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Bulletin of Pharmaceutical Research 2012;2(1):15-21 An Official Publication of Association of Pharmacy Professionals
ISSN: 2249-6041 (Print); ISSN: 2249-9245 (Online)

RESEARCH ARTICLE

CHARACTERIZATION AND EX-VIVO SKIN PERMEATION STUDY OF DOMPERIDONE MALEATE TRANSDERMAL PATCH
Irfan Newaz Khan*, Maria Islam Khan, Kishor Mazumder, Marzina Ajrin, Newton Sen, Afsana Rashid and Md. Abdul Motaleb Bhuiya
Department of Pharmacy, Faculty of Basic Medical and Pharmaceutical Science, University of Science and Technology Chittagong (USTC), Chittagong-4202, Bangladesh *E-mails: irfan352@yahoo.com Tel.: +88-01717026373, +88-659070-1 Received: November 16, 2011 / Revised: April 04, 2012 / Accepted: April 08, 2012

The present study was designed to develop a suitable matrix type transdermal drug delivery system (TDDS) of domperidone maleate using blends of three different polymeric combinations of polyvinylpyrrolidone (PVP) and ethylcellulose (EC). Physical studies including moisture content, moisture uptake and flatness to study the stability of the formulations were performed. In-vitro dissolution as well as ex-vivo skin permeation studies of the experimental formulations were also performed. Ex-vivo skin permeation study was conducted across the depilated rat abdominal skin using a modified Franz’s diffusion cell. Drug-excipient interaction studies were carried out using TLC (Thin Layer Chromatography) method. All the formulations were found to be suitable for formulating in terms of physicochemical characteristics and there was no significant interaction noticed between the drug and polymers used. It was observed that as the concentration of the hydrophilic polymer (PVP) increased in the formulation, the rate of dissolution increased subsequently and the best result found for the polymer ratio PVP:EC, 3:5. From the study of release mechanism, it was found that the Higuchi plot showed reasonably straight line with high correlation coefficient. Ex-vivo skin permeation study also shows that the permeation of the drug (Domperidone maleate) through the depilated rat abdominal skin was reasonably better in the formulation where PVP concentration was high. It was also found that there was no significant reaction developed during the contact of patch with the dermis. Hence, it can be reasonably concluded that domperidone maleate can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP:EC, 3:5) was found to be the best choice for manufacturing transdermal patches of domperidone maleate among the formulations studied.
Key words: Domperidone maleate, Transdermal patch, Polyvinylpyrrolidone, Ethyl cellulose, Ex-vivo skin permeation, Franz diffusion cell. INTRODUCTION Transdermal drug delivery is the delivery of drugs across epidermis to achieve systemic effects. The success of transdermal patches lies in their commercialization. Transdermal patches control the delivery of drugs at controlled rates by employing an appropriate combination of hydrophilic and lipophilic polymers (Mohabe et al 2011). For many medications, it is important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of compliance by a patient. Oral administration is one that is commonly used because it is a relatively simple regime to follow. However, the oral administration route is also complicated because of the complications associated with gastrointestinal irritation, drug metabolism in the liver and is also impractical if a patient is vomiting or nauseous.

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Khan et al Another popular mode of oral administration includes different forms of novel drug delivery systems for enhanced patient compliance (Dahiya and Gupta, 2011; Kumar and Dureja, 2011). However, transdermal patches offer added advantages such as maintenance of constant and prolonged drug level, reduced frequency of dosing, minimization of inter and intra patient variability, self administration, and easy termination of medication, leading to patient compliance (Keith, 1983). However, transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism. Domperidone is a peripheral dopamine antagonist and structurally related to the butyrophenones with antiemetic and gastroprokinetic properties. Domperidone effectively increases esophageal peristalsis and lower esophageal sphincter pressure (LESP), increases gastric motility and peristalsis, enhances gastro duodenal co-ordination and consequently facilitates gastric emptying and decreases small bowel transit time. The mechanism of action of domperidone is related to its peripheral dopamine receptor blocking properties. Emesis induced by apomorphine, morphine or levodopa through stimulation of the chemoreceptor trigger zone (situated outside the blood-brain barrier) can be blocked by domperidone. There is indirect evidence that emesis is also inhibited at the gastric level, since domperidone also inhibits emesis induced by oral levodopa. Domperidone does not readily cross the blood-brain barrier and therefore is not expected to have central effects. Domperidone Maleate (anti-emetics) is absorbed orally, but Bioavailability is only below 15% due to first pass metabolism (Bennett, 2003; Tripathi, 2004). So the administration of physiologically active agents, such as domperidone maleate (anti-emetics), through the skin (transdermal drug delivery) has received increased attention because it provides a relatively simple dosage regime and a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation. The aim of the present study was to develop and characterize the transdermal matrix patches of Domperidone Maleate with varied ratios of polyvinylpyrrolidone (PVP) and ethyl cellulose (EC) and to evaluate the release kinetics and ex-

