Review article

LIPID POLYMER BASED NANO PARTICLES FOR THE TREATMENT OF ULCERATIVE COLITIS-REVIEW

B.SHRISTAVA1*, K.VENKATA GOPAIAH1, G.SUDHAKARA RAO2,1. JAIPUR NATIONAL UNIVERSITY, JAIPUR, RAJASTHAN2. VISHWA BHARATHI COLLEGE OF PHARMACEUTICAL SCIENCES, GUNTUR-A.P.

Abstract: Conventional treatment of inflammatory bowel disease is based on the daily administration of high doses of immune-suppressant or anti-inflammatory drugs, is very complicated by serious adverse effects. A carrier system that delivers the drug specifically to the inflamed intestinal regions and shows prolonged drug release would be desirable. It may enter any portion of the gastrointestinal tract though it is mostly found in the terminal ileum often with extension into the cecum and sometime into the ascending colon. Half of the cases, multiple areas of both small and large intestine are involved in segmental fashion i.e. lengths of normal intestine separate areas of disease called skip area. Crohn’s disease granulomatous colitis. Lesions of the small and large bowels are associated with anal lesions it is the first manifestation of the disease Inflammatory bowel disease is mostly common in western countries and in some areas of northern latitude. Polymeric nanoparticles can increase the permeability of an ulcerative colitis through biological barriers, such as the mucosal barriers, skin barriers and cell membrane barrier. The conventional treatments are mostly restricted to control inflammations. However, the main Aim of clinical ulcerative colitis therapy is to not only to control inflammation, but also to achieve mucosal healing. Therefore, the novel therapeutic strategies are urgently needed for addressing the limitations of existing treatments will Increase the stability of any of the volatile pharmaceutical agents, easily and also can be cheaply fabricated in large quantities by a multitude of methods. Delivers a higher concentration of pharmaceutical agent to a desired location.

Key words: Dissociation of the drug molecules from the bounded polymer (or) release from the swelled nanoparticles is observed very clearly.

INTRODUCTIONHistoryThe word ulcerative colitis was first referred in the year 1859 by sir .Samuel wilks .in the1756 Charles ,predator of the throne is suffered from ulcerative colitis but is treated by avoiding the milk food in diet .Than the clinical and biological studies if ulcerative colitis done by wilks.Statistical Data for Ulcerative ColitisInflammatory bowel disease is most prevalent in western countries and in areas of northern latitude. The reported rates of inflammatory bowel disease are highest in Scandinavia, Great Britain and North America. Crohn’s disease has an incidence of 3.6-8.8 per 100,000 persons in the United States and a prevalence of 20-40 per 100,000 people (12, 13). The incidence of Crohn’s disease varies considerably among studies, but has clearly increased dramatically over the last 3 or 4 decades. Ulcerative colitis incidence ranges from 3-15 cases per 100’000 persons per year among the while population with a prevalence of 80 to 120 per 100,000. The incidence of ulcerative colitis has remained relatively constant over many years. Although most epidemiologic studies combined ulcerative proctitis with ulcerative colitis, 17% to 49% of cases are classified as proctitis. Both sexes are affected equally with inflammatory bowel disease, although some studies show slightly greater numbers of women’s with Crohn’s disease and males with ulcerative colitis. Ulcerative and Crohn’s disease have bimodal distributions in age of initial presentations. The peak incidence occurs in the second or third decades of life, with a second peak occurring between 60&80 years of age.Classification of Inflammatory Bowel Disease

I. 5-amino salicylic acid (5-ASA) compounds Sulfasalazine (salicylazo sulfapyridine)

II. Corticosteroids Prednisolone Methyl prednisolone Triamcinolone Hydrocortisone dexamethasoneIII. Immunosuppressant Tacrolimus, Azathioprine, Cyclosporine, prednisoloneIV. TNF α-Inhibitor Etanercept Infliximab Adalimunab

Nanotechnology Nanotechnology is the science and engineering carried out in the Nano scale i.e. 10 -9 m Nanoparticles are solid colloidal particles ranging in size 10-1000nm and consist of a polymeric macromolecular material which can be of synthetic or natures. A nanotechnology deal with developing materials, devices, or other structures consists of at least one dimension size ranges from 1 to 100 nano meters. Nanotechnology may be able to create many new materials and devices with a high range of applications in medicine, electronics, biomaterials and energy production. Nanotechnology is a multidisciplinary scientific field undergoing explosive development Nanoparticles have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and most recently nucleotides. Heterogeneous catalysts were among the first

examples, developed in 19th century. This technology also includes photographic processes that rely on finely divided silver halide. In the Pharmaceutical field, the term nanoparticle has been rather loosely applied to structures less than 1Bm in diameter. They can be produced by either chemical or mechanical means. Other effects are tissue or cell specific targeting of drugs and reduction of unwanted side effects by a controlled release.

1. Nanotechnology: Nanotechnology is the engineering of functional systems at the molecular scale. This covers both current work and concepts that are more advanced work.

2. Nanoparticles: A particle having one or more dimensions of the order of 100nm or less.3. Nano capsules: Nano capsules are vesicular systems in which the drug is confined to a cavity surrounded

by a unique polymeric membrane. The targeting of nano capsules to sites other than Reticule Endothelial System (RES) presents an important challenge to improve bioavailability of the drug associated with nano capsules.

4. Nano spheres: Nano spheres are matrix systems in which the drug is dispersed throughout the particles.5. Nano suspensions: Nano suspensions consist of pure poorly water soluble drug without any matrix mate-

rial suspended in dispersion. It is sub-micron colloidal dispersion of pure particles of drug stabilized by surfactants.

6. Nano crystals: The micro particles are subjected to pearl milling and the resulting particles are suspended in a surfactant solution are called as Nano crystals.

