“FORMULATION, OPTIMIZATION AND EVAULATION OF …



DESIGN AND EVALUATION OF NOVEL "TABLET IN CAPSULE" DRUG DELIVERY DEVICE OF LOSARTAN POTASSIUM

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED

TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA

BY

Ms. SARITHA.N

I M.PHARM (2011-2012)

DEPARTMENT OF PHARMACEUTICS

M.S. RAMAIAH COLLEGE OF PHARMACY

BANGALORE-560054

KARNATAKA

DEC 15th 2011

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR P.G. DISSERTATION

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|1. |NAME OF THE CANDIDATE AND ADDRESS |Ms. SARITHA.N, |

| |(IN BLOCK LETTERS) |D/o: Sri N.ESWARAPPA, |

| | |3-177, BANGALORE ROAD, |

| | |PAPPIREDDI PALLI, |

| | |MADANAPALLI-517325, |

| | |CHITTOOR Dist, |

| | |ANDHRA PRADESH. |

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|2. |NAME OF THE INSTITUTION |M.S.RAMAIAH COLLEGE OF PHARMACY |

| | |M.S.R.NAGAR |

| | |M.S.R.I.T POST |

| | |BANGALORE-560 054. |

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|3. |COURSE OF STUDY AND SUBJECT |MASTER OF PHARMACY |

| | |IN |

| | |PHARMACEUTICS |

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|4. |DATE OF THE ADMISSION |20th APRIL 2011 |

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|5. |TITLE OF THE TOPIC |

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| |"DESIGN AND EVALUATION OF NOVEL "TABLET IN CAPSULE" DRUG DELIVERY DEVICE OF LOSARTAN POTASSIUM" |

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| |BRIEF RESUME OF THE INTENDED WORK |

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| |6.1 NEED FOR THE STUDY |

| |The oral route of drug delivery is typically considered as the favoured and the most user friendly means of drug administration having the highest|

| |degree of patient compliance, as a result of which much effort are aimed to identify orally active candidates that would provide reproducible and |

|6. |effective plasma concentrations in vivo. |

| |Many systems in the human body such as cardiovascular, pulmonary, hepatic and renal systems show variation in their function throughout a typical |

| |day. They are naturally synchronised by the internal body clocks and are controlled by the sleep wake cycle Each bodily system exhibits a peak |

| |time of functionality that is in accordance with these rhythmically cycles. Similarly, disease state affects the function of some of these systems|

| |in the body and exhibit a peak time of activity within a circadian rhythm. |

| |However in the field of modern drug therapy, growing attention has lately been focussed on "Oral pulsatile drug delivery systems", which have |

| |been accepted as potentially useful to the chronotherapy of some common diseases such as bronchial asthma, hypertension, allergic rhinitis and |

| |osteo-/rheumatiod arthritis with mainly night or early morning symptoms. |

| |A delivery system with a release profile that is characterized by a time period of no release (Lag time) followed by a rapid and complete drug |

| |release (pulse release) can be called as an ideal "pulsatile drug delivery system". |

| |The pulsatile release of an active agent is desirable when treating diseases that require drug delivery in a manner to maintain therapeutic levels|

| |albeit circadian rhythms1. |

| |Losartan potassium is an angiotensin-receptor blocker (ARB) that may be used alone or with other agents to treat hypertension. Losartan potassium |

| |lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system(RAAS); they compete with angiotensin II. Unlike |

| |angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough. Losartan potassium may be used to treat |

| |hypertension, isolated systolic hypertension, left hypertropy and diabetic nephropathy. It may also be used as an alternative for the treatment of|

| |systolic dysfunction, myocardial infarction, coronary artery disease, and heart failure. Losartan potassium is well absorbed after oral |

| |administration. The systemic bioavailabilty of losartan potassium is approximately 33%, protein binding is 99.7% primarily to albumin, the |

| |plasma half-life is about 2 hours and that of metabolite E-3174 is 6-9 hours2. |

| | |

| |The purpose of the study is to develop a pulsatile tablet in capsule dosage form of losartan potassium for controlled delivery. In the majority of|

