analysis of nodal involvement in patients treated with preoperative chemotherapy eur j gynaecol oncol montero ca, gimferrer jm, baldo x and ramirez j mediastinal metastasis of ovarian carcinoma eur j obstet gynecol reprod biol zakaria er, simonsen o, rippe a and rippe � transport of tracer albumin from peritoneum to plasma role of diaphragmatic, visceral, and parietal lymphatics am } physiol h yuan zy, rodela h, hay jb, oreopoulos d and johnston mg crrbcs and albumin as markers to estimate lymph drainage of the peritoneal cavity in sheep } appl physiol flessner mf, parker rj and sieber sm peritoneal lymphatic uptake of fibrinogen and erythrocytes in the rat am j physiol h hirano � and hunt ca losartan mecanismo de accion lymphatic transport of liposomeencapsulated agents effects of liposome size following intraperitoneal administration ] pharm sci sharma a, sharma us and straubinger rm paclitaxelliposomes for intracavitary therapy of intraperitoneal p leukemia cancer lett markman m et al phase i trial of intraperitoneal taxol a gynecoloic oncology group study } clin oncol lee mj et al intraperitoneal gene delivery mediated by a novel cationic liposome in a peritoneal disseminated ovarian cancer model gene ther hribaschek a et al prophylaxis of peritoneal carcinomatosis in experimental investigations int j colorectal dis hribaschek a et al intraperitoneal treatment using taxol is effective for experimental peritoneal carcinomatosis in a rat model oncol rep eltabbakh gh, piver ms, hempling re, recio fo and intengen me clinical losartan mecanismo de accion picture, response to therapy, and survival of women with diffuse malignant peritoneal mesothelioma j surg oncol grinberg lm, abramova fa, yampolskaya ov, walker dh and smith jh quantitative pathology of inhalational anthrax i quantitative microscopic findings mod pathol jackson pj et al pcr analysis of tissue samples from the sverdlovsk anthrax victims the presence of multiple bacillus anthracis strains in different victims proc natl acad sci usa perezsoler r et al phase i clinical and pharmacological study of liposome entrapped nddp administered intrapleurally in patients with malignant pleural effusions clin cancer res perng rp et al a phase i feasibility and pharmacokinetic study of intrapleural paclitaxel in patients with malignant pleural effusions anticancer drugs hughes rs malignant pleural losartan mecanismo de accion mesothelioma am } med sci hagiwara a, takahashi t, ueda t, iwamoto a and torii t activated carbon particles as anticancer drug carrier into regional lymph nodes anticancer drug des hagiwara a et al methotrexate bound to carbon particles used for treating cancers with lymph node metastases in animal experiments and a clinical pilot study cancer minato h et al survival of patients with gastric cancer treated with intralymph nodal injection of activated carbon particles absorbed mitomycin c gan to kagaku ryoho natsugoe s et al locoregional treatment for esophageal cancer with bleomycin adsorbed to activated carbon particles anticancer res hagiwara a et al selective drug delivery to peritumoral region and regional lymphatics by local injection of aclarubicin adsorbed losartan mecanismo de accion on activated carbon particles in patients with breast cancer � a pilot study anticancer drugs huang y et al local injection of mch combined with ip hyperthermic hypo osmolar infusion is an effective therapy in advanced gastric cancer anticancer drugs edwards jm and pheils pj endolymphatic isotope and bcg in the management of malignant melanoma aust n zj surg vebersik v direct endolymphatic therapy using radioisotopes strahlentherapie chiappa s, uslenghi c, galli g, ravasi g and gonadonna g lymphangiography and endolymphatic radiotherapy in testicular tumours br j radiol dellepiane g, tetti a and davitti l endolymphatic radioisotope therapy in uterine carcinomas minerva med stauch gw, heissen e and magnus l lungdosimetry within the framework of endolymphatic radionuclide therapy losartan mecanismo de accion experimental and clinical results med welt kenda r, musumeci r and uslenghi � endolymphatic radiotherapy in malignant lymphomas its potential prophylactic value in cases with negative lymphograms lymphology wisner er, theon a, griffey sm and mclntire gl longterm effect of irradiation on lymph node uptake of interstitially delivered nanoparticulate contrast media invest radiol wisner er, theon ap, katzberg rw, griffey sm and mclntire gl lymph node uptake of interstitially delivered particulate contrast media before and after irradiation in dogs acad radiol currier ma, adams lc, mahller yy and cripe tp widespread intratumoral virus distribution with fractionated injection enables local control of large human rhabdomyosarcoma xenografts by oncolytic herpes simplex viruses cancer gene ther duncan �, fourie pa and alberts losartan mecanismo de accion as direct percutaneous intratumoral bleomycin injection for palliative treatment of impending quadriplegia ajnr am } neuroradiol duvillard c, romanet p, cosmidis a, beaudouin n and chauffert � phase study of intratumoral cisplatin and epinephrine treatment for locally recurrent head and neck tumors ann otol rhinol laryngol hilger i et al thermal ablation of tumors using magnetic nanoparticles an in vivo feasibility study invest radiol gopalan � et al nanoparticle based systemic gene therapy for lung cancer molecular mechanisms and strategies to suppress nanoparticlemediated inflammatory response technol cancer res treat bao a, goins b, klipper r, negrete g and phillips wt reliposome labeling using resnss complexes in vitro stability, imaging, and biodistribution in rats j nucl med ueno nt losartan mecanismo de accion et al systemic gene therapy in human xenograft tumor models by liposomal delivery of the ea gene cancer res villaret d et al a multicenter phase ii study of tgdccela for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma head neck nishikawa m and hashida m pharmacokinetics of anticancer drugs, plasmid dna, and their delivery systems in tissueisolated perfused tumors adv drug del rev nomura t et al intratumoral pharmacokinetics and in vivo gene expression of naked plasmid dna and its cationic liposome complexes after direct gene transfer cancer res bao a et al theoretical study of the influence of a heterogeneous activity distribution on intratumoral absorbed dose distribution med phys emfietzoglou d, kostarelos losartan mecanismo de accion � and sgouros g an analytic dosimetry study for the use of radionuclideliposome conjugates in internal radiotherapy } nucl med kostarelos � and emfietzoglou d tissue dosimetry of liposomeradionuclide complexes for internal radiotherapy toward liposometargeted therapeutic radiopharmaceuticals anticancer res � kostarelos � et al binding and interstitial penetration of liposomes within avascular tumor spheroids int j cancer tsyb af, drozdovskii b, ikonnikov al and mukhamedzhanov i intralymphatic administration of open radionuclides in complex treatment of rheumatoid arthritis med radiol mosk van der zant fm et al radiation synovectomy of the ankle with mbq colloidal rheniumsulfide effect, leakage, and radiation considerations j rheumatol galvao mm, ianhez le and sabbaga e endolymphatic irradiation a useful method for immunosuppression in renal transplantation losartan mecanismo de accion amb rev assoc med bras galvao mm, peixinho zf, mendes nf, ianhez le and sabbaga e endolymphatic irradiation in preparation for renal transplantation a years followup sao paulo med j polymeric nanoparticles for delivery in the gastrolntestinal tract mayank d bhavsar, dinesh b shenoy and mansoor m amiji oral drug delivery in the last few decades, there has been a tremendous explosion in the research pertaining to novel or advanced drug delivery systems majority of the efforts have been directed towards development of better formulations of existing andor offpatent drugs the betterment being mostly aimed at improving the performance of the drug by altering the disposition and pharmacokinetics similarly, the trend is also being extrapolated to novel therapeutic losartan mecanismo de accion compounds that are still in the pipeline, with the additional objective of positioning the molecule in highly competitive, technologybased intellectual property environment the outcome has been phenomenal and the market size of advanced drug delivery systems is expected to swell to whopping us$ billion by , from its current size of us$ billion noninvasive therapeutics has been the timetested and most favored mode of drug administration oral route remains the frontrunner in this segment current market share of the oral dosage forms is approximately of all the formulations marketed and amounts to approximately us$ billion when a new chemical entity nce is being developed, the first target of a formulation scientist would be to exploit the oral route often, a losartan mecanismo de accion quick test to evaluate the oral bioavailability of the nce is to fill the drug into hard gelatin capsules along with lactose, as this constitutes the simplest formulation that could be developed for oral administration with the majority of novel drugs being highly hydrophobic or being of biotechnology origin, they pose serious and complicated challenges to the formulation scientists besides the ease of administration and patient compliance, the variety of excipients available or being investigated and the lesser cost involved for developing oral dosage forms, favor developments in this area of formulation science, compared with other delivery systems, especially those that involve invasive administration the st century is being dedicated to nanobiotechnological advancements and this has not spared losartan mecanismo de accion the pharmaceutical product development section nano is the most widely used keyword that has penetrated almost every walk of life, and nanotechnology has become the key driving force behind the thriving high technology based pharmaceutical drug delivery industry this chapter focuses on one of the components of widely explored product development showcase, that of polymeric nanoparticles anatomical and physiological considerations of gastrointestinal tract git for delivery to explore opportunities that are available for the delivery of bioactive compounds throughout the git, one has to