Review Article

Received: 28 May 2013, Accepted: 21 June 2013

ISSN: 2321-2969

Int. J. Pharm. Biosci. Technol. To cite this Article: Click here

International Journal of Pharma Bioscience and Technology. 2013; 1(2): 64-82

Journal home page: www.ijpbst.com

SURFACE MODIFICATION TECHNIQUES FOR ACTIVE TARGETING OF POLYMERIC NANOPARTICLES

Sagar D. Mandawgade, Sushant C. Patil, Vandana B. Patravale*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai 400019, India. Corresponding Author* E-mail address- vbp_muict@yahoo.co.in

ABSTRACT: The past few decades have witnessed extensive research in the area of drug delivery using nanoparticulate delivery systems as carriers for small as well as large molecules. The current focus of research in this area has generated a broad spectrum of carriers with better biological performance in terms of both circulation time and target specificity. Surface modification of particulate systems like nanoparticles has proved to be useful in offering multi-functionality and to improve the pharmacokinetic and pharmacodynamic properties of various drugs. Surface modification techniques are not only used to protect the drug entity in the systemic circulation, but also to restrict access of the drug to the chosen sites and to deliver the drug at a controlled and sustained rate to the site of action. Here, we review various types of nanoparticles and environmentally friendly techniques for the production of nanoparticles using various polymers, which is a quite promising area of research. The review also covers the various aspects of nanoparticles formulation, and invivo behavior and their applications in drug delivery for therapeutic enhancement. Key words: Polymeric Nanoparticles, Surface modification techniques, Drug Carriers, Supercritical Fluids, Nanoparticle-Coating. INTRODUCTION The improvement of drug delivery and the absorption of poorly water soluble drugs has become an important point in pharmaceutical industry. Despite several efforts dedicated to the design of oral peptide delivery systems and parenteral formulations of insoluble therapeutic molecules, optimal dosage form of these sensitive molecules still remains a challenge [1]. One of the primary objective in the development of drug delivery systems is the controlled delivery of a drug to its site of action with an optimum rate and in the most efficient way. Targeting drugs to its site of action can improve the therapeutic efficacy. Further it also enables the reduction in total dose of drug required to achieve a therapeutic response with minimization of the side effects. Nanoparticulate drug delivery systems is one of the promising method to achieve targeting of drugs. Nanoparticles are materials ranging in size from 1 to 1000 nm and are found to be useful as drug carriers[1]. Several methods exist for the manufacturing of polymeric nanoparticles. However the challenge towards oral as well as parenteral peptide drug delivery systems still remains due to the hostile conditions of the gastrointestinal tract coupled with limited permeability of the intestinal barrier which makes the situation very complex for the oral delivery of proteins and peptides; the solution to these problems is a great challenge [2]. While for the parenteral drug delivery systems the rapid uptake of intravenously injected particulate drug carriers by cells of the mononuclear phagocyte system (MPS) in liver and spleen is advantageous only when the drug is to be targeted for treating illness of the reticuloendothelial system, otherwise it is the major limitation if the drug is to be targeted to other sites in the body [3]. Further Intravenously Pg. 64

Mandawgade et al

Int. J. Pharm. Biosci. Technol. administered nanoparticles are easily recognized by bodys immune system and as a consequence they do not remain long-enough in the circulation to reach the desired target site [4]. Recently, a milestone step taken to overcome these drawbacks is the development of stealth nanoparticles and active cell targeting in-vivo. A relatively successful approach for prolonging the circulation time of nanoparticles in the blood is to create a steric surface barrier of sufficient density [5]. The purpose of this review is to give a brief insight into the different techniques and advancements in the techniques of modifications of nanoparticles surface in order to achieve longcirculating and target-specific nanoparticles. Surface modification of nanoparticles has been achieved mainly by two approaches which encompass many technology advancements. One approach is of surface coating with hydrophilic polymers and surfactants and other approach is of development of biodegradable co-polymers with hydrophilic segments for direct drug loading[4]. Surface coating techniques can differ depending upon, the type of surface to be coated, surface characteristics (e.g. membrane phospholipid composition, surface charge, surface antigens), bulk properties (e.g. size, shape and their extent of deformability) and polymer properties (chain length, coating density) [6-10]. Biodegradability is also a very important property of nanoparticles especially for parenteral administration as it has substantial influence the drug release rate. Natural polymers such as albumin, gelatin or starch are biodegraded and eliminated rather rapidly due to enzymatic digestion [11]. Technology Advancements for Production of Actively Targeted Polymeric Nanoparticles Cap Coat Technology The rationale for designing drug eluting medical implants includes possibility of incorporating drugs on or inside the implant for subsequent controlled release from the device surface after implantation (For example, the surfaces of a catheter, stents, vascular grafts, valves, discs and joints). However, there remain challenges to effectively control drug delivery to the site of disease or injury. Generally, drugs are released from medical implants by mechanism of diffusion. However many controlled release implants also releases the drug by mechanism of bulk erosion, as the polymeric coating is physically or chemically eroded. Cap coating technique provides methods for controlled drug release rate. Cap coat usually refers to the outermost coating layer applied over another coating. In cap coating process the drug are nanopulverized by any processes like milling, precipitation and homogenization to produce the nanoparticle compounds, size ranging from approximately 10 nm to 1000 nm. The nanopulverized compounds are suspended or blended in a polymer matrix (primer coats). The polymer matrix can then be applied to surface of the medical implant by spraying, dipping, brushing and vacuumdeposition. Over the nanoparticle-containing polymer, an additional polymer cap coat may be applied (polymer caps coats). The cap coat may optionally serve as a reservoir and/or diffusion barrier to control elution rate of biological agent. Such a matrix has openings of similar or variable sizes and release of the drug compounds from this matrix can be regulated by the size of the openings through which the drug compounds travel. Cap coat may be merely of a biocompatible polymer which can be either synthetic or natural bio-absorbable polymers such as fibrin, fibrinogen, cellulose, starch, collagen, etc. [12]. Supercritical Fluids for Drug and Polymer Processing This process has wide ranging applicability for example, for coating and/or encapsulation of pharmaceuticals, cosmetics, food products, chemicals and polymers [13]. In the area of drug delivery, the skill to control the size, morphology and also the release pattern of drug loaded particles is very important for good targeting, but is often unachievable due to harsh processing conditions or inadequate methods. However, the use of supercritical fluids (SCF) such as supercritical CO2 (scCO2) has provided a clean and effective alternative to traditional methods of drug and polymer processing. In particular, scCO2 has a number of unique properties that make it possible to process both bioactive molecules and amorphous polymers without using toxic organic solvents or elevated temperatures. The use of SCF can be employed to avoid many of the problems that are associated with traditional methods, at the same time use of this technique can lead to a better control in formulation of various drug delivery systems [14]. Carbon dioxide is relatively inert and environmentally friendly when compared to organic solvents and has a low critical point of 73.8 bar and 31.10C, permitting processing in ambient conditions. A number of SCF techniques have been used for micronization of drug particles in which they are liquefied in scCO2 before spraying through a nozzle, on depressurization. It can be achieved with use of nonsolvent techniques such as the rapid expansion of supercritical solutions and particles from gas saturated solution. At elevated temperatures polymers either remain soluble or can plasticize in Pg. 65

Mandawgade et al

Int. J. Pharm. Biosci. Technol. scCO2, allowing them to become viscous liquids without incorporation of organic solvents. Once liquefied, the polymer can either be casted into a porous controlled-release matrix for subsequent impregnation, or can be used to produce drugcarrying microparticles. Alternatively, scCO2 can also be used as an anti-solvent for the precipitation of drugs already dissolved in organic solvents [14,15]. Rapid Expansion of Supercritical Solutions RESS is the most simplistic SCF technique to produce fine drug particles. Here, the solute (the drug) is dissolved within the supercritical gas without the need for additional organic solvents [15-16]. The mixture is then depressurized through a nozzle resulting in rapid precipitation of drug particles into a collection chamber [17, 18]. Progesterone, medroxyprogesterone and ibuprofen have successfully been micronized using RESS, yielding greater dissolution rates [1921]. Highly CO2-phobic molecules, organic solvent such as acetone [22] and various surfactants [23] have been used in combination with scCO2 to developed micro- and nano-scale particles using rapid expansion into solution. This technique has also been used in the coprecipitation of drugs with polymers to form composite microparticles capable of controlled release. A variety of polymers such as PLA, PLGA and PEG have been used in the production of microparticles. These polymers appear most frequently in scCO2 based applications, as they have strong interactions with CO2, and are relatively nontoxic and have full FDA approval [24]. Lovastatin loading into the amorphous form of PLA, poly(D,L-lactic acid) has been reported by this method.[25] Particles from Gas Saturated Solutions (PGSS) The underline rationale of this process is based on depression of viscosity and melting point achieved by diffusion of pressurized gas through the solute phase. [26]. Subsequently the particle can be formed by depressurizing the solution through a nozzle as the gas is released from the condensed phase. The particle size distribution can be controlled by changing the processing parameters such as temperature, pressure and nozzle diameter which are the most important factors. The technique has been applied for micronization of drugs such as nifedipine and anti-hypertensive drugs [27]. The PGSS technique has several benefits when compared with RESS. It uses lower pressures than RESS resulting in lower gas consumption. This versatility has been further demonstrated by using N2 to control the particle size of PDLLA by creating a backpressure within the collecting chamber [28]. The backpressure maintains the low viscosity of the CO2 /polymer (PDLLA) mixture for sufficient time to allow formation of droplet, before the formation of particles and then solidification by a combination of CO2 escape and N2 displacement. This technology has been used to coprecipitate thermally labile proteins such as calcitonin and insulin with PDLLA to form composite microparticles (10-300m) in a single step and under ambient conditions [29]. Gas Anti-Solvent Techniques Gas anti-solvent techniques differs from both RESS or PGSS process, as the gas is used as an antisolvent to reduce the solvating power of the organic solvent in which the solute is dissolved. Because of the ability of pressurized gases (CO2) to dissolve and expand organic solvents, they are useful for the precipitation of solid from organic solutions [14]; the expanded solvent can then be purged from the system. Particles can then be removed from the collection chamber upon depressurization. Many variations in the antisolvent technique exist, which includes the use of original gas/supercritical anti-solvent technique, precipitation of compressed anti-solvent (PCA) technique and the use of aerosol solvent extraction system (ASES). The GAS technique has been used most extensively to produce protein powders such as insulin [30, 31], lysozyme and trypsin [32] within 1-5 m size range. In addition to protein micronization, the GAS technique has been used successfully in micronization of non-proteins such as copper indomethacin [33]. Here, particles were formed that showed an eight-fold increase in the dissolution rate in water, compared with the unprocessed drug. In another technique, precipitation from a compressed anti-solvent has been used for the production of biologically active powders or polymeric microparticles. With PCA, a solid (drug/polymer) is dissolved in an organic solvent. This liquid is sprayed continuously in small amounts into a container filled with scCO2. The solvent then dissolves into scCO2, but not the solute, resulting in the precipitation of micronized particles [30]. This technique has been used to form polymer/drug microparticles with poly (LLactic acid) (PLLA) and wide range of pharmaceuticals (naloxone, naltrexone and gentamycin) dissolved in methylene chloride [34]. Continuous optimization of the process has lead to the formation of smaller more controllable particles [35, 36]. ASES is a variation of the other anti-solvent processing methods. Microparticles containing indomethacin, parahydroxybenzoic acid and lysozyme have been produced using this Pg. 66

