A Review on Chitosan Nanoparticle as a Drug delivery system

 

Gupta Durgesh Kumari1, Goswami Raksha2, Kumawat Deepak3, Gupta Anjana3,

Chandy Steffy Mary3

1AKS University, Satna (M. P.)

2Oriental College of Pharmacy and Research, Indore (M. P.)

3Acropolis Institute of Pharmaceutical Education and Research, Indore

*Corresponding Author E-mail: durgeshgupta7477@gmail.com, rakshag23@gmail.com

 

ABSTRACT:

Chitosanis a characteristic polysaccharide arranged by the N-deacetylation of chitin. Chitosan arebiologically safe, biocompatible biodegradable, non-toxic polysaccharide. Chitosan nanoparticles carry more study in drug delivery system because it shows better stability, low toxicity, simple and mild preparation method and they include the various route of administration like oral, nasal, IV and ocular. Chitosan contain the various functional groups that can be adjust to achieve a specific goals and making it a polymer with a huge range of inherent applications. Nanoparticle are prepared with the chitosan and chitosan derivatives and they hold a positive surface charge and mucoadhesive properties such as that can adhere to mucus membranes and the drug released payload in a sustained release manner. Chitosan has itself many medicinal properties like antimicrobial, antioxidant, and low immunogenicity etc. Chitosan-based nanoparticle have attracted increasing attention for their wide application in non-parenteral drug delivery for the treatment of cancer, gastrointestinal diseases, pulmonary diseases, drug delivery to the brain and ocular infections. Chitosan have low toxicity both in vitro and some in vivo models. In evaluation of nanoparticles various parameters are used such as Drug Content / Drug entrapment, Particle Size, Zeta Potential, Surface Morphology, In-vitro release Study, Kinetic Study, and Stability of nanoparticles. InThis review explores recent research on chitosan based nanoparticle for drug delivery, chitosan properties, and modification, toxicity, preparation, evaluation and application studies.

 

KEYWORDS: Chitosan, Drug delivery, pulmonary diseases, Drug entrapment, Zeta potential.

 

 


INTRODUCTION:

Drug delivery system:

Drug delivery system is a term that a suggest to method and organization of a pharmacologically movement of compound with the end goal of giving accomplished medication plasma fixation, and in addition conveying the medication to the particular site of occupation.

 

Various methodologies have been used to squash some medication responsibility issues in the gastrointestinal tract, control the medication exude, improve the Trans mucosal retention, and incorporation get the medication into its area of activity. Despite the fact that nanoparticles offer numerous focal points as medication transporter frameworks, there are stillnumerous impediments to be understood, for example, poor oral bioavailability, precariousness available for use, insufficient tissue conveyance, and toxicity. For instance, their little size and extensive surface territory can prompt to molecule accumulation, making physical treatment of nanoparticles troublesome in fluid and dry structure [1].

 

Nanoparticle:

Nanoparticles are defined as the solid particle and particulate dispersion drug carrier which is a simply means dwarf. The term nanoparticle is a combined form of both that may or may not be biodegradable. The drug is encapsulated and entrapped, attached or dissolve to a nanoparticle matrix. The ‘Nano’ Word is derived from Greek term nanosphares and Nano capsules[2]. Drug is compressed to a cavity enclosed by a individual polymer membrane called Nano capsules, while Nano spheres are matrix systems in which the drug is physically and undeviating dispersed. The term nanoparticle is a combined form of both nanosphares and Nano capsules. Whereconventional techniques reaches their limits, nanotechnology provides opportunities for the various medical applications[3].

 

The Nanoparticles are contain liposomes, polymericNano sphere, hydrogel, Nano emulsions, polymer micelles, hydrogels, and solid nanoparticles etc. it is generally used as a potential drug carriers for alternative of conventional dosage forms. Because they shows the unique advantages which involve the capacity to protect the drugs from the degradation, reduce the toxicity and ability of the drugs and target the drugs to the site of operation. Various type of Polymeric nanoparticles that are used for the preparation of nanoparticles it can be either natural or synthetic polymers. A various number of natural polymers such as starch, carrageenan, cellulose, gellan gum, heparin, dextran, gelatin, alginate, chitosan have been intently investigated. Synthetic polymers include polyethylene glycol, poly anhydride, polylactic, poly vinyl alcohol etc. [4].

