Drug â€excipient Interaction of Anti-tubercular Drugs

Drug –excipient Interaction of Anti-tubercular Drugs Drug –excipient interaction of anti-tubercular drugs and its in-silico evaluation Abstract Isoniazid and Pyrazinamide are the first line anti tubercular drugs. Lactose is mainly used as the excipient in solid dosage forms of isoniazid and pyrazinamide. These drugs contains primary and secondary amino functional group which interacts with lactose by maillard reaction and form adduct. The maillard reaction adducts of isoniazid and pyrazinamide with lactose were synthesized at 60oC in alkaline borate buffer pH 9.2 and characterized by UV, FT-IR, DSC, HPLC and MS. Docking study for in-sillico evaluation of isoniazid-lactose adduct and pyrazinamide-lactose adduct was performed to study its effect on pharmacological activity. The present study shows the presence of incompatibility between isoniazid and pyazinamidewith lactose which leads to loss the therapeutic effect of isoniazid and pyrazinamide. Keywords: isoniazid, pyrazinamide, lactose, maillard reaction, excipient, incompatibility, dosage form. Introduction Excipients are traditionally better known as promoters of degradation than as stabilizers of drug substances (Crowley 1999). Physicochemical and physiological process e.g. stability, physiological pH, gastrointestinal transit time, disintegration, dissolution, permeability and bioavailability can be altered by drug excipient interaction (Jackson, Young et al. 2000). The interactions of drug with excipients can leads to changes in the chemical, physical and therapeutic properties can be termed as incompatibilities (Chadha and Bhandari 2014) and it may cause the drug degradation (Narang, Desai et al. 2012) and loss of pharmacological activity (Patil and Patil 2013). Lactose is most widely used as the excipient in the solid dosage forms. Lactose is available in different form and different grade with different physical characteristics. Lactose is very popular excipient because of low cost and inertness but in other hand lactose have interaction drug with amino functional group i.e. lact ose undergoes maillard [Monajjemzadeh, 2009]The maillard reaction is named Louis Maillard who reported over 80 years ago that some amine and reducing sugars interact each other and forms brown pigments. The first product of this reaction is simple glycosamine (Wirth, Baertschi et al. 1998). In this study, we attempted to explore the modes of interaction and energy binding of the different isomers of isoniazid adduct, pyrazinamide adduct and also study the biological activity of isoniazid adduct and pyrazinamide adduct compare with the help of various molecular modelling techniques. In treatment of tuberculosis, isoniazid and pyrazinamide are key components of first line regimen (Hemanth, Sudha et al. 2012). Isoniazid is chemically isonicotohydrazide and pyrazinamide is chemically pyrazine-2-carboxamide. Isoniazid and pyrazinamide is susceptible for hydrolysis and oxidation interact with excipient particularly carbohydrate and reducing sugars to form hydrazones. The hydrazone is mainly form by the interaction of isoniazid with lactose. There are also reported incompatibilities between lactose and other drugs containing primary and secondary amino functional group (Haywood, Mangan et al. 2005). In this study we were investigated the interaction between lactose with isoniazid and pyrazinamide for that different analytical technique were used and also done the in-sillico evaluation of isoniazid and pyrazinamide. Materials and methods Materials Isoniazid and Pyrazinamide was generously supplied as a gift sample by Macleods Pharmaceuticals Ltd., Wapi (Gujarat), India. Lactose monohydrate was purchased from Merck, Merck specialtiesPvt.Ltd. Mumbai, India. All other chemicals were of high-performance liquid chromatography (HPLC) and analytical grade. Methods Analytical methods UV-visible spectrophotometry The Ultraviolet-visible spectra of Isoniazid, Pyrazinamide and the Isoniazid–lactose adduct, Pyrazinamide-lactose adductwere recorded on a double beam UV-visible spectrophotometer (UV-1700; Shimadzu, Japan). An accurately weighed quantity of about 10 mg of isoniazid, 10 mg of pyrazinamide, 11.66 mg isoniazid-lactose adduct (equivalent to 10 mg isoniazid), 13.33 mg of pyrazinamide-lactose adduct (equivalent to 10 mg pyrazinamide) each dissolved separately in 100 ml of distilled water. From this, one ml of solution was diluted to 10.0 mL with of