Mandawgade et al

Int. J. Pharm. Biosci. Technol. system.[37-38]. The model peptide tetracosactide has been encapsulated within PDLLA and PLGA microparticles [39] by ASES, and has shown favorable results in terms of polymer degradation properties compared with traditional methods. ASES technique has also been used for micronization (1-5 m) of steroids [40]. Method for Producing Particles using HighPressure Gases Several techniques such as solution-enhanced dispersion by supercritical fluids (SEDS) and supercritical assisted atomization (SAA) have been developed that added a unique step to improve the particle properties or to gain greater control over particle size. In the SEDS technique [41], solvent acts as a precipitating agent and modifier, allowing CO2 to remove water. Many of the problems seen with other methods, such as agglomeration and long drying times have been reduced by this technique [42]. Another interesting application of this technique is production of plasmid DNA-loaded particles with potential for delivery via inhalation or through the skin (transdermally) [43]. In SAA, a thermostated packed contactor is used to solubilize scCO2 in a liquid solvent containing the solute. This process was used successfully to micronize griseofulvin and ampicillin [44, 45]. Incorporating Drugs into Controlled Matrices In addition to particle formation, high-pressure or supercritical CO2 has been used to fabricate porous polymeric controlled release matrices. These porous matrices can often have a dual purpose; one example of this is in tissue engineering applications. Here, they act as both, support for cell growth [46] and release devices for the delivery of growth factors. Vascular endothelial growth factor [47] and basic fibroblastic growth factor [48] have been impregnated successfully within scCO2-fabricated PLGA. A novel one-step supercritical mixing technique has been developed that allows the incorporation of thermally labile bioactive molecules into controlled matrices during processing. Growth factor bone morphogenetic protein-2 (BMP-2) has been incorporated into the polymer matrix during with subsequent controlled release by changes in the depressurization speed. [49] Process Developments for Production of Actively Targeted Polymeric Nanoparticles (PNPs) Polymeric Coating Nanoparticles with Bioactive

This method was patented by Sheppard Cuesta and Lauer Palmer [50]. The underlying principle of this process is attachment on the surface of a coating, consisting of adding bioactive molecule to the formulation of polymeric nanoparticles (1 to 50 nm) via linkage. The bioactive molecule is linked to the polymeric nanoparticle (PNP) via either covalent or ionic bonds. The term "bioactive molecule" means, functionalities incorporated into the PNP either during or after polymerization that will cause the PNP to become biologically active, regardless of whether or not the functionality by itself is biologically active. The bioactive functional PNP may then function as the bioactive molecule itself or the bioactive functionality may be released from the PNP. The bioactive molecule may either cleave off by hydrolysis from the polymeric nanoparticle to become the biologically active molecule or it may remain linked to the polymeric nanoparticle, thus making the polymeric/bioactive molecule the biologically active entity. Such bioactive molecules may comprise amine groups containing one or more amine functionalities. The amines can be selected from the group consisting of primary, secondary, tertiary and quaternary amines or biguanide groups. The formation of PNPs bearing bioactive amine functional groups may be achieved by the introduction of these amine monomers during all or part of the polymerization portion of PNP preparation. Suitable amine-containing monomers include, N,N-dimethylaminoethyl (meth) acrylate, N,N-diethylaminoethyl (meth) acrylate, monomers having pyridine functionality which include, 2vinylpyridine and 4-vinylpyridine, monomers having piperidine functionality such as, vinylpiperidines and monomers having imidazole functionality which include, vinyl imidazole. Suitable bioactive amphoteric monomers include, N-vinylimidazolium sulfonate inner salts and N,NDimethyl-N-(3-methacrylamidopropyl)-N-(3- sulfo propyl.) ammonium betaine. PNPs linked to bioactive molecules can be prepared by postfunctionalization of a preformed PNP. A monomer bearing a first reactable group (the co-reactive monomer) is incorporated into the PNP during the polymerization portion of PNP preparation. At some point, a modifying compound bearing the second reactable group (the co-reactive bioactive compound) is combined with the co-reactive monomer to tightly associate the stabilizing group with the PNP. When polymeric nanoparticles are used in a coating formulation in combination with another polymer/s, post-functionalization of PNPs can proceed before or after the combination of the PNP with the other polymer/s. Optionally, the Pg. 67

Mandawgade et al

Int. J. Pharm. Biosci. Technol. polymer/s with which the PNP is being combined may contain reactable groups complementary to that in the co-reactive bioactive compound. For example, titanium polymers may become bioactive molecules upon cleavage such as, by hydrolysis from the PNP after application of the coating. The level of titanium-bearing monomer may range from 0.5 to 95%, based on total weight of PNP. As other examples, PNPs have been prepared which contain bioactive molecules comprising phosphonium, sulfonium salts and carbamate groups. The aqueous composition of such bioactive PNPs is also feasible. In an aqueous dispersion having a mean diameter from 1 to 50 nm, the particles as polymerized units contain at least one multiethylenically unsaturated monomer and at least one ethylenically unsaturated water soluble monomer. The steps included in preparation of aqueous dispersion of PNPs are, preparing a nonaqueous dispersion containing PNPs dispersed in at least one solvent and combining the nonaqueous PNP dispersion with an aqueous medium. An aqueous PNPs composition containing polymerized units, ionic monomers, is optionally partially or completely neutralized prior to, during or after combining with the aqueous medium. Preparation of Nanoparticle Coated Microparticles by Spray-Drying Technique Nanoparticles are polymeric colloidal systems that have been widely studied with the purpose of drug targeting and as controlled drug delivery systems [51-54]. However, these aqueous colloidal suspensions presented some disadvantages during storage such as, microbial contamination, polymer hydrolysis and physico-chemical instability due to particle agglomeration and sedimentation [55]. Among the several methods, the spray-drying technique has been successfully employed in the preparation of microparticulate delivery systems [56-60]. Use of spray-drying technique was determined for morphological control of the micro-powder coating by the use of nanosphere suspension (polymeric matrix) or nanocapsule suspension (vesicular nanostructure). This method exhibits advantages such as a rapid and one step process; it is applicable to heatsensitive materials and presents an easy industrial transposition [61]. Despite the more complex and onerous production of multiple-unit drug delivery systems, they present several advantages relative to the single-unit systems, including ready distribution on a large surface area, more constant plasma levels, higher accuracy in reproducibility doseby-dose and less decrease in bioavailability [62Mandawgade et al 63]. Spray-drying coating technique was evaluated to design and prepare new nanoparticle-coated drug-loaded inorganic microparticles using diclofenac [64] as a drug model. Polymeric nanocapsule or nanosphere suspensions were used as organic coating on diclofenac-loaded silicon dioxide core. Regarding the chemical nature of some non-steroidal antiinflammatory drug (NSAID) molecules (indomethacin, diclofenac, ibuprofen and others) and silicon dioxide, the drugs in their hydrophobic form present a carboxylic acid moiety that can interact with hydroxylic groups on the surface of silicon dioxide [65] by hydrogen bonds and the corresponding hydrophilic forms present a carboxylate group, which can interact with the silicon dioxide surface by ion-dipole forces [66]. The use of diclofenac, acid or salt forms as molecular models to investigate the potential application of those nanoparticle coated microparticles is appropriate due to the possibility of minimizing the influence of structural differences of models drug. The nanocapsules (NC) and nanospheres (NS) were prepared from Eudragit S100 or poly ("-caprolactone) [64]. Microencapsulation of Lipid Nanoparticles In this method, encapsulation of lipid nanoparticles into the polymer matrix has been performed to demonstrate that the solid form of lipid nanoparticles can be utilized as a delivery system for lipophilic drugs by oral route. Coagulated O/W emulsion, however, is not suitable for lipid nanoparticles due to leakage of nano-sized lipid particle from the polymer matrix. To overcome this difficulty, a cationic lipid nanoparticle with cationic surfactant has been prepared and encapsulation of cationic lipid nanoparticles into an anionic polymer network has been performed via ionic interaction. Lovastatin was used as a model drug. The drug-loaded lipid phase was composed of lovastatin, lipid (propylene glycol monocaprylate), surfactant (diethylene glycol monoethyl ether) and cosurfactant (oleyl amine). The aqueous phase was composed of aqueous polymeric solution of sodium alginate and hydroxylpropyl methyl cellulose (HPMC). For the encapsulation of lipid nanoparticles into the polymer network, the drugloaded oil phase was transferred into the polymer aqueous solution and the polymeric emulsion beads were prepared as a function of composition of the polymer aqueous solution. Lovastatinloaded lipid nanoparticles having diameter of 25 nm were observed. For application as an oral drug delivery system, enteric coating was performed with polymeric emulsion bead using HPMCP (2.8%) and Triacetin (0.4%). Release experiments Pg. 68