 

Recently, silver and gold nanoparticles have gathered significant interest due to their remarkable applications in development of novel antibacterial agents. But previously some toxic effects and instability were also reported in silver nanoparticles. This toxicity was due to the association of silver nanoparticles that resulted in the impairment of mitochondrial function because of their penetration and accumulation in the mitochondrial membrane. As compare to silver nanoparticle, gold nanoparticles are more stable, inert, non-toxic and size controllable. It has also been reported that the antibacterial activity of gold nanoparticles doesnot trigger reactive oxygen species (ROS) generation, which can prevent harmful side-effects in mammalian host cells [5,6].

 

A natural and synthetic polymer shows various advantage and disadvantage. Apart from the liposomal and polymeric nanoparticles iron and gold nanoparticles are also developed and it have been appeal to the enlargement of new generation of anti-cancer drug delivery systems. Several gold nanoparticle used in anticancer drug delivery systems have been reported and it shows a good in-vitro result.

 

Advantage and Disadvantage of synthetic and natural polymer:

 

Natural polymer

Synthetic polymer

Advantage

·     Biodegradable

·     Biocompatible

·     Easily availability

·   High degree of variability present in natural materials derived from animal sources.

·   Structurally more complex

·   Extraction process very complicated

·   High cost

Disadvantage

·     Biocompatible

·     Non degradable

·   Synthetic process is very complicated.

·   High cost

·   Toxic

 

The advantages of using Chitosan Nanoparticles as a drug delivery system include the following:

1.     The Nanoparticles are tiny molecule which act as a stable molecule with respect to its transport and maintain its properties.

2.     Drug delivery of our need can be achieved by modifying particle size of the nanoparticle.

3.     Nanoparticles control the release of the drug during the transportation and at desired site.

4.     Site-specific targeting can be reach by join specific ligands to surface of particles or wield of magnetic guidance.

5.     The nanoparticle can be used for various routes of administration involvenasal, oral, parenteral, intra-ocular etc[7].

6.     Nanoparticles can deeply enter into the small areas of in the body.

7.     7.Nanoparticlelow toxicity, better stability and biodegradability and it can be easily administered by oral, nasal, parental and other routes[8].

 

CHITOSAN:

Chitosan nanoparticle are biodegradable, biocompatible, cationic and relatively non-toxic in nature. So they are widely used in drug delivery system. Chitosan is a natural polysaccharide made by the N-deacetylated of chitin [5]. It was firstly discovered by Rouget in 1859 and formally named by Hoppe-Seyler in 1894.Chitosan is a reorganize natural carbohydrate polymer made by the partial N-deacetylated of chitin, a natural biopolymer derived from crustacean shells such as crabs, shrimps, and lobster.[9] Chitosan shows many advantages in spread nanoparticles including, biodegradability, biocompatibility and low immunogenicity. The high positive charge density also confers its mucoadhesive properties and makes it an ideal candidate for the delivery of drugs to mucosal tissues. Chitosan also show a very low toxicity in this manner it has drawn expanding consideration for pharmaceutical and biomedical applications. Chitosan nanoparticles had also been employed as a gene carrier to enhance gene transfer efficiency in cells.[4] Chitosan is a deacetylation type of chitin which is a polysaccharide found in exoskeleton of shellfish, for example, lobster, shrimp or crabs and cell mass of parasites etc. The isolation of polymer includes arrangement of the specimens from gathered unrefined skeleton took after by deproteinization with 4M Caustic soda and smashed into pieces. The ground exoskeleton is then demineralised utilizing 1% HCl and took after by deacetylation with half Caustic soda to get chitosan and at last extricated by dissolving chitosan in acidic corrosive and re-precipitated with pH change. Economically accessible CS has a normal atomic weight going somewhere around 3800 and 20,000 daltons and is 66 to 95% deacetylated. Chitosan has a partition coefficient of roughly 6.5 on the amine bunches. It is insoluble at impartial pH, yet at acidic pH it is solvent as the amino gathering of chitosan gets protonated and turn out to be decidedly charged. The dissolve ability of chitosan in unbiased and fundamental pH can be expanded by quaternization. The physicochemical and organic properties of chitosan are enormously impacted by its atomic weight and level of deacetylated. The level of deace0tylation is influenced by the quantity of proton table amine gatherings and it decides the polymer properties including solvency, hydrophobicity, and the capacity to collaborate electrostatically with polyanions. The sub-atomic weight has likewise key significance. For the most part chitosan having lower sub-atomic weights and lower degrees of deacetylated displays more noteworthy dissolvability and speedier debasement than their high sub-atomic weight partners. Nitty gritty attributes of chitosan for biomedical applications are very much portrayed in a far reaching review. Because of the nearness of receptive useful gathering Chitosan has been transform in different structures like thiolated, carboxyalkyl, bile corrosive adjusted, quaternized (N, N, Ntrimethyl chitosan; TMC), sugar-bearing and cyclodextrinlinked chitosan. For instance, thiolation of chitosan remarkable enhances its mucoadhesive properties in light of the development of disulfide bonds with cysteine-rich sub spaces of body fluid glycoprotein.

