Oral Fast Disintegrating Anti-allergic Film Using Hot-melt

Oral Fast Disintegrating Anti-allergic Film Using Hot-melt Development and Evaluation of an Oral Fast Disintegrating Anti-allergic Film Using Hot-melt Extrusion Technology Manjeet B. Pimparade1, Anh Vo1, Abhijeet S. Maurya1, Joseph T. Morott1, Xin Feng1, Dong Wuk Kim1, Vijay I. Kulkarni1, Roshan Tiwari1, K. Vanaja2, Reena. Murthy2, H. N. Shivakumar2, D. Neupane3, S. R. Mishra3, S. N. Murthy1, Michael. A. Repka1,4* 1Department of Pharmaceutics Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS, USA 2Institute for Drug Delivery and Biomedical Research, Bangalore, India 3Department of Physics, University of Memphis, Memphis, TN, USA 4Pii Center for Pharmaceutical Technology, The University of Mississippi, University, MS, USA *Address for correspondence: Michael A. Repka, D.D.S., Ph.D. Professor and Chair, Department of Pharmaceutics and Drug Delivery Director, Pii Center for Pharmaceutical Technology School of Pharmacy The University of Mississippi, University, MS 38677 Abstract The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11 s) and more than 95% dissolution in 5 min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for e valuation of extent of taste masking and disintegration. Keyword: Hot-melt extrusion, Orally disintegrating film, Taste-masking, Pediatric and geriatric, Modified starch, Human panel taste evaluation, Continuous manufacturing, Chlorpheniramine maleate Introduction It is estimated that 26-50% of the patient population find difficulty in swallowing tablets and hard gelatin capsules [1]. These patients mainly include the elderly who have difficulty taking conventional oral dosage forms because of hand tremors and dysphagia, and pediatric patients who are often fearful of taking solid oral dosage forms owing to their underdeveloped muscular and nervous systems [2]. In addition, patients who are mentally ill, developmentally disabled, uncooperative, on reduced liquid-intake plans or nauseated, and travelers who may not have access to clean water also are candidates for ODFs [3, 4]. The traditional alternative to swallowing difficulties is formulating a drug substance in liquid dosage form. However, liquid dosage forms have several limitations, such as the need for measuring, bulkiness, physical, chemical, and microbial stability issues, spoilage, inaccurate dosing, and organoleptic properties of drug and drug formulations [5]. Conventional solid oral formulations contributed significantly to minimizing the shortcomings of liquid dosage forms. The crushing of tablets or opening of capsules is a straightforward way for patients or caregivers to lessen the swallowing difficulties. However, serious consequences may be associated with modified-release, enteric-coated, and cytotoxic or hormonal medicines, as these formulations are designed for special cases [6]. Moreover, European Medical Agency does not recommend the splitting or crushing of tablets because the active pharmaceutical ingredient (API) is not evenly distributed in the tablet [7, 8]. Thus, it is very convenient to develop a formulation that disintegrates in the oral cavity and eases the swallowing process. In recent years, fast disintegrating oral formulations established their importance in patient population suffering from dysphagia, stroke, thyroid disorder, Parkinsons disease, multiple sclerosis, and cerebral palsy [9]. Commercially available orodispersible tablets (ODT) and orodispersible films (ODF) are the most successful platforms for pharmaceutical product development. ODTs are solid oral dosage forms that disintegrate rapidly, typically within 30 s, with or without the administration of additional water [10]. They provided great comfort to patients with swallowing difficulties [11]. Despite the benefits of ODTs, there are some challenges in their processing and handling owing to their fragility and brittleness, which warrant special package for protection during storage and transportation [12]. The films are flexible and not as fragile as most ODTs. Hence, there is ease in transportation, consumer handling, and storage of ODFs. ODF can be defined as a dosage form that employs a water-soluble polymer (generally a hydrocolloid, which may be a bioadhesive polymer), which allows the dosage form to quickly wet, adhere, and dissolve to release the drug when placed on the tongue or in the oral cavity [5]. ODF alleviated patient discomforts associated with swallowing disabilities without compromising the therapeutic effect. In addition, it could ease the administration of drugs to pediatric patient population [13]. Moreover, ODF can be helpful in curtailing dose variations in younger patients, in whom liquid formulations are the most accepted way of drug delivery. Currently, solvent casting methods are commonly employed to produce ODFs, owing to its ease of production and low set up costs [14, 