Human health is threatened by many serious diseases which are difficult to treat with systemically delivered drugs. Examples are autoimmune, neurodegenerative, metabolic and cancer diseases. Traditional pharmacotherapy involves the use of
drugs whose absorption and bioavailability are affected by many factors, such as solubility, pKa, molecular weight and chemical stability. These factors may hinder the achievement of the desired therapeutic response. Generally, the nature of traditional therapy, especially their low molecular weight, gives them the ability to cross through various body compartments and access many cell types and sub-cellular organelles. Because of that, these drugs are appropriate for treatment of diseases. However, this random distribution results in many side effects and the need for high doses of the drug to achieve the desired pharmacological response [1].

In addition, protein binding, lipophilicity, ionizability and rapid renal clearance as a result of the low molecular weight of these drugs require frequent administration and a higher dose to achieve a therapeutic response. These disadvantages initiate the need to conduct more studies to develop new formulations that ensure a greater pharmacological response with lower doses, side effects and improved bioavailability. The bioavailability of a drug is affected by several factors such as the physical and chemical properties of this drug, the dose, the frequency of dosing and the route of administration. Therefore, drug delivery systems were developed to improve the pharmacological activity of drugs by improving the pharmacokinetics and pharmacodynamics properties [1].

Active pharmaceutical ingredients are rarely administered alone, where other substances which are known as excipients or additives are added to the dosage forms. These excipients are applied in order to improve the acceptance of the drug by the patients and the bioavailability. The pharmaceutical excipients used in dosage form formulations may include one or more of the following; emulsifiers, dyes, lubricants, diluents and stabilizers. Also, binders, disintegrants, colorant and flavoring agents can be added to enhance the physiochemical properties of the active ingredients in the formulations, during storage periods or following administration. Excipients, initially, were considered inert substances as they do not exert any therapeutic action nor they modify the biological effect of a drug. However, recently many studies have reported that some of these excipients may affect the speed and extent of drug absorption, hence modify its bioavailability. In this regard, many studies are being conducted to improve drug release and absorption [1].

Drug delivery system is defined as a formulation or a device that delivers a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time and place of drug release in the body. Drug delivery system is an interface between the patient and the drug. Therefore the production of new drug delivery systems can offer more advantages to those mentioned above and may, also, improve the release of poorly soluble drugs. Drugs in these systems can be administered directly to the organ affected by a disease or given systemically and, inconsequence, targeting the diseased organ. Additionally, these systems can offer protection of the active ingredients from defense mechanisms such as enzymes and mucus. Furthermore, they may enhance patient compliance and adherence because of their simple administration and less dosing frequency. Therefore, drug delivery systems are beneficial to improve the pharmaceutical profile, enhance stability of drugs, ensure the correct concentration to be delivered and achieve effective biocompatibility. In addition drug delivery systems can significantly decrease undesirable side effects, stabilize the drug in vivo and in vitro, ensure that the drug is accumulated at the appropriate site of action and increase the contact time as long as possible. Dr.hedaya

Polymers are substances with high molecular weight also are known as macromolecules. Polymers are composed of many repeated monomer units, they owe their unique properties to their size, shape and their asymmetry. Hence that polymers in which all their monomeric units are identical are called homopolymers whereas, those formed from more than one monomeric type are called copolymers. On the other hand, the highly branched polymers are known as the dendrimers. Polymers, recently, became increasingly important in pharmaceutical applications especially as drug delivery systems. Polymers, generally, are used in pharmaceutical formulations as binders in tablets, viscosity and flow controlling agents in liquids, suspensions and emulsions. Moreover, they can also be used as film coatings to hide unpleasant taste of a drug, enhance drug stability and modify the release. Examples of polymers that have been tested as potential drug delivery systems include nano- and micro-particles, nano- and micro-spheres, capsosomes, micelles and dendrimers, in which the drug can be encapsulated or conjugated. Hence, transporting the drugs to their appropriate site of action is the main function of polymeric carriers. Dr.yaquob
Drugs, in polymeric carriers, are protected from interacting with other substances that could cause a change in the chemical structure of the active ingredient leading to decrease or loss of the therapeutic action. Moreover, polymeric carriers prevents the interaction between the drug and macromolecules such as proteins, which could enrapt the active ingredient and prevent its arrival to the site of action. It is important to design a type of polymeric structure with specific characteristics that will allow obtaining the desired release conditions. Therefore, the polymeric structure can be 1.biodegradable, which means the chemical bonds that build up its chemical structure break or 2.disassemblable, that means the pieces making the polymer separate but the chemical bonds do not break or 3.undisassemblable, here the chemical bonds do not separate or break, that is, the polymer will remain unchanged or 4. Smart polymers are also available and are beneficial. These types of polymers release drugs when they are induced by a specific stimuli that causes a change in their structure, thus the drug is released at the desired time and place. In the first two situations, micro-sized polymeric carriers can be used. However, if the polymeric structure of the polymer remains unchanged, then nano-sized polymers must be used, thus can be eliminated by the kidneys [1].

