Sodium Alginate and Polymer Drug Delivery Systems

Sodium Alginate and Polymer Drug Delivery Systems Sodium alginate is a hygroscopic material, although, stable at low humidities and at cool temperatures. Aqueous solutions of sodium alginate are most stable at ph 4-10. Below ph3, alginic acid is precipitated. Sodium alginate solutions are susceptible to microbial spoilage during storage, which may effect on solution viscosity. Subsequent loss of viscosity due to depolarization was observed when sodium alginate was heated above 70Â °c. Preparations containing sodium alginate for external use may be preserved by the addition of 0. 1% chlorocresol, chloroxylenol, or parabens and if the medium is acidic, benzoic acid may be used. Bulk material should be stored in an airtight container in a cool and dry place. Sodium alginate is incompatible with acridine derivatives, crystal violet, phenyl mercuric acetate and nitrate, heavy metals and ethanol in concentrations greater than 5%w/v. Low concentrations of electrolytes cause an increase in viscosity but high electrolyte concentrations causing salting out of sodium alginate; salting out occurs if more than 4% of sodium chloride is present. Sodium alginate is used in variety of oral and pharmaceutical formulations. In tablet formulations, sodium alginate may be used as both a binder and disintegrant. It has also been used as a diluents in capsule formulations and also been used in the preparation of sustained release oral formulations, since it can delay the dissolution of a drug from tablets, capsules and aqueous suspensions. Recently, sodium alginate has been used for the aqueous microencapsulation of drugs in contrast with the more conventional microencapsulation techniques which use organic solvent systems. It has also been used in the formation of nanoparticles. The adhesive nature of hydrogels prepared from sodium alginate has been investigated and the drug release from oral mucosal adhesive tablets based in sodium alginate has been reported. Hydrogel systems containing alginates have also been investigated for delivery of proteins and peptides. Therapeutically sodium alginate has been used in the combination with an h2 receptor antagonist in the management of gastroesophageal reflux and as a haemostatic agent in surgical dressings. Alginate dressings, used to treat exuding wounds often contain significant amounts of sodium alginate as this improves the gelling properties. Sodium alginate is also used in cosmetics and food products at concentrations given in table 4 Safety Sodium alginate is widely used in cosmetics, food products, and pharmaceutical formulations, such as topical products, including wound dressings. It is generally regarded as a nontoxic and non-irritant material, although excessive oral consumption may be harmful. The WHO has not specified an acceptable daily intake for alginic acid and alginate salts as the levels used in foods do not represent a hazard to health. Handling precautions. Sodium alginate may be irritant to eye or respiratory system if inhaled as dust;eye protection, gloves, dust respirator are needed while handling. Sodium alginate should be handled in a well ventilated environment. Related substances The various substances related to sodium alginate include alginic acid, potassium alginate, calcium alginate, propylene glycol alginate. CHITOSAN Chitosan is a derivative of chitin and it is a unique polysaccharide and hydrophilic polymer. Non Proprietary Names BP: Chitosan hydrochloride Ph Eur : Chitosan hydrochloridum Chemistry Preparation The principle derivative of chitin, namely Chitosan (C6H11O4N)n is a unique polysaccharide and hydrophilic polymer which is taken from the chitin, a polysaccharide found in exoskeletons of crustaceans. it is processed by removing the shells from shellfish such as shrimp, lobusters and crabs. The shells are then ground into a pulverous powder. This powder is then deacetylated. This involves boiling chitin in concentrated alkali (50%) for several hours. This will yield chitosan with a degree of acetylation between 20-30%, the most popular commercial form of Chitosan. In such a chitosan, the acetyl groups are uniformly distributed along the polymer chain. This is in contrast with the Chitosan of similar degree of acetylation, but isolated from fungal cell walls in which the acetylresidues are grouped into clusters. Special chemical treatments are required to obtain completely de-acetylated forms of chitosan. CHITIN Functional category It is used as a coating agent; disintegrant; film forming agent; mucoadhesive, tablet binder; viscosity increasing agent etc. Chemical character Chitosan is a cationic polyamine with a high charge density at ph The amino group in chitosan has a pka value of approximately 6. 5, thus chitosan is positively charged and soluble in acidic to neutral solution with a charge density depend on ph and the %da. Numerous studies have demonstrated that the salt form, molecular weight, and degree of deacetylation as well as ph at which chitosan is used all influence how this polymer is utilized in pharmaceutical application. Chitosan is incompatible with strong oxidising agent. Typical properties Chitosan is a cationic polyamine with a high charge density at ph Acidity / alkalinity pH=4-6(1%w/v aqueous solution) Density 1. 35-1. 49g/cm3 Particle size distribution Stability and storage conditions Chitosan is a stable material at room temperature although it is hygroscopic after drying. Chitosan should be stored in a tigjtly closed container in a cool and dry place. Incompatibilities Chitosan is incompatible with strong oxidizing agents. Safety Chitosan is being investigated widely for use as an excipient in oral and other pharmaceutical formulations. It is also used in cosmetics. chitosan is generally regarded as biodegradable, nontoxic and non irritant material. it is biocompatible with both healthy and infected skin. Applications Chitosan is found useful in many fields like sustained drug delivery, components of mucoadhesive dosage forms, rapid release dosage forms, improved peptide delivery, colonic drug delivery systems and use for gene delivery. Chitosan is processed into several pharmaceutical forms including gels, beads, films, microspheres tablets and coatings for liposomes. PROPRANOLOL HYDROCHLORIDE (ÃŽÂ ²-adrenergic blocking agents) Adrenergic nonselective ÃŽÂ ²-receptor antagonist. (antihypertensive, antianginal and antiarrhythmic. ) STRUCTURE Chemical name (ÂÂ ±)-1-isopropylamino-3-(1-naphthyloxy) propan-2-ol hydrochloride Molecular formula C16H21NO2. HCl Molecular weight 295. 