first understand the anatomical and physiological conditions of the system because the secret of innovative formulation lies in exploiting these conditions as modulators for a wellprogrammed drug disposition the human digestive system is specialized to losartan mecanismo de accion perform functions such as ingestion, digestion and absorption the organs of digestion are essentially divided into two main groups the gastrointestinal tract or the alimentary canal and the auxiliary structures the gastrointestinal tract is continuous tubelike structure beginning with the mouth oral cavity and extending further as pharynx, esophagus, stomach, small intestine, large intestine, rectum and finally culminating into the anal canal the auxiliary structures include teeth, tongue, salivary glands, liver, gall bladder and pancreas for the purpose of this chapter, our discussion will be limited to the anatomy and physiology of the gastrointestinal tract in its relation to oral drug delivery figure provides a quick understanding of the gi targets, principles of formulation development that could be losartan mecanismo de accion utilized and the application opportunities of the nanoparticlesbased drug delivery system throughout the git different portions of the gastrointestinal tract serve different functions, but almost all the portions of the digestive tract are made up of four basic layers i mucosa, which is the mucus membrane, principally consisting of epithelial tissue and forming the inner most lining of the tract in esophagus and anal canal, the mucus epithelium is specialized for protection of the underlying tissue in other oral cavity local or systemic therapeutics principles of controlled delivery or quick onset or bioadhesion may be applied applications periodontitis, candidosis large intestine mostly for local therapeutics principles of delayed release or triggered release may be used applications inflammatory bowel diseases losartan mecanismo de accion fig git targets, formulation principles, opportunities and applications stomach local or systemic therapeutics principles of bioadhesion or gastric retention may be applied to enhance efficacy applications gastric ulceration, mucosal immunization, gene delivery lithium cr2 battery specifications small intestine mostly for systemic therapeutics principles of controlled delayed sustained pulsatile research maybe applied possibility of utilization of stimuliinduced drug disposition applications gene delivery, vaccination, proteinpeptide delivery, enhancement of bioavailability, controlled release areas of the gastrointestinal tract, the epithelium is specialized for the secretion of mucus or digestive juices or for absorption, ii submucosa, a thick layer of connective tissue containing nerves, blood vessels and glands, iii muscularis, two layers of smooth muscles the outer muscle layers are arranged longitudinally and the inner layer of losartan mecanismo de accion muscles encircle the wall of the tract, iv visceral peritoneum, the outermost layer of the tract and is a serous membrane, also known as serosa the mouth or the oral cavity comprises of the lips, cheeks, tongue, hard palate, soft palate and the floor of the mouth the oral cavity is lined with the mucous membrane oral mucosa and includes the buccal, sublingual, gingival, palatal and labial mucosae the oral mucosal surface has varied thickness with buccal mucosa having a thickness of xm, while the palates, gingivae and floor of the mouth measuring xm the buccal and sublingual tissues are the principal focus for drug delivery via the oral cavity, because of the fact that they are more permeable losartan mecanismo de accion than the other mucosal regions of the mouth the oral mucosal surface comprises of less than of the total surface area of the gastrointestinal tract, but is high vascularized, allowing the drugs to diffuse from the oral mucosa and directly accessing the systemic circulation, thus, the drugs entering the systemic circulation through the oral mucosa can bypass gastrointestinal tract and the first pass metabolism in liver the permeability of the oral mucosa is greater for sublingual cavity, followed by buccal cavity and than the palatal surface an enzymatic barrier also exists in the oral mucosa, which causes a rapid degradation of the peptides and proteins the cells of the oral mucosa are surrounded by an environment of mucus, which losartan mecanismo de accion is secreted by the mucous membrane, and is believed to play a role in the bioadhesion of mucoadhesive drug delivery systems, the pharynx and the esophagus also have the same anatomy and physiology as the rest of the gastrointestinal tract, but they are not generally considered as sites for drug delivery, and hence will not be discussed in this chapter the esophagus ends into the stomach and is separated from the stomach by a cardiac sphincter muscle which acts as a valve system it is a jshaped, baglike structure and described to have two curvatures, the concave curvature known as the lesser curvature and the convex curvature known as the greater curvature stomach is also essentially composed of losartan mecanismo de accion the same four layers as the rest of gastrointestinal tract, which include the mucosal layer, submucosa, muscularis and serosa the gastric mucosa contains many deep glands these glands contain parietal cells which are responsible for the secretion of hydrochloric acid and the chief cells which secrete pepsinogens mucus is also secreted by these glands the major barrier or alternatively the opportunity for drug delivery to the stomach is the low ph that exists in the organ because of the secretion of hydrochloric acid the functions of stomach lie more in the digestion and it has very limited absorptive function delivery of proteins via the oral route faces a major hurdle in the stomach because of pepsinogens present in the losartan mecanismo de accion gastric fluids which are responsible for the breakdown of proteins the stomach ends into the small intestine and this region is guarded by a pyloric sphincter the small intestine is further divided into three major parts which include the duodenum cm in length, jejunum meters long and the ileum meters long the walls of the small intestine composed of the four layers previously described the mucosa of the small intestine contains solitary lymph nodules and aggregated lymph nodules peyers patches peyers patches are found on the side opposite to the mesenteric wall of the intestine they are usually oval in shape and occur more frequently in the distal areas of the small intestine and also at the terminal losartan mecanismo de accion end of the colon the peyers patches is comprised of four zones i the germinal center which is in turn made up of three different cell types ie lymphocytes, macrophages and the dendritic reticular cells, ii small lymphocytic zone which shows the presence of lymphocytes and macrophages, iii interfollicular zone that is made up of lymphocytes which are loosely packed with large intercellular spaces, and iv subepithelial zone which shows large accumulation of macrophages and plasma cells the peyers patches are lined above the lymphoid follicles by a membranous layer of epithelial cells called the follicleassociated epithelium fae fae is composed of absorptive cells, goblet cells, m cells and the enteroendocrine cells these cells assist the peyers patches to losartan mecanismo de accion transport macromolecules and particulate matter from the git into lymphaticsystemic circulation in addition to the general structure, the small intestine also shows the presence of tiny fingerlike structures known as villi, which are made of epithelial tissue overlying the blood and lymph capillary network the free edges of the cells of the villi are divided into microvilli, which form the brush border throughout the length of the small intestine, the mucous membrane is covered by villi the main function of small intestine is digestion and absorption of the food that is passed down from the stomach the epithelial cells of the mucosa of the small intestine are specialized for the absorption of nutrients the process of absorption in losartan mecanismo de accion the small intestine is also assisted by its length and a very large surface area the delivery of the drugs to the small intestine is preferred because drugs typically exhibit maximal absorption from this site, compared with other regions of the gastrointestinal tract the absorption of drugs and particulate delivery system from the small intestine is believed to occur through gut associated lymphoid tissue and also from other non lymphoid tissue the mucus covers the mucosal layer of the small intestine that controls the absorption of nutrients, electrolytes and fluids, and also forms a physical barrier to the environment and absorption of drugs the brush border enzymes form an enzymatic barrier for the absorption of proteins from the small losartan mecanismo de accion intestine the other major barrier to drug absorption to the small intestine is the action of atpdependent efflux protein pglycoprotein pumps pgps, which exists on the cell membrane of the intestinal epithelium pgps transport certain drugs actively back into the intestinal lumen pgps are a part of the protective barrier of the small intestine that limits absorption of potentially toxic substances the small intestine ends into the large intestine it is called the large intestine because of the larger diameter of the tract compared to the small intestine it is approximately m in length beginning at caecum and ending in rectum and the anal canal there is a difference between the wall of the large intestine and small intestine losartan mecanismo de accion the large intestine shows absence of villi structure and contains simple columnar cells with numerous goblet cells the goblet cells secrete mucus that lubricates the colonic content as it passes through the colon the submucous layer of the large intestine consists of more lymphoid tissue than any other part of the alimentary canal to provide nonspecific defense against invasion by microbes in the food and the bacterial flora that resides in the gut drug delivery to the large intestine via the oral route for local action is a challenging task, as the drug carrier system will have to face the rigors of the