15]. Despite its wide application, products with batch-to-batch variation may be produced because of multiple steps involved in the production. In addition, air entrapment in the films is commonly observed in solvent casting methods, which leads to dose variations and inappropriate esthetic appearance of the product [15]. The use of large amounts of solvent is one of the biggest shortcomings of this method as solvent removal and disposal is a long and tedious process. Thus, it is very beneficial to develop a solvent-free, quick, and continuous process that could diminish the shortcomings of the current manufacturing method. Hot melt extrusion (HME) is a one-step, solvent-free continuous manufacturing process, which established itself in the pharmaceutical arena for the development of various solid oral formulations [16-25]. This technology involves the use of temperature and shear to process polymer blends and extrude them through a die of the desired design [26]. HME could be an effective alternative to the solvent casting method as it diminishes the inherent shortcomings, such as the use of solvents and problems involved in the mixing and drying steps. This ultimately makes HME process efficient and cost effective for patients [27, 28]. This study has three main objectives: to 1) develop a robust patient-friendly orally fast disintegrating film of chlorpheniramine maleate (CPM); 2) evaluate these formulations with different in vitro and in vivo techniques, and 3) demonstrate the feasibility of HME techniques for continuous manufacturing of ODF without the use of solvents. To the best of our knowledge, there is no published literature on the manufacturing of orally fast disintegrating formulations using HME technology and evaluation of films using in vitro and in vivo techniques. Materials and Methods 2.1. Materials CPM was purchased from MP Biomedicals, LLC (Solon, OH, USA). Lycoat RS 780 (modified starch) was supplied by Roquette America Inc. (Keokuk, IA, USA). Citric acid and glycerol were ordered from Fisher Scientific (Pittsburgh PA, USA). Magnasweet sample was gifted by Mafco worldwide LLC (Camden, NJ, USA). Sucralose was supplied by JK Sucralose Inc. (Edison, New Jersey, USA). 2.2. Thermal analysis Thermogravimetric analysis (TGA) studies (Perkin Elmer Pyris 1, Shelton, CT, USA) were performed to estimate the thermal stability of the API and excipients during HME processing. Data were analyzed using Pyris software. The API excipients were heated from 30-160à ¢Ã¢â‚¬Å¾Ã†â€™ at 20à ¢Ã¢â‚¬Å¾Ã†â€™ /min. 2.3. Material preparation and blending CPM, citric acid, and Lycoat RS 780 were dry mixed at amounts outlined in Table 1 using a V-shell blender (GlobePharma, Maxiblend, New Brunswick, NJ, USA) after passing through an ASTM #30 mesh. The plasticizer (glycerol with dissolved sucralose and Magnasweet) was incorporated slowly into a high-shear mixer (Model RSI 3VG, Robot Coupe Industrial Division, Ridgeland, MS, USA) containing the previously mixed blend with all excipients and allowed to blend for 10 min. 2.4. Hot melt extrusion The blends were melt-extruded using a co-rotating twin-screw extruder (16 mm Prism EuroLab, ThermoFisher Scientific, Pittsburgh, PA, USA) at 30-50 rpm over a temperature range of 100-  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   110à ¢Ã¢â‚¬Å¾Ã†â€™. A degassing port was introduced in the last zone of the barrel to release excess water vapor, which would otherwise produce unwanted bubbles in the films. Additionally, the film die was installed with preset thickness. The physical blend of the formulation was manually fed into the hopper, and the films were collected, wrapped in wax paper, sealed, and stored in polyethylene bags at 25à ¢Ã¢â‚¬Å¾Ã†â€™ with 40% relative humidity. 2.5. Film characterizations 2.5.1 Film thickness and mechanical properties The mechanical properties of the films were evaluated using the TA.XTPlus texture analyzer equipped with 5 kg load cell (Texture Technologies, Scarsdale, NY, USA). The films were cut into dumbbell shaped specimens with a width and length of 1.55 and 15.5 mm, respectively, and placed longitudinally in tensile grip probe on the texture analyzer. The films were tested at a crosshead speed of 2 mm/min and held between two clamps positioned at 5 mm. The results of film samples that broke at and not between the clamps were not included in the calculations. Each film formulation was measured with ten replicates [29]. The tensile strength (Ts) and percent elongation (%E) were calculated using the results from texture analyzer. Film thickness was measured using an electronic caliper (Fisher Scientific, Pittsburgh, PA, USA) at different positions. 2.5.2 Disintegration test The film was cut into an appropriate size as per the dose (4 mg) and placed in a petri dish. Then, 100  µL artificial salivary media was added, and the time for complete disintegration of the film was recorded (n =10). 