8 Description: A white powder, odourless and bitter in taste Solubility: Soluble Soluble 1 in 2 of water and ethanol Slightly soluble in chloroform I . PHARMACOLOGICAL ACTIONS a. Cardiovascular-Propranolol diminishes cardiac output, heart rate, and force of contraction. These effects are useful in the treatment of angina. b. Peripheral vasoconstriction-Blockade of ÃŽÂ ²-receptors prevents ÃŽÂ ²2-mediated vasodilation. The reduction in cardiac output leads to decreased blood pressure. c. Bronchoconstriction-Blocking ÃŽÂ ²2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle. Î’-blockers are thus contradicted in patients with asthma. d. increased Na+ retention-reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ and plasma volume. in some cases this compensatory response tends to elevate the BP. For these patients, ÃŽÂ ²-blockers are often combined with a diuretic to prevent Na+ retention. II. THERAPEUTIC EFFECTS a. Hypertension-propranolol lowers BP in hypertension by decreasing cardiac output. b. glaucoma-propranolo is effective in diminishing intraocular pressure in glaucoma. c. migraine-propranolol is also effective in reducing migraine episodes by blocking the catecholamine induced vasodilation in the brain vasculature. d. angina pectoris-propranolol decreases the oxygen requirement of heart muscle and therefore effective in reducing the chest pain in angina. e. myocardial infarction-propranolol and other ÃŽÂ ²-blockers have a protective effect on the myocardium. thus, patient who have had one myocardial infarction appear to be protected against a second heart attack by prophylactic use of ÃŽÂ ²-blockers. III. ADVERSE EFFECTS a. broncho constriction-when propranolol is administered to an asthmatic patient, an immediate contraction of the bronchiolar smooth muscle prevents air from entering the lungs. Therefore, propranolol must never be used in treating any individual with obstructive pulmonary disease. b. arrhythmias-treatment with the ÃŽÂ ²-blockers must never be stopped quickly because of the risk of precipitating cardiac arrhythmias. c. disturbances in metabolism- ÃŽÂ ² bloackade leads to decreased glycogenolysis and decreased glucagon secretion. d. drug interaction-drugs that interfere with the metabolism of propranolol, such as cimetidine, furosemide and chlorpromazine may potentiate its antihypertensive effects. conversely those that stimulate is metabolism, such as barbiturates, phenytoin and rifampicin can mitigate its effects. PHARMACOKINETICS Propranolol is well absorbed after oral administration but has low bioavailability due to high first pass metabolism in liver. it is highly bound to plasma proteins. Metabolism of propranolol is dependent on hepatic blood flow. DOSE Oral 10mg BD to 10mg QID (average 40-60mg/day) I. V 2-8mg injected over 10min with with constant monitoring. it is not injected S. C or I. M because of irritant property. MATERIALS NAME OF THE MATERIALS NAME OF THE COMPANY Propranolol hydrochloride Sodium alginate AR Hi-Media biosciences Ltd, Mumbai. Calcium chloride AR S. D Fine chemicals Ltd, Mumbai Barium chloride AR Qualigens Fine Chemicals Ltd, Mumbai Chitosan AR Fluca Biochemicals Ltd, Switzerland. (Viscosity 200-400 mPa. s) Acetic acid EQUIPMENTS USED Name of equipment Name of company UV/Vis Spectrophotometer JASCO V-530 IR Spectrophotometer Jasco-FT-IR 8201 PC Differential scanning calorimeter DSC-60 (Shimadzu, Tokyo, Japan) Optical Microscope and Stage Micrometer Erma. Japan Scanning Electron Microscope JSM 6400 x-ray diffractrometer Bruker AXS D8 Dissolution apparatus Electrolab TDT-08L, USP XXIV Type I Apparatus. Chennai Remi Hi-speed motor Universal motors. Mumbai Digital balance Denver Instruments 18002098899 simi INTRODUCTION MICROENCAPSULATION A process in which very thin coatings of polymeric materials are deposited around particles of solids or droplets of liquid. Different terms for solid particle systems are employed in drug delivery among them pellets, beads, microcapsules, microspheres, millispheres are few. The terminologies of most relevant multiparticulate systems are provided here. Pellets can be defined as Small, free flowing spherical particles manufactured by agglomeration of fine powders or granules of drug substances and excipients using appropriate processing equipment. The size of these particles rae usually between 0. 5 and 1. 5mm. sphericity and intra granular porosity are the two important quality attributes of pellets. The terms spherical granules and beads have been applied interchangeably to pellet system. Microspheres are solids approximately spherical particles ranging in size from 1 to 1000ÂÂ µm. They are made of polymeric, waxy, or other protective materials, that are biodegradable synthetic polymers and modified natural products such as gums, proteins, waxes etc. Microsphere: the enbtrapped substance is dispersed throughout the microsphere matrix. Microcapsule: the entrapped substance is completely surrounded by distinct capsule wall. The similiarities between microsphers and microcapsules are clear and illustrations of these particles are shown in Fig: Encapsulation methods Two major classes of encapsulation methods have evolved, viz chemical and physical. The first class of encapsulation involves polymerisation during the process of preparing the microcapsules. examples of this class are usually known by the name of interfacial polymerisation or in situ polymerisation. The second type involves controlled precipitation of a polymeric solution where in physical changes usually occur. The precipitation and or gelation listed in table cover many techniques. one example isthe precipitation of water soluble polymers such as gelatin with water miscible solvents such as isopropranol. other examples include the precipitation of ethyl cellulose from cyclohexane agin by cooling, and gelation of sodium alginate with aqueous calcium salt solutions. in all cases the objective is to precipitate a performed polymer around the core (sometimes a multi-particulate) to cause encapsulation. Process Coating