It is important to recognize the pathway by which these polymers are removed from the body. The excretion can be directly by kidneys (renal clearance) or biodegraded (metabolic clearance) into smaller molecules, which are then excreted. Excretion through the renal glomerular membrane is limited to molecules with a molecular weight below 50 KDa; however, this value can vary depending on the chemical structure of the molecule. Molecular weight is important to considered for substances that are not biodegradable. On the other hand, macromolecules with a molecular weight lower than the glomerular limit can be removed from the body easily, thus preventing their accumulation and potential toxicity [2].

Another aspect to be considered in case of biodegradable polymers design is the chemical structure of these polymers including the degree of their hydrophobicity, covalent bonds between monomers. This is because the speed and degradation condition, hence the rate and site of drug release, can be manipulated by modulating the chemical structure of the polymer. In case of non-biodegradable polymer, the drug can be covalently bind to the polymeric structure and this attachment can be degraded under some conditions such as in an acidic medium or by different enzymes. On the other hand, targets can be bound covalently to the surface which will guide the vector to the site of action [1].

Systemic delivery of the drugs administrated via the nasal route is being extensively studied. Hence, most drugs have been administrated nasally for many reasons including therapeutic, recreational or addictive purposes. Nasal route for drug administration provides an interesting and promising alternative achieving systemic therapeutic response comparing to the parenteral route, which can be inconvenient and invasive. Moreover, nasal route can be an alternative option for oral administration, which can result in undesirable low bioavailability to some drugs such as proteins and peptides [3]. Nasal route is characterized by high blood network and supply. Additionally, hepatic first-pass metabolism is avoided following nasal administration. Furthermore, large absorptive surface area of the nasal cavity and the relatively high blood flow are factors promote rapid drug absorption. Self-administered of drugs through the nose is easy and convenient therefore, patients adherence would be significantly improved [4].

To understand the mechanism of nasal drug delivery it is important to know the anatomy and physiology of the nose. The nostrils are pair of cavities separated by a nasal cartilage, having a total volume of approximately 15 cc3 and a surface area of 150 cm3. These cavities are covered by a mucosal layer, which is of two to four millimeters in thickness. The mucosal layer function is 20% olfactory and 80% respiratory. The nasal epithelium is highly permeable and only two cell layers separate the nasal lumen from the blood vessels present in the lamina propria cavity. The lamina propria cavity consists of three types of epithelia, squamous, respiratory and olfactory[5], [6]. The mucosa in the anterior part of the nasal cavity is squamous with no cilia. On the other hand, the posterior part of the nasal cavity contains the olfactory epithelium. Within the anterior nostrils, there is a transitional epithelium that comes before the respiratory epithelium. The epithelium has ciliary cells that permit and control the flow of mucus to the pharynx [7]. The clearance of inhaled particles or drug molecules will be rapid if deposited in the ciliated posterior part of the nasal cavity than the anterior part. Therefore, the devices used in nasal drug delivery must generate aerosol droplets of appropriate size, ensuring deposition in the nasal anterior region [8].
The physiology of the nasal cavity has an important protective role. Nasal cavity can heat and humidify air before reaching lungs. Also, depending on the size, any inhaled molecules or microorganisms are trapped and removed by the hairs in the nasal vestibule or by the mucosal layer that covers the nasal cavity. In addition, because of the mucociliary clearance property, the inhaled molecules will be carried to the back of the throat, down toward the esophagus, and then into the gastrointestinal tract where they will be eliminated. Moreover, the nasal mucosa has a metabolic ability that converts any endogenous substances into compounds that can be more easily eliminated [9]. Examples of enzymes that involve in the nasal metabolic process are cytochrome P-450, peptidase and protease, which may hinder the delivery of peptides and proteins. In order to design a successful nasal drug delivery system, the above obstacles should be considered to ensure appropriate aerosol deposition, thus, maintaining drug bioavailability.
Mucoadhesion is the ability of the substance to adhere to the mucosal layer of the nose and provide a temporary retention. According to that, polymers that have the ability to adhere to the nasal mucus can be used as a drug delivery system. Advantages of mucoadhesive polymers include increased dosage form residence time, enhanced drug bioavailability and reduced administration frequency and side effects. Additionally, simplified administration of a dosage form, termination of therapy when needed and ability of targeting specific organs or tissues are considered advantages of mucoadhesive polymers. The mucoadhesion process includes proper wetting and swelling of the polymers, and a mutual close contact between the polymer and the mucosa of the nose. After that, the swollen mucoadhesive polymer enters into the tissue fissures leading to interpenetration between the polymer chain and protein chain of the nasal mucus. For the drug to be absorbed efficiently, the formulation should spread well across the nasal mucosa. According to that, the spreadability is an important aspect for the liquid mucoadhesive formulations, whereas the flowability and wettability are important aspects for the solid mucoadhesive formulations [10].