| |individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulations with constant/ |

| |programmable delivery rates make it possible to deliver drug at definite time or controllable rate in chronopharmacokinetic studies. Thus, this |

| |approach can provide a useful means for timed release of losartan potassium and may be beneficial to patients with morning surge. |

| | |

| |6.2 REVIEW OF LITERATURE |

| |A system was designed by imparting a timed-release function and a pH-sensing function to a hard gelatin capsule for colon-targeted delivery of |

| |drugs. The technical characteristics of the system are to contain an organic acid together with an active ingredient in a capsule coated with a |

| |three-layered film consisting of an acid-soluble polymer, a water-soluble polymer, and an enteric polymer. As a result, it was found that: various|

| |organic acids can be used for this system; a predictable timed-release mechanism of a drug can be attained by adjusting the thickness of the |

| |eudragit layer and the outer enteric coating with HPMC provided acceptable acid-resistibility. All these results suggested that this approach |

| |could provide an useful and practical means for colon-targeted delivery of drugs3. |

| |A modified pulsincap dosage of metronidazole was developed to target drug release in the colon. Bodies of hard gelatin capsules were made |

| |insoluble by treating it with formaldehyde and keeping the caps as such. Drug pellets prepared by extrusion-spheronization method incorporated |

| |into the specialized capsule shells and plugged with polymers guar gum, hydroxypropylmethylcellulose 10K, carboxymethylcellulose sodium and sodium|

| |alginate with different concentration. The filled capsule were coated with 5 % cellulose acetate phthalate to prevent variable gastric emptying. |

| |The capsule was assessed for in vitro drug release studies at different buffer pH. The results indicated that significant drug release occurred |

| |only after 5 h from the start of experiment. Thus, metronidazole could be successfully colon targeted by the use of the modified pulsincap, |

| |thereby reducing systemic side effects4. |

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| | |

| |A time dependent modified pulsincap that would ensure chronotherapeutic delivery of diclofenac sodium in the colon for the rheumatoid arthritis |

| |was developed. Bodies of hard gelatin capsule made insoluble and drug pellets equivalent to 100 mg were filled into the treated capsule shells, |

| |plugged with hydrogel polymers HPMC, HPC and sodium alginate at different concentrations and enteric coated with 5 % cellulose acetate phthalate. |

| |The formulations were assayed to determine the drug content followed by in vitro drug release studies and the accelerated stability studies |

| |carried out for three months as per ICH guidelines. It proved that the formulations were stable and thus diclofenac sodium can be used as modified|

| |pulsincap5. |

| |An oral colon specific pulsatile device to achieve site specific release of theophylline was developed. Here the insoluble hard gelatin capsule |

| |body, filled with eudragit microcapsule of theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so that the |

| |variability in gastric emptying time can be overcome and a colon-specific release could be achieved. The theophylline microcapsules with varying |

| |polymer ratios were evaluated for the particle size, drug content and in vitro release profile. One better formulation was selected for further |

| |fabrication of pulsatile capsule. Different hydrogel polymers were used as plug, to maintain suitable lag period and it was found that the drug |

| |release was controlled by the proportion of polymers used. Then the gamma scintigraphic study done for the release of the drug in lower parts of |

| |GIT. The results indicated the successful chronotherapeutic drug delivery of theophylline6. |

| |The aim of the present study was to prepare a pulsatile release formulations consisting of two-layered tablets appropriate for preventing ischemic|

| |heart diseases. For this reason the active core was constituted by a FELO/ PVP 10/90 w/w solid dispersion while for the adjustment of the drug |

| |release time the coating layer was composed of PVP/ HPMC blends at different compositions, acting as a stimulus responsible layer. These blends as|

| |was found by DSC studies are miscible in the entire composition range, ensured by the interactions taking place between hydroxyl groups of HPMC |

| |and carbonyl groups of PVP. The miscibility of the system enhances the mucoadhesive properties of the blends, compared with those of pure HPMC, |