material Suspended medium Interfacial polymerization Water soluble and insoluble monomers Aqueous/organic solvents Complex coacervation Water soluble polyelectrolyte Water Simple coacervation Hydrophobic polymers Organic solvents Thermal denaturation Proteins Organic solvents Salting out Water-soluble polymer Water Solvent evaporation Hydrophilic or hydrophobic polymer Organic or Water Hot melt Hydrophilic or hydrophobic polymer Aqueous/organic solvents Solvent removal Hydrophilic or hydrophobic polymer Organic solvents Spray drying Hydrophilic or hydrophobic polymer Air, nitrogen Phase separation Hydrophilic or hydrophobic polymer Aqueous/organic solvents POLYMER BASED DRUG DELIVERY SYSTEM There has been growing interest in polymer based bioadhesive drug delivery systems. one of the goals of such systems is to prolong the residence time of a drug carrier in the Gastro Intestinal tract(GIT). The bioadhesive bond can be of a covalent, electrostatic, hydrophobicor hydrogen bond nature. ionic polymers are reported to be more adhesive than neutral polymers, and an increased charge density will also give better adhesion suggesting that the electrostatic interactions are of great importance. except for the oesophagus, the entire GI tract including the stomach is covered with a continous layer of insoluble mucus gel. The mucus gel mainly consists of glycolproteins and due to their content of ester sulphate and sialic acid groups, the mucus layer has an overall strong net negative charge. The mucus layer has been considered as a possible site for bioadhesion and drug delivery by several groups. Natural polymers Recently, the use of natural polymers in the design of drug delivery formulation has received much attention due to their excellent biocompatibility, biodegradability, non toxicity and easy in availability. Polymers as carriers used in drug delivery system The different types of polymers for extended release preparations are given below. Biodegradable polymers The biodegradable polymers comprised of monomers linked to one another through functional groups and have unstable linkages in the backbone. They are biologically degraded or eroded by enzymes or generated by living cells. Natural Albumin, alginate, collagen, starch, chitosan, dextran, casein, gelatine, fibrinogen etc. Synthetic Polyalklyl-cyanoacrylate, poly ethyl cyano acrylate, poly amino acids, poly amides, poly acryl amides etc. Aliphatic polyesters Poly(maleicacid), poly (glycolic acid), poly(hydroxyl butyrate), poly (lactic acid), poly vinyl alcohol(PVA) etc. Non-biodegradable polymers Poly ethylene vinyl acetate(EVA), poly ether urethane(PEU), cellulose acetate, poly vinyl chloride(PVC), ethyl cellulose etc. In recent years a lrge number of biodegradable polymers have been investigated for their potential use as drug delivery systems. among them, sodium alginate and chitosan are very promising and have been widely exploited in pharmaceutical industry for sustained drug release. polysaccharides such as alginic acid, agar, chitin and chitosan have been used to agglomerate drugs for controlled drug delivery systems. Chitosan is a anaturally occurring polysaccharide comprosing of glucosamine and N-Acetyl glucosamine with unique poly cation characteristics. The polycationic nature of chitosan leads to a strong interaction with negatively charged alginate. when alginate is dropped into chitosan solution, the electrostatic interaction of carboxylic groups of alginate with the amino groups of chitosan results in the formation of a membarane on the surface of sodium alginate and improves the stability and drug content. This process has been widely used in the preparation of alginate chitosan membaranes with a solid calcium-alginate gel core. There are many advantages of the chitosan coating, such as the improvement of drug loading and bioadhesive property, as well as the prolonged drug release properties etc. Alginate(ionic, hydrophilic polymer) is a negatively charged polysachharide with high charge density and has been reported to be bioadhesive. among polyanionic polymers, alginate has been widely studied and applied for its possibility to modulate the release according to the properties of its carboxyl groups as well as its biodegradability and absence of its toxicity. alginate is a naturally derived anionic polysaccharide mainly from algae belonging to the family of phaeophyceae. Alginic acid is an algal polysaccharide and a species of poly carboxylic acid. alginate consists of two sugar moieties ÃŽÂ ²-D mannuronic acid and ÃŽÂ ±-L guluronic acid which exist either in blocks or random sequences and their relative proportions determines the biofunctional properties of alginc acid. alginate is known to form complexes with divalent cations, such as Ca2+, Ba2+, and Sr2+ in aqueous solution. depending upon the composition of two sugar residues and sequential distribution within the molecules, the complexes form either precipitates or hydrogels. guluronic acid blocks are known to form a rigid buckled structure, the so called egg box array, in which chelating calcium ions are nestled in the aqueous environment of the ordered gel structure due to the spatial arrangements of guluronic block oxygen atoms of carboxyl and hydroxyl groups. Alginate has been widely used as food additive, a tablet disintegrator or gelation agent, and the mechanism of its gelation have been extensively investigated. when an aqueous solution of sodium alginate(SA) is added dropwise to an aqueous solution of calcium chloride, spherical alginate beads with regular shape and size are produced, since an insoluble calcium alginate matrix is formed by the cation exchange between sodium and calcium ions. alginates are known to form reticulated structure when in contact with calcium chloride ions and this characteristic has been used to produce SR particulate systems for a variety of drugs. GEL FORMATION (GENERAL MECHANISM) A gel in classical colloidal terminology, is defined as a system which owes its characteristic properties to a cross linked network of polymeric chains which form at the gel point. a considerable amount of research has been carried out in recent years to elucidate the nature of the crosslinks and determine the structure of alginate gels. alginate beads can be prepared by extruding a solution of sodium alginate containing the desired drug or protein, as droplets, into a divalent crosslinking solution such as Ca2+, Ba2+, and Sr2+ . monovalent cations do not induce gelation while Ba2+, and Sr2+ ions produce stronger alginate gels than Ca2+. other divalent cations such as Pb2+, Cu2+, Cd2+, CO2+, Ni2+, Zn2+, Mn2+ will also cross link alginate gels but their use is limited due to their toxicity. The gelation and cross linking of the polymers are mainly achieved by the exchange of divalent cations and stacking of these guluronic acids with the divalent cations, and the stacking of these gul uronic groups to form the characteristic egg-box structure shown in fig LARGE BEAD PREPARATION In general, beads greater than 1. 