2.5.3 Surface pH of film The film was moistened using 5  µL water and a contact electrode touched the surface of the film (Oaktonà ¢Ã¢â‚¬Å¾Ã‚ ¢ pH meter, Fisher Scientific, Pittsburgh, PA, USA), followed by pH measurement (n=6) 2.6. Analytical method A Waters high performance liquid chromatography (HPLC) system equipped with a Water 600 binary pump, Waters 2489 UV/detector, and Waters ® 717 plus autosampler (Waters Technologies Corporation, Milford, MA, USA), and a Phenomenex Luna 5  µm C18 (2) 250 x 4.6 mm column (Torrance, CA, USA) were used at a detection wavelength of 254 nm. The mobile phase consisted of 7.5 mM monobasic potassium phosphate in methanol and water at a ratio of 62.5:37.5 (v/v). The mobile phase flow rate was maintained at 1.0 mL/min, and an injection volume of 10 ÃŽÂ ¼L was used [30]. HPLC data were analyzed using Empower 2 software (Milford, MA, USA). 2.7. In vitro dissolution studies The films for dissolution studies were cut into sizes relative to the dose of CPM (4 mg). The drug profile was evaluated using a USP dissolution apparatus-I (Hanson SR8, Chatsworth, CA) maintained at 37  ± 0.5à ¢Ã¢â‚¬Å¾Ã†â€™ and having a shaft rotation speed of 100 rpm. The dissolution test was performed using 900 mL phosphate buffer (pH 6.8). The samples were withdrawn at 5, 10, and 30 min and analyzed using the HPLC- UV system. 2.8. X-ray diffraction studies (XRD) X-Ray diffraction (Bruker D8 Advance, Madison, MI, USA) was used to determine the physical state of the drug, excipients, and film formulations. The X-ray diffraction apparatus used CuK radiation at 40 mA, 40 kV, a scanning speed of 2à ¢- ¦/min, and diffraction angle (2ÃŽÂ ¸) range of 5-55. 2.9. Scanning electron Microscope (SEM) The surface morphology of the films was evaluated using SEM analysis. The samples were mounted on adhesive carbon pads placed on aluminum and sputter coated with gold using a Hummer sputtering system (Anatech Ltd, Springfield, VA, USA) in a high vacuum evaporator. A JEOL JSM-5600 SEM operating at an accelerating voltage of 10 kV was used for imaging. 2.10. In vivo taste evaluation Twenty-one naÃÆ' ¯ve adult male Sprague-Dawley rats (175-200 g) were ordered from Harlan Laboratories (Houston, TX, USA) for the study. The rats were housed in Plexiglass cages with Corncob bedding in a vivarium that maintained a 12 h light/dark cycle and an ambient temperature of ~22à ¢Ã¢â‚¬Å¾Ã†â€™. Food and water were available without any restriction, except during the training and taste evaluation experiments as mentioned below (2.10.1). All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at The University of Mississippi, University, USA (protocol no. 15-026). This study was performed as per the procedure in our previous publication on taste assessment method for bitter drugs [31]. 2.10.1. Training paradigm The rats were trained for licking behavior (response to thirst) by depriving them of water for 22 h, but they had ad libitum access to food. After the water deprivation period, the Plexiglass cage was divided using plastic transparent dividers to provide an individual water bottle to each animal. Eventually, the rats were provided with graduated water bottle for 30 min, and the amount consumed at 15 and 30 min were recorded. This training paradigm was performed for 2 days before the taste evaluation experiment. 2.10.2. Evaluation of bitterness sensitivity of rats To determine the concentration of CPM for this study, a sensitivity test for bitterness was performed in rats. After depriving the rats of water for 22 h, sensitivity toward 0.5 mg/mL CPM solution was evaluated on the first day, followed by a washout period of 24 h. Subsequently, the effect of 1 mg/mL CPM solution was examined, and the results were recorded. 2.10.3. Experiment The experiment was performed for 30 min with 30 mL test formulation following the 22 h water deprivation period. After each experiment, the rats had a washout period of 24 h to avoid any memory of the taste of the previous formulation. The rats had ad libitum access to food during the experiment and washout period. The amount of solution remaining at 15 and 30 min was noted and subtracted from the original test volume. Varying results caused by spilling of the test solution while measuring or leaking of bottle knob were omitted from the study. Notably, animal behavior responses such as jaw smacking, oral grooming, and retreating were observed, which was not the focus of this study. Formulations N2, N7, and N9 at 0.5 mg/mL CPM were used for bitterness evaluation study in rat model. The average amount of solution consumed by all animals was calculated and expressed as the mean standard deviation. The mean scores between the physical mixture and formulation were compared using a student t-test at 95% confidence level and P 2.11. Film evaluation by human panel The evaluation of film for palatability, disintegration time (DT), and organoleptic characteristics was performed at the Institute for Drug Delivery and Biomedical Research, Bangalore India (Protocol number VIPS/2013/12). The subjects were recruited after obtaining informed consent. This study is also in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). The experimental procedure for this study was as per our previously published work [10, 32]. 