 

Source of chitosan:

As a natural polysaccharide, chitosan is manufactured on a large scale by alkaline N-deacetylation of chitin in commercial production. Chitin is an abundant biopolymer isolated from the exoskeleton of crustaceans, such as crabs and shrimps. Deacetylation of chitin and protonation of chitosan. The proportion of the two repeating units (glucosamine and N-acetylglucosamine units) determines the degree of De acetylation of the polymer[7].

 

Specifications and characteristics of pharmaceutical-grade chitosan:

The pharmaceutical chitosan includes[10].

S. No.

Characteristics

Properties

1.

Color

White or yellow appearance (powder or flake)

2.

Odour

No taste

3.

Smell

No smell

4.

particle size

< 30 m

5.

Density

Between 1.35 and 1.40 g/cm3

6.

pH

6.5 to 7.5

7.

Moisture content

< 10%

8.

Protein content

<0.3%

9.

Insoluble matter

<1%, heavy metals (As) <10 ppm, heavy metals (Pb) <10 ppm

 

Properties of chitosan in a drug delivery system:

·       Anionic drug delivery properties

·       Mucoadhesive properties

·       Permeation enhancing properties

·       Bio adhesive

 

Anionic drug delivery properties:

When a process of drug release cannot be achieved by using a simple drug dissolution method such as diffusion, membrane layer along with hand grip erosion as well as osmotic, retardation mediated by ionic correlation is often used. The latter approach can be carried out with regard to cationic drugs by using anionic polymeric ingredient such as poly acrylates, alginate, or carboxyl methyl cellulose etc. However, in the anionic drug delivery systems, chitosan is the singular selection. Chitosan was used as a medication contributor matrix to identify medication release contrivance for the anionic medication naproxen. It was found that the interconnection between chitosan and the therapeutic agent was more perceptible, and steady complexes can also be formed from which this medicine can be construct, actually traverse a more extended period counted on an ionic cross-linking. For example, the delivery systems of enoxaparin/chitosan Nano particle provided a more stable complexes and result in significantly improved drug uptake. Some anionic polymeric excipients are such as carrageenan, pectin, and polyacrylates can be homogenized with chitosan, major to high-density, relatively stable complexes. However, a similar result can be attain by homogenizing chitosan with an alternative to multivalent anionic and inorganic polymer anions such as sulfate or tri poly phosphate[8].

 

Mucoadhesive properties:

The chitosan are perhaps accountable to its cationic character. Additionally, hydrophobic interactions may support with the mucoadhesive components. The mucoadhesive properties of chitosan are weak as collate with various anionic polymeric excipients such as hyaluronic acid, and carbomer. In order to attain substantial mucoadhesive attributes, a polymerconsider have a high cohesive properties because adhesive bond normally fails within the mucoadhesive polymer as incompatible to involving the polymer along with the mucous gel layer. Regarding chitosan’s, these cohesive properties swing to be comparatively weak. It may be upgrade by the formation of complexes with multivalent anionic drug treatments, multivalent anionic polymeric ingredients, and also multivalent inorganic anions. This strategy is productive to a very limited extent, as the cationic raft foundation of chitosan being responsible for mucoadhesion over ionic interactions while using the mucous are blocked in such cases. Demonstrated a significantly enhance oral bioavailability involving buserelin. However, this certain effect could not be acquire anymore when chitosan was mixed with polyanionic carbomer in the same formulation. More cationic temper of the polymer is provided by the tri methylation of the primary amino group of chitosan[8].