distilled water to obtain concentration of 10 ppm. All solutionswere scanned in UV-Visible range at 420 and 490 nm (Yates, Jones et al. 2003). Fourier-Transform infrared spectroscopy The Fourier-transform infrared spectroscopy (FTIR) spectra of isoniazid, pyrazinamide, lactose, a isoniazid–lactose physical mixture, pyrazinamide-lactose physical mixture and the isoniazid–lactose adduct, pyrazinamide-lactose were recorded. The spectra were obtained using the diffuse reflectance scan method using KBr on an FT-IR spectrophotometer (IR Affinity 1; Shimadzu, Japan). The scanning range was 400–4000 cm-1. Each sample was scanned 45 times consecutively to obtain FT-IR spectrum. HPLC analysis The HPLC (Gradient) system used for analysis consisted of Agilent Technologies 1200 series equipment, a G1315D quaternary pump, a G1315D diode array detector and a rheodyne injector fitted with a 20  µL loop. Data were recorded and evaluated using the EZChrome Elite software package. Samples were analyzed using LunaC18 column (250 Ãâ€" 4.6 mm i.d. Ãâ€" 5  µm) (Phenomenex) as stationary phase. The mobile phase was water: methanol (95:05, v/v), flow rate of 0.8 mL/min with detection at 266 nm for isoniazid and 269 nm for pyrazinamide. Differential scanning calorimetry Thermal analysis of Isoniazid, pyrazinamide, isoniazid–lactose adduct and pyrazinamide-lactose was performed by differential scanning calorimetry (DSC) using a TA 6000 Mettler toledo thermal analyzer. Individual samples as well as the Maillard adduct (about 2 mg) were weighed in the DSC aluminum pan and were scanned in the temperature range of 25–300 °C. A heating rate of 10 °C/min was used. The thermograms were reviewed for evidence of interaction. Mass Spectrometry The Mass spectrometry was performed using 410 Prostar binary LC with 500 MS with Electro spray Positive ionization and Negative Ionization mode and Mass range is 50-2000 amu. The Isoniazid-lactose, Pyrazinamide-lactose adduct solution dissolved in mobile phase to obtain concentration about 100 µg/mL. In the positive ion mode with electrospray ionization technique, the sample was analyzed. Determination of lactose in pharmaceutical tablet dosage forms The presence of lactose in DOTs tablets was initially examined according to Indian Pharmacopoeia 2007 by taking 5ml saturated solution of tablet powder and then add 5ml 1 M NaOH, Heat and cool at room temperature finally add potassium cupri tatatarate the solution becomes red color shows presence of lactose. Preparation of adduct Sample Prepared in alkaline borate buffer Accurately weighed quantity of Isoniazid 300 mg (equivalent to dose of isoniazid) and 50 mg lactose monohydrate dissolve in alkaline borate buffer pH 9.2 by stirring and ultrasound in 100 ml round bottom flask. In similar way 750 mg pyrazinamide (equivalent to dose of pyrazinamide) was dissolve with 250 mg lactose monohydrate in alkaline borate buffer pH 9.2 in 100 ml round bottom flask. The cleared solutions were refluxed at 600C for 12 hour on water bath. The reaction mixture filtered was diluted with menthol: water (1:1). The adduct was subjected to HPLC analysis (gradient and isocratic run) and Mass spectrometry (LC-MS) analysis. The intensity of brown color was determined was spectrophotometrically after dissolving weighed quantity in distilled water. Docking study The molecular docking tool, GLIDE (Schrodinger Inc., USA) (2006) was used for ligand docking study. The protein preparation was carried out using ‘protein preparation wizard’ in Maestro 9.0. Result UV-Visible spectroscopy The UV-visible absorption spectrum of the isoniazid–lactose adduct and pyrazinamide–lactose adduct had shown an increase in absorption in the visible range as compared with isoniazid and pyrazinamide in distilled water as the solvent. The increased absorption the visible region (brown color) is due to Melanoidins production as the end products of the Maillard reaction as reported earlier (Shen, Tseng et al. 2007). FT-IR spectroscopy The FT-IR absorption patterns of Isoniazid, Pyrazinamide, lactose, Isoniazid–lactose physical mixture immediately after mixing and pyrazinamide-lactose physical mixture immediately after mixing as well as Isoniazid–lactose adduct, Pyrazinamide-lactose adduct were recorded. The peak at 1678 cm−1 in the IR spectrum of Isoniazid-lactose adduct, 1614 cm−1 Pyrazinamide-lactose adduct can be attributed to the imines formation. The peak of N–H bending is present at 1552 cm−1 and 1583 cm-1 in the IR spectrum of