Particle size range for different Nanotechnology techniques Nanoparticles are small colloidal particles ,which are made of non-biodegradable and biodegradable polymers .their diameter is generally around 200nm .they are distinguished into two types ; they are nanospheres –which are matrix system and Nano capsules-which are reservoir systems composed of a polymer membrane surrounding an oil or aqueous core .Nano spheres-in this whole particle consist of a continuous polymer network .Nanocapsules-present a core cell structure with a liquid core surrounded by a polymer cell .These systems were developed in the early 1970s.This approach was attractive because the method of preparation of particles were simple and easy to scale-up. The particles formed were stable and easily freeze –dried .Due to these reasons nanoparticles made of biodegradable polymers were developed for drug delivery. Indeed, nanoparticles were able to achieve with success tissue targeting of many drugs (antibiotics, cytostatic, peptides, and proteins nucleic acids. etc.). In addition, nanoparticles were able to protect drugs against chemical and enzymatic degradation and were also able to reduce side effects of some

S.No Technique Size range1 Nanoparticles 10 to 1000 nm2 Liposome’s 15nm to several nm3 Micelles 10 -80 nm4 Solid lipid nanoparticles 50nm to 1000 nm5 Nano emulsion 50nm to 1000 nm6 Lipid Nano capsule Less than 100 nm7 Nano crystals 10 to 400 nm

active drugs. This review focuses on the preparation and characterization method of nanoparticles. The main applications of these systems are also described A Nanoparticle is a microscopic particle whose size is measured in nanometers (nm). It is defined as a particle with at least one dimension <200nm.or nanoparticles are solid colloidal particles ranging in size from 10nm to 1000nm. Nanoparticles (NP) have been studied extensively as particulate carriers in several pharmaceutical and medical fields. Nanoparticles, in can be used to provide targeted (cellular/tissue) delivery of drugs, to sustain drug effect in target tissue, to improve oral bioavailability to solubilize drugs for intra-vascular delivery and to improve the stability of therapeutic agents against enzymatic degradation. Nanoparticles represent very promising carrier system for the targeting of anti- cancer agents to tumors. Nanoparticles exhibit a significant tendency to accumulate in a number of tumors after iv injection. Nanoparticles can also be used in Brain Drug Targeting. Poly (butyl cyanoacrylate) nanoparticles represent the only nanoparticles that were so far successfully used for in vivo delivery of drugs to brain.

Need of Nanoparticles Drug Delivery Conventional drug therapy in tumor is associated with problems of drug intolerance and toxicity lead-

ing to permanent damage in certain organs. The long duration of therapy and the drug related toxicity are common causes for non-compliance re-

sulting in multi-drug resistant tuberculosis. . Need to develop drug delivery forms that can be directly administered to the lungs as Nano particulate

to reduce the systemic side effects associated with the present anti-cancer drugs. Nanoparticles of pulmonary surfactant can be employed as delivery agents for the anti-cancer drugs to

the infected lung tissue. High stability. High carrier capacity. Feasibility of incorporation of both hydrophilic and hydrophobic substances, and feasibility of variable

routes of administration Advantages of nanotechnology techniques

Nanotechnology-based delivery systems can also protect drugs from degradation. Longer shelf-stability High carrier capacity Ability to incorporate hydrophilic and hydrophobic drug molecules Can be administered via different routes Longer clearance time Ability to sustain the release of drug Can be utilized for imaging studies Targeted delivery of drugs at cellular and nuclear level Development of new medicines which are safer Prevent the multi-drug resistance mediated efflux of chemotherapeutic agents Product life extension Improved products may be available with a change in the physical properties when their sizes are

shrunk. Reduction of dose. Make treatment a better experience and reduce treatment expenses. Nano-based systems allow delivery of insoluble drugs.

Drug targeting can be achieved by taking advantage of the distinct pathophysiological features of dis-eased tissues.

An ideal targeting system should have long circulating time; it should be present at appropriate con-centrations at the target site.

It should not lose its activity or therapeutic efficacy while in circulation. Tumors allow an enhanced permeability and retention effect. Passive targeting of drugs to the macrophages present in the liver and spleen. Improve the oral bioavailability of the agents that are not effectively used orally

Disadvantages of Nanoparticles Involves higher manufacturing costs which may in turn lead to increase in the cost of formulation. Involves use of harsh toxic solvents in the preparation process May trigger immune response and allergic reactions Extensive use of poly (vinyl alcohol) as stabilizer may have toxicity  issues

Applications Cancer therapy Intracellular targeting Prolonged systemic circulation Vaccine adjuvant Perioral absorption Ocular delivery

Classification of Nanoparticles i) Polymeric Nanoparticles

Polymeric nanoparticles are nanoparticles which are prepared from polymers. The drug is dissolved, entrapped, encapsulated or attached to a nanoparticles and depending upon

the method of preparation, nanoparticles, nanospheres or nanocapsules can be obtained. Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a

polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed. As name only suggest polymeric nanoparticles are nanoparticles which are prepared from polymers. The drug is dissolved, entrapped, encapsulated or attached to nano-particles and depending upon the method of preparation.

Polymeric Nanoparticles are mainly two types:

Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a polymer membrane.

Nanospheres are matrix systems in which the drug is physically and uniformly dispersed.Need of Polymeric Nanoparticles for Ulcerative Colitis:

Polymeric nanoparticles can increase the permeability of an ulcerative colitis through biological barriers, such as the mucosal barriers, skin barriers and cell membrane barrier.

Biocompatible and biodegradable. Non toxic Water soluble They are easy to synthesize, inexpensive.

The conventional treatments are mainly restricted to control inflammation. However, the main goal of clinical ulcerative colitis therapy is to not only control inflammation, but also achieve mucosal healing. Therefore, novel therapeutic strategies are urgently needed to address the limitations of existing treatments. Polymeric Nanoparticles:

The polymeric nanoparticles (PNPS) are prepared from biocompatible and biodegradable polymer in size between 10-1000 nm where the drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix. Depending upon the method of preparation nanoparticles, nanospheres or nanocapsules can be obtained. Nanocapsules are systemic in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matric system in which the drug is physically and uniformly dispersed. The field of polymer nanoparticles (PNPS) is quickly expanding and playing an important role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, sensors, medicine, biotechnology, pollution control and environmental technology. PNPS are promising vehicles for drug delivery by easy manipulation to prepare carriers with object of delivering the drugs to specific target; such an advantage improves the drug safety. Polymer- based nanoparticles effectively carry drugs, proteins, and DNA to target cells and organs. Their nanometer-size promotes effective permeation through cell membranes and stability in the blood stream. Polymers are very convenient materials for the manufacture of countless and varied molecular designs that can be integrated into unique nanoparticles construct with many potential medical applications Advantages of Polymeric Nanoparticles:

Increase the stability of any volatile pharmaceutical agents, easily and cheaply fabricated in large quantities by a multitude of methods.