Bull. Pharm. Res. 2012;2(1) vivo skin permeation of the drugs. MATERIALS AND METHODS Materials Domperidone maleate (BASF), polyvinyl alcohol (BDH Chemicals Ltd, England), ethyl cellulose (EC; Colorcon Asia Pvt. Limited, India), di-nbutylphthalate (Merck Ltd, Mumbi), chloroform (VWR International Ltd, England), Menthol (Local source), polyvinylpyrrolidone (PVP; BASF) were used as received without any further purification. Methods Development of the domperidone maleate transdermal patch Matrix type transdermal patches of the domperidone maleate were prepared by solvent evaporation technique in both sides open cylindrical glass molds. Different ratios of PVP and EC were used. The bottom of the mold was glued to the aluminum foil on which the backing membrane was casted by pouring 4% w/v PVA solution followed by drying at 40°C for 6 h. Both polymers were weighed in requisite ratio and then, dissolved in chloroform. Di-n-butylphthalate 30% w/w of polymer composition was used as a plasticizer. The drug was added to the 20% w/w of the total weight of polymers, in the homogeneous dispersion by vortexing. Menthol 0.1% w/w was used as a skin permeation enhancer. The matrix was prepared by pouring the homogeneous dispersion of the drug with lipophilic polymer (EC) and hydrophilic polymer (PVP) in chloroform on the backing membrane in glass moulds. The above dispersion was evaporated slowly at 60°C for 6 h to achieve a drug-polymer matrix patch. The wax papers were used to give a protective covering. This was the final shape of the formulation. The dry patches were kept in desiccators until use (Arora and Mukherjee, 2002). Three different types of domperidone maleate patches were prepared by using PVP and EC polymer ratio of 1:2, 1:3 and 3:5 (Table 1). Solubility studies The solubility studies were performed in phosphate buffer solution, pH 7.4 by adding excess amounts of drug and keeping the excess drug containing phosphate buffer flasks on a water bath shaker for 24 h at 32°C. After 24 h, solutions were analyzed spectrophotometrically at 284 nm (Fang et al 2000).

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Khan et al Table 1. Composition of prepared patch
Sr. no. 1. 2. 3. Formulation code DPM1 DPM2 DPM3 Ratio of PVP and EC 1:2 1:3 3:5 Total weight of PVP and EC 300 300 300 Chloroform (ml) 10 10 10 Di-n-butyl phthalate 30% w/w of polymer 30% w/w of polymer 30% w/w of polymer

Bull. Pharm. Res. 2012;2(1)

Menthol 0.1% w/w of polymer 0.1% w/w of polymer 0.1% w/w of polymer

Drug 20% w/w of polymer 20% w/w of polymer 20% w/w of polymer

Evaluation of physical characteristics of the prepared films Moisture content: The prepared films were marked, weighed individually and kept in desiccators containing activated silica at room temperature for 24 h. The films were weighed again individually until it showed a constant weight. The percentage of moisture content was calculated as a difference between initial and final weight with respect to final weight (Baichwal, 1983). Moisture uptake: A weighed film kept in desiccators at normal room temperature for 24 h was taken out and exposed to 84% relative humidity (saturated solution of potassium chloride) in desiccators until a constant weight for the film was obtained. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight (Baichwal, 1983). Flatness Longitudinal strips were cut out from each film, one from the center and two from either side. The length of each strip was measured and the variation in the length because of nonuniformity in flatness was measured by determining percent constriction, considering 0% constriction is equivalent to 100% flatness (Baichwal, 1983). Constriction (%) = (l1–l2)l2 ´ 100 Where l1 = Initial length of each strip; l2 = Final length of each strip. In vitro dissolution studies The dissolution of patches was performed using USP Basket Type Dissolution Apparatus. The patches were placed in respective baskets with their drug matrix exposed to phosphate buffer, pH 7.4. All dissolution studies were performed at