preceding sections of the git before reaching the desired site of action rectal delivery of losartan mecanismo de accion drugs is an alternative for local action, but it suffers the disadvantage of patient compliance the mucus layer of the large intestine can take up particles in a particular size range and this property could be exploited for delivery of the drug to the large intestine introduction to polymeric nanoparticles as carriers modern day drugs are very effective in treating disease, but many of these drugs have limitations when it comes to the route of administration major advances in the field of biochemistry and biotechnology have led to the findings of a large number of bioactive molecules and vaccines, which are based on peptides, proteins and nucleic acids oral route is the most desired for administration for all drugs losartan mecanismo de accion and bioactive molecules, but some of these drugs and molecules cannot be administered orally due to the fact that they become inactive in the git before getting absorbed, mainly due to enzymatic degradation hence, the parenteral route of drug administration becomes a very effective route for dosing of such drugs however, the parenteral route of drug administration has the problem of being inconvenient for self administration by the patient and hence reduces patient compliance, in the last few years, we have seen rapid development of drug delivery systems for the treatment of human diseases, which is the direct result of the extensive research being done on the applications of materials for medical and pharmaceutical product development these advanced losartan mecanismo de accion drug delivery systems include mostly colloidal carriers like liposomes, niosomes, nanoparticles, dendrimers, nanosuspensions, micelles and nanomicroemulsions these drug carrier systems offer many advantages like improved efficacy, reduced toxicity and improved patient compliance, and are also cost effective in many cases over conventional drug delivery systems among the above mentioned colloidal drug delivery systems, nanoparticles represent the most appealing therapeutic nanocarrier systems by comprehensively addressing majority of the issues like stability, scalability, reproducibility, and by offering the best compromise between the efficacy and applicability nanoparticles can be defined as solid colloidal particles, produced by mechanical or chemical means, which are typically in the nanometric size range to nm, nanoparticles, especially those prepared from polymeric materials, enjoy tremendous popularity due to losartan mecanismo de accion ease of preparation, easy to tune the physico chemical properties eg through an array of polymeric materials, possibility of surface modification, excellent stability, and scalability to industrial production since their conception in the mid s, nanoparticles have found applicability in almost every section of medicine and biology besides host of other fields in general, and also for controlled andor targeted delivery of drugs and genetic materials in particular the basis in the development of nanoparticles lies in paul elrichs idea of designing magic bullet carrying active molecules in them and being able to target specific sites in the body for the desired therapeutic effects depending on the process by which they are prepared, these systems can be classified losartan mecanismo de accion as nanospheres nanoparticles having a dense and solid polymeric network monolithic matrix, or as nanocapsules which consist of a hollow core surrounded by a polymeric shell drugloaded nanoparticles have been developed for almost every route of administration, ie nasal, ocular, mucosal, inhalation, oral, transdermal and parenteral clinically, they have found applications for diagnosing and treating a wide range of pathological conditions nanoparticles can be prepared from both synthetic and natural the polymeric materials could be either biodegradable or nonbiodegradable, but should be essentially biocompatible poly dllactidecoglycolide plga, poly e caprolactone pcl, poly alkylcyanoacrylates, poly styrenecomaleic anhydride, poly divinylethercomaleic anhydride, poly vinyl alcohol, poly ethylene glycol are some examples of synthetic, nonimmunogenic polymers extensively used for nanoparticle preparation similarly, poly losartan mecanismo de accion amino acids, albumin, gelatin, hyaluronic acid, dextran, starch, and chitosan are some of the natural biodegradable polymers while each of polymers poses its own advantages and nanoparticles can be synthesized with high degree of reproducibility from a majority of them, natural polymers, due to their natural origin, have preference, considering nontoxicity and biodegradability the striking advantage of synthetic polymers remains the possibility to synthesize them reproducibly with welldefined physicochemical properties advancement in biotechnology is helping the natural polymers to overcome this drawback and we can expect a surge in delivery systems based on them polymeric nanoparticles have been extensively researched for their applicability as oral drug carrier systems in the following sections, we will discuss how they are losartan mecanismo de accion being explored in buccal cavity therapeutics, as stomach specific delivery systems, for mucosal targeting in the small intestine, and for the treatment of inflammatory bowel disease preparation of polymeric nanoparticles there are several methods on the preparation of polymeric nanoparticles and incorporation of bioactive compounds into them in general, one of the two principles methods is utilized controlled precipitation or controlled dispersion of the polymer few of the popular methods include solvent displacement, saltingout, emulsionsolventevaporation, emulsionsolventdiffusion, polymerization, complexation and supercritical fluid technology figure provides an overview of fig schematic representation of methods used for preparation of polymeric nanoparticles the methodologies and technologies available for the preparation of polymeric nanoparticles in the case of solvent displacement method, which is the losartan mecanismo de accion simplest of all, the polymer is dissolved in a good solvent that maybe partiallypolar and watermiscible solvent such as ethanol or acetone when the drug is to be incorporated into the particles, it can be dissolved in the same phase along with the polymer this polymer phase is introduced into a nonsolvent aqueous phase containing a stabilizer generally a hydrophilic surfactant at a controlled rate under continuous mixing as the partiallypolar solvent diffuses rapidly into the aqueous phase ie as the partiallypolar phase is displaced by the polar phase, the polymer starts precipitating due to changes in its solubility, resulting in the formation of nanoparticles the surfactant present in the aqueous phase helps in preventing particle aggregation choice of losartan mecanismo de accion a drugpolymersolventnonsolvent system is the major limitation of this method and hence its applicability is confined to hydrophobic drugs and polymers salting out technique is generally used for the preparation of drugloaded biodegradable nanoparticles this method was first applied to pseudolatexes it is based on the separation of watermiscible solvent from aqueous solutions by a salting out effect an ow emulsion is formed by adding a solution of the polymer and the drug in a water miscible solvent into an aqueous gel containing a saltingout agent and a colloidal stabilizer water is added to dilute this mixture, as a result of which nanoparticles are formed solvent and saltingout agents are then removed by crossflow filtration the use of losartan mecanismo de accion this method results in a very high loading efficiency along with high yield and also the scaleup is fairly easy, but this method can only be used for the loading of lipophilic drugs emulsificationsolventevaporation is based on the formation of a biphasic �w or wo or triphasic wow or �wo emulsion generally, a preformed polymer is dissolved in an organic solvent which is water immiscible along with the drug, and is emulsified in an aqueous solution ow emulsion the formed emulsion is then exposed to high energy mixers eg highspeed or highpressure homogenizers, colloidal mills or ultra sonic devices to reduce globule size the organic solvent is removed either by using heat or vacuum or even both at times losartan mecanismo de accion nanoparticles are obtained as fine aqueous dispersions which can be collected and purified the process variables involved in this method are complex and manifold, and the nanoparticles obtained are often polydisperse however, this method is very popular for preparing polymeric microparticles rather than nanoparticles, as it facilitates industrial applicability and scalability emulsionsolventdiffusion method is another method which is used for nanoparticles preparation it is a modified saltingout technique and differs mainly in the organic solvent which is partially miscible with water in this case this solvent is presaturated with water to achieve initial thermodynamic equilibrium between water and the organic phase solvent diffuses out upon addition of water and results in the formation of nanoparticle suspension controlled complexation losartan mecanismo de accion induced by electrostatic interactions between oppositely charged polymers can yield stable colloidal dispersions the interacting polymers could be therapeutically active eg oligonucleotides and plasmid dna or may have tailored properties eg phsensitivity a wide variety of charge bearing polymers can be utilized to manufacture composite nanoparticles and varying physicochemical properties supercritical fluid technology is an emerging science for the production of micro and nanoparticles, in this method, an organic liquid solution of the polymer and the active moiety is sprayed through a nozzle into a chamber containing a gas that is miscible with the solvent, but in which the polymer and the active compound are not soluble the gaseous phase in this case is a super critical fluid eg losartan mecanismo de accion supercritical c the dispersion of the liquid solution in such a condition generates a high degree of supersaturation, leading to the formation of fine, uniform colloidal particles the particles