They offer a significant improvement over traditional oral and intravenous method of administration in terms of efficiency and effectiveness.

Delivers a higher concentration of pharmaceutical agent to a desired location. The choice of polymer and the ability to modified drug release from polymeric nanoparticles have

made them ideal candidates for cancer therapy, delivery of vaccines, contraceptives and delivery of targeted antibiotics.

Polymeric nanoparticles can be easily incorporated into other activities related to drug delivery, such as tissue engineering.

Mechanism of Drug Release The polymeric drug carriers deliver the drug at the tissue site by any one of the three general physico-

chemical mechanisms.1. By the swelling of the polymeric nanoparticles by hydration followed by release through diffusion.2. By an enzymatic reaction resulting in rupture or cleavage or degradation of the polymer at site of de-

livery, there by releasing the drug from the entrapped inner core.3. Dissociation of the drug from the polymer and its de-adsorption / release from the swelled nanoparti-

cles (46-48).Preparation of Nanoparticles

Conventionally, NPs have been prepared mainly by two methods:i) Dispersion of the preformed polymersii) Polymerization of monomers.

Dispersion of Preformed Polymers: Several methods have been suggested to prepare biodegradable NPs from PLA, PLG, PLGA and poly (€-caprolactone) by dispersing the preformed polymers.Emulsification Diffusion Method

Preparation of drug loaded nanoparticles was prepared by emulsification diffusion method (49-50).

Polymer and drug was dissolved in ethyl acetate. add the above solution to aqueous phase containing surfactant and emulsified by homogenization using homogenizer (20000rpm\10min) .add large volume of water to the emulsion and gentle stirring with magnetic bar, allow the ethyl acetate to leave the drop lets (51,

52) .The organic solvents and a part of water were removed by evaporation under reduced pressure for 3 hours

to get purified and concentrated suspension. Final product was obtained by centrifugation (12000rpm\20min), re-dispersion and freeze drying (53, 54, 55).

Solvent Evaporation Method

In this method, the polymer is dissolved in an organic solvent like dichloromethane, chloroform, or ethyl acetate. The drug is dissolved or dispersed into the preformed polymer solution, and this mixture is then emulsified into an aqueous solution to make an oil (O) in water (W) i.e., O/W emulsion by using a surfactant for emulsifying agent like gelatin poly(vinyl alcohol) poly sorbet 80 poloximer 188 etc. (56,57).After the formation of stable emulsion, the organic solvent is evaporated either by increasing the temperature/under pressure or continuous stirring the effect of process variables on the properties of NPs was discussed earlier .The W/O/W method has been also used to prepare the water soluble drug –loaded NPs. Both the methods use a high-speed homogenization or sonication. However, these procedures are good for a laboratory-scale operation, but for a large –scale pilot production, alternative methods using low –energy emulsification are required. In this pursuit, following approaches have been attempted

Schematic Representation of the Solvent-Evaporation Technique

Spontaneous Emulsification/Solvent Diffusion Method

In a modified version of the solvent evaporation method. The water –soluble solvent like acetone or methanol along with the water insoluble organic solvent like dichloride methane or chloroform were used as an a oil phase due to the spontaneous diffusion of water-soluble solvent (acetone or methanol) an interfacial turbulence is created between two phases leading to the formation of smaller particles. As the concentration of water –soluble solvent (acetone) increases, considerable decreases in particle size can be achieved.

Schematic Representation of the Emulsification/Solvent Diffusion Technique

Salting Out /Emulsification –Diffusion Method

The methods discussed above require the use of organic solvents, which are hazardous to the environment as well as to the physiological system. The USFDA has specified the residual amount of organic solvents in injectable colloidal system. In order to meet these requirements, Allemann and co-workers have developed two methods preparing NPs. The first one is a salting –out method. While the second one is the emulsification –solvent diffusion technique (61-64).

Schematic Representation of the Salting Out TechniqueProduction of Nps Using Supercritical Fluid Technology

Production of NPs with the desired physico chemical properties to facilities the targeted drug delivery has been a topic of renewed interested in pharmaceutical industry. Conventional methods like solvent evaporation, coacervation and in situ polymerization often require the use of toxic solvent and /or surfactant. Therefore, research efforts have been directed to develop the environmentally safer en-capsulation methods to produce the drug –loaded micron and sub-micron size particles. If solvent impurities remain in the drug-loaded NPs, then these become toxic and may degrade the pharmaceutical with in the polymeric matrix. Supercritical fluid have now became the attractive alternatives because these are environmentally friendly solvents and the method can be profitably use to process particles in high purity and without any trace amount of the organic solvent. Literature on the production of drug-loaded microparticlas using supercritical fluids enormous. However comparatively much less has been investigated to produce NPs.It is beyond the scope of

the present review to give an entire coverage supercritical fluid technology; we will discuss only two of the most commonly used methods of producing micro or nanoparticles

Experimental Set-Up for the Rapid Expansion of Supercritical Fluid Solution into Liquid Solvent Process

In the rapid expansion of supercritical solution (RESS) method the solute of interest is solubilised in a

supercritical fluid and the solution is expanded through a nozzle. Thus, the solvent power of supercritical fluid dramatically decreases and the solute eventually precipitates. This technique is clean because the precipitated solute is completely solvent free. Unfortunately, most polymers exhibit little or no solubility in supercritical fluid, thus making the technique less of practical interest.Ress was very popular in late 80s and early 90s for particle production of bio erodible drug-loaded polymers like PLA. A uniform distribution of drug inside the polymer matrix can be achieved by this method for low molecular mass (<10 000) polymers. However, the RESS method cannot be used for high molecular mass polymer due to their limited solubility in supercritical fluids. For these reasons, much less information is found in the literature over the past 6-7 years on this technique. In the supercritical anti-solvent (SAS) method, the solution is charged with the supercritical fluid in the precipitation vessel containing solute of interest in an organic solvent. At high pressures, enough anti-solvent will enter into the liquid phase so that the solvent power will be lowered and the solute precipitates. After precipitation, when the final operating pressure is reached, the anti-solvent flows through the vessel so as to strip the residual solvent. When the solvent content has been reduced to the desired level, the vessel is depressurized and the solid product is collected. In a modified version of the SAS technique, the solid of interest is first dissolved in a suitable solvent and then this solution is rapidly introduced into the supercritical fluid through a narrow nozzle .The supercritical fluid completely extracts the solvent, causing the supercritical fluid insoluble solid to precipitate as fine particles. This method, also called as gas anti-solvent (GAS) technique, has been successfully used to produce micro particles as NPs.