37°C, at 50 rpm, with each dissolution jar carrying 900 ml of buffer. Samples were withdrawn at different time intervals and analyzed using a UV spectrophotometer at 284 nm against blank, Cumulative amounts of drug released was plotted against time for different formulations (Arora and Mukherjee, 2002). Ex-vivo skin permeation studies The ex-vivo skin permeation of domperidone maleate from the selected TDDS through depilated rat abdominal skin was conducted using a modified Franz diffusion cell. The study was conducted in accordance with the Helsinki declaration and animal care and facilities in Principles and Methods of Toxicology (Arora and Mukherjee, 2002). Preparation of skin: The abdominal skin of Long-Evans rat was used. Hairs on the abdominal area were shaved after sacrificing by prolonged chloroform inhalation. Abdominal skin was excised and the subcutaneous tissue was surgically removed. Dermis side was wiped with isopropyl alcohol (IPA) to remove residual adhering fat. The skin was then washed with distilled water. The prepared full thickness skin was treated with 2M sodium bromide solution in water for 6 h. The epidermis was separated by using a cotton swab moistened with distilled water. Then, epidermis sheet was cleaned by washing with distilled water. The skin so prepared was wrapped in aluminum foil and stored in a freezer at -20°C till further use (Scott et al 1986). Assembling of the Franz diffusion cell: The skin membranes were first hydrated for 30 min in the buffer solution (pH 7.4) at room temperature to remove extraneous debris and leachable enzymes. They were then placed between the donor and receptor compartments of the cells, with the dermal side in direct contact with the receptor medium. Approx. 150 ml

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Khan et al of the phosphate buffer (pH 7.4) was placed in the receptor compartment. Its temperature was maintained at 37±0.5 °C using a thermostatic water bath (Dureja et al 2001). This whole assembly was kept on a magnetic stirrer and solution in the receiver compartment was continuously stirred during the whole experiment using magnetic bead. The samples were withdrawn (200 µml each time) at different time intervals and an equal amount of phosphate buffer (pH 7.4) was replaced each time. Absorbances of the samples were read spectrophotometrically at 280 nm taking phosphate buffer solution (pH 7.4) as blank. The amount of drug permeated per square centimeter at each time interval was calculated and plotted against time. A similar set was run simultaneously using the patch (without drug) at the donor compartment as a skin patch control system to avoid the influence of inherent extracts from the skin or leaching of any material from the patch without drug on the absorbance at 284 nm (Arora and Mukherjee, 2002). Evaluation of skin irritation potential of polymeric matrices The primary skin irritation studies were carried out using modified Draize test (Draize et al 1944). The hair of rats were removed by shaving from the dorsal area on both sides 24 h before test. One side of the back of each rat i.e. untreated skin area served as the control for the test. Medicated patch was secured on experimental side using adhesive tape and the non-medicated patch was adhered on the control side of 6 rats (Kligman and Christophers, 1963). These patches were covered with occlusive covering to approximate the condition of use. The medicated patches were changed after 48 h and the fresh patches were secured at the same site. However, the patches on the control side were not changed. The patches were secured on the back for seven days. After removal of patch on completion of a week, each of the areas were examined for any sign of erythema or edema. RESULTS AND DISCUSSION The results of solubility studies revealed that the media phosphate buffer (pH 7.4), was able to maintain sink conditions in dissolution as well as in permeation studies. Thus, phosphate buffer was chosen as the dissolution and permeation media because sufficient amount of drug dissolved in it (4-5 times the drug incorporated

Bull. Pharm. Res. 2012;2(1) in patch), which is necessary to maintain sink condition. The physicochemical studies like moisture content, moisture uptake, flatness etc. provided information regarding the stability of the formulations. The moisture content and moisture uptake (Figure 1, 2) varied to a small extent in all the formulations studied. However, there was increase in moisture content with an increase in hydrophilic polymers. The results of moisture uptake studies for different formulations were very unusual as it showed some negative values which may be due to the presence of menthol which prevented the moisture uptake as well as menthol itself is volatile in nature and the overall effect was loss of weight. An ideal patch should be formulated in such a way that it possesses a smooth surface and it should not constrict with time. Flatness studies were performed and the results showed that some of the formulations had very little differences in the strip lengths before and after their cuts. It indicated almost or very near to 100% flatness in the formulated patches.