 

Permeation enhancing properties:

Based on the positive impose of chitosan, it was found that these impose are accountable for the mechanism of permeation enhancer, which can interchange with the cell membrane of chitosan, resulting in a structural establishment of tight junction-associated proteins[9]. A primary amino group that conduct to a more pronounced cationic character using the trimethylation plan did not conduct to further development of permeation enhancing properties[10]. It was demonstrated that the permeation improvement properties and toxicity to a large expanse were applicable to the structural properties of chitosan counting the degree of DE acetylation and molecular mass[11]. Chitosan with high molecular mass and high degree of deacetylation display a comparatively higher increase in epithelial penetrable, which able be due to molecular mass and other permeation enhancing polymers such as polyacrylates[12]

 

Bio adhesiveness:

The amino and carboxyl groups in the chitosan molecule can be incorporate with glycoprotein in mucus to form a hydrogen bond, essential to an adhesive effect. As mucoprotein in mucus is positively charged, chitosan and mucus are entrance to each other to prolong the retention time of drugs and continual drug release in vivo as well as improve drug bioavailability.

 

preparation of chitosan nanoparticles:

Nanoparticle are defined as the colloidal structure with a structures with a varying size range of 1–1000 nm. Chitosan nanoparticles can be prepared by various methods are used to preparation of chitosan nanoparticles. Some of them are as a follows:

 

Fig 1: Types of Methods of preparation of chitosan nanoparticles

 

Fig 2: Schematic representation of preparation chitosan nanoparticle

 

1.     Ionic gelation method:

It is used for mostly of chitosan nanoparticles[3]. In this method suitable concentration of chitosan is dissolved in glacial acetic acid. Sodium tri polyphosphate is mostly used for cross-linking agent. Both of these phases are dissolved in separate glass bottles and mixed under stirring until it’s leads to formation of chitosan nanoparticles due to inter and intra molecular interaction between chitosan polymer and sodium tripolyphosphate. Anticancer drug can be filled in these chitosan nanoparticles during the mixing between chitosan and sodium tri polyphosphate the size of nanoparticles can be assorted by changing degree of deacetylation of chitosan [13].

 

2.     Coacervation / Preparation:

This method used for the physicochemical characteristics of chitosan since it is insoluble in alkaline pH medium, but precipitates/coacervate when it comes in connection with alkaline solution. Particles are produced by bluster chitosan solution into an alkali solution like sodium hydroxide, methanol or ethanediamine using a crimp air nozzle to form coacervate droplets. Separation and purification of particles was done by filtration/centrifugation followed by sequential washing with hot and cold water. Varying squeeze air pressure or spray-nozzle diameter controlled the size of the particles and then using a cross linking agent to harden particles can command the drug release In the another technique, sodium sulphate solution was added in drop wise to an aqueous acidic sol. of chitosan carrying a surfactant under stirring and ultra-sonication for 30 min. Nano spheres purified by centrifugation and re-suspended in demineralized water. Particles are cross-linked with glutaraldehyde. Particles produced by this method show better acid stability and then observed by other methods [14].

 

3.     Micro emulsion method:

Chitosan nanoparticle prepared by this method It was first developed this technique is based on formation of chitosan nanoparticle in theaqueous core of reverse micelle droplets and subsequently cross-linked through glutaraldehyde. In this method, a surfactant was dissolved in N-hexane. Then, chitosan in acetic solution and glutaraldehyde were added to surfactant or hexane solution under continuous stirring at room temperature. Nanoparticles were prepared in the presence of surfactant. The system was agitated overnight to complete the cross-linking process, which the free amine group of chitosan conjugates with glutaraldehyde. The organic solvent is then removed by the evaporation of under low pressure. Theyields calculated were the cross-linked chitosan nanoparticleand excess surfactant. The excess amount of the surfactant was removed by precipitate with CaCl2 and the remaining precipitant was removed by the centrifugation method. The final nanoparticleswas separate before lyophilization method. This technique offers narrow distribution of particle sizeless than 100 nm and the particle size can be regulated by differ the amount of glutaraldehyde that modify the degree of cross-linking. However, it shows the some disadvantages[14].