2.11.1. Human subject selection criteria Six human subjects belonging to either sex were recruited. They were asked to abstain from coffee/tea and other beverages for 12 h. The subjects were allowed to drink only water for 12 h. Moreover, they were asked not to eat chocolates or other candies for over 6 h. The inclusion criterion was healthy human subjects aged 18-42 years, and the exclusion criteria were subjects suffering from fever, mouth ulcers, dry mouth, cold, nose block, and wounds as well as smokers.   2.11.2. Data collection Before data collection, the subjects were asked to wash their mouth with water at ambient temperature. The surface temperature of the tongue was recorded using an infrared (IR) thermometer, and a difference of  ±5à ¢Ã¢â‚¬Å¾Ã†â€™ relative to the body temperature was considered an exclusion criteria. 2.11.2.1. Bitterness perception The subjects were asked to taste aqueous solutions of CPM, beginning with very dilute solutions and progressing to higher concentrations, by placing 2 mL solution for 30 s on the tongue/buccal cavity. The concentrations screened were 0, 0.5, 1, 2.5, and 4 mg. The volunteers were asked to report the perception each time: 1- I feel bitter taste, 2- I feel something but cannot identify the taste, and 3-I do not feel the taste. The subjects who reported 2 or 3 were asked to taste higher concentrations of the solution until they expressed perception 1. This was recorded as the threshold for an individual. For individuals who reported a score of 1, at least 1/5th the drug concentration of the actual dose was only allowed for testing the products. A few high concentration API solutions above the individuals perception threshold were made for tasting, and the subjects were subsequently asked to provide a score for each solution (Table 3). The highest concentration of the solution contained C PM equivalent to the dose present in the products tested. The scoring pattern followed was according to modified hedonic scale: 0-no taste, 1- taste something (threshold), 2-slightly bitter, 3-moderately bitter, 4-bitter, and 5-strongly bitter. 2.11.2.2. Formulation evaluation and data analysis A washout interval of 12-24 h was allowed after screening the standard solution. The individuals were asked to taste the products (physical mixture or ODF) randomly (blinded) and score the product. The products were placed on the tongue/buccal cavity for 30-40 s, and the subjects were asked to score the bitterness on a scale of 0-5 for each product. Moreover, volunteers were asked to report the time for complete disintegration of the film. Sufficient washout time was allowed between the products, and the volunteers were allowed to drink copious amounts of water after tasting each product. The average of the scores given by all individuals were taken and expressed as the mean standard deviation. The mean scores between the physical mixture and formulation were compared using a student t-test at 95% confidence level, and P Results and Discussion 3.1. Preparation of hot-melt extruded film Modified starch is very difficult to extrude because of its high glass transition temperature. Thus, there is a need to introduce a plasticizer during extrusion, which could reduce the melt viscosity and increase the free volume of starch chains. For this study, glycerin was used as a plasticizer in different proportions, and it exhibited excellent extrudability with significantly lower torque (4.8-7.2 Nm) values than typically encountered. The barrel design was modified with a degassing port to remove excess amount of water vapor from the molten mass. Initial studies without a degassing port demonstrated the presence of bubbles as well as unequal distribution of drug in the film samples. Standard screw configuration (Figure 1) with three mixing zones was utilized for this study. It provided enough shear for dispersive and distributive mixing of the drug and helped get excellent content uniformity in all the extruded film formulations. The extruded films were stretched using the roll connected to the extruder assembly. This aided in making thin films with uniform thickness, and the roll speed was optimized for steady collection of the film. The combination of processing and formulation parameters helped to manufacture uniform, clear, and very thin films (60-110  µm) using melt extruder. 