Fig. 1. Comparative % moisture content of formulations

Fig. 2. Percentage of moisture uptake from formulations

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Khan et al Thus, a very little amount of constriction was observed in the film of different formulations and it indicated smooth flat surface of the patches. A 100% flatness of all the formulations indicated no amount of constriction in formulated transdermal membrane strips. Thus, this does not constrict when it is applied on to the skin. Moreover, the moisture content and moisture uptake of the various formulations showed that with the increase in concentration of hydrophilic polymer (PVP), both the percentage moisture content and moisture

Bull. Pharm. Res. 2012;2(1) uptake increased. The small moisture content in the formulations helps them to remain stable and from being a completely dried and brittle film. Again, a low moisture uptake protects the material from microbial contamination and bulkiness of the patches. No amount of constriction in the formulated transdermal patches ensured their 100% flatness. Thus, this does not constrict when it is applied on to the skin. On the other hand, thicknesses were also measured to understand the content uniformity and found satisfactory (Table 2).

Table 2. Data for % flatness and thickness (cm) uniformity of the films
Formulation code DPM1-1 DPM1-2 DPM2-1 DPM2-2 DPM3-1 DPM3-2 Mean ±SD Polymer ratio (PVP:EC) 1:2 1:3 3:5 % Flatness 99.87 99.99 99.97 99.87 99.88 99.97 99.925 0.052202 Thickness 0.009 0.008 0.009 0.008 0.009 0.008 0.0085 0.000548

The results of dissolution studies indicated that with the increase in concentration of hydrophilic polymer (PVP) in the formulations, the rate of

dissolution increased subsequently and the best results were found in the polymer ratio PVP:EC, 3:5 (Table 3).

Table 3. Data for % drug release from developed formulations
DPM1 Time (min) Polymer ratio 1:2 0.75 0.675 0.945 1.245 16.35 23.355 30.87 35.45 45.77 55.34 70.455 71.44 71.77 71.7 71.79 Formulation DPM2 % Drug released Polymer ratio 1:3 0.75 0.78 0.825 1.125 16.47 23.37 31.83 37.44 48.235 59.025 72.89 71.41 71.59 71.55 71.69 DPM3 Polymer ratio 3:5 0.81 0.81 1.065 1.425 16.425 23.67 35.325 42.56 52.88 65.87 78.125 78.233 78.37 78.4 78.4

15 30 45 60 120 180 240 300 360 420 480 540 600 660 720

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Khan et al The release kinetics was studied to identify the best possible release mechanism of the drug. Among the zero order plots, Higuchi plot and the first order plot, the Higuchi plot showed reasonably straight line with high correlation coefficient. The ex-vivo drug permeation studies of transdermal patches were performed on excised rat abdominal skin. The results of these studies showed marked variations in permeation profiles of domperidone maleate. The reason for

Bull. Pharm. Res. 2012;2(1) this could be the different ratio of Hydrophilic polymer (PVP) and hydrophobic polymer (EC) in the different patches. The formulation DPM3 showed highest and linear permeation of domperidone maleate. This indicated that hydrophilic polymer has significant effect on permeation of domperidone maleate. This conclusion was supported by the higher permeation rate values of formulation DPM3 (Figures 3, 4 and Table 4).

Fig. 3. Ex-vivo skin permeation of domperidone maleate from formulations

Fig. 4. Percent cumulative drug release profiles of formulations

Table 4. Data for mean cumulative amount of drug released (%) from different matrix films prepared by using different ratios of PVP and EC with menthol (n=6).
Formulation code DPM2 DPM3 Mean cumulative amount released (%) Polymer ratio Polymer ratio Polymer ratio 1:2 1:3 3:5 20.39 21.41 33.99 21.41 25.87 34.86 23.76 27.19 36.18 34.65 35.33 44.52 51.28 55.67 56.14 57.03 57.11 67.05 60.15 63.2 69.22 70.85 71.01 72.48 DPM1

Time (min)

30 60 120 180 240 300 360 720

Skin permeation study is known for their value for studying the rate and mechanism of percutaneous absorption of drugs (Chien, 1987). The study is predictive of an in vivo performance of a drug. With a little variation of ratio of PVP and EC from 1:2 to 3:5, an “initial burst effect” was noticed. Again, when skin permeation studies were conducted, the rates of skin permeation in formulation DPM3 (PVP:EC, 3:5) were high. It may be because the formulations lost their polymeric chain network and provide

an “initial burst” effect and an opening for the drug cluster for faster release through them. The SEM images showed the comparatively uniform distribution of drugs in the polymer matrix (Figures 5-7). The results of skin irritation potential of polymeric matrices showed that the prepared systems (both blank and drug loaded) and USP adhesive tape produced negligible erythema and edema. On the other hand, standard irritant, formalin produced severe erythema and edema (Table 5).