Int. J. Pharm. Biosci. Technol. were performed at two pH conditions (pH 1.2 and 7.4) for 2 h using the polymeric emulsion beads with 50% of HPMC content. Because of pHsensitive dissolution of HPMCP (an enteric coating material), minimal release was observed at pH 1.2 and more than 85% of totally loaded Lovastatin was released at pH 7.4. In sodium alginate/HPMC composite, with the increase of HPMC content, the release rate was increased. By enteric coating, the polymeric emulsion bead exhibited a pH-sensitive release pattern; this indicates that enteric coated polymeric emulsion bead is suitable as an oral controlled release delivery system for the lipophilic drug [67-69]. Preparation of Nanoparticles Coated with Carbohydrate-Carrying Polymers C.S. Cho et. al. [70] reported a new technique to modify biorecognition of nanoparticles by changing the surface structures. A diafiltration method was developed for simple preparation of nanoparticles based on polymeric micelles [71]. The nanoparticles prepared by the reported method displayed high yield, no-aggregate formation, and narrow size distribution in one step procedure. This study reported formation of nanoparticles from poly (-benzyl L-glutamate) (PBLG) or PLA, having carbohydrate chains on their surfaces by the diafiltration method using a carbohydrate-carrying polystyrene which served as both an emulsifier and a surface coater. PBLG as one of the synthetic poly (amino acids) was chosen for possible use in a variety of biomedical applications [72]. In the reported procedure, PBLG (or PLA) was dissolved in DMSO and subsequently poly (vinylbenzyl lactonamide) (PVLA) was added. The solution was stirred at room temperature. To form nanoparticles and to remove DMSO, the solution was dialyzed against 2 liters of distilled water using dialysis membrane (M.W. CO; 2000). During the first 3 h, water was exchanged three times, two times in the following 6 h and then four times in the following 15 h. After dialysis, the particles were centrifuged at 20,000 g for 1 h and washed with distilled water several times to remove uncoated PVLA. The high density carbohydrate chains on the particles were recognized by hepatocytes. This result indicated that carbohydrate chains on nanoparticles influenced receptor-mediated endocytosis and thus has a huge potential for active drug targeting [73, 74]. Surfactant Coating on Nanoparticles for Active Targeting using Stabilizers Stabilizers such as Dextran 12,000 or Polysorbate 85 are used during the polymerization process help to deliver the nanoparticles to a specific target. A drug is either incorporated into or adsorbed onto the stabilized nanoparticles. This drug/nanoparticle complex is then administered to the organism by any route such as oral adminstration, injection or inhalation. In this technique, an appropriate monomer such as butyl cyanoacrylate (BCA) is selected and polymerized to poly-butyl cyanoacrylate (PBCA), said polymer being existent in the polymerization system in the form of nanoparticles. During or after the polymerization of monomer, the drug is added so that it is either incorporated into nanoparticles or adsorbed onto the surface of nanoparticles. Nanoparticles have been prepared using an acidic polymerization medium containing polysorbate 85 as stabilizer. [75]. Preparation of Surface-modified nanoparticles by Lyophilization and Epoxy Derivatization Biodegradable controlled release nanoparticles are sustained release bioactive agent delivery vehicles to target binding of the nanoparticles to tissues or cells. PLGA is a popular biocompatible material, however it degrades relatively rapidly and thus, its use for long-term sustained release drug delivery systems is limited. In addition, it has been difficult to chemically link a significant amount of bioactive agent to the polymer chain. Thus it was desirable to synthesize a range new biocompatible polymers with long-term bioerosion and more hydrophilic characteristics with potential for further derivatization. An example of such polymer having hydrophobic and hydrophilic characteristics which has long-term bioerosion characteristics was developed from Polycaprolactone (PCL). A new polymer was prepared from polylactone-polyether block copolymers by initiation polymerization technique of lactone monomers using a poly-glycol as an alcoholic type initiator. Hence, the small nanoparticles (10 nm to 35 nm) comprise of hydroxy-terminated or epoxide-terminated and/or activated multiblock copolymers having hydrophobic segments of polycaprolactone and hydrophilic segments such as poly (ethylene glycol) introduced into polymer chain. The novel polycaprolactone-based polymers therefore have more desirable characteristics, controllable biodegradation kinetics and potential for derivatization than conventional polycaprolactone through the addition of reactive epoxy groups. Techniques for modifying the surface of these nanoparticles include lyophilization to produce a physically adsorbed coating and epoxyderivatization to functionalize the surface to covalently bind molecules of interest. Reactive groups for coupling of heparin, albumin, and other Pg. 69

Mandawgade et al

Int. J. Pharm. Biosci. Technol. biologically active molecules are attached onto the polymer. In a further advancement, a multiple emulsion was found to be advantageous method for adsorbing a surface modifying agent onto the nanoparticles. It involves the steps of suspending the nanoparticles in a solution of the surface modifying agents and freeze drying the suspension to produce a coating over nanoparticles. Evaporation of organic solvent solidifies the liquid droplets into small solid particles, termed as the "polymeric core". Bioactive agent could be dissolved in either an aqueous or organic phase which then becomes part of the polymeric core matrix. Such novel epoxy-derivatized and activated PCL nanoparticles loaded with bioactive molecule are useful for local intravascular administration of smooth muscle inhibitors, anti-thrombogenic agents as part of balloon angioplasty, direct application to tissues and/or cells for gene therapy, or oral administration in an enteric capsule for delivery of protein and peptide based vaccines. This nanoparticle form is particularly suited for catheter-based local drug delivery at any site and sustained release of protein and peptide vaccine for immunization [73]. Active Targeting with Carriers by PEGylation Particulate Drug from 100 upto 800 nm can be prepared. Nonstealth and stealth nanoparticles are used as an injectable drug carrier. Non-stealth nanoparticles are of great interest for passive targeting of macrophages and the MPS while stealth nanoparticles and long circulating liposomes could enhance localization of hydrophobic drugs. Sodium cholate and serum albumin are added as surfactant in water to prepare stealth and nonstealth nanoparticles respectively [3, 74]. The main goals of PEGylation method are to: Create larger PEG polymers to improve the pharmacokinetic and pharmacodynamic effects. PEGs attachment to polypeptide drugs. Preparation of branched-PEGs of greatly increased molecular masses upto 60 kDa or more [75]. The utility of polymeric micelles formed through multi molecular assembly of block copolymer, is as novel core-shell typed colloidal carriers for drug and gene targeting. Particularly, newer approaches for the formation of functionalized PEG layers as hydrophilic outer shell are focused to attain receptor mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Block copolymers with amphiphilic character having a large solubility difference between hydrophilic and hydrophobic segments, have a tendency to self-assemble into micelles in selective solvents [76-79]. This selfassembling property of amphiphilic block copolymers provides their high utility in the biomedical field as drug carriers, surface modifiers and colloidal dispersants [80-83]. The biocompatibility was achieved by the dense PEG shell, which endowed the micelle with a stealth character in the blood compartment, achieving a long circulation [84]. PEG chains attached to a surface of a nanosphere exhibits rapid chain motion in an aqueous medium. The steric repulsion resulting from a loss of conformational entropy contributes to the enhancement physiological properties of nanoparticles covered with PEG [85-91]. PEG grafted onto surfaces of biomedical devices is also found to increase their biocompatibility [92-95]. Recent developments in drug targeting have led to the design of drug carriers with application of block copolymer micelles as a novel carrier system for anticancer agents because of the high drug-loading capacity. Polymeric micelles have a size of 30-50 nm in diameter, ranging closely to Pg. 70

One possibility to prolong the circulation time is so-called stealth approach, the covalent attachment of polyethylene glycol (PEG) chains onto the polymer. This process is called PEGylation (or pegylation) of particles. The PEG chains are protruding from the nanoparticle surface into the aqueous environment yielding a hydrophilic shield around the particles and minimizing the adsorption of opsonins, compounds from the bloodstream that trigger the endocytotic uptake by macrophages and other cells of the RES [3]. To obtain coating, PEG is attached to the di-block copolymers (PLA/PLGA). PLA-PLGA (biodegradable, di-block, hydrophobic copolymer) nanoparticles could be obtained by high pressure emulsification-solvent evaporation technique using human serum albumin as colloidal stabilizer. PEG-R copolymers can be formed by the direct reaction of the terminal amino group from monoamine monomethoxy PEG with carboxyl end group of copolymer. The PEG-R polymers have amphiphilic properties where PEG due to its good water solubility represents the hydrophilic and R, being very soluble in organic phases, represents hydrophobic part. For this reason, nanoparticles can easily be formed by the solvent evaporation, solvent displacement methods or using salting-out process. The production can easily be optimized and particles Mandawgade et al