3.2. Physiochemical evaluation of films TGA is very critical before performing HME because the drug and excipients are exposed to high temperature during the extrusion process, and there are possibilities of drug degradation or thermally-induced chemical reactions or both [16]. The TGA results (Figure 2) specified that API, polymer, and excipients were chemically stable in the HME processing temperature range. Lycoat RS 780 demonstrated a loss of weight (33]. XRD was used to investigate the physical state of the drug after HME process. The XRD results (Figure 3a 3b) of CPM illustrated prominent peaks at 2ÃŽÂ ¸ angles of approximately 13, 19, and 20 degrees, while citric acid showed peaks at 2ÃŽÂ ¸ angles of 18, 19, and 26. The melt-extruded formulation did not show any peak that confirmed the presence of drug in an amorphous form. The reasons behind the complete conversion of drug to an amorphous form were the high shear during extrusion, low drug load, and relatively high amounts of glycerin. The presence of CPM and excipients in an amorphous form aided the flexibility and clear appearance of the film. 3.3. Dissolution studies Lycoat RS 780 is a comparatively new modified starch-based polymer, which demonstrated its significance in film coating for tablets and oral film development using solvent casting method [34, 35]. Being a non-gelling and highly water-soluble polymer, it provides rapid disintegration and dissolution to formulations. Visual inspection during dissolution demonstrated rapid disintegration of the film when it touched the dissolution media. This characteristic helps in the rapid onset of action of the formulation, because the drug can diffuse from the oral mucosa and reach the systemic circulation [36]. During dissolution studies, the formulations rapidly release CPM, and it was attributed to hydrophilic excipients and Biopharmaceutics Classification System (BCS) class I drug. These films had very low thickness (60-110  µm) and higher surface area, which enabled interaction with dissolution media and rapid disintegration following complete dissolution. Dissolution results (Figure 4a 4b) showed ~95% drug release in the first 5 min of the dissolution experiment, and at 10-min time points, there was complete release of the drug. 3.4. SEM evaluation The surface morphology was examined by SEM for all film formulations. SEM images did not exhibit CPM crystals, indicating an amorphous nature of drug in formulations (Figure 5). The formulations showed very smooth surface at low magnification. This affirmed the smooth texture of film surface, which is one of the esthetic attributes of films. However, at microscopic level, there was high surface area, which helped in the rapid disintegration of the film. 3.5. Film characterizations As illustrated in Table 2, the film formulations demonstrated excellent D.T of 6-11 s, which was attributed to the thickness of the film and presence of water-soluble materials in the film. The formulations contained water-soluble excipients and APIs such as CPM, citric acid, glycerin, and modified starch. The most crucial parameter for disintegration is the low thickness of the film. As the films had a thickness range of 60-110  µm, they aided in the faster disintegration of all film formulations. In addition to the low thickness of the film, the amount of saliva in the oral cavity is very critical for rapid disintegration. The normal flow of saliva in a healthy person is 0.34 mL/min, and it can be increased by the addition of agents that simulate salivary production, including citric, malic, lactic, ascorbic, and tartaric acids [14]. Citric acid is the most preferred saliva-stimulating agent, and it was estimated that citric acid could increase salivary flow approximately 5- fold in 2-6% proportion in the formulation [14]. With the addition of citric acid, the pH of the films was found to be in the range of 2.9-3.4 and it could contribute in improving rate of salivary flow after administration of formulation which will aid in rapid disintegration of film product. All the film formulations were tested for their Ts and %E (Table 2). Ideally, the film should have desirable mechanical properties so that it can remain intact during handling and transport. ODFs showed appropriate strength and %E. These excellent mechanical properties were attributed to the presence of glycerol, citric acid, and CPM, which reduced film stiffness via disruption of intermolecular forces of the polymer owing to the accommodation of these compounds between the strands, thereby providing elasticity to the films [37, 38]. 