology.Making the switch to commercial production is really challenging.
• Challenging Reduced capacity for dosage modification Extremely sophisticated technology.
• To manufacture, you will require specific abilities.
• A key worry is the dose form's stability.due of its tiny size Recycling is very expensive.

7. Polymeric Conjugates:

In nanoparticle-based drug delivery systems (NDDS), Polymeric conjugates are essential because they provide a flexible and efficient method for targeted drug administration. These pharmaceutical compounds are bonded to a polymer chemically. The polymers serve as carriers, increasing the drug's solubility, stability, and bioavailability. Polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), and poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) are examples of commonly used polymers. Targeting ligands, such as peptides or antibodies, can be used to modify the surface of polymeric nanoparticles by binding selectively to receptors that are overexpressed on the target cells, such as cancer cells. By doing this, the medication can be administered precisely where it is needed, reducing side effects. Drugs can be conjugated to polymers to create regulated release patterns that can be triggered by changes in temperature or pH or by the polymer's backbone breaking down.

Types of polymer conjugates:

Polymer conjugates are a crucial component of contemporary drug delivery systems because they provide a number of approaches to improve the specificity and efficacy of medicinal medicines. They can be categorized according to the kind of polymer, the drug release mechanism, or the intended use. The primary kinds of polymer conjugates that are frequently employed in drug delivery systems (NDDS) and nanomedicine are as follows:

Drug Conjugates Polymeric:

Drugs are joined to a linear polymer backbone via covalent bonds to form linear polymer-drug conjugates. The medication may be released via enzymatic breakdown or hydrolysis. Examples that are frequently given are PEGylated medications, which improve solubility and circulation time by utilizing polyethylene glycol (PEG).

Branched Polymer-Medicine Combinations:

These can transport several medicinal molecules due to their dendritic or branched polymer nature. Examples include star-shaped polymers, dendrimers, and hyperbranched polymers. They provide regulated release with a high drug-loading capacity.

Protein-Polymer Conjugates:

 Polymers can be conjugated to proteins (such as enzymes or antibodies) to enhance their stability, prolong their half-lives, and lessen their immunogenicity. This group includes PEGylated proteins, such as PEGylated interferons, which are used to treat hepatitis.