Int. J. Pharm. Biosci. Technol. that of viruses and apparently, this size range is favorable for extravasation to achieve so-called Enhanced Permeation Retention (EPR) effect [96]. However, physical coagulation forces may not be stable enough to maintain the micelle structure in the process of surface fixation. A disruption of the micelle upon attachment to the surface is reported both experimentally and theoretically [97-99]. This discrepancy may be solved by the preparation of reactive and structurally stabilized micelles. Heterobifunctional block copolymers of PEG-PLA that possess reactive group at the PEG-end and polymerizable group at the PLA-end were successfully prepared. The polymerization of PLA-end after micellization resulted in the formation of core polymerized micelles with high stability in harsh environment [100]. Then, the core-stabilized reactive micelles were covalently linked to the surface, forming a single layer of micelle as well as multilayered highly organized micelle hydrogel [101-103]. Surface covered with core-polymerized reactive micelle was evaluated by protein adsorption measurements. Quantitative analysis of adsorbed proteins on the surface was carried out by micro BCA (Bicinchoninic Acid) method [104]. It was noted that protein adsorption reduced with increasing the number of micelle coating. The micellar gel has another unique property that is not typical of conventional hydrogels. The gel consists of micelles that have hydrophobic cores of ~10 nm in size. The micelles on a surface are expected to hold drugs in the same manner as the ones in the solution and to release them in a controlled manner. As a model drug, pyrene was incorporated into the micellar solution. The results indicated that the loading capacity and the release-rate of a drug can be controlled by the number of coatings [105]. The use of gold colloid in biological applications began in 1971, and since that time, the labeling of targeting molecules, with gold nanoparticles has revolutionized the visualization of cellular components by electron microscopy techniques. [106]. Although metal and inorganic nanoparticles can be prepared from various materials by several methods [107-111], the coupling and functionalization with biological components has only been carried out with a limited number of chemical methods. On decreasing gold colloidal particle size, however, colloidal stability decreases significantly due to increased particle surface energy. Such gold nanoparticles aggregate in high ionic strength milieu as well as adsorb biomolecules such as proteins and DNA nonspecifically, resulting in reduced sensitivity and selectivity when used as colloidal sensor systems in biological fluids. PEG block copolymer micelles could be used successfully as nanoreactors for noble metal colloid formation. Furthermore, by controlling metal and semiconductor structure precisely through the concept to construct functionalized PEG layers, one can modify the nanostructures to better suit their integration with biological systems; for example, modifying their surface layer for enhanced aqueous solubility, biocompatibility and more importantly biorecognition [112]. The use of exquisite recognition properties of biomolecules in organizing non-biological inorganic objects into functional has led to new applications including ultrasensitive bioassays and multicolor fluorescent labels for high-throughput detection and imaging. In one of the studies carried out to investigate the influence of PEG coating on drug release rate from amoxicillinloaded polyethylcyanoacrylate (PECA) nanoparticles and their uptake by phagocytes, It was observed that PEG added in polymerization medium during the nanoparticle preparation, influences particle size, zeta potential, drugloading capacity, drug release rate and phagocytic uptake. Drug release studies in human plasma evidenced that the drug release is reduced as molecular weight of PEG rises. Phagocytosis studies showed significant differences between nanoparticles prepared in the presence or in the absence of PEG and demonstrated that PEG coating reduces macrophage uptake. Therefore, it could be concluded that nanoparticles prepared by emulsion polymerization of ethylcyanoacrylate in the presence of PEG, could be an injectable colloidal system with an ability to evade MPS recognition after intravenous injection. Drug release studies at pH 1.1 evidenced that the amoxicillin entrapped into PECA nanoparticles could be protected from the gastric acid degradation. Drug release studies performed at pH 4 in the presence of urease showed that this enzyme increases the drug release rate owing to its ability to catalyze the degradation process of nanoparticles by hydrolysis of ester bond in the side chain. Experimental results, mucoadhesive properties of polyalkylcyanoacrylate nanoparticles and activity of amoxicillin versus Helicobacter pylori, suggested that the colloidal drug delivery system could be useful for the treatment of diseases caused by H. pylori by per oral administration [113]. In the study on mechanochemical and interactive features of PEG-covered bilayers and monolayers lipid surfaces, special emphasis was made on characterizing the barrier properties of grafted Pg. 71

Mandawgade et al

Int. J. Pharm. Biosci. Technol. PEG layers. The information gained from such studies not only characterizes the membrane and other lipid surfaces and their inter-surface interactions but also provides essential materials property data that is required for successful design and deployment of lipid-based carriers socalled stealthy surface. Of importance here is the ability to measure the following, for a single particle: The binding of fluorescent molecular ligands to surface linked receptors, as was used to measure the surface density [114]. The uptake and desorption of various membrane-soluble components such as, lysolecithin (e.g. mono oleoyl phosphatidylcholine,) [115-117] and glycocholate [118] as monomer and micelle, manifested by a change in vesicle membrane area that can be converted, through molecular areas to concentrations of these surfactants in the bilayer. -The extent of vesicle membrane-membrane or other particle-surface interactions [119]. A rational design approach has made possible the deliberate engineering of surfaces with desirable properties and performance. For example, contact-mediated interactions of a surface with large macromolecules, lipoproteins and cells can be opposed by the repulsive presence of large PEGs (2000-5000 MW) at the surface. Similar resistance of the surface to smaller molecules can be effected by shorter PEGs (750 MW) at maximum surface density. A combination of the two PEG layers can therefore create a molecular scale filter which can provide either complete or selective protection of the surface to an extent dependent on the precise composition of the bimodal layer. If the binding moiety is located in an accessible region relative to the PEG layer then specific adhesion can occur without sacrificing the steric stabilization afforded by PEG. The interactive performance of a surface can therefore be finetuned by controlling such parameters as, polymer composition, size, density, and derivatization. An understanding of these design principles is imperative for the engineering of improved colloidal diagnostic and therapeutic carrier systems, which are often required to exhibit both longevity and targetspecificity [120]. The availability of large molecular weight proteinand peptide-based drugs are attractive, as their role in physiotherapy is better understood and because of the progress made in biotechnology and bioengineering, particularly, development of DNA-recombinant technology. Because of their poor transport across biological barriers due to poor diffusivity and low partition coefficients, parenteral administration through particulate biodegradable delivery systems is safe and can be controlled. Proteins and peptides are unstable in PLGA because of the hydrophobicity and acidity of PLGA. Another problem is the fast release of protein drugs from PLGA matrices. In order to circumvent these problems, different approaches have been explored to modify the properties of PLGA matrices by using the hydrogel nanoparticles [121-124]. Synthetic hydrogels offer a possibly effective and convenient way to administer these drugs. Hydrogels are hydrophilic, three-dimensional structures, which are capable to take up large amounts of water or biological fluids and thus resemble to biological tissues. Such materials can be utilised to respond to a number of physiological stimuli such as pH, ionic strength and temperature. A summary of monomers most commonly used in the preparation of polymeric materials in the pharmaceutical field is given in Table 1.

Table 1: Monomers most often used in the synthesis of synthetic hydrogels for pharmaceutical applications Abbreviation HEMA HEEMA EGDMA NVP NIPAAm MDEEMA Name of monomer Hydroxyethyl methacrylate Hydroxyethoxyethyl methacrylate Ethylene glycol dimethacrylate N-vinyl-2-pyrrolidone N-isopropyl AAm Methoxydiethoxyethyl methacrylate Abbreviation MEEM MEMA HDEEMA PEGA PEGMA PEGDA PEGDMA Name of monomer Methoxyethoxyethyl methacrylate Methoxyethyl methacrylate Hydroxydiethoxyethyl methacrylate PEG acrylate PEG methacrylate PEG diacrylate PEG dimethacrylate

Mandawgade et al

Pg. 72

Int. J. Pharm. Biosci. Technol. Hydrogels are also used as carriers that can interact with the mucosal lining in the gastrointestinal (GI) tract, colon, vagina, nose and other parts of the body due to their ability to prolong their residence time at the delivery location. The interaction between such carriers and glycoproteins in the mucosa is thought to occur primarily via hydrogen bonding. Therefore, materials containing a high density of carboxyl and hydroxy groups appear to be promising for this type of application. Monomers most often used for the synthesis of mucoadhesive polymers include acrylic and methacrylic acid (MAA). Undoubtedly, peroral delivery of peptides and proteins to the GI tract is one of the most challenging issues. There are many hurdles, including protein inactivation by digestive enzymes in the GI tract and poor epithelial permeability of these drugs. However few hydrogels may help to overcome some of these problems by appropriate molecular design or formulation approaches. For example, Akiyama et al. [125] reported novel per oral dosage forms of hydrogel formulations with protease inhibitory activities using Carbopol (C 934P), a poly(acrylic acid) product, which has been shown to have an inhibitory effect on the hydrolytic activity of trypsin. Recently, oral insulin delivery using pHresponsive complexation hydrogels was reported by Lowman et al. [126] The hydrogels used to confer protection to insulin against the inhospitable acidic environment in the stomach prior to its release in the small intestine, were crosslinked copolymers of PMAA with graft chains of polyethylene glycol (P(MAA-g-EG)). Insulincontaining P(MAA-g-EG) microparticles demonstrated strong dose-dependent hypoglycemic effects in in-vivo oral administration studies using both healthy and diabetic rats. It is worth noting that these effects were observed without the addition of additives such as, absorption enhancers or protease inhibitors. Several hydrogels are currently being investigated as potential devices for colon-specific drug delivery. Cross linked polysaccharides such as, dextran and amidated pectin are designed to be highly swollen or degraded in the presence of colonic enzymes or micro flora, that can result in colon-specific drug delivery. In recent years, transdermal route has been considered as a possible site for the systemic delivery of drugs. Gayet and Fortier [127] reported hydrogels obtained from the copolymerization of bovine serum albumin (BSA) and PEG. Current studies on implantable hydrogels have been directed towards the development of biodegradable systems requiring no follow-up surgical removal once the drug supply is depleted. Recently, two types of novel degradable PEG-hydrogels for controlled release of proteins were developed by Zhao and Harris [128]. One type is prepared by a polycondensation reaction between difunctional PEG acids and branched PEG polyols. Upon hydrolysis of the resulting ester linkages, these gels degrade into only PEG and PEG derivatives. The other is PEG-based hydrogels having functional groups in which protein drugs can be covalently attached to the gel network via ester linkage. Thus, the release of the protein drugs immobilized would be controlled by the hydrolysis of the ester linkage between the gel and the protein, followed by the diffusion of the protein out of the gel and by the degradation of the gel. Extensive research efforts on degradable dextran hydrogels have been carried out by Hennink and his coworkers [129, 130]. These hydrogels are based on acrylate derivatives of dextran. In their studies, application of hydrogels to the controlled release of protein was comprehensively investigated. Insulin release from these hydrogels was regulated by the surface degradation of PEG-Dex microdomain-structure. Other hydrogels which hold great promise as a drug delivery vehicles include neutral gels of PEO or PVA and gels of star molecules and other complex structures [131]. Other Extensively Used Techniques for NPs Preparation and Its Coating Despite the important efforts dedicated to the design of oral peptide delivery systems, the oral administration of these sensitive molecules remains a challenge. Many peptide drugs are quickly degraded by peptidases in the gut and poorly transported through the intestinal epithelium. As a consequence of the extremely limited oral bioavailability the administration of this peptide is restricted to the parenteral route and alternatively, to the nasal route where the absorption is still poor and highly variable [132]. Among the approaches that have been explored so far to make feasible the oral administration, the use of colloidal carriers represents a promising strategy. The known ability of lipids to protect peptides from degradation has motivated the design of lipid-based colloidal delivery systems, such as nanoemulsions, nanocapsules, liposomes or complexes-containing nanoparticles, intended for oral administration. A different approach towards the same goal has been based on improving the interaction of the colloidal carrier with the intestinal mucosa through the use of mucoadhesive polymers like, Carbopol [133, 134], chitosan (CS) [135, 136], poly(Nisopropylacrylamide) or poly(vinylamine) [137]. Besides their mucoadhesive properties, these Pg. 73