Isonizid and Pyrazinamide and its physical mixture respectively. The peak present in spectrum of Isonizid and Pyrazinamide and its physical mixture are absent in Isoniazid-lactose adduct and Pyrazinamide-lactose adduct both these observations support the formation of adduct. The N–H stretching band of secondary amine appears at 3302 cm−1 and at 3292 cm-1 for Isonizid and Pyrazinamide respectively. The peak for the lactose O–H appears at 3522 cm−1 in the infrared spectra of lactose. The peaks for N–H and O–H stretching appear in the spectrum of the physical mixture, but the peak for N–H disappears in the spectrum of the adduct. This may indicate the reaction of the amine with the red ucing sugar, or it may be due overlapping of N–H stretching peak with that of O–H. The FTIR spectra of Isoniazid, Pyrazinamide, Lactose physical mixture, Isoniazid-lactose adduct and Pyrazinamide-lactose adduct shows an interaction between Isoniazid and Pyrazinamide with lactose leading to the formation of a Maillard product (Pavia et al 2009). Differential scanning calorimetry The DSC thermograms show the presence of melting points for isoniazid and pyrazinamide at 171.61ÃŽ ¿C and 189.55 ÃŽ ¿C. The DSC thermogram of lactose shows the peak at 209.83 ÃŽ ¿C. The adduct shows the disappearance of the melting point peak of isoniazid, pyrazinamide, paracetamol and vildagliptine in adduct samples confirms the formation of adduct. Gradient HPLC analysis Initially a gradient run of water and methanol was performed to obtain preliminary information regarding the unknown peaks in maillard reaction products (Shen, Tseng et al. 2007). The mobile phase was optimized to separate the Isoniazid-lactose adduct and Pyrazinamide-lactose adduct was water: methanol (95:05, v/v) with a flow rate 0.8ml/min at ambient temperature. The Isoniazid-lactose adduct and Pyrazinamide-lactose adduct elutes at 3.833min and 1.613 min respectively. The control samples for isoniazid and pyrazinamide (without lactose) were also analyzed which proves method selectivity. Isocratic HPLC analysis The optimized isocratic HPLC analysis of the Isoniazid-lactose adduct and Pyrazinamide-lactose revealed one extra peak that eluted before Isoniazid and Pyrazinamide elution respectively. Performing analysis under same chromatographic parameters, no another peak was observed in control samples. Mass spectrometry The Isoniazid-lactose and Pyrazinamide-lactose adduct dissolve in mobile phase to obtain drug concentration about 100 µg/ml. In the positive ion mode with electrospray ionization technique, the sample was analyzed. The MS spectra show the precursor ion for Isoniazid-lactose adduct and Pyrazinamide-lactose adduct was protonated molecule ([M+H]+) m/z 463.3 and 448.1 respectively. The Isoniazid-lactose adduct and Pyrazinamide-lactose adduct molecular mass was consistent with Isoniazid-lactose adduct and Pyrazinamide-lactose adduct condensation product respectively. The loss of one water molecule from parent leads to maillard-type condensation product. Docking study Isoniazid In docking study, isoniazid shows binding with ARG-38 amino acid in the selected structure of protein (PDB code: 3I6N) and isoniazid-lactose adduct shows binding with ASN-72, SER-69, SER-173, ALA-134 and PRO-132 amino acid in the selected structure of protein (PDB code: 3I6N) as shown in Table No. 1.1. Pyrazinamide Pyrazinamide shows binding with ALA-131 amino acid in the selected structure of protein (PDB code: 3PL1) and pyrazinamide-lactose adduct shows binding with ASP-133 and LEU-131 amino acid in the selected structure of protein (PDB code: 3PL1). Discussion On the above observation difficulties in the formulating a new pharmaceutical dosage form have often experienced because of the interaction between the lactose and active ingredients itself i.e. isoniazid and pyrazinamide. Although the nature and intensity of this interaction may alter the stability, dissolution rate and consequently absorption of the drug and also affect the pharmacological effect. it indicates that such interactions involving in the formation of the complexes and it studied by different analytical techniques. The UV results shows increased absorption in the visible region (brown color) is due to Melanoidins production as the end products of the Maillard reaction as reported earlier in Shen, Tseng et al. 2007. The FTIR spectra of Isoniazid, Pyrazinamide, Lactose physical mixture, Isoniazid-lactose adduct and Pyrazinamide-lactose adduct shows peak