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Khan et al

Bull. Pharm. Res. 2012;2(1)

Fig. 5. SEM photograph of DPM2 (PVP:EC, 1:2)

Fig. 6. SEM photograph of DPM2 (PVP:EC, 1:3) Table 5. Results of skin irritation test

Fig. 6. SEM photograph of DPM2 (PVP:EC, 3:5)

Formulation Normal Adhesive tape (USP) DPM (Domperidone maleate patch) Blank (Patch without drug) Formalin (0.8% v/v)

Visual observation Erythema 0.00±0.00 1.33±0.21 1.56±0.35 1.53±0.14 3.77±0.18 Edema 0.00±0.00 1.60±0.25 1.24±0.17 1.18±0.42 3.39±0.36

*Values are expressed as Mean±SE, n=6; *Significant compared to formalin (p < 0.05).

CONCLUSION The studies concluded that proper combination of hydrophilic and hydrophobic polymers is required in formulation development of transdermal patches of domperidone maleate. However, further in vivo and in vitro investigations are required. REFERENCES
Arora P, Mukherjee B. Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethyl ammonium salt. J. Pharm. Sci. 2002;91(9):2076-89. Baichwal RW. Advances in Drug Delivery Systems, MSR Foundation, Bombay: 1983; 136-47. Bennett PN, Brown MJ. Clinical Pharmacology, 9th Edition, Churchill Livingstone, London: 2003. Chien YW. Development of transdermal drug delivery systems. Drug Dev. Ind. Pharm. 1987;13(4-5):589-651. [DOI: 10.3109/03639048709105212] Dahiya S, Gupta ON. Formulation and in vitro evaluation of metoprolol tartrate microspheres. Bull. Pharm. Res. 2011; 1(1):31-9. Draize JH, Woodard G, Calvery HO. Method for the study of irritation and toxicity of substances applied topically to the skin and mucous membrane. J. Pharmacol. Exp. Ther. 1944;82(3):377-90. Dureja H, Tiwary AK, Gupta S. Simulation of skin permeability in chitosan membranes. Int. J. Pharm. 2001;213(1-2):193-8. [http://dx.doi.org/10.1016/S03785173(00)00666-9] Fang J-Y, Wang R-J, Huang Y-B, Wu P-C, Tsai Y-H. Passive

ACKNOWLEDGEMENT Authors are grateful to Prof. M Mohi Uddin Chowdhury, Head, Dept. of Pharmacy, Southern University, Bangladesh for giving continuous support. We are also grateful to Mohammad Nurul Islam, Production Manager, Amico Lab Ltd. for providing the polymers and drug. and iontophoretic delivery of three diclofenac salts across various skin types. Biol. Pharm. Bull. 2000;23(11): 1357-62. [http://dx.doi.org/10.1248/bpb.23.1357] Keith AD. Polymer matrix consideration for transdermal devices. Drug Dev. Ind. Pharm. 1983;9(4):605-25. [DOI: 10.3109/03639048309044695] Kligman AM, Christophers E. Preparation of isolated sheets of human stratum corneum. Arch. Dermatol. 1963; 88(6):702-5. [DOI: 10.1001/archderm.1963.0159024002 6005] Kumar M, Dureja H. Development and characterization of factorially designed 5-fluorouracil microspheres. Bull. Pharm. Res. 2011;1(1):54-61. Mohabe V, Akhand R, Pathak AK. Preparation and evaluation of captopril transdermal patches. Bull. Pharm. Res. 2011;1(2):47-52. Scott RC, Walker M, Dugard PH. In vitro percutaneous absorption experiments: A technique for the production of intact epidermal membrane from rat skin, J. Soc. Cosmet. Chem. 1986;37:35-41. Tripathi KD. Essentials of Medical Pharmacology, 5th Edition, Jaypee Brothers Medical Publishers, New Delhi: 2004.

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...Parenting Movie Analysis The movie “Little Miss Sunshine” is about a 7 year old girl named Olive Hoover whose dream is to be entered into a pageant called Little Miss Sunshine.The movie includes an extended family including their uncle and grandparent. Moreover, when she discovers that she’s been entered her family face many difficulties. Though they do want Olive to achieve her dream they are so burdened with their own quirks and problems that they can barely make it through a day without some disaster occurring. This movie relates to the Caregiver Identity Theory because the Caregiver Identity theory is the theory “Multidimensional roles caregivers play when they are both a loved one of the patient and the caregivers”. This relates to...