Swelling, or hydration, of the polymer has an essential role in the mucoadhesion process, through which the polymer chains are liberated and the interaction with the biological tissue results [11]. During the hydration process, the hydrogen bonds in the polymer chains are dissociated. When the polymer-water interaction exceeds the polymer-polymer interaction, a sufficient free polymer chains will be available and ready for interaction between the polymer and mucosal tissue. Generally, it is important to consider the critical degree of hydration required to achieve optimum mucoadhesion. The polymer chains which penetrate into the tissue fissures have the ability to restrain the ciliary movement leading to increase in the retention time of the drug in the nasal cavity. Furthermore, the presence of a mucoadhesive carrier can reduce the contact between the drugs and the enzymes of the nasal mucosa. Dehydration, on the other hand, of the epithelial cells after hydration can also result in tight junction opening between the epithelial cells and enhances the paracellular absorption of the macromolecules drugs. Moreover, mucoadhesion can affect the speed of mucociliary clearance.

Various mucoadhesive polymers of different origins and sources for nasal drug delivery are available. Cellulose derivatives, for example, are widely used as drug delivery systems in different administration routes. Examples include soluble cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and carboxymethyl cellulose. Additionally, insoluble cellulose derivatives such as ethylcellulose and microcrystalline cellulose can be used [3]. Due to the mucoadhesive property of the cellulose derivatives, they can significantly prolong the residence time of drugs in the nasal cavity [12]. In addition, according to their high elasticity and viscosity after hydration in the nasal mucosa, cellulose derivatives are able to sustain the release of drugs [13]. Therefore, cellulose derivatives can enhance the drug absorption and improve the bioavailability following nasal delivery. Another example of mucoadhesive polymers is polyacrylates. These polymers are used in nasal delivery of drug due to their significant mucoadhesive property and gel forming ability. In addition to polyacrylates mucoadhesive porperty, it has been reported that they can open the tight junctions between the nasal epithelial cells during the swelling process in the nose temporarily, hence leading to an improvement of paracellular absorption of drugs [14]. Moreover, starch is of the most popular mucoadhesive polymer used as a nasal drug delivery system. Starch is used to enhance the absorption of both small hydrophobic and hydrophilic macromolecular drugs. Pharmaceutically, Maize starch is the most used type due to its superior bioadhesive property [15].

Chitosan [2-amino-2-deoxy-(1'4)-??-d-glucopyranan] is a linear cationic polysaccharide polymer that is produced by a process of deacetylation from chitin, which is a structural element of the protective shells of carbs and shrimps. Chitosan is insoluble at natural and alkaline pH because of the NH2 groups that result from the deacetylation process. On the other hand, chitosan can form water soluble salts if mixed with inorganic and organic acids such as glutamic acid, hydrochloric acid, lactic acid and acetic acid. Chitosan, recently, is preferred to be used in oral, ocular, nasal, implant, parenteral and transdermal drug delivery due to its low cost, inert, safe biodegradable and biocompatible [3].
Chitosan and its derivatives have excellent mucoadhesive properties; hence they have showed the ability to enhance the intranasal drug absorption. In addition, it was proved that coating micro- and nanparticulates with chitosan led significant improvement in drug adsorption to mucosal surfaces [16]. Chemical and biological properties of chitosan such as mucoadhesion and the ability to improve nasal absorption depend on many factors. These factors are; the types of derivatives, degree of deacetylation and molecular weight. Due to poor water solubility of chitosan, some derivatives were, therefore, synthesized. One of these derivatives is N- trimethyl chitosan (N-TMC), which is soluble and effective in improving intranasal absorption even at natural pH [17]. N-TMC hydrochlorides are more mucoadhesive and have better bioavailability in vivo than unmodified chitosan [18].
Various studies exploring the potential of N-TMC as a vehicle for the nasal administration of proteins and peptides were conducted. In one study, N-TMC nanoparticles loaded with FITC- labeled albumin were prepared and characterized. The method of preparation used was ionotropic gelation of cationic N-TMC with tripolyphosphate (TPP) anions. This was performed under mild conditions with TPP as cross linker and evaluated as a carrier for nasal delivery of proteins. Proteins are sensitive molecules to various stressful factors; hence mild preparation conditions are useful to manufacture protein loaded nanoparticles. Following proper preparation, stable N-TMC nanoparticles having a small size and a limited size distribution were obtained. The results showed that N-TMC nanoparticles have an excellent loading efficiency (up to 95%) and capacity (up to 50% (w/w) ) for proteins and a positive surface charge, which make it possible for the nanoparticles to remain attached to nasal mucosa. According to the results of the release studies more than 70% of the FITC- labeled albumin remained associated with the N-TMC nanoparticles for at least three hours on incubation in phosphate buffered saline (pH 7.4) at 37 'C. In addition, the results of the cytotoxicity tests with Calu-3 cells showed no toxic effects of the N-TMC nanoparticles; however, there was a partially reversible cilio-inhibiting effect on the ciliary beat. Moreover, in vivo experiments results showed that when N-TMC nanoparticles loaded with FITC- labeled albumin applied to the nose they were capable to cross the mucosal layer. After crossing the mucosal layer, the nanoparticles were taken up by nasal epithelia and the nasal associated lymphoid tissue cells, and then distributed to sub-mucosal layers [19].