Mandawgade et al

Int. J. Pharm. Biosci. Technol. hydrophilic coatings are supposed to provide protection to the peptide against proteolytic enzymes and/or to enhance the transport of the peptide through the intestinal mucosa [138-139]. Development of surface-modified colloidal systems for transmucosal drug delivery represents nowadays an alternative to polymeric nanoparticles. The results of these studies have shown that the coating of hydrophobic polymeric nanoparticles and nanocapsules with hydrophilic polymers such as chitosan (CS) and PEG, has a clear benefit in their ability to enhance the transmucosal transport of the associated compounds, following either nasal, oral or ocular administration [140]. While the mechanisms responsible for this positive behavior are being investigated, evidence from the experiments performed until now is that hydrophilic coating improves the stability of the colloidal system in contact with the mucosal environment and in some cases, favors the interaction with epithelia, as demonstrated in different cell culture models [141]. In a comparative study for suitable excipients for surface-modification, new nanoparticulate delivery system was developed, consisting of lipid nanoparticles coated with CS, with potential application for oral administration of peptides. Furthermore, using salmon calcitonin (sCT) as a model peptide, the association and release characteristics of sCT from this new vehicle were compared with those of PEG-coated lipid nanoparticles. The results showed that the nature of the coating may affect the surface association and hence, the immediate release of the peptide, being this effect reduced for the nanoparticles coated with CS as compared to those coated with PEG. Finally, both coated nanoparticulate systems were able to provide a continuous delivery of the associated peptide [2]. One of the techniques reported for preparation of long-circulating nanoparticles as protein peptide delivery carriers makes use of merits of PEGPLGA nanoparticles with double emulsion method (w1/o/w2) for drug encapsulation [142]. Herein, monomethoxy-PEG induced lactide and glucolide ring opening polymerization reaction was employed to achieve PEG-PLGA with BSA as a model protein. BSA solution was emulsified in dichloromethane (DCM) containing PEG-PLGA by homogenization in ice bath. Thereafter, this emulsion was poured into PVA aqueous solution and homogenized in ice bath. The double emulsion was further diluted in PVA solution. DCM was rapidly evaporated under reduced pressure to obtain nanoparticles that were collected by centrifugation and washed thoroughly with water prior to lyophilization. The particle size of the nanoparticles was about 200 nm and BSA release from the stealth nanoparticles showed an initial burst followed by sustained release phase. Carbohydrates were also found to avoid MPS uptake when coated onto the surface of NPs. NPs of PLA and poly(L-lysine)-grafted-polysaccharide were developed for the delivery of DNA [143] and these were found to be resistant against selfaggregation and non-specific adsorption of serum proteins. Recently, Duchene et. al. [144] used amphiphilic cyclodextrin NPs to increase the loading of water-soluble drugs and bioavailability of poorly water-soluble drugs intended for targeted delivery. In order to further increase loading capacity, hydroxypropyl cyclodextrins were used. The size, zeta potential and cyclodextrin content were influenced by the nature of cyclodextrin. The smallest size particles were obtained from hydroxypropyl cyclodextrins. The presence of cyclodextrins in these NPs has drastically reduced the surface negativity probably due to their hydrophilicity and hence, the cyclodextrin coated NPs may help in avoiding the MPS. With the aim to determine the optimal PEG coating on biodegradable in terms of thickness and density, nanoparticles, to simultaneously reduce plasma protein adsorption, surface charge and interaction with phagocytic cells, the PEG molecular weight was varied from 200020000 g/mole and the particles were prepared using different PEG contents [145]. 2-DPAGE studies showed that plasma protein adsorption on PEGcoated PLA nanospheres strongly depends on the PEG molecular weight (i.e. PEG chain length at the particle surface) as well as on PEG content in the particles (i.e. PEG chain density at the surface of the particles). Phagocytosis by polymorphonuclear (PMN) cells studied using chemiluminescence and zeta potential data, agreed well with the same. PEG surface density threshold was found to ensure simultaneously efficient steric stabilization and to avoid the uptake by PMN cells. Size of PLA-PEG NPs depends on molecular weight of copolymers and PEG chain length and applying different techniques of preparation. PEG coating efficiency was affected by PLA molecular weight and preparation techniques. Greatest PEG surface density was achieved for lowest molecular weight PLA-PEG. The nanoparticles prepared by nanoprecipitation technique were notably larger than those obtained by the emulsification techniques. In emulsion procedures, high energy applied generates droplets of well defined diameter which became nanoparticles following the solvent evaporation. PEG coating density of the particles made with higher PLA-PEG molecular weight was sufficient to prevent their aggregation and permit their Pg. 74

Mandawgade et al

Int. J. Pharm. Biosci. Technol. transport as individual particles. More specifically, PLA-PEG particles with a high PEG coating density and a small size were more significantly transported than both noncoated PLA nanoparticles as well as PLA-PEG nanoparticles with a lower coating density [146]. Polymeric nanoparticles and micelles were also studied in terms of the statistical behavior of polymer [147]. A mechanism was proposed which assumes that the surface-grafted chains of flexible and hydrophilic polymers form dense conformational clouds thus preventing other polymers from interaction with the surface even at low concentrations of protecting polymeric layer. A theoretical model of repulsion of proteins from the solid substrate was also proposed [148]. This model provides a basis for the prevention of opsonins deposition. High surface density and long chain-lengths of PEG are necessary for low protein adsorption. However, surface density has a greater effect than the chain-length on steric repulsion. The optimum surface density of PEG on NPs plays an important role in steric repulsion. In addition, the distance between PEG chains on the surface of NPs is critical to avoid the adsorption of plasma proteins. Conclusion Long circulation of drugs in the body is the key requirement for successful drug delivery and drug targeting to the site of action. Many polymeric nanoparticles have been developed for this purpose. Certainly, surface modification is useful in achieving these goals. In this article we have scrutinized the wide range of approaches in the design of colloid based long-circulating drug carrier systems. The current focus of research in this area has generated a broad spectrum of carriers with the majority showing better biological performance in terms of both circulation time and target specificity. Production of polymeric nanoparticles using environmentally friendly processes is quite a promising area of research. Although many important goals have been reached in achieving stabilization of drugs in circulation, yet more investigations are needed to develop the newer materials in this area. At present, the research focus tends to be on a single strategy rather than using a range of potentially complimentary tactics for engineering of longcirculatory particles. Finally, a major factor that has been ignored is genetics. Future considerations must be given towards the immunogenetic and pharmacogenetic differences and related polymorphisms. Findings from newer technologies and advanced study models could be useful in designing of long-circulating nanoparticles having low interactions with plasma proteins and phagocytic cells. Moreover, the Mandawgade et al knowledge of the type of plasma proteins adsorbed as a function of the core type and the invivo studies which are underway with these nanoparticles could help determining the role played by these proteins in the fate of the carriers. REFERENCES 1. Trevor MJ. Improved drug delivery: a perspective from industry. In: Prescott LF, Nimmo WS. Editors, Novel Drug/delivery and its therapeutic applications. Chichester: Wiley; 1989. 23-32. 2. Garcia-Fuentes M, Torres D, Alonso MJ. New surface-modified lipid nanoparticles as delivery vehicles for salmon calcitonin. International Journal of Pharmaceutics. 2005; 296(1-2): 122132. 3. Norris DA, Puri N, Sinko PJ. The effect of physical barriers and properties on the oral absorption of particulates. Advanced Drug Delivery Reviews. 1998; 34(2-3): 135 154. 4. Kreuter J, In: Kreuter J. Colloidal Drug Delivery Systems. New York; Marcel Dekker: 1994. 219315. 5. Hbel S, Loos A, Appelhans D, Schwarz S, Seidel J, Voit B, Aigner A. Maltose- and maltotriose-modified, hyperbranched poly(ethylene imine)s (OM-PEIs): Physicochemical and biological properties of DNA and siRNA complexes. Journal of Controlled Release. 2011; 149(2): 146-158. 6. Moghimi SM, Hunter AC, Murray JC. Longcirculating and Target Specific Nanoparticles: Theory to Practice. Pharmacological Reviews. 2001; 53(2): 283318. 7. Weiss L, Tavassoli M. Anatomical hazards to the passage of erythrocytes through the spleen. Seminars in Hematology. 1970; 7: 372380. 8. Schnitzer B, Sodeman T, Mead ML, Contacos PG. Pitting function of the spleen in malaria: ultrastructural observations. Science. (Wash DC). 1972; 177 (4044):175177. 9. Chen LT, Weiss L. The role of the sinus wall in the passage of erythrocytes through the spleen. Blood. 1973; 41(4): 52937. 10. Moghimi SM. Mechanisms of splenic clearance of blood cells and particles: towards development of new splenotropic agents. Advanced Drug Delivery Reviews. 1995; 17(1): 103115.