can be recovered from the solution by depressurizing the chamber and allowing the gas to escape while all of the above mentioned procedures employ preformed and well characterized polymers, there are other techniques for obtaining fine nanoparticles from monomers via in situ polymerization pathway the most popular example for this method of synthesis is the nanoparticles made from poly methylmethacrylates, poly alkylcyanoacrylates and poly methylidenemalonates generally, a water insoluble monomer is dispersed in an aqueous medium containing a colloidal stabilizer, and the polymerization is induced and controlled by the losartan mecanismo de accion addition of a chemical initiator or by variations in physical parameters such as ph or radiation both hydrophilic and lipophilic drugs can be entrapped in the polymeric wall when added to the polymerization medium or adsorbed on preformed particles while each of the above mentioned nanoparticle preparation method has its advantages and disadvantages, they can all be finetuned to encapsulate variety of drugs the literature evidence shows that the nanoparticles are mostly employed to incorporate hydrophobic drugs, simply because the majority of the techniques facilitate encapsulation of lipophilic compounds with very high loading approximately up to by weight and capturing efficiencies nearly when hydrophilic drugs are to be incorporated, in situ polymerization or complexation remains the most accepted method losartan mecanismo de accion the collective advancements in nanotechnology and engineering sciences are expected to contribute major breakthroughs for bulk manufacturing of polymeric nanoparticles in the highly competitive pharmabiotech industry, the formulation scientist can concentrate towards development of novel products, irrespective of complexities involved in the procedures as in most cases, majority of the scale up issues can be addressed and solved with the help of parallel advancements in hightechnology engineering design consideration for nanoparticlebased delivery systems polymeric nanoparticles, since their first appearance in the s, have been keenly explored as delivery systems for small drug molecules, and also for macromolecules like nucleic acids, proteins, hormones and peptides with the patent protection to a number of blockbuster drugs expiring in this decade, losartan mecanismo de accion innovative dosage forms, such as polymeric nanoparticles, can form a very powerful drug delivery technology for the pharmaceutical industry such technologybased products can be used for the extension of the patent life of the drug, or to preventdelay the entry of generic versions into the specialized markets in general, the polymeric drug delivery systems offer advantages such as the reduction in the total dose hence also the dosing frequency, reduced side effects, delivery with enhanced efficiency hence better performance, and most importantly, improved patient compliance when designing a polymerbased nanoparticulate drug delivery system, the choice of synthetic or biopolymer is the most important consideration in the following section, we will discuss different characteristics of polymers that play an important losartan mecanismo de accion role in the final product and hence should be considered during prefor mulation stages polymer characteristics polymers have become a vital and integral part for the development of any novel drug delivery system factors such as chemical structure of the polymer, composition, molecular weight, morphology of the polymer amorphouscrystalline residual stresses, size of the delivery system, process of degradation enzymatic or nonenzymatic etc govern the behavior of polymer within the body the polymer selection itself is a judicious process and following factors should be considered while making a decision basic requirements nonreactive chemical inertness with respect to active compound and the biological environment biocompatibility should be compatible with living cells and tissues that come in contact with the polymer losartan mecanismo de accion nonpyrogenic should be free of any pyrogenic factors impurities all the impurities should be wellestablished and present in minimal amounts the impurities, if present, should also be biocompatible or should not pose any toxicity at amounts present byproducts if the polymer undergoes any kind of biotransformation upon introduction into the body, the byproducts should also be biocompatible regulatory issues the polymer should be available in the cgmp grade and must be approved by the regulatory authorities for human use specialized requirements loading capacity if complexation or chemical conjugation is the method used for preparation, then the polymer must have sufficient reactive groups to promote respective interactions permeability permeability to molecules and water will govern the diffusivity and the losartan mecanismo de accion release of the payload swellability this could be of relevance when designing a floating or a bioadhe sive system viscoelasticity could be an important controlling parameter for gelforming and adhesive systems sensitivity to environment the triggering factor could be the ph, specific enzymes, or even the microbial flora prevailing in the git while the maneuverability around each of the above factors is very limited for a sterile dosage form, it becomes more flexible while developing an oral product parallel developments in the field of excipient science have contributed to a range of new high performance polymers, making the choice of an approved polymer easier for the formulation scientist we recommend that interested readers should visit the websites of major losartan mecanismo de accion manufacturers of pharmaceutical excipients eg eastman chemicals, fmc biopolymer, colorcon, gattefosse, croda, lipoid, noveon, basf, roehm pharma, degussa, etc to buildup a database drug characteristics the performance of the dosage form for any bioactive compound will depend on physicochemical properties of the drug, as well as the auxiliary factors few of the factors belonging to the former are molecular weight, solubility aqueous or organic, partition coefficient, crystallinity and ionic properties as these are the inherent properties of the drug, there is less scope for tailoring them to manipulate in vivo behavior of the formulation however, factors such as solubility, for example, can be tuned to a certain extent by altering the particle size or using certain excipients eg losartan mecanismo de accion cyclodextrins some of the auxiliary factors that should be considered while designing a nanoparticlebased oral system are the dose of the drug, site of action of the drug eg absorption is limited to certain segments of the git only, stability of the drug both under in vitro and in vivo conditions and the desired pharmacokineticsdistribution profile application characteristics in the majority of the cases, the formulation parameters are decided based on its intended application upon oral administration, the nanoparticles could be expected to exert local action along the git, or could be used to deliver drugs to the systemic compartment, or could be meant for uptake by cells lining the git the duration and kind of desired pharmacological action losartan mecanismo de accion can be used as the guiding principle in designing the delivery module fast versus sustained regular versus controlled unstimulated versus triggered continuous versus pulsatile more of these principles of design have been discussed under following section citing appropriate examples nanoparticles in experimental and clinical medicine many of the principles of drug design and delivery are based on naturally occurring phenomena biomimicking approach and the same principles guide the applicability of nanocarriers in therapeutics the striking advantage of the nanoparticles is the large surface area that they offer when presented in a biological environment and the flexibility to alter the physicochemical properties by manipulating the core polymer or by surface nanoengineering many clinical situations and conditions demand specialized therapeutics losartan mecanismo de accion to achieve improved level of healing in such situations, the requirements are specified by the clinician, which form the basis of product development table gives an overview of the applicability of polymeric nanoparticles via oral route drug delivery in the oral cavity buccal cavity mucosa has been studied for polymeric drug delivery bioadhesive or mucoadhesive used when adhesion is to the mucosal tissue polymers have been extensively used in buccal drug delivery because of the fact that a major limitation of the buccal cavity is the lack of dosage form retention polymers such as poly methacrylate derivatives, cyanoacrylates, epoxy resins, polystyrene, polyurethanes, hydroxypropyl methylcellulose, chitosan and poly acrylic acid have been studied for their potential use in buccal cavity losartan mecanismo de accion therapeutics poly propylcyanoacrylate ppc a nanoparticles have been studied as a potential carrier for the prophylactic treatment of candidosis candida albicans is a common organism which is found in the oral cavity it occurs in the commensal form site of action incorporatedpolymer employedsize reference compoundnm table summary of polymeric nanoparticlebased delivery systems for in the git oral cavity fitc polypropylcyanoacrylate lectingliadin stomach carbazole gliadin amoxicillin gliadin pcmvlacz plga small intestine streptomycin chitosan theophylline plga in depot tablets tetanus toxoid polyethylene glycolpolylactic acid indomethacin plga carbon polymethyl methacrylate pmma fluoroudine polymethylvinyletherco maleic anhydride rbitc polymethylvinyletherco maleic anhydride vancomycin plga iodine polystyrene valproic acid plga pcmvlacz polyethylene oxidepolypropylene oxide sulfobutylatedpolyvinyl alcoholplga phenobarbital plga amifostine plga h pylori lysate plga d chitosan losartan mecanismo de accion pcrarah chitosan mepo gene chitosan rifampicin lectinplga pyrazinamide lectinplga ketoprofen plga isoniazid lectinplga calcitonin polynisopropylacrylamide polynvinylacetamide polytbutyl methacrylate plga heparin pcl plga eudragit� rs and rl table continued site of action incorporated polymer employed size reference compound