Experimental Set-Up for Preparation of Polymer Nanoparticles By Rapid Expansion of Supercritical Fluid Solution

Nano precipitationNano precipitation is also called solvent displacement method. It involves the precipitation of a

preformed polymer from an organic solution and the diffusion of the organic solvent in the aqueous medium in the presence or absence of a surfactant. The polymer generally PLA, is dissolved in a water- miscible solvent of intermediate polarity, leading to the precipitation of nanospheres (69-70).This phase is injected into a stirred aqueous solution containing a stabilizer as a surfactant. Polymer deposition on the interface between the water and the organic solvent, caused by fast diffusion of the solvent, leads to the instantaneous formation of a colloidal suspension. To facilitate the formation of colloidal polymer particles during the first step of the procedure, phase separation is performed with a totally miscible solvent that is also a non-solvent of the polymer . The solvent displacement technique allows the preparation of nanocapsules when a small volume of nontoxic oil is incorporated in the organic phase. Considering the oil-based center cavities of the nanocapsules, high loading efficiency are generally reported for lipophilic drugs when nanocapsules are prepared. The usefulness of the simple technique is limited to water- miscible solvent, in which the diffusion rate is enough to produce spontaneous emulsification (45,46).Then, even though some water-miscible solvent produce certain instability when mixed in water, spontaneous emulsification is not observed if the coalescence rate of the formed droplets is sufficiently high. Although, acetone /dichloromethane (ICH, class 2) are used to dissolve and increase the entrapment of drugs, the dichloromethane increases the mean particle size and in considered toxic (75, 76). This method is basically applicable to lipophilic drug because of the miscibility of the solvent with the aqueous phase, and it is not an efficient means to encapsulation water –soluble drugs. This method has been applied to various polymeric materials such as PLGA, PLA, PCL and poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA).This technic was well adapted for the incorporation of cyclosporine A, because entrapment efficiency as high as 98% were obtained highly loaded Nano particulate systems based on amphiphilic cyclodextrins to facilities the parenteral administration of the poorly soluble anti-fungal drugs Bifonazole and clotrimozole were prepared according to the solvent displacement method.

Schematic Representation of the Nano precipitation TechniqueDialysis

Dialysis offers a simple and effective method for the preparation of small, narrow –distributed NP .Polymer is dissolved in an organic solvent and placed inside a dialysis tube with proper molecular weight cut off. Dialysis is performed against a non- solvent miscible with the former miscible. The displacement of the solvent inside the membrane is followed by the progressive aggregation of polymer due to a loss of solubility and the formation of homogeneous suspensions of nanoparticle. The mechanism of PNP formation by dialysis method is not fully understood at present. It is thought that it may be based on mechanism similar to that of Nano precipitation proposed by the fess et al .A number of polymer and copolymer nanoparticles were obtained by this technique. Poly (benzyl-l-glutamate)-b-poly (ethylene oxide), poly (lactide)-b-poly (ethylene oxide) nanoparticles were prepared using DMF as the solvent. The solvent used in the preparation of the polymer solution affect the morphology and particle size distribution of the nanoparticles.

Schematic Representation of Osmosis Based Method for Preparation of Polymer Nanoparticles

Reported a novel osmosis based method for the preparation of various natural and synthetic PNP.It is based on the use of a physical barrier, specifically dialysis membrane or common semi permeable membranes that allow the passive transport of solvents to slow down the mixing of the polymer solution with a non-solvent; the dialysis membrane contains the solution of the polymer.

Polymerization of Monomers

To attain the desired properties for a particular application, suitable polymer nanoparticles must be designed, which can be done during the polymerization of monomers. Processes for the production of PNPs through the polymerization of monomers are discussed below.

Interfacial PolymerizationIt is one of the well- established methods used for the preparation of polymer nanoparticles It is

involves step polymerization of two reactive monomers or agents, which are dissolved respectively in two phases (i.e., continues-and dispersed-phase), and the reaction takes place at the interface of the two liquids. Nanometer-size hollow polymer particles were synthesized by employing interfacial cross-linking reaction as poly addition and poly condensation or radical polymerization. Oil – containing nanocapsules were obtained by the polymerization of monomers at the oil/water interface of a very fine oil-in-water micro-emulsion The organic solvent, which was completely miscible with water, served as a monomer vehicle and the interfacial polymerization of the monomer was believed to occur at the surface of the oil droplets that formed during emulsification. To promote nanocapsules formation, the use of aprotic solvents, such as acetone and acetonitrile was recommended. Protic solvents, such as ethanol, n-butanol and isopropanol, were found to induce the formation of the Nanospheres in addition to nanocapsules. Alternatively, water- containing nanocapsules can be obtained by the interfacial polymerization of monomers in water- in-oil micro-emulsions. In these systems the polymer formed locally at the water-oil interface and precipitated to produce the nanocapsules shell Emulsion Polymerization

Emulsion polymerization is one of the fastest methods for nanoparticle preparation and is readily scalable. The method is classified into two categories, based on the use of an organic or aqueous continues phase. The continues organic phase methodology involves the dispersion of monomer into an emulsion or inverse micro emulsion, or into a material in which the monomer is not soluble (non-solvent).polyacrylamide Nanospheres were produced by this method As one of the first methods for production of nanoparticles, surfactant or protective soluble polymers were used to prevent aggregation in the early stages of polymerization. This procedure has become less important, because it requires toxic organic solvents, surfactants, monomers and initiator; which are subsequently eliminated from the formed particles. As a result of the non-biodegradable nature of this polymer as well as the difficult procedure, alternative approaches are of greater interest. Later, poly (methylmethacrilate) nanoparticles were produced by dispersion via surfactants into solvents such as cyclohexane [ICH, class 2], n-pentane (ICH, class 3), and toluene (ICH, class 2) as the organic phase. In the aqueous continuous phase the monomer is dissolved in a continuous phase that is usually an aqueous solution, and the surfactants or emulsifiers are not needed. The polymerization process can be initiated by different mechanisms initiation occurs when a monomer molecule dissolved in the continuous phase collides with an initiated molecule that might be an ion or free radicals. Alternatively, the monomer molecule can be transformed into an initiating radical by high-energy radiation, including g-radiation, or ultra violet or strong visible light. Chain growth starts when initiated monomer ions are monomer radicals collide with other monomer molecules according to an anionic polymerization mechanism. Phase separation and formation of solid particles can take place before or after termination of the polymerization reaction Mini-Emulsion Polymerization