0mm in diameter which can be produced by using a syringe, with a needle or a pipette. sodium alginate solution that contains the solubilised drug or protein is transferred dropwise into a gently agitated divalent cross linking solution. The diameter of the beads formed is dependant on the size of the needle used and the viscosity of the alginate solution . a larger diameter needle and higher viscosity solutions will produce larger diameter beads. The viscosity of SA can also influence the shape of the microbeads produced. The beads become more spherical as the concentration of SA increased. however, in general SA solutions of greater than 5% are difficult to prepare. Since, gelation occurs in an aqueous environment, alginate is a promising material as a food additive, drug formulation and useful even for encapsulation of living cells to protect them from immune responses. utilizing this stable complex formation with divalent cations, alginate gels have been utilized for investigation of cells are considered to be the ultimate system for the pulsatile release of biologically active compounds. Formulation of delivery devices for protein and peptide drugs under aqueous conditions are desirable to avoid the undesirable decrease of bioactivities which may occur when using organic solvents or heat during formulations. since relatively stable alginate gels can be formed in aqueous environments through chelation or complexation, which are promising delivery of matrices for bioactive compounds. It has been suggested that the crosslinks were caused either by ionic bridging of 2 carboxyl groups on adjacent polymer chains via calcium ions or by chelation of single calcium ions by hydroxyl and carboxyl groups on each of a pair of polymer chains. although these bonds may play a role in the gelation mechanism which are not sufficiently energetically favourable to account for the gelation of alginate. it has been shown on thebasis of fibre diffraction data and model-building calculations that the shape of both poly-mannuronic acid segments and the polygulutended, and that these extended ribbons can stack together in sheets. on the basis of these data and the properties of gels it has been suggested that the cooperative association of either polymannuronic acid segments or polyguluronic acid segments are involved in the formation of the crosslinked network of polymer chain. This technique has shown attractive applications in different fields, including cell immobilisation, owing to its mild operating conditions. as the encapsulation method is mild, and done at room temperature in aqueous medium, several sensitive drugs, proteins, living cells, enzymes, spermatozoa etc have been successfully encapsulated through alginate beads. The primary structure of alginate depends on the producing species and for the marine species, seasonal and geographical changes might result in variations in alginates extracted from the same species. The polymer is nown to form a physical gel by hydrogen bonding at low pH(acid gel)and by ionic interactions with polyvalent cations such as calcium, the cation acting as a cross linker between the polymer chains. The viscosity and primary structure of polymer are important features determining it swelling and gelling properties. At neutral pH, sodium alginate is soluble and hydrates to form viscous solutions, but below pH3, alginic acid, water swellable but insoluble, which is rapidly formed. since the hydration characteristics of the polymer and the subsequent physical properties of the hydrated gel layer may critically influence drug release. When CA beads are treated with 0. 1M HCl, alginate gels hydrolysed to lower molecular weight fractions of alginic acid. due to conversion of COO- groups into unionised carboxylic groups, the electrostatic attraction between Ca2+ ions and COO- ions in the egg-box junction almost disappears. moreover, there may occur in ion-exchange between H+ ion(presence in the external HCl solution) and free Ca2+ ions inside the beads. thus a reduced Ca2+ ions concentration within the beads results in a weaker Ca2+ cross linked beads when put in phosphate buffer at pH 6. 8. Therefore, the acid-treated beads are loosely crosslinked structure more soluble alginate as constituent. when such beads are put in the phosphate buffer pH6. 8, the beads swell at a faster rate but do not attain a higher water uptake value due to loosely bound structure of the beads which is unable to retain large amount of water within the beads. moreover, there is possibility of ion-exchange between H+ ions produced due to ion isation of carboxylic groups in the buffer at pH. A group of scientists developed a method of enclosing viable cells, tissues, and other labile biological substances within a semipermeable membrane. preliminary in-vitro studies of several types of microencapsulated cells and tissues(redblood cells, sperm cells, hepatica cells, hepatocytes, pancreatic endocrine tissues, and islets) were described by them. essentially, the process involves suspending the living cells or tissues in sodium alginate solution. The cell or tissue suspension is extruded through a device producing micro-droplets which fall into a calcium chloride solution and form gelled microbeads with the cells or tissues entrapped. These cell containing gel microbeads are next treated with polysine which displaces the surface layer of calcium ions and forms a permanent polysalt shell or membrane. finally, the interior calcium alginate is liquefied, either to stay in or to cum out(depending on molecular weight and size of the starting alginate) of the