In another study, Hepatitis-B virus surface antigen (HBsAg) loaded N-TMC nanoparticles were prepared and evaluated for controlled nasal delivery. N-TMC nanoparticles size and surface properties were adjusted by modifying the concentration of N-TMC and found to be 66 ?? 13, 76 ?? 9 nm for 0.25 and 0.5 wt. %, respectively. The N-TMC nanoparticles were loaded with 380 and 760 ??l of HBsAg, which result in 143 ?? 33, 259 ?? 47 nm sized spherical N-TMC nanoparticles. The results showed that these nanoparticles had great loading efficiency (90'93%) and capacity (96'97%). In vitro drug release studies confirmed that 93% cumulative release of HBsAg antigen was established over a long period (approximately 43 days). On the other hand, in vivo immunological study was conducted using 6'8 weeks old female balb mice. The results reveal an adjuvants efficiency of nanoparticles for antigen, which was significantly stable and have more advantages than standard. The results indicated that N-TMC nanoparticles can be used to target and control drug delivery via nasal route, therefore, treat and prevent many diseases such as hepatitis B and allergic rhinitis [20].

Furthermore, a study evaluating the potential of N-TMC nanoparticles as a carrier system for the nasal delivery of a monovalent influenza subunit vaccine was conducted. N-TMC nanoparticles loaded with influenza antigen were formulated by mixing a solution of TMC and monovalent influenza A subunit H3N2 with a TPP solution. This formulation was prepared at room temperature and pH 7.4 while stirring. The nanoparticles had a size of approximately 800 nm, limited size distribution and a positive surface charge. The results of this study showed that the nanoparticles had a loading efficiency of 78% and a loading capacity of 13% (w/w). Moreover, during the incubation of nanoparticles in phosphate buffered saline for approximately three hours, it was confirmed that 75% and more of the protein remained associated with the N-TMC nanoparticles. After a single intranasal immunization with influenza antigen-loaded N-TMC nanoparticles, the results were strong hemagglutination inhibition and total IgG responses. The study, also, confirmed that intranasal antigen'TMC nanoparticles induced higher immune responses in regard to the other intranasal antigen preparations. Additionally, these immune responses were improved following intranasal booster vaccinations. Moreover, among the analyzed preparations only intranasal administered influenza antigen-loaded N-TMC nanoparticles induced significant IgA levels. Therefore, these results demonstrate that TMC nanoparticles are promising delivery system for intranasal administered influenza antigens [21].

Another study was performed to evaluate the ability of N-TMC to deliver tetanus toxoid for nasal immunization, where N-TMC nanospheres were loaded with tetanus toxoid by ionic gelation method. The results of this study showed that the percent of quaternization for N-TMC was 50.4 '10.4%. Moreover, the results reveal that the loading efficiency of tetanus toxoid in N-TMC nanospheres was 60.3 '12.7%. The percent of the released tetanus toxoid after 0.5 hour and 4 hours were 37.02 '27.63% and 86.19 '13.5%, respectively. According to the results of this study, the prepared N- TMC nanospheres loaded with tetanus toxoid showed desired properties as a nasal antigen delivery system [22]. Therefore, N-TMC nanoparticles are considered a promising delivery system for transporting proteins and peptides via the nasal mucosa.

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