of C=N it shows that formation of a Maillard product. HPLC analysis of the Isoniazid-lactose adduct and Pyrazinamide-lactose revealed one extra peak of impurity or maillard reaction product that eluted before Isoniazid and Pyrazinamide elution respectively. The MS spectra show the precursor ion for Isoniazid-lactose adduct and Pyrazinamide-lactose adduct and it has same molecular weight related to maillard-type condensation product. In the docking study of isoniazid adduct and pyrazinamide adduct shows more binding than isoniazid and pyrazinamide but this is pseudo results because this binding present at hydroxyl group and hydroxyl group are responsible for the increase excretion of the isoniazid and pyrazinamide and it may be reduces the therapeutic effect of isoniazid and pyrazinamide. In spite of that analytical study confirm the occurrence of maillard reaction product in lactose containing solid dosage forms of amino functional group containing drugs but lactose is still preferred as excipient in the isoniazid and pyrazinamide containing anti-tubercular formulation i.e. DOT’s. Conclusion The present study reports that antitubercular drugs i.e. isoniazid and pyrazinamide undergoes maillard reaction and that confirmed by UV, FT-IR, HPLC and MS. The docking study of isoniazid adduct and pyrazinamide adduct more binding than isoniazid and pyrazinamide but it is pseudo results pharmacologically the excretion of isoniazid and pyrazinamide increase and it ultimately reduces the therapeutic activity. A drugs- excipient interaction study can be actively used to the advantage of the formulator to increase the bioavailability of the drug. By compiling the data the use of lactose in the formulation of isoniazid and pyrazinamide, secondary amines needs to reconsideration. References: Chadha, R. and S. Bhandari (2014). Drug–excipient compatibility screening—Role of thermoanalytical and spectroscopic techniques. Journal of pharmaceutical and biomedical analysis87: 82-97. Crowley, P. J. (1999). Excipients as stabilizers. Pharmaceutical science technology today2(6): 237-243. Haywood, A., et al. (2005). Extemporaneous isoniazid mixture: stability implications. Journal of Pharmacy Practice and Research35(3): 181. Hemanth, A. K., et al. (2012). Simple and rapid liquid chromatography method for simultaneous determination of isoniazid and pyrazinamide in plasma. SAARC Journal of Tuberculosis, Lung Diseases and HIV/AIDS9(1): 13-18. Indian Pharmacopoeia, (2007). Government of India, Ministry of health and family walefare, published by the Indian Pharmacopoeia Commission, Gaziabad; vol. II III, pp. 658, 478, 628, 1009, 1008. Jackson, K., et al. (2000). Drug–excipient interactions and their affect on absorption. Pharmaceutical science technology today3(10): 336-345. MONAJJEMZADEH, F., HASSANZADEH, D., VALIZADEH, H., SIAHI-SHADBAD, M. R., MOJARRAD, J. S., ROBERTSON, T. A. ROBERTS, M. S. 2009b. Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets. European Journal of Pharmaceutics and Biopharmaceutics, 73, 404-413. Narang, A. S., et al. (2012). Impact of excipient interactions on solid dosage form stability. Pharmaceutical research29(10): 2660-2683. PAVIA, D. L. 2009. Introduction to spectroscopy, CengageBrain. com Patil, D. D. and C. R. Patil (2013). Modification of pharmacological activity of nebivolol due to Maillard reaction. Pharmaceutical development and technology18(4): 844-851. Petrella, Stà ©phanie Gelus-Ziental, Nathalie Maudry, Arnaud Laurans, Caroline Boudjelloul, RachidSougakoff, Wladimir(2011).Crystal structure of the pyrazinamidase of Mycobacterium tuberculosis: insights into natural and acquired resistance to pyrazinamide.PLoS One,6(1):e15785. Singh, Amit K Kumar, Ramasamy P Pandey, Nisha Singh, Nagendra Sinha, Mau Bhushan, AshaKaur, PunitSharma, SujataSingh, Tej P (2010). Mode of Binding of the Tuberculosis Prodrug Isoniazid to Heme Peroxidases BINDING STUDIES AND CRYSTAL STRUCTURE OF BOVINE LACTOPEROXIDASE WITH ISONIAZID AT 2.7 Ã… RESOLUTION.Journal of biological chemistry, 285(2): 1569-1576. Shen, S.-C., et al. (2007). An analysis of Maillard reaction products in ethanolic glucose–glycine solution. Food chemistry102(1): 281-287. Wirth, D. D., et al. (1998). Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine. Journal of pharmaceutical sciences87(1): 31-39. Yates, E. A., et al. (2003). Microwave enhanced reaction of carbohydrates with amino-derivatised labels and glass surfaces. Journal of Materials Chemistry13(9): 2061-2063.