capsule with a calciu m sequestrant such as buffered citrate solution. Gohel et al ., prepared diclofenac sodium microspeheres by using sodium alginate as a polymer and CaCl2 as a cross linking agent. in this investigation stirring speed, concentration of crosslinking agent and heavy liquid paraffin were studied, on the time required for 80% of drug dissolution. a statistical model with significant interaction terms was derived to predict t80 and drug was released by diffusion of anomalous type. The results of multiple regression analysis and F value statistics revealed that, obtaining of controlled drug release and microspheres were to be prepared using relatively lower stirring speed. Literature reports indicate wide spread use of sodium alginate for achieving sustained release of drugs, targeting gastric mucosa and increasing the bioavailability of drugs because of sodium alginates ability to form a stable and bioadhesive gel with calcium ions. Alginate also has several unique properties that have enabled it to be used as a matrix for the entrapment or delivery of a variety of proteins, macromolecules and cells. USES Of Alginate Beads A relatively inert aqueous environment within the matrix. A mild room temperature encapsulation process free of organic solvent A high gel porosity which allows for high diffusion rate of macromolecules The ability to control this porosity with simple coating procedures. Dissolution and biodegradation of the system under normal physiological conditions. Standard graph for propranolol hydrochloride A stock solution of propranolol hydrochloride was prepared by dissolving 100mg of the drug in 100ml of the phosphate buffer of pH6. 8 to give 1mg/ml solution. ten millilitres of stock solution was diluted to 100ml using phosphate buffer f pH6. 8 to produce 100ÂÂ µg/ml working stock solution. from this working solution, dilutions were made with phosphate buffer of pH6. 8 to produce 10, 20, 30, 40 and 50 ÂÂ µg/ml. The ÃŽÂ » max of the drug was determined by scanning the dilutions between 400 and 200nm using a Shimadzu 1400 UV visible spectrophotometer. At this wavelength, the absorbances of all the other solutions were measured against a blank. Standard curve between concentration and absorbance was plotted. COMPATIBILITY STUDIES One of the requirements for the selection of suitable polymers or carriers for pharmaceutical formulation is its compatibility. Therefore in the present work a compatibility study was done by using Infra Red spectroscopy (IR) and Differential Scanning Calorimetry (DSC) to find out if there is any possible chemical interaction between propranolol hydrochloride and the polymers. DIFFERENTIAL SCANNING CALORIMETRY (DSC) Differential Scanning calorimetric analysis was used to characterize the thermal behaviour of the drug substances. It was performed by using DSC-60(Shimadzu, Tokyo, Japan) calorimeter to study the thermal behaviour of selected formulations. The instrument comprised of calorimeter (DSC60), flow controller (FCL60), thermal analyzer (TA60) and operating software(TA 60). The samples were heated in hermetically sealed aluminium pans under nitrogen flow (30ml/min)at a scanning rate of 5Â °C/min from 24 + 1Â °C to 300Â °C. An empty aluminium pan, sealed in the same way as the sample was used as a reference. SCANNING ELECTRON MICROSCOPY Scanning electron microscopy is used to obtain the surface topographical characterization of beads. SEM photographs of prepared formulations were taken with (Instrument JSM-6390)at different magnification ranging from 30 to 5000x at room temperature. The samples were mounted on double sided adhesive tape that has previously been secured on copper stubs. The acceleratio

Socialist Utopia In Nineteen E :: essays research papers

Eric Blair, known to his readers under the English pen name of George Orwell (1903-1950), was a man familiar with the roles of government. He served with the British government in Burma under the Indian Imperial Police. Returning to his European roots, Orwell also sided with the Spanish government as he fought with the Loyalists in their civil war. It wasn't until he wrote professionally as a political writer that Orwell's ideas of government were fully expressed. Orwell, in his political writings, was extremely contradictory. He was a critic of communism, yet he also considered himself a Socialist. He had hatred toward intellectuals, but he too was a political writer. It is only natural that a man of paradoxes would write of them. In his novel Nineteen Eighty-Four, George Orwell develops his Socialist Utopia as a paradoxical society that ultimately succeeds rather than flounders.   Ã‚  Ã‚  Ã‚  Ã‚  The society that Orwell creates is full of paradoxes that existed all the way up to its origins. The founders of the new lifestyle, known as the revolutionaries of the mid-twentieth century, leads the public to believe false intentions of revolt, as these purposes soon become exact opposite outcomes. The original designers seek to create an ideal social order out of England that is beneficial to all. Marin Kessler, a literary essayist, agrees that these 'utopians…had hoped to construct a perfect society in which men and women could enjoy that ultimate degree of happiness which, it was implied denied through the folly and wickedness of their present rulers'; (304). Besides being founded on the concept of a Utopia, the revolutionaries believe they could achieve their goals through Ingsoc, a variation on English socialism (named justly). The main concept of socialism is its stress on social equality, so much that the government distributes any possessions equal ly. In reality, this policy sought to destroy individual property, instead emphasizing collective property, owned by the government for the ultimate purpose of equality. Socialism is also often considered the politics of the working class and lower rà ©gime, since they actually benefited from it. Although the founders claim to create a socialist Utopia with its respective freedoms, the society of Oceania they create is exactly the opposite of their original principles. O'Brien, a major contributor to the government organization known as the Party, describes the contradictory characteristics of the world power of Oceania, 'Do you begin to see then, what kind of world we are creating?