Publications on the mini-emulsion polymerizations and the development of a wide range of useful polymer materials have recently increased substantially. A typical formulation used in mini-emulsion polymerizations consist of water, monomer mixture,co-stabilizer,surfactant,and initiator. The key differences between emulsion polymerizations and mini-emulsion polymerizations is the utilization of a low molecular mass compound as the co-stabilizer and also the use of a high-shear device (ultrasound,etc).Mini-emulsions are critically stabilized, require a high shear to reach a study state and have an interfacial tension much greater

than zero. The various polymer nanoparticles were prepared by using mini-emulsion method as discussed in the literature

Micro- Emulsion polymerizations

Micro-emulsion polymerization is a new and effective approach for preparing nonosized polymer particles and has attracted significant attention. Although emulsion and micro-emulsion polymerisation appear similar because both method can produce colloidal polymer particle of high molar mass, they are entirely different when compared kinetically. Both particle size and the average number of chains per particle are considerably smaller in micro-emulsion polymerization. In micro-emulsion polymerizations, an initiator, typically water-soluble, is added to the aqueous phase of a thermodynamically stable micro-emulsion containing swollen micelles. The polymerisation starts from this thermodynamically stable, spontaneously formed state and relies on high quantities of surfactant systems, which possesses an interfacial tension at the oil/water interface close to zero. Furthermore, the particles are completely covered with surfactant because of the utilization of a high amount of surfactant. Initially, polymer chains are formed only in some droplets, as the initiation cannot be attained simultaneously in all micro droplets. Later, the osmotic and elastic influence of the chains destabilizes the fragile micro-empty micelles, and secondary nucleation. Very small latexes, 5-50nm in size, coexist with a majority of empty micelles in the final product. The types of initiator and concentration, surfactant, monomer and reaction temperature are some of the critical factors affecting the micro-emulsion polymerisation kinetics and the properties of PNP.

Ionic Gelation or Conservation of Hydrophilic PolymersPolymeric nanoparticles are prepared by using biodegradable hydrophilic polymers such as chitosan,

gelatin and sodium alginate. Calvo and co-workers developed a method for preparing hydrophilic chitosan nanoparticles by ionic gelation. Amir Dustgani et al prepared Dexamethasone sodium phosphate loaded chitosan nanoparticles by ionic gelation method. The method involves a mixture of two aqueous phases, of which one is the polymer chitosan, a di-block co-polymer ethylene oxide or propylene oxide (PEO-PPO) and the other is a poly anion sodium tri poly phosphate. In this method, positively charged amino group of chitosan interacts with negative charged tri poly phosphate to form coservates with a size in the range of nanometer. Coservates are forms as a result of electrostatic interaction between to aqueous phases, whereas ionic gelation involves the material undergoing transition from liquid to gel due to ionic interaction conditions at room temperature

Schematic Representation of Ionic Gelation Method

Controlled/Living Radical Polymerization(C/LRP)The primary limitations of radical polymerization include the lack of control over the molar mass, the

molar mass distribution, the end functionalities and macromolecular architecture. The limitations are caused by the unavoidable fast radical-radical termination reaction. The recent emergence of many so-called controlled or ‘living` radical polymerization (C/LRP) processes has opened a new area using an old polymerization technique. The most important factors contributing to this trend of the C/LRP process are increased environmental concern and a sharp growth of pharmaceutical and medical applications for hydrophilic polymers. These factors have given rise to "green chemistry "and created a demand for environmentally and chemically benign solvents such as water and supercritical carbon dioxide. Industrial radical polymerization is widely performed in aqueous dispersed systems and specifically in emulsion polymerization. The primary goal was to control the characteristic of the polymer in terms of molar mass, molar mass distribution, architecture and function. Implementation of C/LRP in the industrially important aqueous dispersed systems, resulting in the formation of polymeric nanoparticles with precise particle size and size distribution control, is crucial for future commercial success of C/LRP. Among the available controlled / living radical polymerization methods successful and extensively studied methods are

1) Nitrox ide –mediated polymerization( NMP2) Atom transfer radical polymerization (ATRP)

The nature and concentration of the control agent, monomer, initiator and emulsion type (apart from temperature) are vital in determining the size of PNPs. Of these, the nature of the control agent is critical in determining the particle size of the final product.Characterization Studies Drug Loaded Nanoparticles:Determination of Particle Size

The mean particle size and size distribution analysis of nanoparticles were performed by the dynamic light scattering (DLS) method at 250c with a 900c scattering angle for optimum detection. Ten milli grams of drug drug loaded nanoparticles was dispersed in 10 ml of deionized water. The dispersion was sonicated for 1 min and size immediately. The results shown (mean± standard deviation (SD)) are representatives of three independent. Determination of Drug Entrapment Efficiency

Drug concentrations were determined by HPLC-MS. Ten milli grams of nanoparticles containing drug were dissolved in 10 ml of methanol. The solution was stirred for 1 hrs and sonicated for 5 min. afterwards the solution was diluted with a specific volume of the mobile phase and injected into HPLC.EE was calculated with following equation: EE (%, w/w) = weight of drug in nanoparticle/weight of drug used in preparation of nanoparticles in 100.Measurement of Zeta Potential:

The zeta potential of prepared nanoparticles was measured by the ELS-8000 zeta potential analyse was triplicate among different batches to assess the surface charge and stability of nanoparticle. Zeta potential of Nano particles was measured in aqueous dispersion. The measurements were carried out using the medium of water. The results (mean ± SD) are representatives of three independent experiments.