Pg. 75

Int. J. Pharm. Biosci. Technol. 11. Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. Role of CD47 as a marker of self on red blood cells. Science. 2000; 288(5473): 20512054. 12. Waser PG, Mller U, Kreuter J, Berger S, Munz K, Kaiser E, Pfluger B. Localization of colloidal particles (liposomes, hexylcyanoacrylate nanoparticles and albumin nanoparticles) by histology and autoradiography in mice. International Journal of Pharmaceutics. 1987; 39(3): 213227. 13. Campbell T, Udipi K. Nanoparticle-based controlled release polymer coatings for medical implants US -20050095267. 14. Ginty PJ, Whitaker MJ, Shakesheff KM, Howdle SM. Drug delivery goes supercritical. Materials Today. 2005; 8(8): 4248 15. Wang Y, Pfeffer R, Dave R. Polymer coating/encapsulation of nanoparticles using a supercritical antisolvent process. WO 2004091571. 16. Foster N, Mammucari R, Dehghani F, Barrett A, Bezanehtak K, Coen E, Combes G, Meure L, Ng A, Regtop HL. Tandya A. Processing Pharmaceutical Compounds Using Dense Gas Technology. Industrial & Engineering Chemistry Research.2003; 42(24): 6476-6493. 17. Woods HM, Silva MMCG, Nouvel C, Shakesheff KM, Howdle SM. Materials processing in supercritical carbon dioxide: surfactants, polymers and biomaterials. Journal of Materials Chemistry. 2004; 14: 1663-1678. 18. Bolanos G, Liu GZ, Hochgeschurtz T, Thies MC. Producing a carbon fiber precursor by supercritical fluid extraction. Fluid Phase Equilibria. 1993; 82: 303-10. 19. Matson DW, Petersen RC, Smith RD. Production of powders and films by the rapid expansion of supercritical solutions. Journal of Materials Chemistry.1987; 22: 1919-1928. 20. Matson DW, Petersen RC, Smith RD. The preparation of polycarbosilane powders and fibers during rapid expansion of supercritical fluid solutions. Materials Letters. 1986; 4(10): 429-432. 21. Alessi P, Cortesi A, Kikic I, Foster NR, Macnaughton SJ, Colombo I. Particle Production of Steroid Drugs Using Supercritical Fluid Processing. Industrial & Engineering Chemistry 35(12): 4718-4726. Research. 1996;

22. Charoenchaitrakool M, Dehghani F, Foster NR, Chan HK. Micronization by Rapid Expansion of Supercritical Solutions to Enhance the Dissolution Rates of Poorly Water-Soluble Pharmaceuticals. Industrial & Engineering Chemistry Research. 2000; 39(12): 4794-4802. 23. Kayrak D, Akman U, Hortasu O. Micronization of Ibuprofen by RESS. The Journal of Supercritical Fluids. 2003; 26(1): 17-31. 24. Hu G, Chen H, Cai J. Deng X. Micronization of griseofulvin by RESS in supercritical CO2 with cosolvent acetone. Chinese Journal of Chemical Engineering. 2003; 11(4): 403-407. 25. Turk M, Lietzow R. Stabilized nanoparticles of phytosterol by rapid expansion from supercritical solution into aqueous solution. AAPS PharmSciTech. 2004; 5(4): 56-66. 26. Tom JW, Debenedetti PG. Formation of bioerodible polymeric microspheres and microparticles by rapid expansion of supercritical solutions. Biotechnology progress. 1991; 7(5): 403-411. 27. Tom JW, Lim GB, Debendetti PG, Prudhomme KR. Applications of supercritical fluids in the controlled release of drugs. ACS Symposium Series. 1993; 514: 238-257. 28. Petra S, Stane SI, Zeljko K, Janez K. Improvement of nifedipine dissolution characteristics using supercritical CO2. International Journal of Pharmaceutics1997; 148(2): 123-30. 29. Kerc J, Srcic S, Knez Z, Sencar-Bozic P. Micronization of drugs using supercritical carbon dioxide. International Journal of Pharmaceutics. 1999; 182(1): 33-39. 30. Hao J, Whitaker MJ, Wong B, Serhatkulu G, Shakesheff KM, Howdle SM. Plasticization and Spraying of Poly (DL-lactic acid) Using Supercritical Carbon Dioxide: Control of Particle Size. Journal of Pharmaceutical Sciences. 2004; 93(4):1083-1090. 31. Whitaker MJ, Hao J, Davies OR, Serhatkulu G, Stolnik-Trenkic S, Howdle SM, Shakesheff KM. The production of protein-loaded microparticles by supercritical fluid enhanced mixing and spraying. Journal of Controlled Release. 2005; 101(1-3): 85-92. 32. Yeo SD, Lim GB, Debenedetti PG, Bernstein H. Formation of microparticulate protein Pg. 76

Mandawgade et al

Int. J. Pharm. Biosci. Technol. powders using a supercritical fluid antisolvent. Biotechnology Bioengineering. 1993; 41: 341346. 33. Yeo S, Debenedetti PG, Patro SY, Przycien TM. Secondary Structure Characterization of Microparticulate Insulin Powders. Journal of Pharmaceutical Sciences 1994; 83: 16511656. 34. Winters MA, Knutson BL, Debenedetti PG, Sparks HG, Przybycien TM, Stevenson CL, Prestrelski SJ. Precipitation of Proteins in Supercritical Carbon Dioxide. Journal of Pharmaceutical Sciences. 1996; 85: 586-594. 35. Warwick B, Dehghani F, Foster NR, Biffin JR, Regtop HL. Micronization of Copper Indomethacin Using Gas Antisolvent Processes. Industrial & Engineering Chemistry Research 2002; 41:1993-2004. 36. Falk R, Randolph TW, Meyer JD, Kelly RM, Manning MC. Controlled release of ionic compounds from poly ( -lactide) microspheres produced by precipitation with a compressed antisolvent. Journal of Controlled Release. 1997; 44 (1): 77-85. 37. Jarmer DJ, Lengsfeld CS, Randolph TW. Manipulation of particle size distribution of poly (L-lactic acid) nanoparticles with a jetswirl nozzle during precipitation with a compressed antisolvent. Journal of Supercritical Fluids. 2003; 27(3): 317-336. 38. Jarmer DJ, Lengsfeld CS, Randolph TW. Nucleation and growth rates of poly (L-lactic acid) microparticles during precipitation with a compressed-fluid antisolvent. Langmuir. 2004; 20(17): 7254-7264. 39. Bleich J, Muller BW. Production of drug loaded microparticles by the use of supercritical gases with the Aerosol Solvent Extraction System (ASES) process. Journal Microencapsulation. 1996;13(2):131-139. 40. Tu LS, Dehghani F, Foster NR. Micronisation and microencapsulation of pharmaceuticals using a carbon dioxide antisolvent. Powder Technology. 2002; 126(2):134-149. 41. Witschi C, Doelkar E. Influence of the microencapsulation method and peptide loading on poly (lactic acid) and poly (lacticco-glycolic acid) degradation during in vitro testing. Journal of Controlled Release. 1998; 51(2-3): 327-341. 42. Steckel H, Thies J, Mller BW. Micronizing of steroids for pulmonary delivery by Supercritical carbon dioxide. International Mandawgade et al Journal of Pharmaceutics. 1997; 152(1): 99110. 43. Hanna M, York P. Method and apparatus for the formation of particles. WO A1 9501221. 44. Beach S, Latham D, Sidgwick C, Hanna M, York P. Control of the physical form of salmeterol xinafoate. Organic Process Research Development. 1999; 3(5): 370-376. 45. Tservistas M, Levy MS, Lo-Yim MY, O'Kennedy RD, York P, Humphrey GO, Hoare M. The formation of plasmid DNA loaded pharmaceutical powders using supercritical fluid technology. Biotechnology and Bioengineering. 2001; 72(1): 12-18. 46. Reverchon E, Porta GD, Spada A, Antonacci A. Griseofulvin micronization and dissolution rate improvement by supercritical assisted atomization. Journal Pharmacy and Pharmacology. 2004; 56(11): 1379-87. 47. Reverchon E, Porta GD, Spada A. Ampicillin micronization by supercritical assisted atomization. Journal Pharmacy and Pharmacology. 2003; 55(11): 1465-1471. 48. Langer R, Vacanti JP. Tissue engineering. Science.1993; 260(5110): 920-926. 49. Sheridan MH, Shea LD, Peters LC, Mooney DJ. Bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery. Journal of Controlled Release. 2000; 64(1-3): 91-102. 50. Hile DD, Amirpour ML, Akgerman A, Pishko MV. Active growth factor delivery from poly (lactide-co-glycolide) foams prepared in supercritical CO2. Journal of Controlled Release. 2000; 66(2-3): 177-185. 51. Guney O, Akgerman A. Synthesis of controlled-release products in supercritical medium. AIChE Journal. 2002; 48(4): 856-866. 52. Palmer LR, Cuesta SA. Polymeric nanoparticle and bioactive coating formulations US 2004063831(A1) 53. Ammoury N, Dubrasquet M, Fessi H, Devissaguet JP, Puisieux F, Benita S. Indomethacin-loaded poly (D,L-lactide) nanocapsules: protection from gastrointestinal ulcerations and antiinflammatory activity evaluation in rats. Clinical Material. 1993; 13(1-4):12130. 54. Guterres SS, Fessi H, Barratt G, Puisieux F, Devissaguet J. Poly (D,L-lactide) nanocapsules containing non-steroidal antiinflammatory drugs: gastrointestinal Pg. 77