nm insulin polyisobutyl cyanoacrylate polyesters polymethacrylic acidgpolyethylene glycol polyalkylcyanoacrylate chitosan polyisobutylcyanoacrylate polyacrylicacidg polyethylene glycol plga polyfumariccosebacic anhydride plga cya polymethacrylic acid methacrylate hydroxypropyl methylcellulose chitosan gelatin plga pcl eudragit� rs and rl fluorescein polystyrene polystyrene nanoparticles coated with poloxamer and large intestine fluorescent dye polystyrene rolipram plga in healthy individuals, but it can become pathogenic to the body under conditions such as cancer chemotherapy, diabetes mellitus and also during antimicrobial therapy the first step in candidosis infection is the adherence of losartan mecanismo de accion the microorganisms to the epithelial cells of the host the basic motivation of the investigation was to evaluate the ability of ppc a nanoparticles to disrupt the process of adherence of the microorganism onto the host cells ppc a nanoparticles were prepared by emulsion polymerization from propylcyanoacrylate monomers different kinds of surfactants were used for stabilization of nanoparticles, which resulted in the formation of nanoparticles having different size ranges surfactants like tween� , pluronic� pi, tetronic� , docusate sodium, sodium oleate and sodium laurylsulfate produced particles in the nanometer range, whereas cetrimide, benzalkonium chloride and cetylpyrimidine chloride produced particles in the micrometer range tetronic� produced the smallest particles of the size � nm c albicans blastospores were treated with the nanoparticle losartan mecanismo de accion suspension and these treated blastospores were exposed to the buccal epithelial cells to check for adherence it was found that nanoparticle treated blastospore adherence per buccal epithelial cells was reduced by up to the findings of this study may offer the basis for a prophylactic treatment of candidosis in immunocompromised patients periodontal diseases are one of the major causes of teeth loss and it includes a number of diseases involving the supporting tissue of the teeth conventional methods of treatment of periodontitis include periodontal surgery and chemotherapy, but both these treatments cannot prevent the reoccurrence of the disease recently, a method for treating periodontitis, by using polymeric nanoparticles loaded with photosensitizer compounds, has been proposed the nanoparticles exhibit losartan mecanismo de accion controlled release of the photosensitizer molecule through the matrix polymer the proposed application uses photosensitizer molecules such as porphyrins, chlorines, pheophorbides, bacteriopheophorbides, phthalocyanines, naphthalocyanines, thi azines, xanthenes, pyrrylium dyes, psoralens, quinones and amenolevulic acids these compounds are either incorporated or complexed with nanoparticles made from biodegradable or nonbiodegradable polymers the effectiveness of photo sensitizers relies on their association with cellular membranes, thereby targeting highly sensitive membranous intracellular organelles that control critical metabolic functions the hydrophobic character of the photosensitizers means that they cannot be administered directly to a hydrophilic environment due to a tendency to aggregate by molecular stacking, precipitation or other mechanisms, which can severely curtail photosensitization processes thus, they require formulation in carriers which are able to losartan mecanismo de accion provide a hydrophobic environment to maintain them in a non aggregated form in both the formulation and in aqueous preparations prior to use these nanoparticles can then be applied by the dentist to the periodontal pockets in the form of gel which hardens on application this allows for a slow and extended period of release, which can be fine tuned by choosing biodegradable or nonbiodegradable polymer of the photosensitizer from the nanoparticles, and hence do not affect the normal cell function the use of nanoparticles prevents the degradation of the photosensitizer molecule in the presence of saliva, white blood cells and other natural defenses in the mouth higher concentrations of the photosensitizer allows for a more effective treatment losartan mecanismo de accion and this can be achieved by using specialized nanoparticles formed out of dendrimerphotosensitizer complexes furthermore, many of the dental diseases are difficult to treat due to a lack of accessibility and quick flushing of the dosage form by the saliva the nanoparticles can be especially useful in such situations the size of the carriers enables them not only to reach deeper parts of the infected area, but also to be retained at the site of action gastric mucosa as a target for oral nanoparticlemediated therapy the major function of the stomach is to digest food and pass down the chyme to the intestine the principal hurdle to the successful delivery of active compounds to the gastric mucosa using conventional losartan mecanismo de accion delivery system is the gastric emptying time these conventional delivery systems do not remain in the stomach for prolonged periods due to their inability to deliver the drug to the desired site in effective concentration and in fully active form the other barrier to the delivery of drug is the mucus layer of the gastric mucosa the primary component of mucus is glycoprotein which forms a dense condensed and complex microstructure, by forming numerous covalent and non covalent bonds with other mucin molecules helicobacter pylori has been recognized as a major gastric pathogen responsible for a variety of clinical manifestation including the development of gastritis, gastric ulcer and gastric carcinoma it is a gram negative, spiral, urease producing losartan mecanismo de accion microorganism isolated by warren and marshall in umamaheshwari et al, studied the effectiveness of mucoadhesive nanoparticles bearing amoxicillin for the treatment of h pylori mucoadhesive nanoparticles prepared from gliadin, having a size range of to nm, were used in the study gliadin is a group of polymorphic proteins extracted from gluten and are soluble in ethanolic solutions they have a very low solubility in water except at extreme ph in vitro stability study of gliadin and amoxicillin was performed in simulated gastric fluid and confirmed by hplc in vivo mucoadhesion capacity was evaluated by oral administration of fluorescent labeled gliadin nanoparticles size dependent mucoadhesive propensity and specificity was exhibited by gliadin nanoparticles with less than nm particles showing mucoadhesion, losartan mecanismo de accion and more than nm particle showing and above mucoadhesion amoxicillin loaded gliadin nanoparticles were administered to mongolian gerbils previously inoculated with human h pylori to study in vivo clearance time hrs, hrs and hrs, and placebo gliadin nanoparticles were also used as a control although amoxicillin loaded nanoparticles showed inhibition of h pyloi within hrs of administration, it could not completely eradicate the h pyroli in vivo this study showed that amoxicillin loaded nanoparticles exhibited a longer gastric residence time than conventional amoxicillin formulation and also that topical action of amoxicillin on the gastric mucosa plays an important role in the clearance of the bacterium gastric mucosa can also be explored for the delivery of genetic material or for losartan mecanismo de accion vaccination a recent investigation explored plga nanoparticle stabilized with a cationic surfactant dimethyldioctyldecylammonium bromide as gene carriers for transport through the gastric mucosal barrier composite polymeric nanoparticles having a magnetic element and loaded with antimetabolites have also been explored for the treatment of gastric tumors the magnetic component helps in external guiding and localization of the nanoparticles at the site of action nanoparticles for delivery of drugs and vaccines in the small intestine gastrointestinal tract provides a variety of barriers, including proteolytic enzymes in gut lumen and on the brush border membrane, mucus layer, gut flora and epithelial cell lining, to the delivery of drugs factors which govern the uptake of particles from the gut include particle size, physicochemical nature of particles, surface charge and attachment of uptake enhancers such as lectins or poloxamer after oral administration of nanoparticles, they could be i directly eliminated in the faeces, ii adhering to the cells bioadhesion andor, iii undergo oral absorption as a whole oral absorption of the nanoparticles results in passage across the gastrointestinal barriers and delivery of the payload into the blood, lymph and other tissues before this translocation can occur, the nanoparticles have to adhere pills glimepiride to the surface of the intestine translocation of particles across the gastrointestinal wall can occur due to intracellular uptake by the absorptive cells of the intestine or para cellular uptake ie between the cells of the intestinal wall, or phagocytic uptake losartan mecanismo de accion by intestinal macrophages, or uptake by the m cells of the peyers patches jani et � have shown that particle size plays a major role in the uptake of particles they measured uptake by using radiolabeled polystyrene nanoparticles ranging from nm to �m they have been able to show that lower size particles nm particles showed a uptake by the cells of the small intestine are taken up at a higher rate by the small intestine when compared to the larger particles fim particles showed only uptake by the cells of the small intestine the lower size particles nm were detected in blood after intestinal uptake whereas larger size particles nm where not detected in blood also, these losartan mecanismo de accion nanoparticles were detected in other tissues such as liver and spleen a low surface charge on the surface of nanoparticles is desirous for good absorption while pluronic� or poloxamer and coating onto the surface of nm polystyrene nanoparticles inhibited uptake in the small intestine, a similar coating on the nm polystyrene nanoparticles showed an increased intestinal uptake there has been yet another report to study the effect of surface modification on the uptake of polymeric nanoparticles using clabeled poly methylmethacrylate pmma, having a mean size of nm and coated