Personal Response- Forrest Gump (Film) Essay

This film follows the life of Forest Gump who struggles to live outside the barriers that society has given him. Forrest is a little ‘slow’; although his mental impairment doesn’t seem to bother him. In fact, the naivetà © that comes from his limited understanding of the world around him gives Forrest a uniquely positive perspective of life. Forest overcomes the challenges in his life, becoming a star football player, a war hero, a successful businessman, and something of a pop icon. Through it all, however, there is one defining element in his life: his love for Jenny. She is never far from his thoughts, no matter what he’s doing or where he is. I believe the director uses the character Forrest Gump to convey the thought that most people are too smart for their own good; he uses Forrest in order to show the audience that escaping from the realities and actualities of the world can have positive outcomes throughout life. While other characters in the film struggle with conflicts in society, Forrest remains unaware of them; this allows him to live in the moment. Forrest goes out of his way to do what is right, as opposed to what is easy, I believe that this movie asks me to look at the imperfections within myself and calls me to become a more selfless person. I highly recommend this film to year 12 students, Forrest has an ability to truly humble another human being, and his optimism, freshness, and emotional honesty are just a few qualities that he teaches us throughout the film. The movie does not seek to reduce every member of the audience to tears; it does however have moments where the true power of message comes from the simplest of things. For example, Forrest says to anyone that will listen, â€Å"Life is like a box of chocolates, you never know what you’re going to get.† Through this quote we see that Forest is able and  willing to go through life taking every opportunity given to him, I believe the way he sees the world is incredibly unique and that I have benefited from seeing his views of life, in many ways this f ilm has changed my perspective of life and I believe that year 12’s will find this film highly enjoyable and beneficial. I believe an aspect that makes this film beneficial for all year 12 students is that it addresses the perspectives of war. The movie shows the different perspectives of the Vietnamese war, in scenes we see thousands of protesters protesting and in the very next frames we see supporters rallying together and congratulating the returned men. This contrast is highly refreshing, it is not common in movies to show multiple perspectives on war; however the film Forrest Gump manages to show the audience three perspectives. During the 60s and 70s, no topic was of higher debate than that of the Vietnam War and those who were sent overseas to fight. Forrest, as might be expected, has a singular viewpoint on his time spent in Vietnam, he narrated during the film saying, â€Å"We took long walks and were always looking for this guy named Charlie.† In Forrest’s observation of the war we see that although he was fighting willingly, he did not know why or what he was fighting for. I believe that this is the underlying message that the Director is trying to portray, on one side of the line there are those for the War, on the other are those against it and in the middle is Forrest Gump. In many ways Forrest teaches us about governments exploiting its citizens, he was sent to a place where he may have died and yet he did not understand why he was there to begin with, however he did enlist himself for the war. I struggle with the double meanings throughout the movie, we see the positives and the negatives of war through the death of Forrest’s best friend, Bubba, and the medal Forrest receives for saving Lt. Dan. In the end I’m left just as confused about the war as Forrest Gump is about life. I challenge year 12’s to watch this movie, keeping in mind that everything Forrest says means something deeper than the definition of each word that leaves his mouth. I believe that the character Forrest Gump teaches me to treasure the moments in my life and to understand why I’m doing what I’m doing. Especially in scenarios that can affect other people. He is some sort of inspiration to me; this is however not in the usual context. He inspires me to never enter situations  where I do not fully comprehend nor understand the consequences of my actions, he inspires me to never let someone take advantage of me and he inspires me to just simply, be me. Throughout the entire film we see Forest Gump’s tragic life; nearly everyone he holds most dear to him dies. Life can be brutal at times, I found myself crying during the moments when Forrest’s life seemed painfully hard. In some ways I could see that with every loved one that he’d lost a part of him had died with them. I can understand this feeling as my best friend’s father passed away only three years ago this month. As she is growing up, she is realising the disadvantages of not having him with her, knowing that he is not there to teach her how to drive or help her get her first job. I see her pain and I know that there is nothing I can do to stop it, I am powerless. I believe that there is finality in death, however in this film Forrest teaches the audience that a part of us may die with a loved one, but that doesn’t stop life from coming back to us. The underlying message that Forrest has to offer on the subject of death is that you should nev er let heart-break or tragedies take over your life. Forrest accepts that dying is inevitable, â€Å"Momma always said dying was a part of life,† he says. â€Å"I sure wish it wasn’t.