| |which is desired for such applications. The enhancement was attributed to the higher rate of wetting and flexibility of the new matrices due to |

| |the faster dissolution of the PVP macromolecules. Upon exposure of the prepared tablets to the release medium it was found that the coating layer |

| |disintegrates first, followed by the immediate |

| | |

| |release of FELO from the active core. The delaying time is based on a complicated mechanism, which is a combination of swelling and erosion of the|

| |PVP/HPMC polymer blends. Varying the PVP/HPMC blend ratios, the exact time that FELO is released during a daytime can be effectively adjusted7. |

| |The purpose of the study was to develop pulsatile capsule dosage form of valsartan for controlled delivery. The prepared system contained |

| |swellable polymer (l-hydroxypropyl cellulose (L-HPC), xanthan gum, polyethylene oxide or sodium alginate) together with drug tablet and erodible |

| |tablet (L-HPC or guar gum) in a pre-coated capsule. Various formulation factors were investigated through series of tests, in vitro dissolution |

| |and ex vivo continuous dissolution–absorption studies. It was found that the type, amount of polymers and erodible tablet influenced the drug |

| |release. The formulation containing 200 mg sodium alginate and erodible tablet (150 mg) containing 50 % guar gum and 46 % lactose showed 5–6 h lag|

| |time and 10 ± 2.1% drug release in initial 6 h following rapid release (99 ± 1.7 % release in 12 h) of drug was observed. The continuous |

| |dissolution–absorption study conducted using everted rat intestinal segment indicated delay in absorption of drug. Thus this approach can provide |

| |a useful means for timed release of valsartan and may be helpful for patients with morning surge8. |

| |Chronopharmaceutical capsules, ethylcellulose-coated to prevent water ingress, exhibited clearly different release characteristics when coated by|

| |organic or aqueous processes. Organic-coated capsules produced a delayed pulse release, whereas aqueous-coated capsules exhibited less delayed and|

| |more erratic release behaviour. Nuclear magnetic resonance microscopy was used to elucidate the internal mechanisms underlying this behaviour by |

| |studying the routes of internal water transport and the timescale and sequence of events leading to the pulse. Images showed that the seal between|

| |the shell and the tablet plug is a key route of water penetration in these dosage forms. There is evidence for a more efficient seal in the |

| |organic-coated capsule, and although some hydration of the contents was evident, erosion of the tablet plug is most probably the controlling |

| |factor in timed release. The premature failure of the aqueous-coated capsule appears to be a result of rapid influx of water between plug and |

| |capsule with hydration of the low substituted hydroxypropylcellulose expulsion agent. As a result of this, the tablet plug remains intact, but |

| |appears unable to be ejected. The resulting significant pressure build-up causes premature release by distortion and splitting of the capsule |

| |shell. These events may be aided |

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| |by a weakening of the aqueous-coated gelatin shell by hydration from the inside, and at the mouth of the capsule where previous electron |

| |microscope studies have shown incomplete coating of the inside by the aqueous process9. |

| |An evaluation of dofetilide pulsincap delivery to the human GI tract was developed. In these studies the effects of the degree of dispersion |

| |versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro-in vivo correlation for|

| |time of release from pulsincap preparation. In scintigraphic analysis, the time of gastric emptying, arrival at the ileocaecal junction and entry |

| |into colon were recorded. The time of capsule opening, as determined by spreading of radiolabel in the GI tract content, was determined by |

| |examination of the scintiscans. Pharmacokinetic parameter values and elimination t1/2 from the solution dose of dofetilide were determined by |

| |using software WinNonlin Version 310. |

| |A multifunctional unit system for oral use was developed by filling versatile mini tablets in a hard capsule . The aim of the present study was to|

| |develop an optimized formula for tablet in capsule containing atenolol and nifedipine for the management of hypertension. Nifedipine planned to |

| |design as the sustained release part by free flowing powder and nifedipine by wet |

| |granulation method. For sustained release portion HPMC k100 polymer was used extragranularly. In the formulation sodium starch glycolate is used |