with polysorbate tween� or poloxamine these nanoparticles were administered orally to rats and they were checked for their organ distribution high radioactivity levels were observed in the stomach contents, below losartan mecanismo de accion radioactivity was detected in the stomach wall for the coated particles highest amount of radioactivity about was found in the small intestine, confirming that these coated particles were absorbed in the small intestine developments in the field of polymer science have made the delivery of proteins and peptide drugs via the oral route possible, by protecting these molecules against phenzymeinduced degradation and also by prolonging the time of delivery to the mucosal sites the most popular peptide used for oral delivery using polymeric nanoparticles is insulin the first attempt to deliver insulin via the oral route was made by couvreur et al in insulin was adsorbed on the surface of nm poly alkylcyanoacrylate nanoparticles and administered orally to losartan mecanismo de accion diabetic rats to seek hypoglycemic effects the investigators did not observe any decrease in glucose level upon oral administration, but good hypoglycemic activity was observed upon subcutaneous administration, suggesting that insulin was getting degraded in the git in another investigation, nanoparticles made out of poly isobutylcyanoacrylate pibca loaded with insulin when administered orally, resulted in a reduction in the blood glucose levels of diabetic rats the onset of action was after days of administration, but was seen for days depending on the insulin dose these results suggested that pibca nanoparticles successfully protected insulin against degradation in the git a publication by the same group reported the ability of pibca nanoparticles to protect insulin from degradation by proteolytic enzymes, and losartan mecanismo de accion thus providing nanoparticles based formulation for biologically active insulin for oral administration insulin labeled with texas red� was used for release studies and microcopy observations the results obtained from fluorescence and confocal microscopy revealed the presence of concentrated fluorescent spots into the mucosa and even in the lamina propria this suggested that these nanoparticles could cross the barrier presented by the intestinal epithelium a patent was issued in for controlled release of insulin from biodegradable nanoparticles insulin was complexed with different polycyanoacrylate monomers at low ph and nanoparticles were prepared from this complex by anionic polymerization process these nanoparticles were dosed orally to rats and blood glucose levels were monitored over four hours a considerable decrease in blood glucose levels was observed in a group dosed with insulin loaded nanoparticles, compared with the untreated group more recently, pan et al studied the effects of bioadhesive chitosan nanoparticles for improving the intestinal absorption of insulin in diabetic rats chitosan was chosen as the polymer for preparing the delivery system, because it exhibits strong electrostatic interaction with insulin, hence improving the loading efficiency of the polymer it was also used for its bioadhesive properties for prolonged stay in the gastrointestinal tract, which in turn resulted in prolonged release times for insulin a dose dependent decrease in blood glucose levels was observed after oral administration of these nm particles in diabetic rats chitosaninsulin nanoparticles showed a higher decrease in blood losartan mecanismo de accion insulin levels when compared with chitosaninsulin solution, suggesting that they could enhance the intestinal absorption of insulin by promoting protection from gastric clearance, and also rendering longer resident time in circulation biodegradable polymers like plga, poly lactic acid pla, and poly fumaric anhydridecosebacic anhydride have been explored for the preparation of nanoparticulate formulations of insulin although the major finding of the study was intact bioactivity of insulin after intraperitoneal injection, it was also indicated that the nanoparticles prepared in the presence of ��� showed the best hypoglycemic results, and were also proved to be orally effective foss et al developed nanospheres from methacrylic acid grafted with poly ethylene glycol and also acrylic acid grafted with poly ethylene glycol as losartan mecanismo de accion oral insulin carriers from the results obtained after oral administration, it can be learned that diabetic animals administered with insulinloaded nanospheres had a significantly reduced serum glucose levels, with respect to the control animals and this effect lasted over hrs cyclosporine a cya is another peptide which has been studied for transport to the gastrointestinal tract using polymeric nanoparticles via the oral route cya is a potent immunosuppressive agent and is widely used for the inhibition of graft rejections in the transplant of organs such as heart, liver, skin, lungs, kidney, etc it is also prescribed in autoimmune diseases such as rheumatoid arthiritis and bechets disease although various formulations of cya such as neoral� solution, sandimmune� microemulsion and losartan mecanismo de accion sangcya� amorphous nanoparticles are being marketed, they are faced with the problem of variable bioavailability, and the patient has to be monitored for the blood levels of cya during the regimen one of the earlier efforts to improve the bioavailability of cya was done by preparation of ph sensitive nanoparticles using poly methacrylic acid and methacrylate copolymer eudragit� the results were compared with neoral� a universal standard for cya oral bioavailability formulation in rats nanoparticles exhibited drug entrapment of for different formulations prepared from different types of eudragit� systems cya nanoparticles prepared from eudragit� si , an anionic polymer, demonstrated the highest relative bioavailability of with respect to neoral� other polymeric nanoparticles also exhibited more than relative bioavailability, except for losartan mecanismo de accion nanoparticles prepared from eudragit� e cyae which is a cationic polymer in vitro release studies of cya from different nanoparticle preparation illustrated that all nanoparticle preparation showed phspecific release of cya at ph , except for cyae nanoparticles which released the whole payload at ph this proves that major cya from cyae was released in the stomach upon oral administration accounting for its low relative bioavailability with respect to other nanoparticle preparations in another study, wang et �, examined hydroxypropyl methylcellulose phthalate hpmcp polymer nanoparticles loaded with cya for oral delivery hpmcp is a common enteric coating excipient used in the pharmaceutical industry for the enteric coating of the tablets it dissolves specifically at a ph of and releases losartan mecanismo de accion the contents in the lower intestine the investigators used two different cya nanoparticle preparations made from different molecular weight of the same polymer again, a high encapsulation efficiency of over was observed with the nanoparticle preparation, due to hydrophobicity of the drug cya nanoparticles made of high molecular weight hpmcp exhibited a relative bioavailability of over , and the ones made from lower molecular weight exhibiting only relative bioavailability against neoral� the difference was attributed to the phindependent property of lower molecular weight polymer which released entire payload within the stomach itself, thus inactivating the peptide drug the results from the above studies indicate that phsensitive nanoparticles loaded with cya can be designed as new carriers for cya, which exhibit losartan mecanismo de accion a better pharmacokinetic profile compared with the currently marketed cya formulations nanoparticles made from cationic polymers have been explored as surface coatings to improve the oral bioavailability of cya male beagle dogs were orally administered with cya nanoparticles coated with chitosan as the poly cationic surface modifier from the results obtained, it was observed that chitosan coated drug nanoparticles showed the highest relative bioavailability of with respect to neoral� oral solution the results were attributed to two properties of the system i cationic polymer facilitated the electrostatic interaction with the negatively charged mucosa, and ii chitosan coated cya nanoparticles facilitated the opening of the tight junctions of the epithelial cells, thus augmenting the paracellular transport pathway a series losartan mecanismo de accion of investigations have been directed towards preparation and evaluation of bioavailability and toxicity profile of cyaloaded polycaprolactone nanoparticles, the nanoparticles, having a diameter of nm were prepared by solventevaporation procedure and evaluated for biodistribution, immunosuppressive activity and nephrotoxicity sandimmune� was used as the standard for this investigation in rats following oral administration a significantly higher tissue especially kidney concentration of cya was achieved with nanoparticles formulations, compared with the solution indicating probability of a higher nephrotoxicity however, further toxicological evaluation with kidney function tests indicated no difference in the profiles of two formulations in vitro lymphocyte proliferative activity an indication of immunosuppressive potential also showed better activity for nanoparticle formulations of comparable doses the conclusion of the investigation was losartan mecanismo de accion that the nanoparticles formulations can be effective at lower dose levels, compared with the solution form and thus may help to reduce drugassociated tissue damage cho et al developed several different oral cya nanoparticle formulations consisting of one alkanol solvent and a polyoxyalkylene surfactant, and tested them in rats for their bioavailability in comparison to sandimmune� oral solution selected formulations based on these preclinical investigations were further tested for their pharmacokinetic profile in humans forty eight healthy males were chosen and a randomized, doubleblinded, threeway crossover study was conducted with sandimmune� oral solution as standard formulation from the results obtained, it is observed that cya nanoparticles