Review on Colon Targeted Drug Delivery Systems

Andersilling et al 2004; assumed on the flow behavior of SLNPs. A significant increase in dispersion viscosity was found in the triglyceride sequence trimyristine < tripalmitine < tristerine. This effect was clearly ascribed to rise in particles shape anisometry with increase in length of the lipid fatty acid chain. Surfactants, which are prevent during the crystallization of the dispersed lipid seems to have an additional effect on the nanoparticles shape (113).

Anh Nguyen et al 2007; prepared ferrocenyl tamoxifen derivative loaded SLNPs for breast cancer treatment. They were used organometallic compounds for binding to hydroxytamoxifen for more stable metal ligand and also enhance cytotoxicity of hydroxytamoxifen and increase the lipophilicity of the compound to facilitate its passage through the cellular membrane. The encapsulation efficiency was determined by UV-VIS spectroscopy the concentration of FC-dioH and DFO in the aqueous phase after centrifugation were determined by the absorbance at 304 nm for FC-dioH and 276 nm for DFO respectively (114).

Bin et al 2006; prepared SLNPs of metoxantrone against breast cancer and its lymph node metastases by using film dispersion ultra-sonication method and evaluated on mice. A thin film was prepared by dissolving assorted amounts of lecithin and compritol-888 in chloroform. Various parameters like encapsulation efficiency, drug content, in vitro drug delivery was initiated by changing the various concentrations of surfactants (115).

Brondsted et. al, 1998, investigated the application of glutaraldehyde cross linked dextran as a capsule material for colon-specific drug delivery. These capsules were loaded with hydrocortisone and dr ug r elease studies were conducted in vitro. Ten percent of drug was released in initial 3h and only about 35% in 24 h at pH 5.4. Addition of dextranase enzyme after 24 h resulted in a rapid degradation of the capsule leading to fast and complete release o f hydrocortisone. However, these results reflect only an experimental condition and not the in vivo situation (116).

Coco et al., 2013 examined how drug loaded polymeric nanoparticles at specific area of swelling and analyzed the impact of various colon-targeted approaches. Three diverse systems were advanced utilizing ovalbumin (OVA) as a model drug. Nanoparticles sensitive to pH were contrived with Eudragit®S100. Trimethyl chitosan (TMC) mucoadhesive nanoparticles were developed. A blend of polymers were utilized to acquire a controlled release. Interplay of nanoparticles accompanying the epithelium was examined using monolayers developed to imitate an inflamed epithelium and later envision. TMC nanoparticles had the greatest permeability. Still, in the inflamed model, no dissimilarity among TMC and polymer blend. Relied on consequences approach be a gifted technique for targeting the colon in IBD (117).

Debnath et al., 2010 have prepared Chitosan nanoparticles for cytarabine for sustain release due to absorption of coating material. The selected polymer chitosan were found to be compatible as exhibited in FTIR. Nanoparticles advanced by ionotropic gelation approach conferring chitosan as a polymer and tripolyphospate as a cross linking agent, surface morphology was outlined by SEM and extended within of 200 nm, found to generate discrete particles of nanosize with substantial stability and release kinetics pursued non-Fickian diffusion. The in-vivo biodistribution results exhibit that the nanoparticles having great distribution correlated to free drug in assorted organs (118).

Dhawale et al., 2010 advanced microspheres by simple oil/water emulsification system with pH-sensitive polymers Eudragit. Technical framework were studied to improve the loading and release profiles. In farther pursuit configuration with Eudragit S100 and L100 were produce to extend delivery. SEM approved structural and surface morphology. The solvent extraction was alternatively through solvent evaporation by an aspect to the encapsulation rate because of the hydrophilic nature of the moiety while delivery pattern was consistent. Study of the morphology led to a homogeneous dissolution of S100 and L 100 over its particle core. Still, confirmed its rationale in-vitro on encouraging for pH-dependent release of moiety. The research was targeted to produce the porous microspheres, that control delivery upto 6 h and therefore it can avoid the acid debase in stomach (119).

DongZhi et al 2003; were employed the altered high shear homogenization and an ultrasound approach to generate SLNPs. The mean particle size was determined by Dynamic light scattering method (DLS). Interaction between drug and lipids were assessed by Differential Scanning Calorimetry and X-Ray Diffraction. The Entrapment efficiency of SLNPs were found to be greater than 87% and exhibits long term stability as the emanation was really small after stored for one month (120).

Elena et al 2002; studied the inclusion of cyclosporine A in SLNPs. In present study SLNPs of cyclosporine A prepared from warm o/w emulsion, is consists of stearic acid, phosphatidylcholin and taurocholate. Cyclosporine A loaded SLNPs were evaluated. The average particle size is below 300 nm and TEM exhibits to be spherical (121).

Hu et al., 2012 prepared mesalamine loaded nanoparticles utilizing Eudragit® S100 as pH-sensitive polymer through SEDS approach and analyze the effects of assorted parameters on surface morphology, mean particle size, efficiency of nanoparticles. Eudragit is an anionic copolymer established on methacrylic acid and methyl methacrylate (1:2 ratios). It is a pH dependent solubility solution at pH 7 or above. It was wonted to resist mesalamine from debase and acknowledge to release in colon. These acquired were evaluated by SEM, DLS, HPLC, XRD, DSC and FTIR spectroscopy (122).

Ji-Yao et al 2006; prepared amorphous cefuroxime axetil SLNPs by precipitation method without surfactant. Prepared nanoparticles were evaluated for particle size distribution, fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution testing. This explains controlled nanoprecipitation approach is a direct and feasible approach for nanoparticle preparation (123).

Krishnaiah et. al, 1999, evaluated guar gum as a compression coating to protect the drug core of 5 - ASA in upper GIT. Percent drug release from tablet increased considerably from 11 hr and the tablets were completely disintegrated in 26 hr in the presence of the rat cecal medium. The results of drug release studies on compression coated tablets suggested th at the thickness of guar gum coa ting in the range of 0.61-0.91 mm was sufficient to deliver the drugs selectively to the colon (124).

Krishnaiah et. al, 2002, studied to develop colon targeted drug delivery systems for metronidazole using guar gum as a carrier. Matrix, multilayer and compression coa ted tablets of metronidazole containing various proportions of guar gum were prepared. Matrix tablets and multilayer tablets of metronidazole failed to control the drug release within 5h of the dissolution study in the physiological environment of stomach and small intestine. The compression coated formulations released les than 1 % of metronidazole in the physiological environment of stomach and small intestine. The results of the study show that compression coated metronidazole tablets with either 275 or 350 mg of guar gum coat is most likely to provide targeting of metronidazole for local action in the colon owing to its minimal release of the drug in the first 5 hr (125).