3.6. In vivo taste evolution Firstly, the taste perception of rats was evaluated by administering 0.5 and 1 mg/mL CPM dissolved in distilled water. These results were important to avoid taste variability between animals (Figure 6), and showed that the rats consumed ~10 and ~14 mL of water in 15 and 30 min, respectively. The results of this study were comparable with those of the study published by Tiwari et.al. Thus, the rate and extent of consumption of water were reduced significantly to ~3 and ~5 mL in 15 and 30 min with the administration of 0.5 mg/mL CPM solution. At a higher concentration of 1 mg/mL, there was notable reduction in consumption of water to ~1.6 and ~2 mL at 15 and 30 min. Notably, this reduction in consumption of CPM solution despite deprivation of water for 22 h affirmed an aversion toward CPM. Moreover, aversion behaviors (Figure 7), such as jaw smacking, oral grooming, nose wrinkle, paw wipe, forelimb flail, head shake, paw shakes, and retreating confirmed the dislike of rats toward the d rug solution [39]. As illustrated in Figure 6, the rats consumed ~10 and 12.5 mL of N 2 solution (5% CPM in the film) in the first 15 and 30 min, and the amount was comparable with the consumption of water. In addition, N7 (10% CPM) exhibited consumption of ~ 4.7 and ~8 mL at 15 and 30 min. Furthermore, N9 (7.5% CPM) showed consumption of ~6.3 and 10 mL at 15- and 30-min time point. These results indicated that with increasing concentrations of CPM, there was noticeable reduction in the consumption of formulation. The rats did not show aversion behavior such as forelimb flail with N2 formulation. However, there was a surge in the aversion behavior response upon increasing the drug concentrations in N7 and N9,. The results of this study were very helpful to understand about the taste of pure drug and formulation. It provided an insight into the taste of products, which helped to screen this formulation for human studies. 3.7. Film evaluation by human panel Before evaluation of taste of the formulation, it is very important to understand the taste perception of human volunteers to minimize intra-subject variability. Taste perception study was performed on six healthy human volunteers. Initially, different concentrations of CPM in 2 mL of water were administered to the human subjects. Three subjects had threshold at 0.5 mg and the remaining three subjects reported moderate bitterness at the same concentration. A dose of 2.5 mg demonstrated bitterness in all subjects, and only three volunteers could taste higher concentration of CPM (4 mg, Table 3). This initial evaluation confirmed the appropriateness of the subjects for taste masking study. The results of taste masking evaluation in animal model suggested that formulation N2 with 5% CPM had significant taste masking. Moreover, this formulation had an excellent D.T (7 s) in in vitro studies. Based on t

Thomas Hobbes Answer to Davenants Preface to Gondibert :: Answer to Davenants Preface to Gondibert

Thomas Hobbes' Answer to Davenant's Preface to Gondibert    In his "Answer to Davenant's Preface to Gondibert," Thomas Hobbes takes a stab at literary theory. He is prompted to write the reply because Davenant mentions Hobbes in the preface to the epic poem, Gondibert. Hobbes notes up front that he is hindered in two ways because he is 1) incompetent in poetry and 2) flattered by the praise Davenant has lauded him. These hindrances don't prevent Hobbes from detailing a general theory of poetry. He delineates the different types of poetry, discusses the poet and mode of composition, and addresses issues of form, content, and style. His ideas are based largely on his philosophy of rational thought and empirical evidence.    Hobbes begins by dividing poetry into three types that correspond with the three types of philosophy and the three "regions of mankind." Philosopy can be divided into "celestial, aerial, and terrestrial." Mankind divides itself into "court, city, and country." Poets write about these three different regions of mankind in "three sorts of poesy, heroic, scommatic, and pastoral." Each of these types of poetry can be conveyed in either a narrative or dramatic form. Hobbes writes:    the heroic poem narrative...is called an epic poem. The heroic poem dramatic is tragedy. The scommatic narrative is satire, dramatic is comedy. The pastoral narrative is called simply pastoral...; the same dramatic, pastoral comedy.    In this way he describes the "six sorts of poesy;" there can be no more or less than that. On the subject of what is a poem, Hobbes reiterates the Aristotelian concept that verse alone does not make poetry. Hobbes sums up the difference between historical or philosophical verse and poetic verse like so:    But the subject of a poem is the manners of men, not natural causes; manners presented, not dictated; and manners feigned, as the name of poesy imports, not found in men.    He goes on to allow that "fictions writ in prose" may be given entrance into the world of poetry because prose delights both in fiction and in style, but, were prose and poetry to contend toe-to-toe, it would be as if prose were "on foot against the strength and wings of Pegasus."    Hobbes addresses briefly the conventions of verse and rhyme in poetry. He iterates that ancient poets created verse to go along with musical accompaniment, which was necessary because of their religious beliefs.