Int. J. Pharm. Biosci. Technol. tolerance following intravenous and oral administration. Pharmaceutical Research1995; 12(10): 15451547. 55. Guterres SS, Fessi H, Barratt G, Devissaguet J, Puisieux F. Poly (D, L-lactide) nanocapsules containing diclofenac: I. formulation and stability study. International Journal of Pharmaceutics. 1995; 113(1): 5763. 56. Skiba M, Morvan C, Duchene D, Puisieux F, Wouessidjewe D. Evaluation of gastrointestinal behaviour in the rat of amphiphilic -cyclodextrin nanocapsules, loaded with indomethacin. International Journal of Pharmaceutics. 1995; 126(1): 275 279. 57. Magenheim B, Benita S. Nanoparticle characterization: a comprehensive physicochemical approach. STP Pharma Sciences. 1991; 1: 221241. 58. Bodmeier R, Chen H. Preparation of biodegradable poly (+/-) lactide microparticles using a spray-drying technique. Journal of Pharmacy and Pharmacology. 1988; 40(11): 754757. 59. Conte U, Conti B, Giunchedi P, Maggi L. Spray dried polylactide microsphere preparation: influence of the technological parameters. Drug Development and Industrial Pharmacy. 1994;20 (3) :235258. 60. Palmieri GF, Bonacucina G, Martino P, Martelli S. Spray-drying as a method for microparticulate controlled release systems preparation: advantages and limits. I. Watersoluble drugs. Drug Development and Industrial Pharmacy. 2001; 27(3): 195204. 61. Palmieri GF, Wehrle P. Stamm A. Evaluation of spray-drying as a method to prepare microparticles for controlled drug release. Drug Development and Industrial Pharmacy. 1994; 20 (18): 28592879. 62. Huang YC, Chiang CH, Yeh MK. Optimizing formulation factors in preparing chitosan microparticles by spray-drying methods. Journal of Microencapsulation. 2003; 20: 247 260. 63. Wan LSC, Heng PWS, Chia CGH. Spray drying as a process for microencapsulation and the effect of different coating polymers. Drug Development and Industrial Pharmacy. 1992; 18(9): 9971011. 64. Lin S, Kao Y. Tablet formulation study of spray-dried sodium diclofenac entericcoated microcapsules. Pharmaceutical Research. 1991; 8 (7): 919924. 65. Kawashima Y, Iwamoto T, Niwa T, Takeuchi H, Hino T. Uniform and improved bioavailability of newly developed rapid and sustained release suspensions of ibuprofen microspheres. International Journal of Pharmaceutics.1993; 89(1): 917. 66. Watanabe T, Wakiyama N, Usui F, Ikeda M, Isobe T, Senna M. Stability of amorphous indomethacin compounded with silica. International Journal of Pharmaceutics2001; 226(1-2): 8191. 67. Fessi H. Puisieux F, Devissaguet J. Proceed de preparation dessystemes colodaux d'une substance sous forme de nanocapsules. European Patent 0274961 A1. 68. Beck RCR, Pohlmann AR, Guterres SS. Nanoparticle-coated microparticles: preparation and characterization. Journal of Microencapsulation. 2004; 21(5): 499512. 69. Lee, KE, Cho SH, Lee HB, Jeong SY, Yuk SH. Microencapsulation of lipid nanoparticles containing lipophilic drug. Journal of Microencapsulation. 2003; 20(4): 489496. 70. Cho CS, Jeong YI, Ishihara T, Takei R, Park JU, Park KH, Maruyama A, Akaike T. Simple preparation of nanoparticles coated with carbohydrate-carrying polymers. Biomaterials. 1997; 18(4): 323-326. 71. Lasic DD. Mixed micelles in drug delivery. Nature. 1992; 135(6357): 279-80. 72. Kwon GS, Naito M, Yokoyama M, Okano T, Sakurai Y. Kataoka K. Physical entrapment of adriamycin in AB blocks copolymer micelles. Pharmaceutical Research.1995; 12(2): 192195. 73. Stella VJ, Rajewski RA, Rao VM, McGinity JW, Mosher LG. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations, US 6046177. 74. Verrecchia T, Spenlehauer G, Bazile DV, Murry-Brelier A, Archimbaud Y, Veillard M. Non-stealth (poly(lactic acid/albumin)) and stealth ( poly(lactic acid-polyethylene glycol)) nanoparticles as injectable drug carriers. Journal of Controlled Release. 1995; 36(1-2): 49-61. 75. Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Natural Reviews Drug Discovery. 2003; 2(3): 214-221.

Mandawgade et al

Pg. 78

Int. J. Pharm. Biosci. Technol. 76. Moffitt M, Khougaz K, Eisenberg A. Micellization of ionic block copolymers. Accounts Chem Res. 1996; 29(2): 95102. 77. Munk P, Prochazka K, Tuzar Z, Webber SE. Exploiting polymer micelle technology. Chemtech. 1998; 28(10): 2028. 78. Tuzar Z, Kratochvil P. Micelles of blocks and graft copolymers in solutions. Surface and Colloid Science. 1993; 15(1) :183. 79. Allen C, Maysinger D, Eisenberg A. Nanoengineering block copolymer aggregates for drug delivery. Colloids and Surfaces B: Biointerfaces.1999; 16(1-4): 327. 80. Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Advanced Drug Delivery Reviews. 2001; 47(1): 113131. 81. Cammas-Marion S, Okano T, Kataoka K. Functional and site-specific macromolecular micelles as high potential drug carriers. Colloids and Surfaces B: Biointerfaces. 1999; 16(1-4): 207215. 82. Kramarenko EY, Potemkin II, Khokhlov AR, Winkler RG, Reineker P. Surface micellar nanopattern formation of adsorbed diblock copolymer system. Macromolecules. 1999; 32(10): 34953501. 83. Antonietti M, Goltner C. Superstructures of functional colloids: chemistry on the nanometer scale. Angewandte Chemie International Edition. 1997; 36(9): 910928. 84. Kataoka K, Kwon GS, Yokoyama M, Okano T, Sakurai Y. Block copolymer micelles as vehicles for drug delivery. Journal of Controlled Release. 1993; 24(1-3): 11932. 85. Kataoka K. Design of nanoscopic vehicles for drug targeting based on micellization of amphiphilic block copolymers. Journal of Macromolecular Science, Part A: Pure and Applied Chemistry. 1994; 31(11): 17591769. 86. Yokoyama M, Okano T, Sakurai Y, Ekimoto H, Shibazaki C, Kataoka K. Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood. Cancer Research. 1991; 51(12): 32293236. 87. Yokoyama M, Mitauchi M, Yamada N, Okano T, Sakurai Y, Kataoka K, Lnoue S. Polymer micelles as novel drug carrier: adriamycinconjugated poly (ethylene glycol) - poly (aspartic acid) block copolymer. Journal of Controlled Release. 1990; 11(1-3): 269278. Mandawgade et al 88. Peracchia MT, Vauthier C, Puisieux F, Couvreur P. Development of sterically stabilized poly(isobutyl 2-cyanoacrylate) nanoparticles by chemical coupling of poly(ethylene glycol). J Biomedical Materials Research. 1997; 34(3): 317326. 89. Bergstrm K, Osterberg E, Holmberg K, Hoffman AS, Schuman TP, Kozlowski A, Harris JH. Effects of branching and molecular weight of surface-bound poly(ethyleneglycol) on protein rejection. J Biomaterials Sciences Polymer Edition. 1994; 6(2): 123132. 90. Gref R, Minamitake Y, Peracchia MT, Torchilin V, Trubetskoy V, Langer R, Biodegradable long-circulating polymeric nanosphere. Science. 1994; 263(5153):1600 1603. 91. Peracchia MT, Vauthier C, Desmaele D, Gulik A, Dedieu JC, Demoy M, Angelo J. Couvreur P. Pegylated nanoparticles from a novel methoxypolyethylene glycol [cyanoacrylate- hexadecyl cyanoacrylate amphiphilic copolymer. Pharmaceutical Research 1998; 15(4): 550556. 92. Holmberg K, Bergstrom K, Brink C, Sterberg EO, Tiberg F, Harris JM. Effects on protein adsorption, bacterial adhesion and contact angle of grafting PEG chains to polystyrene. Journal of Adhesion Science and Technology. 1993; 7(6): 503517. 93. Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications. Advanced Drug Delivery Reviews. 2003; 55(3): 403419. 94. Deible CR, Beckman EJ, Russell AJ, Wagner WR. Creating molecular barriers to acute platelet deposition on damaged arteries with reactive polyethylene glycol. Journal Biomedical Material Research. 1998; 41(2): 251256. 95. Jo S, Park K. Surface modification using silanated poly-(ethylene glycol)s. Biomaterials. 2000; 21(6): 605616. 96. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Research.1986; 46(12): 63876392. 97. Farinha JPS, Oliveira JMR, Martinoho JM, Xu R, Winnik MA. Structure in tethered chains: polymeric micelles and chains anchored on