Kumar et al 2007; prepared nitrendipine loaded SLNPs by using assorted lipids such as tripalmitin and glyceryl monostearate by various methods. Further the prepared SLNPs were characterized by particle size, zeta potential measurement, crystallinity and in-vitro studies. Nitrendipine minimize first pass metabolism by developing as SLNPs (126).

Lorenzo -lamosa et. al, 1998, prepared and demonstrated the efficacy of a system, which combines specific biodegra dability and pH dependent release behavior. The systemconsists of chitosan microcores entrapped within acrylic microsphers containing dic lofenac sodium as model drug. The drug was efficiently entrapped within the chitosan microcores using spray drying a nd then microencapsulated into Eudragit@ L100 using and Eudragit@ S100 using an oil -in-oil solvent evaporation method. Release of the drug from chitosan multi reservoir system was adjusted by changing the chitosan molecular weight or the type of chito san salt. No release was seen in acidic pH for 3hr, but at higher pH Eudragit dissolved and swelling of chitosan started leading to continuous drug diffusion which completed in the next 4hr. Furthermore, by coating the chitosan micro cores with Eudragit@, perf ect pH - dependent release profiles were attained.

Mahkam et al., 2012 developed Silica-poly (methacrylic acid) nanoparticles produced via implant of methacrylic acid against vinyl-bond adjusted silica. The grafting process subsist of surface awakening with 3-TMSM or TMVS, pursued by free-radical implant MAA in ethyl acetate. The silica Nano capsules were obtained marking with hydrofluoric acid. The polymeric Nano capsules were portrayed by FTIR and SEM. A

classic drug, naproxen was implicated in these systems and in-vitro delivery, entangled individually in simulated gastric and intestinal fluids respectively. The conclusions were advanced from the smart nanocapsules has function as colon targeted delivery system (127).

Michele et al 2003; prepared SLNPs by solvent emulsification diffusion technique. Prepared GMS nanodispersion was with narrow size distribution. The aggregate utilization of two or more emulsifying agent emerged to produce accumulated surfactant film at the interface acquiring great surfactant extension as well as adequate viscosity to advance stability (128).

Milojevic et. al, 1995, evaluated A mylose-Ethocel@ system for their potential as microbial degradable colon drug carrier. Amylose -Ethocel@ coating system resistant to gastric acid and small intestinal enzymes, but degradable by colonic bacteria. Varying concen tration of Amylose and Ethocel@ in the form of aqueous dispersions were use to coat 5 -ASA pellets. Coating formulation comprising Amylose and Ethoce l@ in the ratio of 1:4 w/w showed optimum drug release retarding properties in gastric and intestinal fluids (129).

Pertuit et al., 2007 have advanced mesalamine loaded NPs beneficial to examine their medication efficiency of IBD. Mesalamine was covalently destine to poly (caprolactone) preceding to all formulation. Nano precipitation procedure was utilized for NP advancement. Particle size extends either 200 or 350nm for emulsification. In-vitro release exhibited essentially retention within the formulation. Toxicology of various assorted formulations was characterized on Caco-2 and HEK cell culture that raised mesalamine implicated NP in correlation to blank NP (130).

Rainer et al 2000; studied SLNPs for controlled drug delivery. It reviews regarding production approaches, drug characterization and specifically on drug release. Also stated the relevant issues pertaining to excipients, tolerance, sterilization and stability. They also mentioned different analytical tools for SLNPs characterization (132).

Rama Prasad et. al, 1998. Evaluated the suitability of guar gum as a carrier in colonic drug delivery. In this study, matrix tablet of indomethacin with guar gum were prepared . These tablets were found to retain their integrity in 0.1M HCl for 2 hr and in Sorensen’ s phosphate buffer (pH -7.4) for 3 hr releasing only 21% of the drug in these 5 hr. However, in presence of 2% rat cecal contents the drug release increased and further increased with 4% concentration of cecal contents. The drug release improved to about 91% in 4% cecal content medium after enzyme induction of rats (134).

Rubinstein et. al, 1992, developed cross-linked chondroitin as a drug carrier for colon-specific delivery. Chondroitin sulphate was cross -linked with 1, 12- diaminododecane via di cyclohexylcarbodiimide activation. Cross -linked chondroitin sulphate was used to for m a matr ix tablet with indomethacin. Release of indomethacin from the tablet was studied in the presence of rat cecal contents as compared to release in phosphate buffer saline. A significant difference in drug release was observed after 14 hr in the two dissolution media. Also, different degrees of cross-linked chondroitin sulphate were used to study their effect on drug release from the matrices. The cumulative percent release of indomethacin from cross -linked chondroitin matrix tablet showed that release was increased in the presence of rat cecal contents. Studies on rat cecal contents with various cross -linked chondroitin sulphate showed greater cum ulative drug release when cross -linking was less and as cross - linking increased the cumulative release decreased i.e. a linear relationship was found between the degree of cross -linking of polymer and the amount of drug released in rat cecal content (135).

Rubinstein et. al, 1993, showed calcium salt of pectin as a promising colon drug targeting matrix since significant difference between indome thacin levels were observed in the presence of rat cecal content and control, at each time. Matrix tablets of indomethacin were prepared with calcium pectinate and also with pectin. Releases of indomethacin from these matrices were studied in presence of ( a) pectinolytic enzymes, (b) Bacteroides ovatus and (c) rat cecal contents. The increase in percentage of pectinolytic enzymes in the dissolution medium increased the release of indomethacin (136).

Rubinstein et. al, 1995 showed that calcium pectinate -indomethacin tablets of both types, i.e. compression coated and matrix tablets give no release of indomethacin at a pH -1.5 for 2 hr. When these tablets were shaken at a pH -7.4 a drug leak was seen in plain matrix tablets but not in compression coated tablets. In the presence of pectinolytic enzymes, a sudden release of indomethacin was seen in both, the types of tablets but the rate and the percentage of release were lower (only 57.6#2.5% ) in compression coated tablets as compared to plain matrix tablets (74.2#4%) after 12hr (137).