The Return: Midnight Chapter 20

Meredith usual y found her parents funny and sil y and dear. They were solemn about al the wrong things like, â€Å"Make sure, honey, that you real y get to know Alaric – before – before – â€Å"Meredith had no doubts about Alaric at al , but he was another of those sil y, dear, gal ant people, who talked al around things without getting to the point. Today, she was surprised to see that there was no cluster of cars around the ancestral home. Maybe people had to stay home to fight it out with their own children. She locked the Acura, conscious of the precious contents given by Isobel, and rang the doorbel . Her parents believed in chain locks. Janet, the housekeeper, looked happy to see her but nervous. Aha, Meredith thought, they have discovered that their dutiful only child has ransacked the attic. Maybe they want the stave back. Maybe I should have left it back at the boardinghouse. But she only realized that things were truly serious when she came into the family room and saw the big La-Z-Boy deluxe lounging chair, her father's throne: empty. Her father was sitting on the couch, holding her mother, who was sobbing. She had brought the stave with her, and when her mother saw it, she broke into a fresh burst of tears. â€Å"Look,†Meredith said, â€Å"this doesn't have to be so tragic. I've got a pretty good idea of what happened. If you want to tel me about how Grandma and I real y got hurt, that's your business. But if I was†¦contaminated in some way†¦Ã¢â‚¬  She stopped. She could hardly believe it. Her father was holding out an arm to her, as if the somewhat rank condition of her clothes didn't matter. She went to him slowly, uncomfortably, and let him hug her regardless of his Armani suit. Her mother had a glass with a few sips left of what looked like Coke in front of her, but Meredith would bet it wasn't al Coke. â€Å"We'd hoped that this was a place of peace,†her father orated. Every sentence her father spoke was an oration. You got used to it. â€Å"We never dreamed†¦Ã¢â‚¬ And then he stopped. Meredith was stunned. Her father didn't stop in the middle of an oration. He didn't pause. And he certainly didn't cry. â€Å"Dad! Daddy! What is it? Have kids been around here, crazy kids? Did they hurt somebody?† â€Å"We have to tel you the whole story from that time long ago,†her father†¦said. He spoke with such despair that it wasn't anything like an oration. â€Å"When you were†¦al attacked.† â€Å"By the vampire. Or Grandfather. Or do you know?† Long pause. Then her mother drained the contents of her glass and cal ed, â€Å"Janet, another one, please.† â€Å"Now, Gabriel a – â€Å"her father said, chiding. â€Å"‘Nando – I can't bear this. The thought that mi hija inocente†¦Ã¢â‚¬  Meredith said, â€Å"Look, I think I can make this easier for you. I already know†¦Well, first, that I had a twin brother.† Her parents looked horrified. They clung together, gasping. â€Å"Who told you?†her father demanded. â€Å"At that boardinghouse, who could know – ?† Calming down time. â€Å"No, no. Dad, I found out – Well, Grandpa talked to me.†That was true enough. He had. Just not about her brother. â€Å"Anyway, that was how I got the stave. But the vampire that hurt us is dead. He was the serial kil er, the one who kil ed Vickie and Sue. His name was Klaus.† â€Å"You thought that there was only one vampire?†her mother got out. She pronounced the word the Hispanic way, which Meredith always found more scary. Vahm-peer. The universe seemed to start moving slowly around Meredith. â€Å"That's just a guess,†her father said. â€Å"We don't real y know that there was more than the very strong one.† â€Å"But you know about Klaus – how?† â€Å"We saw him. He was the strong one. He kil ed the security guards at the gate with one blow each. We moved to a new town. We hoped you would never have to know you had a brother.†Her father brushed his eyes. â€Å"Your grandfather spoke to us, right after the attack. But the next day†¦nothing. He couldn't talk at al .† Her mother put her face in her hands. She only lifted it to cal , â€Å"Janet! Another, por favor!† â€Å"Right away, ma'am.†Meredith looked to the housekeeper's blue eyes for the solution to this mystery and found nothing – sympathy, but no help. Janet walked away with the empty glass, blond French braid receding. Meredith turned back to her parents, so dark of eye and hair, so olive of skin color. They were huddling together again, eyes on her. â€Å"Mom, Dad, I know that this is real y hard. But I'm going after the kind of people who hurt Grandpa, and Grandma, and my brother. It's dangerous, but I have to do it.†She dropped into a Taekwondo stance. â€Å"I mean you did have me trained.† â€Å"But against your own family? You could do that?†her mother cried. Meredith sat down. She had reached the end of the memories that she and Stefan had found. â€Å"So Klaus didn't kil him like Grandmother. He took my brother with him.† â€Å"Cristian,†wailed her mother. â€Å"He was just un bebe. Three years old! That was when we found the two of you†¦and the blood†¦oh, the blood†¦Ã¢â‚¬  Her father got up, not to orate, but to put his hand on Meredith's shoulder. â€Å"We thought it would be easier not to tel you – that you wouldn't have any memories of what was happening when we came in. And you don't, do you?† Meredith's eyes were fil ing with tears. She looked to her mother, trying to silently tel her she couldn't understand this. â€Å"He was drinking my blood?†she guessed. â€Å"Klaus?† â€Å"No!†cried her father as her mother whispered prayers. â€Å"He was drinking Cristian's, then.†Meredith was kneeling on the floor now, trying to look up into the face of her mother. â€Å"No!†cried her father again. He choked. â€Å"La sangre!† gasped her mother, covering her eyes. â€Å"The blood!† â€Å"Querida – † her father sobbed, and went to her. â€Å"Dad!†Meredith went after him and shook his arm. â€Å"You've ruled out al the possibilities! I don't understand! Who was drinking blood?