| |as super disintegrant. The free flowing powder of atenolol was evaluated for weight variation study. The compressed nifedipine tablets were also |

| |evaluated for weight variation, hardness, friability, drug content, in vitro drug release. The formulation showing promising results was |

| |considered as the optimized formulation11. |

| |A pulsatile drug delivery system based on an insoluble capsule body filled with lornaxicam microcapsules and sealed with HPMC k4m plug. Lornoxicam|

| |microcapsules were prepared by solvent evaporation method using eudragit L/S100. Optimized microcapsule formulation were selected by percentage |

| |drug content and in vitro studies. The plugs of varying thickness and hardness were prepared by direct compression which was then placed in a |

| |capsule opening. The drug delivery system was designed to deliver the drug at such a time when it was needed (nocturnal asthma). Formulated |

| |dosage forms were evaluated for in vitro drug release might be consistent with a release time expected to deliver the drug to the colon depending |

| |on the thickness and hardness of the hydrogel plug. In this study we found out |

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| |that pulsatile device of lornoxicam is suitable for the site specific delivery of drug in colon as controlled manner. Formulation which was found |

| |to be diffusion controlled and followed zero order kinetics was the best suited one 12. |

| |Oral dosage forms are known to provide a zero order or first order release in which the drug is released at a substantially steady rate of release|

| |per unit time where maintaining a constant blood level of drug is not desirable. In such cases a pulsatile drug delivery may be more advantageous,|

| |which is classified into site specific systems in which drug is released at the desired site within the intestinal tract (e.g.: colon) or time |

| |controlled devices in which the drug is released after a well defined time period. The drug release from time controlled systems is controlled |

| |primarily by the delivery system. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches |

| |including single or multiple unit systems provided with release controlling coatings, capsular devices and osmotic pumps13. |

| |Pulsatile drug delivery causes the rapid and transient release of certain amounts of drug molecules within a short time period immediately after a|

| |predetermined off release period, i.e., lag time. This system provides spatial and temporal delivery of drug and are designed according to |

| |circadian rhythm of the body which delivers the drug at right time at right place and in right amount thus increasing patient compliance. These |

| |systems are beneficial for diseases where night dosing is required, such as cardiovascular diseases, arthritis, asthma, diabetes, neurological |

| |disorders, cancer, hypertension. These systems release the drug in a pulsatile manner and maintain plasma drug level within therapeutic range. |

| |Some examples for recent advances in oral pulsatile drug delivery technology are Accu-break technology, SODAS technology, IPDAS technology, CODAS |

| |technology, GEOCLOCK technology, PULSYS technology, Intelli matrix technology, Eurand's pulsatile and Chrono release system and Versetrol |

| |technology14. |

| |A timed delayed capsule device of terbutaline sulphate intended for chronotherapy was developed. It was prepared by sealing the drug tablet and |

| |expulsion excipient inside the insoluble hard gelatin capsule body with erodible tablet plug. The erodible tablets were prepared by direct |

| |compression. Influence of formulation factors such as type of material, different plug composition, erodible tablet weight and hardness was |

| |investigated to characterize the lag time(t10).The results indicated that drug release from the time delayed capsule exhibited an initial lag |

| |period, followed by a stage of rapid drug release. Erodible |

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| |tablet plugs prepared using higher molecular weight of polyethylene oxide resulted in longer lag times. A good correlation was observed between |

| |erodible tablet weight and lag time. In accordance with the chronomodulated therapy of asthma the lag time criterion of 5 h was satisfied by |

| |formulation containing 90mg of WSR N-10 (low molecular weight polyethylene oxide) in the erodible tablet plug15. |