Saha et al., 2010 have prepared Ampicillin rehydrate-loaded chitosan nanoparticles by ionic gelation approach. Aforementioned framework as mean particle size, polydispersity index, efficiency, zeta potential and in vitro delivery were characterized for optimization. SEM affirmed that these were within the range of nanosize but variable in geometry. Altered concentrations of chitosan and sodium tripolyphosphate comprised the excellent circumstances for the advancement of the nanoparticles. In-vitro data exhibited a primary burst pursued by gradual extended delivery. The nanoparticles exhibited supremacy antimicrobial action in correlation with plain and the remark, due apparently synergistic response of chitosan and active moiety. Altered process can be employed for the advancement of chitosan nanoparticles of ampicillin trihydrate. Polymer and cross linking concentrations and sonication time are rate-limiting factors for the advancement of the best formulation. The chitosan nanoparticles advanced be adequate of extended delivery (138).

Shinha et. al, 2004, evaluated polysaccharide (combined xanthan gum and guar gum) matrices for microbially triggered drug delivery to the colon. Matrix tablets were prepared using xanthean gum and guar gum in vary in proportions using indomethacin as model drug. The ability of the prepared matrices to retard drug release in the upper gastrointestinal tract and to undergo enzymatic hydrolysis by the colonic bacteria was evaluated in the presence of rat cecal content. Guar gum alone as a drug release retarding excipient in the matrices does not achieve the desired retardation. Presence of xanthan gum in the tablets not only retard the initial drug release from the tablets, but due to high swelling, make them more vulnerable to digestion by the microbial enzymes in the colon (139).

Sivabalan et al., 2011 have generated and assessed chitosan and Eudragit® nanoparticles of 5- Fluorouracil for cancer medication, prepared by utilizing chitosan, Eudragit® S 100, and polysorbate-20 using Emulsion droplet coalescence approach. The range of the polymers were opted implied on the results on exploration screening. The advanced nanoparticles were assessed for surface morphology, efficiency, in-vitro release and in-vitro anticancer activities. In-vitro anticancer results depicts that the advanced nanoparticles were found to have substantial cidal activity on cancer cells in sustained manner (140).

Tamizhrasi et al., 2009 have prepared and evaluated polymethacrylic acid nanoparticles enclosing lamivudine in assorted drug to polymer ratio by Nano precipitation approach. SEM remarked that nanoparticles have a distinct spherical structure beyond aggregation. The average particle size was initiate to be 121 ± 8 - 403 ± 4 nm. The particle size of the nanoparticles was progressively raised with an elevation in the proportion of polymethacrylic acid polymer. The drug content of the nanoparticles was raised on elevating polymer concentration up to a distinct concentration. No substantial variation was noticed in the intensity of degradation of product extent of 60 days in that, the nanoparticles were stored at assorted temperatures. FT-IR studies determined that there was no chemical interplay among the drug and polymer and, the stability of drug. The in-vitro release profile from all the drug loaded groups was found to be zero order and maintained sustained release over a period of 24 hrs. This study suggests the specificity of these matrices for enzyme trigger in the colon to release the drug (141).

Tominaga et. al, 1998, evaluated chitosan as compression coated material for colon specific drug delivery system. Cores of acetaminophen were coated with chitosan as inner coating layer and gastric acid resistant material phytin as an outer coat. Phytin protected the core from gastric pH and dissolved in the small intestine. Chitosan protected the core in the small intestine and released the core upon biodegradation of chitosan in the colon (142).

Turkoglu et. a l, 2002, evaluated the pectin -HPMC system for compression coated core tablets of 5 -aminosalicylic acid (5 -ASA) for colonic delivery. Drug dissolution/system erosion/ degradation studies

were carried out in pH 1.2 and 6.8 buffers using a pectinolytic enzyme. The system was designed based on the gastrointestinal transit time concept, under the assumption of colon arrival times of 6h. It was found that pectin alone was not sufficient to protect ate core tablets and HPMC a ddition was required to control the solubility of pectin. The optimum HPMC concentration was 20% and such system would protect the course up to 6 h that corresponded to 25 -35% erosion and after that under the influence of pectinase the system would degrad e faster and delivering 5 -ASA to the colon. The pectin -HPMC envelope was found to be a promising drug delivery system for those drugs to be delivered to the colon (143).

Vervoort et. al, 1997, synthesized Methacrylated insulin and aqueous solutions of Methacrylated insulin upon free radical polymerization, were converted to cross -linked hydrogels. Rheological studies and characterization of there hydrogels showed that higher substituted insulin had better network and higher mechanical strength. These hydrogels were there studied for their swelling properties and degradation in vitro. Degradation studies carried out in presence of inulinase showed that increasing enzyme concentration and incubation time degraded insulin faster. However, increasing the substitution on insulin molecules resulted in stronger hydrogels with less enzyme diffusion thereby less degradation (144).

Vobalaboina et al 2004; prepared and characterized clozapine loaded SLNPs. SLNPs of clozapine was advanced by referring assorted triglycerides, soylecithin 95%, poloxamer 188 as surfactant. Drug release studies were performed at double-distilled water, 0.1 N HCl, and phosphate buffer, pH 7.4 by modified Franz diffusion cell. Stable clozapine loaded SLNPs having mean particle size range of 60–380 nm and zeta potential range of −23 to +33 mV were advanced. Greater than 90% clozapine was entrapped in SLNPs (145).

Waree et al 2007; studied on advancement and evaluation of curcuminoids loaded SLNPs. SLNPs of curcuminoids have been successfully developed using microemulsion technique

Wissing et al 2004; describe the benefits of nanoparticles allocated on SLNPs for parenteral administration. Assorted production approaches included for large scale, stability issues, drug loading approaches and biological activity of parenterals enforced for SLNPs (146).

Wolfgang et al 2001; assumed about production, characterization, applications of SLNPs. This paper overlooks for the choice of selection of excipients such as lipids, fatty acids, surfactants etc. and assorted production techniques of SLNPs (147).

Objectives:

To develop Drug loaded polymeric Nano particles and optimise the formulation parameters. To develop nanoparticles containing Drug with higher stability and better release profile. To reduce the overall dose of Drug require for ulcerative colitis treatment by loading in nano carriers. To study the physicochemical properties of Drug loaded polymeric nano particles. To study the drug release profile of prepared Nano particles.

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