Globalization and World Trade Organization Essay

Often perceived as the strongest instrument of globalization and supporter of economic liberalism, the other facet of the World Trade Organization brings its existence as an adamant global regime. For the concerned reason, Debi Barker and Jerry Mander have called WTO as a form of ‘Invisible Government’ in one of their publications for the International Forum on Globalization (IFG). China and Globalization: Behind China’s ready reaction to globalization with full potential of leading the global economy, thinkers consider an aspiration to supplant the existing super power of the world. But for China, globalization is a double edged sword since it brings forth both the threats and favours for world’s fastest growing economy. According to Peter Drysdale, it is because of China’s access to the global market that it has reached the first rank among the developing countries of Asia. Exposure to foreign market free of trade barriers has provided with a number of opportunities to enhance the business circle of Chinese companies. In a matter of two decades starting from 1978 to 1997, China doubled its status in terms of its capital gains by elevating to the tenth position from the twentieth rank in the world’s economy. This fact suggests that China’s excel in the international trade does not completely depend on its entrance in the WTO. In fact the country had embarked its way towards economic pre-eminence long before joining WTO. This means that China’s success though boomed by WTO had its very beginning with the economic globalization. Attitudes of Chinese towards Globalization: Just like any other existing phenomenon in the scene of human existence, globalization cannot be confined in a single frame of thought and any rigid point of view merely makes it a matter of perception rather than rationality. With both the negative and positive impacts of globalization for China standing clear, there are three types of attitudes existing among people regarding the relentless process of globalization. According to Charles Andrews, there people advocate and favour one of the three stands namely, Pro-globalization, Anti-globalization and Reformist Approach. 1: Pro-Globalization: The first group of people hold a positive view of globalization for China by measuring the country’s success in terms of strengthening economic position in the global market and increasing cognizance of the world about China. Lin Yifu, a professor of economics at the University of Beijing, is among such people who vision no challenge of globalization to China. Pro-globalists involve a group of liberal minded people who condones the risks of globalization in favour the opportunities it has provided. 2: Anti-Globalization: Contrary to pro-globalization, Anti-globalization rejects every bright angle of increasing globalization. It is because integration is a two way process. When China permeates foreign countries, these countries are equally permitted to invade China’s domestic market. As many fruits and cereals are cheaper in the global market as compared to that of China’s, when the exporters of these goods invade China they leave the country men (whose livelihood depends on the agriculture) at the edge of starvation Apart from such risks, the anti-globalists also take an account of translational terrorism by cross-border criminal activities and the proliferation of weapons. Certain events of recent past also favour such allegations against globalization. It s because of the cross border criminal activities and stalking that events like 9/11 trampled one of the most lucrative economic centres of the world. Anti-globalists belong to various walks of life with their opposition to globalization in terms of their field. For instance, many linguists across the globe talk about linguistic genocide and the overwhelming role of English as a lingua franca which is causing the death of many regional languages. In short, for the group of people who are propelled to anti-globalization, ‘globalization is nothing but a trap. Jumping into this trap would crush the whole domestic industry, agriculture, and service sectors. ’ 3: Reformist Approach: The reformists hold a balanced point of view towards globalization. With an over all positive attitude towards globalization, they believe that while the advantages of globalization are long term, the short term threats of globalization for China cannot be ignored. For them, at one hand globalization means increased financial gains, growth of domestic industry by competition with foreign companies and aggrandizing compatibility of China with the global community. At the other hand, they also bring under consideration the issues like growing unemployment as a result of declining industries facing foreign competitions and by widening the gap between classes by further lowering down the farmers and other such people to a still lower status. The threat to the farmer’s livelihood is clear in China that has over-emphasized the manufacture of non-agricultural products in the wake of the last few years. Consequently, innumerable farmers of China were left with their decline resulting from unemployment. China and World Trade Organization: â€Å"The progressive integration of China into the world trading system- spurred by its membership of WTO in 2001- has provided China with secure, open and predictable export markets. † According to the economists, behind the rapid rise of China in the global economy lies one key factor: the entrance of China in the World Trade Organization. The economic and financial analysts of global market base this opinion on the foundation that the major boom of China occurred after 2001 (the time when China joined WTO). In the words of David Dollar, the World Bank country director for China, â€Å"Since China joined the WTO, its exports have grown at an average rate of 29 percent per year. † It was in December 2001 that China (the sixth largest economy with a population of 1. 