exhibited a cmax which was twice as high as those achieved by sandimmune� losartan mecanismo de accion oral solution and the tmax was much shorter for cya nanoparticles compared with the standard one also, the auc observed for nanoparticle formulations was significantly higher than the standard formulation polymeric nanoparticles, because of their ability to effectively transport active molecules across the gastrointestinal tract have been studied as delivery systems for gene therapy and vaccination chen et alm used dnacomplexed with chitosan for transfection of erythropoietin gene to the intestinal epithelium of mice erythropoietin is a glycoprotein, which stimulates production of red blood cells erythropoietin is used in patients with anemia associated with chronic renal failure, and in cancer patients for simulation of erythropoieisis chitosan nanoparticles, containing plasmid dna encoding for erythropoietin mepo, were administered orally to losartan mecanismo de accion one group of mice along with other appropriate control dosage forms erythropoietin gene expression was registered every two days by measuring the hematocrit of the mice mice which were administered with chitosan loaded mepo showed a increase in hematocrit over other dosage forms, indicating successful transfection of mepo gene across the intestinal epithelium these results suggests that chitosan nanoparticles were able to prevent the mepo from degradation against dnases and hence the possibility of using them as gene delivery vehicles via the oral route in another study, nanoparticles prepared from cationic biopoly mers chitin, chitosan and their derivatives were proposed to be the carriers for oral administration of bioactive compounds for gene therapy the nanoparticles with encapsulated plasmid dna losartan mecanismo de accion encoding for human coagulation factor ix pfix were prepared the molecular weight of the cationic biopolymers ranged from to kda the nanoparticles in the size range of nm were generated by the complex coacervation method and were used for oral administration to mice human factor ix was detected in the systemic circulation of the mice within days following oral delivery, but declined after days the investigators also demonstrated the bioactivity of the factor ix transgene product in factor ix knockout mice heamophilia � is an xlinked bleeding disorder caused by a mutation in the factor ix gene after orally feeding factor ix transgeneloaded nanoparticles to the knockout mice, the clotting time was reduced from min to min, which losartan mecanismo de accion was comparable with the clotting time of min observed with wildtype mice the investigators proposed that intestinal epithelium was the site of nanoparticle absorption and transfection a range of polycationic polymers including gelatin, chitosan, polylysine, pol yarginine, protamine, speramine, spermidine and polysaccharides could be used to prepare the coacervates of the nucleic acids which result in the formation of discrete nanoparticles roy et a, used such coacervates for effective vaccination by the oral route chitosan nanoparticles in the size range of nm were prepared by saltingout technique with the plasmid dna parah, which encodes for the peanut allergen arah the nanoparticles were orally fed into the mice and the serum and fecal levels of igg or iga were measured losartan mecanismo de accion periodically high levels of antiarah igg were observed in the titer of the group which was fed with low molecular weight chitosan nanoparticles housing the plasmid dna pdna, compared with other groups which were administered with high molecular weight chitosan nanoparticles, with or without booster dose the mice from all groups were challenged with crude peanut extracts four weeks after the booster dose and positive antibody response were detected in groups immunized by dna nanospheres these results suggest that chitosanpdna nanoparticles delivered through the oral route can modify the immune system in mice and protect against food allergen induced hypersensitivity kim et a prepared plga nanoparticles housing h pylori lysates by solvent evaporation method these nanoparticles were administered losartan mecanismo de accion orally into mice and antibody induction was assayed in serum and gastrointestinal tract serum igg subclasses were determined by elisa the mean antibody titers for serum igg and gut iga responses were significantly higher than those of the groups immunized with the soluble antigen alone cholera toxin ct � a wellestablished potent mucosal adjuvanth pylori had a higher antibody titer compared with plgah pylori nanoparticles the results of this study indicates that plgah pylori nanoparticles could stimulate h pylorispecific mucosal and systemic immune responses in mice, and also that nanoparticles can be used for vaccination against h pylori spraydried plga nanoparticles have been investigated for the oral delivery of amifostine amifostine is an organic thiophosphate prodrug and is dephos losartan mecanismo de accion phorylated by alkaline phosphatase in the tissue to the active free thiol metabolite the major drawback of the drug is that it cannot be administered orally in an active form and when administered systemically, it is rapidly cleared from the body plga nanoparticles containing amifostine were administered to mice orally and tissue distribution was observed for the administered dose within min post oral administration, the drug was detected in almost all the tissues including blood, brain, spleen, kidney, muscle and liver wheat gram agglutinin wga lectinfunctionalized plga nanoparticles have been successfully prepared and used to encapsulate isoniazid, rifampicin and pyrazinamide, which are the three frontline drugs employed in the treatment of tuberculosis these plga nanoparticles encapsulating antitubecular drugs losartan mecanismo de accion at therapeutic dosage were administered for their in vivo drug disposition studies to guinea pigs which were previously infected with mycobacterium tuberculosis to develop the infection results obtained for plasma concentration of different drugs suggested that plgananoparticles helped to improve the plasma residence time of different drugs after oralnebulized administration rifampicin was detected for to days in the plasma after oralaerosolized administration of plganp, when compared with free drug which was detected only for day similarly, isoniazid and pyrazinamide were maintained for more than days in plasma, compared with a single day for the free drug the presence of these drugs in the tissues such as liver, lungs and spleen for a long time favors its application against tuberculosis losartan mecanismo de accion where infection is largely localized in the tissues chemotherapeutic studies revealed that three doses of oralaerosolized lectincoated nanoparticles for days could yield undetectable mycobacterial colony forming units, compared with days of oral administration of the free drug to achieve the same results this study suggests that polymeric nanoparticles could be favorably used for the effective treatment of tuberculosis popescu etal, have proposed the use of biodegradable nanoparticles, prepared from naturally occurring polymers such as chitosan, dextran sulfate, dermatan sulfate, chondroitin sulfate, keratin sulfate etc for oral delivery of highly cationic active compounds which are highly hydrophilic and could be substrates for pgp such active compounds include the likes of aminoglycosides, polypeptides, proteins, terefenamate, proglumetacin, tiaramide, apazone, etc currently, there losartan mecanismo de accion are no technologies for delivery of hydrophilic, cationic drugs by oral administration as an example, we will consider streptomycin, which was loaded to chitosan nanoparticles and tested for in vivo efficacy using m tuberculosis infected mice streptomycin was successfully loaded with an encapsulation efficiency of or higher, with a minimal drug loading of ww of polymer after oral administration of these chitosan nanoparticles in mice a one logio reduction in colonyforming units of the bacilli was achieved, compared with the control group these results show that the nanoparticlesbased technology can be a breakthrough for the oral administration of aminoglycoside antibiotics, which are otherwise inactive via oral route nanoparticles for colonspecific delivery the large intestine, which represents the last losartan mecanismo de accion segment of the gastrointestinal tract can suffer from two major inflammatory bowel diseases which are ulcerative colitis and crohns disease ulcerative colitis occurs more in the distal segment of the large intestine and crohns disease develops over a very large area of the colon, approximately very little is known about the pathomechanisms involved in both the disease conventionally, treatment of these diseases involves daily intake of anti inflammatory drugs which include aminosalicylic acid formulations, glucocorticoids and immunosuppressive drugs such as azathioprine, which is taken along with methotrexate the major draw back with these conventional formulations is that they have to be taken at high doses daily by the oral route, resulting in the absorption of these compounds by the losartan mecanismo de accion small intestine causing possibly strong and undesirable effects several strategies have been employed for the development of oral delivery system for the transport of drugs to the inflamed sites in the colon these include sustained release devices such as prodrugs, macroscopic systems such as phcontrolled drug release systems, timecontrolled drug release system, enzyme controlled drug release systems and also microsized delivery forms such as microspheres and nanoparticles the phcontrolled system relies on the physiological difference in the ph of the acidic stomach and that of the distal small intestine, timecontrolled drug release occurs after a predetermined time lag which is similar to the transit time of the system in the small intestine and it ensures delivery of the losartan mecanismo de accion drug into the large intestine enzymecontrolled release systems make use of the variety of enzymes that are produces by the colonic mucosa to achieve colon specific drug delivery these prodrugs and controlled release devices also have the risk of causing