† Death occurs not only in Forrest’s personal life, but also in the larger community. This film has a historical setting and we see the main events of the 60’s, 70’s and 80’s through the eyes of Forrest. In this era, death of high valued people within America rocked the foundations of its society; numerous assassinations took place including JFK, RFK and John Lennon. Forrest struggles with the necessity of death as he watches those he loves fall to illness and war and those he admires fall to random attack. During this time the death of Martin Luther King Jr. created the greatest conflict within society and he is still remembered to day for his fight against racism and war. The King family and others believe that the assassination was carried out by a conspiracy involving the US government and that James Ear l Ray was a scapegoat. At the time the thought of this alone was enough to spark a civil war within America, although this was avoided by Senator RFK, who spoke to a crowd directly after being informed of Martin L. King’s passing. In his speech he said, â€Å"I had a member of my family killed, but he was killed by a white man.† RFK’s attempts at avoiding  severe rioting based on race was only semi successful, however his speech is widely considered one of the greatest speeches in American history. King was a beloved leader in the civil rights movement, and also an advocate for nonviolence. His death led some people to feel angry and disillusioned; from his death they began to believe that the only effective resistance to racism is violence. King was used as a martyr, however his cause for non-violence was ignored and he was used as a reason for blacks to shed blood. Dying is a part of life, only two months after RFK said his speech he too was assassinated, this shows that it does not matter who you are or if you are ready to die because in the end death will come for you when your least expecting it . I don’t expect to die anytime soon. But Forrest’s life teaches me that it could happen this moment, while I am writing. Steve Jobs once said â€Å"No one wants to die. Even people who want to go to heaven don’t want to die to get there. And yet death is the destination we all share. No one has ever escaped it. And that is as it should be, because Death is very likely the single best invention of Life. It is Life’s change agent. It clears out the old to make way for the new.† I believe this quote shows that death is inevitable, in the end we all die, we may try to avoid death but it will always come for us one day, it may be tomorrow, it may be in fifty years from now, but it’s coming for us all.

The Debate Over Essay Writing Topics English

The Debate Over Essay Writing Topics English In case you have any questions, you can get in touch with our friendly support team night and day and get immediate assistance. For growth-mindset folks, on the flip side, effort is the thing that makes you smart or talented. A team is waiting to do a lot of the work for those who want it the most. It's important to acquire decent excellent help in order to give yourself a good probability of landing the very best grade. Writing an essay may be a tedious and demanding task that could wind up occupying all of your time after school. Students want to learn how to synthesize knowledge based on these healthcare references. The ACT Writing test isn't bound to check your knowledge about a specific topic, but it's rather designed to assess your English writing skills. An individual should gather all the appropriate information regarding the assigned essay topic. The subject of the essay has to be clear in the very first paragraph. 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Car Rental Business Plan - 4055 Words

Car Rental Services Table of Contents S.no Description Page Introduction 3 1.0 Executive Summary 4 2.0 Business Description 5 2.1 Business plan 5 2.2 Long term goals of the company 5 2.3 Starting plan Expenses 5 2.4 Company strength Uniqueness of service 7/8 2.5 Potential of the business 8 3.0 Marketing Plan 9 3.1 Marketing segments Target segments 9 3.2 Market needs 10 3.3 Competition 10 3.4 Promotion Advertising strategy 11 3.5 Pricing Strategy 11 3.6 Marketing Budget 12 4.0 Operation Plan 13 4.1 Various service offered 13 4.2 Selling price Sales revenue 14 5.0 Management Plan 15 5.1 Management team 15 5.2 Role of Employees 16 6.0 Financial Plan 17 6.1 Profit loss statement 18 6.2 Cash flow statement†¦show more content†¦In the past 5 years, the Kingdom of Bahrain has undergone a sea of change, with major developments happening in the private sector public sector. Many ambitious projects such as residential office buildings, resorts and other various developments are being sanctioned by the government. This recent developments have increased tourism and foreign investments into the country and with these developments, the car rental and the hotel business has started booming. 2.2) Long term goals of the Company For the company to be successful, it is important to fix and fulfill all its goals that have been set to be achieved. Our future goals or targets are: ï‚ § To expand the company business into Saudi Arabia ï‚ § To set up a driving training institute ï‚ § To form a Limited Liability Corporation (LLC) for liability protection of personal and company assets. 2.3) Starting plan Expenses The Owner will finance the start-up expenses for the company. The property on Exhibition road will be leased in January 2007 for a minimum of three years. The location is already fixed and secured the lease for BD 600 per month. 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