 

Disadvantages: some disadvantages exist such as

·       Time consuming process

·       Use of the organic solvent

·       Complexity in the washing step

4.     Emulsion Droplet Coalescence Method:

This method employ the concept of emulsion crosslinking and the precipitation. In the first step, a stable emulsion contain aqueous solution of chitosan polymer along with the drug is produced in liquid paraffin oil. In the second step, another stable emulsion contain aqueous solution of chitosan in sodium hydroxide is prepared. Then both emulsions should be mixed in under high speed stirring, whereby the droplets of each colloidal emulsion at random and coalesce, thereby the precipitation of chitosan droplets a give small-sized particles[16].

 

5.     Solvent evaporation:

In this technique, a polymeric drug solution in a volatile solvent such as acetone is prepared and emulsified into the non-aqueousphase such as liquid paraffin. The mixture are kept under the stirring until absolute evaporation of the solvent and the formed microspheres are filtered, and this microsphere washed with a suitable solvent like petroleum ether, and finally dried. Drying is usually done by air or under vacuum pressure. Metformin-loaded chitosan microspheres were successfully obtained by using this method. generally, the entrapment efficiency and particle size of the prepared chitosan microspheres particulate systems are affected by various processing and formulation parameters such as concentration of chitosan microspheres, molecular weight of chitosanmicrospheres, type of the chitosan microspheres derivative, nature of the drug, initial drug concentration which is used, ratio of drug–polymer, nature of the cross-linking agent, type of the surfactant and also the concentration of the surfactant, and stirring speed. Optimizing all these parameters using suitable optimization technique. Which is helpful for achieving the desired particles[17].

 

6.     Polyelectrolyte complex (PEC):

Polyelectrolyte complex is also known as self-assemble polyelectrolyte. It is a term used to relate complexes formed by self-assembly of the cationic charged polymer and DNA plasmid. Mechanism of Polyelectrolyte complex formation involves charge neutralization between cationic polymer and the DNA leading to a fall in hydrophobicity as the polyelectrolyte element self-assembly. Various cationic polymers such as gelatin, polyethylenimine etc. it also possess this properties. In general, this method offers simple and easy preparation method without any harsh conditions involved. The chitosan nanoparticles extempore formed after addition of DNA solution into chitosan are dissolved in acetic acid solution, under the mechanical stirring at or under room temperature[15]. The particle size can be varied from 50nm to 700nm[18].


 

Various type of chitosan nanoaparticle preparation and their Application[13]

S. No.

Drug

Method of preparation

Polymer used

Applications

References

1

Amphotericin B

Dialysis method

Polylactic acid-grafted chitosan polymer

Used in Ocular treatment

[14]

2

5-Fluorouracil

Emulsion droplet coalescence method

Chitosan andeudragit S100 polymer

Used in Colon cancer

[15]

3

Gemcitabine

Inotropic gelation method

Chitosan polymer

Used in Hematologicalmalignancies

[16]

4

Doxorubicin

Inotropic gelationmethod

Thiolated chitosan polymer

Used in Breast cancer

[17]

5

Silver

Inotropic gelationmethod

Chitosan polymer

Used in Lung cancer

[18]

6

Didanosine

Inotropic gelationmethod

Chitosan polymer

Used in Brain cancer

[19]

7

Curcumin

Inotropic gelationmethod

Chitosan and pluronic 127polymer

Used in Skin cancer

[20]

8

Oxaliplatin

14

Solvent evaporation method

Chitosan andeudragit S100 polymer

Used in Colorectal cancer

[21]

 


Functions of chitosan nanoparticles:

Chitosan Nano formulations are generally used in cancer treatment up till now, multi-functional chitosan Nanoparticle are showing ability in personalized therapy. The nanoparticles may show improved anti-tumor efficacy and specific targeting ability due to modification of chitosan Nano carriers or the encapsulation of multiple therapeutic agents.