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Little Miss Sunshine Hoover Family

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Compare Little Miss Sunshine and Juno

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Mr Ahmed

...in support of the explanation which I have just offered to you?" I saw Miss Halcombe change colour, and look a little uneasy. Sir Percival's suggestion, politely as it was expressed, appeared to her, as it appeared to me, to point very delicately at the hesitation which her manner had betrayed a moment or two since. I hope, Sir Percival, you don't do me the injustice to suppose that I distrust you," she said quickly. "Certainly not, Miss Halcombe. I make my proposal purely as an act of attention to YOU. Will you excuse my obstinacy if I still venture to press it?" He walked to the writing-table as he spoke, drew a chair to it, and opened the paper case. "Let me beg you to write the note," he said, "as a favour to ME. It need not occupy you more than a few minutes. You have only to ask Mrs. Catherick two questions. First, if her daughter was placed in the Asylum with her knowledge and approval. Secondly, if the share I took in the matter was such as to merit the expression of her gratitude towards myself? Mr. Gilmore's mind is at ease on this unpleasant subject, and your mind is at ease—pray set my mind at ease also by writing the note." "You oblige me to grant your request, Sir Percival, when I would much rather refuse it." With those words Miss Halcombe rose from her place and went to the writing-table. Sir Percival thanked her, handed her a pen, and then walked away towards the fireplace. Miss Fairlie's little Italian greyhound was lying on the rug. He held out his...

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Missed Appt

...time, they may have avoided the ambush or avoided the Vbid that hit them in the bottleneck. It sounds extreme but time management plays a critical role in the Army. When you make an appointment that spot has been reserved for you. That means if you have been given the last slot someone else is going to have to wait for another one to open up. This could be one day or one month. And because you missed it someone else is still going to have to wait when they could have had that spot and been there. If you are going to miss the appointment or cannot make it due to mission they do allow us to cancel the appointment with in twenty four hours. The Army allows us to make appointments for whatever we need. Be it for a medical appointment, house goods, CIF, Smoking Sensation or whatever we need these recourses are available to us. But when Soldiers start missing appointments theses systems start to become inefficient. What a lot of Soldiers do not realize is that when they miss an appointment it does not just affect them; it affects the entire chain of command from the Squad Leader all the way to the First Sgt. When a Soldier misses an appointment the squad leader must answer for the Soldier, the Squad leader must answer to the platoon Sgt., the Platoon Sgt. Must answer to the First Sgt., and the First Sgt., must answer to the...

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...be communicated through stu mail, notice board and Facebook. * Marketing in other colleges will be done via the Student council of the institutes. The market can be divided into three types of users: 1. Hot users: These users are open to the idea of the app since they see great utility in the app. They are users who are have missed deadlines and want the help of the app. They will be willing to pay the specified fee. 2. Warm users: These users are relatively neutral to the idea. They use the app because others use it. They don’t mind paying the fee. 3. Cold users: These are users who don’t see the utility in the app. This could be because they are conditioned to checking notice board, mails etc. regularly and very rarely miss deadlines. Some users may also be using schedulers available on Google Play...

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Evdinces

...the right to see what is going on with Alex and why he never showed to this last appointment. When Alex came into the officer Maria was talking to Alex and asking him question Alex was not making eye contact with Maria while he was answering her question he was avoiding eye contact. Marias has assumed that he is hiding something from her because he was advoiding eye contact with the parole officer. Alex did miss one of his appointments but would make contact to tell her why he misses his appointment so she knows something was not right. Maria has a lot of power to get Alex in a lot of trouble. Alex seems to be nervous and doesn’t want to talk to Maria about why he wasn’t there for his appointment. In most circumstances with avoiding eye contact might also show a sign of shyness or maybe even embarrassed but in this case it show that he had done something he shouldn’t have and doesn’t want to tell Maria about it. He is advoiding it in every possible way instead of just telling her what happen or why he is making her know that something is up. If Alex would say why he miss and make eye contact he would be fine. He not making eye contact is going to get him in a lot of trouble because something is not right. Not making eye contact with someone is very disrespectful and is not right when you are talking to someone you make eye contact or if they are talking...

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