Pg. 79

Int. J. Pharm. Biosci. Technol. polystyrene latex spheres. Langmuir. 1998; 14(9): 22912296. 98. Bijsterbosch HD, Stuart MAC, Fleer GJ. Adsorption kinetics of diblock copolymers from a micellar solution on silica and titania. Macromolecules. 1998; 31(26): 92819294. 99. Jonner A, Joanny JF. Block copolymer adsorption in a selective solvent: a kinetic study. Macromolecules.1990; 23(26): 5299 5311. 100. Iijima M, Nagasaki Y, Okada T, Kato M, Kataoka K. Core-polymerized reactive micelles from heterotelechelic amphiphilic block copolymers. Macromolecules. 1999; 32(4): 11401146. 101. Emoto K, Nagasaki Y, Kataoka K. Coating of surfaces with stabilized reactive micelles from poly (ethylene glycol)-poly (D, L-lactic acid) block copolymer. Langmuir. 1999; 15(16): 52125218. 102. Emoto K. Nagasaki Y, Kataoka K. A core shell structured hydrogel thin layer on surfaces by lamination of a poly-(ethylene glycol)-b-(D,L-lactide) micelle and polyallylamine. Langmuir. 2000; 16(13): 57385742. 103. Emoto K, Iijima M, Nagasaki Y, Kataoka K. Functionality of polymeric micelle hydrogels with organized three-dimensional architecture on surfaces. Journal of the American Chemical Society. 2000; 122(11): 26532654. 104. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto FK, Goeke NM, Olson BJ, Klenk DC. Measurement of protein using bicin-choninic acid. Analytical Biochemistry. 1985; 150(1): 7685. 105. Kwon GS, Suwa S, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly (ethylene oxide-aspartate) block copolymeradriamycin conjugates. Journal of Controlled Release. 1994; 29(1-2):1723. 106. Beesley JE. Colloidal Gold: Principles, Methods and Applications. In: Hayat MA. Editors. New York: Academic Press; 1989. pp. 421-425. 107. Schmid G. Large clusters and colloids. Metals in the embryonic state. Chemical Reviews. 1992; 92(8):17091727. 108. Kreibig U, Vollmer M. Optical Properties of Metal Clusters. New York: Springer; 1995. 109. Alvisatos AP. Semiconductor clusters, nanocrystals, and quantum dots. Science. 1996; 271(5251): 933937. 110. Feldheim DL, Keating CD. Self-assembly of single electron transistors and related devices. Chemical Society Reviews.1998; 27(1): 112. 111. Shipway AN, Katz E, Willner I. Nanoparticle arrays on surfaces for electronic, optical, and sensor applications. ChemPhysChem. 2000; 1(1): 1852. 112. Mirkin CA, Taton TA. Semiconductors meet biology. Nature. 2000; 405: 626627. 113. Fontana G, Licciardi M, Mansueto S, Schillaci D, Giammona G. Amoxicillin-loaded polyethylcyanoacrylate nanoparticles: Influence of PEG coating on the particle size, drug release rate and phagocytic uptake. Biomaterial. 2001; 22(21): 2857-2865. 114. Noppl-Simson D, Needham D. Avidinbiotin interactions at vesicle surfaces: adsorption and binding, cross-bridge formation, and lateral interactions. Biophysical Journal. 1996; 70(3): 1391-1401. 115. Needham D, Zhelev DV. Lysolipid exchange with lipid vesicle membranes. Ann Biomed Eng. 1995; 23(3): 287-298. 116. Zhelev DV. Exchange of monooleoylphosphatidylcholine with single egg phosphatidylcholine vesicle membranes. Biophysical Journal. 1996; 71(1): 257-273. 117. Needham D, Stoicheva N, Zhelev DV. Exchange of monooleoyl phosphatidyl choline as monomer and micelle with membranes containing poly (ethylene glycol)-lipid. Biophysical Journal. 1997; 73(5): 2615-2629. 118. Evans E, Rawicz W, Hofmann AF. Lipid bilayer expansion and mechanical disruption in solutions of water soluble bile acid, The Thirteenth International Bile Salt Meeting. Bile Acids in Gastroenterology: Basic and Clinical Advances Falk Symposium, San Diego, 1994. 119. Evans E, Metcalfe M. Free energy potential for aggregation of giant, neutral lipid bilayer vesicles by Van der Waals attraction. Biophysical Journal. 1984; 46(3): 423-426.

Mandawgade et al

Pg. 80

Int. J. Pharm. Biosci. Technol. 120. Needham D, Kim DH. PEG-covered lipid surfaces: bilayers and monolayers. Colloids and Surfaces B: Biointerfaces. 2000; 18(3-4): 183195. 121. Couvreur P, Puiseux F. Nano and microparticles for the delivery peptides and proteins. Advanced Drug Delivery Reviews.1993; 10(2-3): 141-162. 122. Uchida T, Yagi A, Oda Y, Dakada Y, Goto S. Instability of bovine insulin in poly (L-coglycolide) microsperes. Chemical & Pharmaceutical Bulletin. 1996; 44(1): 235-236. 123. Lin JK, Wang N, Wu XS. A novel biodegradable system based on gelatin nanoparticles and PLGA microspheres for protein and peptide drug delivery. Journal of Pharmaceutical Sciences. 1997; 86(8): 891895. 124. Wang N, Wu XS, Li JK. A heterogeneously structured composite based on PLGA microspheres and Poly (vinyl) alcohol hydrogel nanoparticles for long term protein drug delivery. Pharmaceutical Research. 1999; 16(9):1430-1435. 125. Akiyama Y, Lueen HL, de Boer AG, Verhoef JC, Junginger HE. Novel peroral dosage forms with protease inhibitory activities. II. Design of fast dissolving poly (acrylate) and controlled drug releasing capsule formulations with trypsin inhibiting properties. International Journal of Pharmaceutics. 1996; 138(1): 13-23. 126. Lowman AM, Morishita M, Kajita M, Nagai T, Peppas NA. Oral delivery of insulin using pH-responsive complexation gels. Journal of Pharmaceutical Sciences. 1999; 88(9): 933937. 127. Gayet JC, Fortier G. High water content BSA-PEG hydrogel for controlled release device: evaluation of the drug release properties. Journal of Controlled Release. 1996; 38(2-3): 177-184. 128. Zhao X, Harris JM. Novel degradable poly (ethylene glycol) hydrogels for controlled release of protein. Journal of Pharmaceutical Sciences. 1998; 87(11): 1450-1458. 129. Hennink WE, Talsma H, Borchert JCH, De Smedt SC, Demeester J. Controlled release of proteins from dextran hydrogels. Journal of Controlled Release. 1996: 39(1): 47-55. 130. Franssen O, Vandervennet L, Roders P, Hennink WE. Degradable dextran hydrogels: controlled release of a model Mandawgade et al protein from cylinders and microspheres. Journal of Controlled Release. 1999; 60(2-3): 211-221. 131. Peppasa NA, Buresa P, Leobandunga W, Ichikawa H. Hydrogels in pharmaceutical formulations. European Journal of Pharmaceutics and Biopharmaceutics. 2000; 50(1): 27-46. 132. Lee WA, Ennis RD, Longenecker JP, Bengtsson P. The bioavailability of intranasal salmon calcitonin in healthy volunteers with and without permeation enhancer. Pharmaceutical Research 1994; 11(5): 747 750. 133. Baluom M, Friedman DI, Rubinstein A. Absorption enhancement of calcitonin in the rat intestine by carbopol containing submicron emulsion. International Journal of Pharmaceutics. 1997; 154(2): 235243. 134. Yoo HS, Park TG. Biodegradable nanoparticles containing protein-fatty acid complexes for oral delivery of salmon calcitonin. Journal of Pharmaceutical Sciences. 2004; 93(2): 488495. 135. Kawashima Y, Yamamoto H, Takeuchi H, Kuno Y. Mucoadhesive dl-lactide/glycolide copolymer nanospheres coated with chitosan to improve oral delivery of elcatonin. Pharmceutical Development Technology. 2000; 5(1): 7785. 136. Takeuchi H, Matsui Y, Yamamoto H, Kawashima Y. Muchoadhesive properties of carbopol or chitosan-coated liposomes and their effectiveness in the oral administration of calcitonin to rats. Journal of Controlled Release. 2003; 86(2-3): 235242. 137. Sakuma S, Ishida Y, Sudo R, Suzuki N, Kikuchi H, Hiwatari K, Kishida A, Akashi M, Hayashi M. Stabilization of salmon calcitonin by polystyrene nanoparticles having surface hydrophilic polymeric chains, against enzymatic degradation. International Journal of Pharmaceutics. 1997; 159(2): 181189. 138. Dodane V, Khan MA, Merwin JR. Effect of chitosan on epithelial permeability and structure. International Journal of Pharmaceutics. 1999; 182(1): 2132. 139. Lueben HL, Verhoef JC, Borchard G, Lehr CM, Boer AGD, Junginger HE. Mucoadhesive polymers in peroral peptide drug delivery. II. Carbomer and polycarbophil are potent inhibitors of the intestinal proteolytic enzyme trypsin. Pharmaceutical Research. 1995; 12(9): 12931298. Pg. 81

Int. J. Pharm. Biosci. Technol. 140. Campos AMD, Sanchez A, Gref R, Calvo P, Alonso MJ. The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa. European Journal Pharmaceutical sciences. 2003; 20(1): 7381. 141. Behrens I, Pena AIV, Alonso MJ, Kissel T. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: the effect of mucus on particle adsorption and transport. Pharmaceutical Research. 2002; 19(8): 1185 1193. 142. Li YP, Pei YY, Zhang XY, Gu ZH, Zhou ZH, Yuan YF, Zhou JJ, Zhu JH, Gao XJ. PEGylated PLGA Nanoparticles as protein carriers: synthesis, Preparation and biodistribution in rats. Journal of Controlled Release. 2001; 71(2): 203-211. 143. Maruyama A, Ishihara T, Kim SW, Akaike T. Nanoparticle DNA carrier with poly (Llysine) grafted polysaccharide copolymer and poly (D, L- lactic acid). Bioconjugate Chemistery. 1997; 8(5): 735-742. 144. Duchne D, Wouessidjewe D, Ponchel G. Cyclodextrins and carrier systems. Journal of Controlled Release. 1999; 62(1-2): 263-268. 145. Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnisch S, Blunk T, Muller RH. Stealth corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids and Surfaces B: Biointerfaces. 2000; 18(3-4): 301 313. 146. Vila A, Gill H, McCallion O, Alonso MJ. Transport of PLA-PEG particles across the nasal mucosa: effect of particle size and PEG coating density. Journal of Controlled Release. 2004; 98(2): 231-244. 147. Torchilin VP. Polymer-coated longcirculating microparticulate pharmaceuticals. Journal of Microencapsulation. 1998; 15(1): 1-19. 148. Joen SI, Lee JH, Andrade JD, De Gennes PG. Protein-surface interactions in the presence of polyethylene oxide: I. Simplified Theory. Journal of Colloid Interface Sciences. 1991; 142(1): 149-158.

Mandawgade et al

Pg. 82

Int. J. Pharm. Biosci. Technol.

How to cite this article APA style Mandawgade, S. D., Patil, S. C., & Patravale, V. B. (2013). Surface modification techniques for active targeting of polymeric nanoparticles. International Journal of Pharma Bioscience and Technology, 1(2), 6482. Elsevier Harvard style Mandawgade, S.D., Patil, S.C., Patravale, V.B., 2013. Surface modification techniques for active targeting of polymeric nanoparticles. Int. J. Pharm. Biosci. Technol. 1, 6482. Vancouver Style Mandawgade SD, Patil SC, Patravale VB. Surface modification techniques for active targeting of polymeric nanoparticles. Int. J. Pharm. Biosci. Technol. 2013;1(2):6482.
To receive bibliographic information in RIS format (For Reference Manager, ProCite, EndNote): Send request to: ijpbst@yahoo.com