† â€Å"You! You!† her mother almost screamed. â€Å"From your own brother! Oh, el aterrorizar!† â€Å"Gabriel a!†moaned her father. Meredith's mother subsided into weeping. Meredith's head was whirling. â€Å"I'm not a vampire! I hunt vampires and kil them!† â€Å"He said,†her father whispered hoarsely: â€Å"‘Just see she gets a tablespoon a week. If you want her to live, that is. Try a blood pudding.'He was laughing.† Meredith didn't need to ask if they had obeyed. At her house, they had blood sausage or pudding at least once a week. She had grown up with it. It was nothing special. â€Å"Why?†she whispered hoarsely now. â€Å"Why didn't he kil me?† â€Å"I don't know! We Stilldon't know! That man with his front al dripping with blood – your blood, your brother's blood, we didn't know! And then at the last minute he grabbed for the two of you but you bit his hand to the bone,†her father said. â€Å"He laughed – laughed! – with your teeth clamped in him and your little hands pushing him away, and said, ‘I'l just leave you this one, then, and you can worry about what she wil turn out to be. The boy I'm taking with me.'And then suddenly I seemed to come out of a spel , for I was reaching for you again, ready to fight him for both of you. But I couldn't! Once I had you, I couldn't move another inch. And he left the house Stilllaughing – and took your brother, Cristian, with him.† Meredith thought. No wonder they didn't want to hold any kind of celebration on the anniversaries of that day. Her grandmother dead, her grandfather going crazy, her brother lost, and herself – what? No wonder they celebrated her birthday a week early. Meredith tried to stay calm. The world was fal ing to pieces around her but she had to stay calm. Staying calm had kept her alive al her life. Without even having to count, she was breathing out deep, and in through her nostrils, and out through her mouth. Deep, deep, cleansing breaths. Soothing peace throughout her body. Only part of her was hearing her mother: â€Å"We came home early that night because I had a headache – â€Å" â€Å"Sh, querida – â€Å"her father was beginning. â€Å"We got home early,†her mother keened. â€Å"O Virgen Bendecida, what would we have found if we had been late? We would have lost you, too! My baby! My baby with blood on her mouth – â€Å" â€Å"But we got home early enough to save her,†Meredith's father said huskily, as if trying to wake her mother from a spel . â€Å"Ah, g racias, Princesa Divina, Vigen pura y impoluto†¦Ã¢â‚¬ Her mother couldn't seem to stop crying. â€Å"Daddy,†Meredith said urgently, aching for her mother but desperately needing information. â€Å"Have you ever seen him again? Or heard about him? My brother, Cristian?† â€Å"Yes,†her father said. â€Å"Oh, yes, we have seen something.† Her mother gasped. â€Å"‘Nando, no!† â€Å"She has to learn the truth sometime,†her father said. He rummaged among some cardboard file folders on the desk. â€Å"Look!†he said to Meredith. â€Å"Look at this.† Meredith stared in utter disbelief. In the Dark Dimension Bonnie shut her eyes. There was a lot of wind at the top of a tal building's window. That was al her mind had a thought for when she was out of the window and then back into it and the ogre was laughing and Shinichi's terrible voice saying, â€Å"You don't real y think we'd let you go without questioning you thoroughly?† Bonnie heard the words without them making sense, and then suddenly they did. Her captors were going to hurt her. They were going to torture her. They were going to take her bravery away. She thought she screamed something at him. Al she knew, though, was that there was a soft explosion of heat behind her, and then – unbelievably – al dressed up in a cloak with badges that made him look like some kind of military prince, there was Damon. Damon. He was so late she'd long ago given up on him. But now he was flashing a there-and-gone bril iant smile at Shinichi, who was staring as if he'd been stricken dumb. And now Damon was saying, â€Å"I'm afraid Ms. McCul ough has another engagement at that moment. But I wil be back to kick your ass – immediately. Move from this room and I'l kil you al , slowly. Thank you for your time and consideration.† And before anyone could even recover from their first shock at his arrival, he and Bonnie were blasting off through the windows. He went, not out of the building backward as if retreating, but straight ahead forward, one hand in front of him, wrapping them both in a black but ethereal bundle of Power. They shattered the two-way mirror in Bonnie's room and were almost al the way through to the next room before Bonnie's mind tagged the first â€Å"empty.†Then they were crashing through an elaborate videoset-window – made to let people think they had a view of the outdoors, and flying over someone lying on a bed. Then†¦it was just a series of crashes, as far as Bonnie was concerned. She barely got a glimpse of what was going on in each room. Final y†¦ The crashing stopped. This left Bonnie holding on to Damon koala-style – she wasn't stupid – and they were very, very high in the air. And mobilizing in front of them, and off to the sides, and as far as Bonnie could see, were women who were also flying, but in little machines that looked like a combination of a motorcycle and a Jet Ski. No wheels, of course. The machines were al gold, which was also the color of each driver's hair. So the first word Bonnie gasped to her rescuer, after he had blasted a tunnel through the large slave-owner's building to save her, was, â€Å"Guardians?† â€Å"Indispensable, considering the fact that I didn't have the first idea where the bad guys might have taken you and I suspected that there might be a time limit. This was actual y the very last of the slave-sel ers we were due to check. We final y†¦lucked out.