adverse side effects, which might result from systemic absorption of drug which might occur due to nonspecific delivery of the drug all over the colon polymeric nanoparticles offer an attractive advantage over these systems in that they are preferentially absorbed by the mucosal cells of the colon based on their size mucoadhesion is another property of the polymers, which could be used for site specific delivery of the drug to the colon polymers such as polysaccharides, which include chondroitin losartan mecanismo de accion sulfate, pectin, dextran and guar gum, have been researched for their use as colon specific systems chitosan, which is one of the most abundant natural polysaccharide, has also been investigated for the development of colon specific delivery system due to its well known mucoadhesive properties a recent study by zhang et al on rats also showed that chitosan gets degraded by the cecal and colonic enzymes factors which affected the degradation of chitosan in colon include its molecular weight and the degree of acetylation a sizedependent bioadhesion of nanoparticles and microparticles in the inflamed colonic mucosa has been demonstrated commercially manufactured fluorescent polystyrene particles of different sizes including , and , nm were used in the study the experiments were losartan mecanismo de accion conducted in rats, which were rectally catheterized and treated with trinitrobenzenesulfonic acid tnbs, for inducing inflammatory bowel disease polystyrene particles were administered orally to the rats and were assessed for localization and deposition of the particles in the git myeloperoxidase mpo activity was determined to ensure and quantify the inflammation in the colonic area sizedependent particle deposition was found in the gastrointestinal tract of control group and also in the inflamed tissue it was found that lower size particles exhibited higher incidence of particle deposition in the inflamed tissue, with the lowest particle size of nm showing a fold increase in percentage particle binding, when compared with particle binding of the same size in the healthy control group the losartan mecanismo de accion overall distribution of the nanoparticles in the git was assessed by confocal laser scanning microscopy and again it was found that nm particles had a higher percentage of localization in the mucus of the inflamed tissue, compared with for nm and only for , nm particles this study proves that nanoparticles are better localized and deposited by the macrophages of the inflamed tissue, and that sizedependent deposition of particles in the inflamed tissue should be given importance, when designing a nanoparticle carrier system for inflammatory bowel disease the same group developed a biocompatible and biodegradable nanoparticle system for targeted oral delivery to the inflamed tissues of the colon for patients suffering from inflammatory bowel disease using plga two different losartan mecanismo de accion molecular weights of plga and , were used to prepare nanoparticles containing rolipram, an anti inflammatory drug emulsificationsolventevaporation method was used for nanoparticles synthesis to yield particle size of less than nm, with an encapsulation efficiency of colonic inflammations were induced into the rats using tnbs and were checked for the severity of colitis by measuring mpo activity plga nanoparticles were orally administered to the rats daily for five days and the control group received only saline plga nanoparticles exhibited a local anti inflammatory effect by controlled drug release and also proved to be as efficient as the free drug in decreasing inflammation of the colitis charged interactions of the negatively charged plga nanoparticles mw � , and the positively charged losartan mecanismo de accion proteins of the ulcerated tissue showed a further enhancement of the binding of these nanoparticles to the inflamed tissue integrating polymeric nanoparticles and dosage forms if the development of a nanoparticlesbased formulation for a drug is a scientifically stimulating job, then development of the means to administer them orally to humans is a challenging art as the scientific community is currently busy solving the problems associated with the former scientific portion, we would like to project a few possible scenarios that could be utilized to develop the art of oral fig flowchart showing integration of drugloaded polymeric nanoparticles and conventional dosage forms administration of polymeric nanoparticles figure provides an overview of conventional formulations that could be used to pack losartan mecanismo de accion the drugloaded nanoparticles for the purpose of oral administration most of the methods used for manufacturing of the nanoparticles yield drug loaded nanoparticles as suspensions generally aqueous if the polymers constituting the nanoparticles remain stable in aqueous environment for the proposed shelflife period, then they could be directly packaged as oral suspensions, along side suitable additives such as flavors, colors, suspending agents and preservatives this would constitute the simplest oral formulation it may be desirable to freeze dry the original drugloaded nanoparticles suspension to limit degradation and also to reduce the levels of organic solvents used during their production in such cases, the drug loaded nanoparticles shall be available as freeflowing powder, with or without added stabilizer ie losartan mecanismo de accion a secondary polymer that is used to prevent aggregation during synthesis of nanoparticles this can be mixed with a standard diluent eg lactose and directly filled into a hard gelatin capsule another appealing strategy is to formulate as a dry power for oral suspension in this case, the nanoparticles power can be mixed with excip ients, including suspending agent, sweetening agent if necessary, flavors, colors and preservatives the contents are to be suspended in water before ingestion softgelatin capsules are popular among conventional oral dosage forms and with the availability of novel excipients from companies such as gattefosse, their application has been extended to meet specialized needs eg sustained release or insitu gelling systems the drugloaded nanoparticles can be losartan mecanismo de accion suspended in a suitable medium usually oilbased and filled into softgelatin capsules special properties can be imparted to the system by including gelforming components or selfemulsifying components that generate a unique system upon dissolution of the gelatin coat in vivo an in situ formed gel can incorporate nanoparticles to extend the dissolution times, or an emulsion may be designed to promote the absorption of drugs from the nanoparticles the delivery module can be made in the tablet form as well however, one has to evaluate the deformations of the drugloaded nanoparticles at the compression conditions employed the nanoparticletablet can be designed as a floating system to increase gastric resident time, or as a bioadhesive system which would increase losartan mecanismo de accion the contact time and hence results in a sustained release, or even a fastdissolving system to expose the nanoparticles quickly to the git for further action coupling osmotic system for delivery of polymeric nanoparticles could be an interesting option to offer a multistep control over drug availability toxicology and regulatory aspects the ultimate mission of the regulatory body governing the approval of pharmaceutical products in the united states food and drug administration � fda is not only to protect, but also to provide improvement of public health by assuring the safety and efficacy of the products for human and veterinary use the fda has taken parallel measures along with the advancements in nanotech nology to meet novel demands and losartan mecanismo de accion challenges there are reasons for the fda to take special steps in promoting the availability of nanotechnology products for public use it is a rapidly growing area of science and is anticipated to lead in the development of novel and sophisticated possibly complex applications in drug delivery systems as the fda only regulates to the claims made by a sponsor, it may be unaware that nanotechnology is being employed to develop that formulation nanotechnology has been currently evaluated under fdas critical path initiative to keep in pace with the developments in the pharmabiotech industry office of combination products of the fda coordinates the regulatory framework for nanotechnology products including nanoparticles, and a dedicated fda center has been proposed losartan mecanismo de accion for taking the primary responsibility of the review of applications many of the fda regulated products are expected to be influenced and revamped under nanotechnology, such as drugs, druggeneprotein delivery systems, vaccines, biotechnology products, medical devices and cosmetics historically, the fda has approved many products and formulations containing solid particulate matter of nanosize range nm it is also understood that many of the bioactive compounds are reduced to nanosize during the process of bioabsorption and there have been no severe safety concerns relating to particle size that have been reported earlier to obtain approval for a nanoparticlebased drug delivery system, the industry has to address the following issues safety the nanoformulations should be evaluated with respect to toxicological screening losartan mecanismo de accion pharmacology, clinical and histopathological analysis, absorption dispositionmetabolismexcretion adme parameters, genotoxicity, developmental toxicity, irritation studies, immunotoxicology and carcinogenicity projection of potential novel and unanticipated reactions and evaluation of excipients effects prior to clinical use an effort should be made to address the following questions with a reduction in the particle size, there could be a change in sizespecific effects on the biological activity of the system hence, it is important to address the issues such as will nanoparticles gain access to tissues and cells that normally would be bypassed by larger particles once nanoparticles enter tissues, how long do they remain intact and how are they cleared if nanoparticles enter cells, what effects do they have on cellular and tissue functions?