1.     Enhancing Anti-Tumor Efficacy

2.     Prolonging Blood Circulation Time

3.     Reversal of Multi-Drug Resistance

4.     Crossing Blood-Brain Barrier

5.     Diagnosis, Detection and Imaging

 

1.     Enhancing Anti-Tumor Efficacy:

In clinical treatment, many anticancer drugs with traditional formulation are being deplore due to certain disadvantages like poor water solubility, in vivo short circulation time, poor targeting and high side effects[22]. Nano medicine shows a great potential in resolving these problems. Nanoparticles have examine to be an efficient carriers because they can stay unremarkable during the blood circulation, and it increases the therapeutic efficacy and reduce the adverse effect of the nanoparticle. As one of drug carriers, chitosan nanoparticle may show enhanced antitumor activity in treatment of cancer. It shows many unique characteristics. Water soluble chitosan nanoparticle are improve water solubility of hydrophobic drugs[23,24]. The biodegradability of chitosan nanoparticle may ensure that encapsulated drugs are released in a controlled manner. The small-sized chitosan nanoparticle can easily pass through the biological barriers.

 

2.     Prolonging Blood Circulation Time:

During the development of productive drug delivery nanoparticles, one major barrier is the rapid clearance from the blood. The capability of drug-loaded nanoparticle are directly circulate in to the blood stream for a long duration of the action and it often the prerequisite for the successfully targeted delivery. They should be evade by phagocytic uptake by reducing the opsonization by the blood proteins, hence it increase the bioavailability of the drugs. In vivo fate of the nanoparticle is mainly dependent on the physical and chemical properties of nanoparticle, it include the size, surface charges and also the surface chemistry. In order to overcome these problems some shielding groups are involve like poly ethylene glycol, poly vinyl alcohol. And poly saccharides are absorbed by the grafted on the surface of nanoparticle because these groups and polymer can hinder the hydrophobic and electrostatic interaction it help the plasma protein binding to particle surface[25.26].

 

3.     Reversal of Multi-Drug Resistance:

It is a major barrier for the limiting therapeutic effects of chemotherapeutic agents in anti-cancer. When a patient suffers from Multi-drug resistance, efficiency of the therapy reduced and leads to the failure of the treatment. In Multi-drug resistance pathway P-glycoprotein-mediated resistance is the mostly studied. In the study it has been confirmed that nanoparticles are able to reverse the drug resistance by avoiding recognition of P-glycoprotein efflux pump. It is endogenous cell entering the cell which help full for the enveloping. Its leads to high intra cellular drugs concentration[27,28].

 

4.     Crossing Blood-Brain Barrier:

The biological interface b/w the blood brain barriers which is responsible for transporting the nutrients and protects the brains. In the brain tissues by the help of blood-brain barrier an efficient organization of tight junctions between endothelial cells were constituted.The blood brain barrier can prevent entry of harmful substances (chemotherapeutic agents) into the brain interstitium and protect the cells of nervous system When chemotherapeutic agents are used due to the existence of blood brain barrier a negative impact on therapeutic effects of brain tumor was found. Therefore, as a second option various nanoparticles are being used for overcoming the problem. In various nanoparticles especially cationic nanoparticles showed prominent efficacy in entering blood brain barrier because of its cationic charge[29,30].

 

 

5.     Diagnosis, Detection and Imaging:

For diagnosis of cancer various tumor-targeting nanoparticles have been designed with the process of Nano medicine and molecular imaging. For getting the biological information of pathological lesions functional NPs are used because they are chemically interact with biomarkers to alter the signals for imaging. Due to which they are used to achieve early diagnosis and improved the therapy in the treatment of various diseased in future [31].

 

Biomedical application of chitosan nanoparticles:

 

CONCLUSION:

In this review we are exploring that chitosan based nanoparticle for drug delivery. The chitosan nanoparticle is novel approach for drug delivery which can be achieve the better therapeutic action, better bioavailability, reduce toxicity. Today nanoparticle are successfully used in the treatment in brain targeting, in cancer therapy etc. nanoparticle gives us an opportunity to enhance the patient compliance for better therapy.

 

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Received on 07.05.2020            Revised on 01.06.2020

Accepted on 20.06.2020   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2020; 10(4):299-306.

DOI: 10.5958/2231-5691.2020.00051.9