†For someone who had lucked out, he sounded a little strange. Almost†¦choked up. Water was on Bonnie's cheeks but it was being flicked away too fast for her to wipe it. Damon was holding her so that she couldn't see his face, and he was holding her very, very tightly. It real y was Damon. He had cal ed out the cavalry and, despite the city-wide mind-gridlock, he had found her. â€Å"They hurt you, didn't they, little redbird? I saw†¦I saw your face,†Damon said in his new choked-up voice. Bonnie didn't know what to say. But suddenly she didn't mind how hard he squeezed her. She even found herself squeezing back. Suddenly, to her shock, Damon broke her koala-grip and pul ed her up and kissed her on the lips very gently. â€Å"Little redbird! I'm going to go now, and make them pay for what they did to you.† Bonnie heard herself say, â€Å"No, don't.† â€Å"No?†Damon repeated, bewildered. â€Å"No,†Bonnie said. She needed Damon with her. She didn't care what happened to Shinichi. There was a sweetness unfolding inside her, but there was also a rushing in her head. It real y was a pity, but in a few moments she would be unconscious. Meanwhile, she had three thoughts in mind and al of them were clear. What she was afraid of was that they would be less clear later, after she had fainted. â€Å"Do you have a star bal ?† â€Å"I have twenty-eight star bal s,†Damon said, and looked at her quizzical y. That wasn't what Bonnie meant at al ; she meant one to record onto. â€Å"Can you remember three things?†she said to Damon. â€Å"I'd gamble on it.†This time Damon kissed her softly on the forehead. â€Å"First, you ruined my very brave death.† â€Å"We can always go back and you can have another try.†Damon's voice was less choked now; more his own. â€Å"Second, you left me at that horrible inn for a week – â€Å" As if she could see inside his mind, she saw this slice into him like some kind of wooden sword. He was holding her so tightly that she real y couldn't breathe. â€Å"I†¦I didn't mean to. It was real y only four days, but I never should have done it,†he said. â€Å"Third.†Bonnie's voice dropped to a whisper. â€Å"I don't think any star bal was ever stolen at al . What never existed can't be stolen, can it?† She looked at him. Damon was looking back in a way that normal y would have thril ed her. He was obviously, blatantly distressed. But Bonnie was just barely hanging on to consciousness at this point. â€Å"And†¦fourth†¦Ã¢â‚¬ She puzzled out slowly. â€Å"Fourth? You said three things.†Damon smiled, just a little. â€Å"I have to say this – â€Å"She dropped her head down on Damon's shoulder, gathered al of her energy, and concentrated. Damon loosened his grip a little. He said, â€Å"I can hear a faint murmuring sound in my head. Just tel me normal y. We're well away from anyone.† Bonnie was insistent. She scrunched her whole tiny body together and then explosively sent out a thought. She could tel that Damon caught it. Fourth, I know the way to the seven legendary kitsune treasures, Bonnie sent to him. That includes the biggest star ball ever made. But if we want it, we have to get to it – fast. Then, feeling that she had contributed enough to the conversation, she fainted.

Introduction. The Very Controversial Issue Being Discussed

Introduction The very controversial issue being discussed in this debate is the question should vaccinations such as HPV be mandated for teenage girls? Two different views are offered. This controversy began when the issue was introduced to the real world in 2006. The FDA announced a prophylactic vaccine against 4 strains of HPV. Most importantly is the fact that this vaccination has about a 70% protection against cervical cancers linked to HPV. More CDC recommends routine vaccination for 11-12-year-old girls. It also recommends 13-26-year-old girls who did not have the opportunity for the vaccinations when they were younger. This three-dose vaccination costs about $375, making this vaccination one of the most expensive. In 2007†¦show more content†¦Charo argues that vaccinations against the human papillomavirus, which is the cause of most cervical cancer cases, should be mandatory with only medical, religious, or philosophical exceptions. B. In the second article Gail Javitt, Deena Berkowitz, and Lawrence O. Gostin argue that there are several issues of concern. In this article, they make a distinction between long term safety and the effectiveness of the vaccine is unknown. They present the concern of these risks and they should be weighed against the states interest in protecting the public from these harms. They have several strong arguments that support the decision that government mandated HPV vaccinations are premature. First statement is that long term safety and effectiveness is unknown. ACIP recommendations are based on assumptions regarding the length of duration for immunity and age of sexual debut. They believe the vaccination is not justified for mandating regarding historical â€Å"public health necessity† principle. Next is the concern that the government is overreaching their authority. They argue this can lead to risk of public backlash. Distrust by the public and confusion regarding gove rnment for profit rather than public health. In conclusion mandating HPV vaccinations would be premature and ill- advised. The distrust could lead to undermining of the current vaccination efforts. C. I will agree with article #2Show MoreRelatedScientific Management - Taylorism Essay990 Words   |  4 Pagesdownfall of scientific management in today’s service economy and furthermore has allowed for the introduction of improved managerial methods. The issues and disadvantages of scientific management will be further discussed and explained why it is no longer considered relevant in our modern day service economy. With the introduction of scientific management in the work organisation there has been a controversial debate over the changes that occur within the workplace. 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