3 billion at that time) joined the World Trade Organization. Previously China had remained one of the twenty three contracting countries of the General Agreement on Tariffs and Trade (GATT). Impacts of WTO membership on China’s Economy: After its membership of WTO, China’s trade rate increased rapidly from 44% to 72% in 2006. It was after a foresight into the future that China compromised on a number of WTO policies in order to enter into the WTO. These were the conditions that apparently conflicted with China’s economy. According to Gregory C. Chow of Princeton University, three most salient conditions for China included: 1. Declining the tariff rates on the import of goods from foreign countries. 2. Being conducive in the practice of free trade by letting the foreign companies sell their products directly in the domestic market of China. 3. Establishment of improved telecommunication and finance industry for the sake of increased competition. Contrary to the analysts’ expectations, both China’s macro economy and micro economy did not suffer a set back after its entrance into the WTO since the net results proved to be favourable thereby compensating the scanty amount of losses. With a rapid growth of China’s exports, its increasing imports do not appear to be a threat for the country’s economy. Impacts of WTO membership on China: China’s acceptance to become the member of the World Trade Organization was not merely a matter of flourishing its economy but a reason for a series of the country’s aims. According to Wayne M. Morrison, China saw a potential of playing a major role in trade laws of WTO and indirectly practice an economic hegemony. In the contemporary world with flourishing business and finance, the economic stability is often seen as a measuring stick to mark the countries’ over all power. So, China’s increasing economic strength does not only suggest its financial stability but its potential to become the super power in future. Morrison also believes that another major goal of China behind the membership is to maintain the status of Most Favored Nation and permanent normal trade relations. Even if the World Trade Organization holds a stringent policy for equal treatment of all nations, the bigger nations with their dominating presence somehow benefit as compared to the under developed countries. Previously, these privileges were dominantly celebrated by the U. S. Impact of WTO membership on China Banking Industry: It is the overwhelming effect of WTO membership that it has left not a single institution of the country untouched. With almost seven years of WTO membership and business people facing free trade, China’s financial sector is now open to foreign banks. This has exposed the customers to a number of innovative and improved management mechanisms and services. In the words of Wang Zhaoxing of the China Banking Regulatory Commission, â€Å"The introduction of competition and strategic investors will be conducive to improving innovation, management and profitability of domestic banks. † With considerable involvement of foreign banks into China, China’s leading banks including the Bank of China, China Construction Bank and the Industrial and Commercial Bank of China have emerged as trusted names in the international banking. Although appearing as a threat for smaller banks, such a scenario is highly favourable for a Chinese customer because in either way, they would get better services.

An Ongoing Adolescence - 1116 Words

Translated to its literal meaning â€Å"pulling in† or â€Å"withdrawal† (Grisafe 2012), hikikomori is a Japanese phenomenon that has been a prominent social issue for years. First coming to light in1998, Japanese physiatrist, Tamaki Saito introduced the mental health issue in his book Hikikomori: An ongoing adolescence (Senju 2013). Today, the issue is increasingly worrying for not only Japan, but other international countries as young to middle aged men and women continue to drive towards the trend of complete reclusive behavior and acute social withdrawal. As of today, over one million people in Japan are hikikomori. A person who is defined as a hikikomori is one who withdraws from society for more than 6 months, usually hiding in their bedroom†¦show more content†¦Due to their parent’s high expectations to succeed in school, many victims may choose to isolate themselves as failure in school and a lack of social support can keep the hikikomori locked away for years. In Japan there is extreme pressure to get into a good university and get a well-paid job. For some, failing to do so results in people shutting themselves in. A large aspect of Japan’s enormous pressure on students comes from the entrance exams that students are required to take to get into specific junior high schools, high schools and universities. Failure to gain entry is a leading factor in becoming a hikikomori. The work required to do well in the infamously difficult entrance exams consists of extended hours of study and cramming schools, otherwise known as gakushÃ… « juku(Ã¥ ­ ¦Ã§ ¿â€™Ã¥ ¡ ¾)or juku (Ã¥ ¡ ¾) for short (Suzuki 2013). These fast paced, late night schools leave students with minimal hours of sleep and social time and extended period of study and cramming. Approximately 60% of all Japanese high school students attend juku (Cram Schools n.d.). Gogatsu-byÃ…  (May Disease, ä ºâ€Ã¦Å"ˆçâ€"…) is another school related motive of the hikikomori. It is when one doesn’t know how to cope with a change in their school or work environment, which results in overwhelming stress. It is closely related with depressi on. The