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| |6.3 OBJECTIVES OF THE STUDY |

| |The present study is planned with the following objectives: |

| |Preformulation studies |

| |To carry out preformulation studies for physico-chemical characterization of drug, excipients and physical blend. |

| |To select the best swellable polymer or mixture of polymers for the hydrogel plug formation. |

| |To formulate a pulsincap dosage form (tablet in capsule type) of losartan potassium. |

| |To evaluate the formulated dosage form for various official and unofficial tests. |

| |To carry out optimization studies by adopting suitable design. |

| |To Carry out short term stability studies of the optimized formulation as per ICH guide lines. |

| |MATERIALS AND METHOD |

| |7.1 SOURCE OF DATA |

| |Library of M.S. Ramaiah College of Pharmacy. |

| |E-library of M.S. Ramaiah College of Pharmacy. |

| |Official books such as IP, BP, USP. |

| |Internet source. |

| |RGUHS Library, Bangalore (J-Gate). |

| |Micromedex® Health Care Series, Drug Information Centre: M.S.Ramaiah College of Pharmacy. |

| |International and National Pharmaceutical Journals. |

| |Lab based studies. |

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| |7.2 MATERIALS |

| |Drug: Losartan potassium IP. |

| |Polymers: HPMC k15, HPC, Eudragit L/S100, Guargum. |

| |Other excipients: Like sodium bicarbonate and citric acid. |

| |All the ingredients used will be of analytical grade procured from authentic sources. |

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| |7.3 METHODS OF DATA COLLECTION |

| |Data will be collected from experimental studies which includes: |

| |Preformulation studies: Drug polymer compatability determination using thermal analysis such as FTIR and DSC techniques. Determination of |

| |absorption maxima (λmax) and construction of calibration curve of pure drug by UV- spectrophotometric method for the estimation of drug loading |

| |efficiency and analysis of in- vitro dissolution studies. |

| |Formulation and development of tablet in capsule of losartan potassium. |

| |To carry out in-vitro dissolution studies of the optimized formulated dosage form. |

| |Evaluation of hydrogel plug: Swellability. |

| |Evaluation of capsule: Disintegration time. |

| |Optimization studies for ascertaining the influence of formulation and processing factors on lag time and percentage drug release from the |

| |formulations. |

| |Evaluation of the optimized formulation for various physico-chemical parameters. |

| |Statistical analysis of the generated experimental data. |

| |To carry out short term stability studies of best formulations as per ICH guidelines. |

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| |7.4 Does the study require any investigation or intervention to be conducted on patients or other human or animals? |

| |-NO- |

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| |7.5 Has ethical clearance been obtained from your institute? |

| | |

| |-NOT APPLICABLE- |

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| |REFERENCES |

| |Singh DK, Poddar AS, Nigade S, Poddar SS. Pulsatile drug delivery system: An overview. Int J Cur Rev and Res. 2011;2(2):55-80. |

| | bank.ca/drugs/DB00678.(accessed on 08/12/2011) |

| |Ishibashi T, Hatano H, Kobayashi M, Mizobe M, Yoshino H. Design and evaluation of a new capsule-type dosage form for colon-targeted delivery of |

| |drugs. Int J Pharm. 1998;168(1):31-40. |

| |Sindhu A and Srinath MS. Development of modified pulsincap drug delivery system of metronidazole for drug targeting. Ind J Pharm Sci. |

| |2007;69(1):24-27. |

| |Sindhu A, Bharath S, Basavaraj BV, Deveswaran R. Modified pulsincap drug delivery system of diclofenac sodium. The Pharm Rev. 2007, Kongposh |

| |Publication Pvt. Ltd, New Delhi, India. |

| |Mastiholimath V S, Dandagi PM, Jain SS, Gadad AP, Kulkarni AR. Time and pH dependent colon specific, pulsatile delivery of theophylline for |

| |nocturnal asthma. Int J Pharm. 2007; |

| |328:49-56. |

| |Evangelos K, Emmanouel G, Dimitrios B. Application of PVP/HPMC blends with enhanced |

| |mucoadhesive properties for adjusting drug release in predictable pulsatile chronotherapeutics. Eur J Pharm and Biopharm. 2006;64(1):115-126. |

| |Usha YN, Gopal VS, Yogendra N, Ranjith KA, Srinivas M, Srinivasa MR et al. Chronotherapeutic drug delivery for early morning surge in blood |

| |pressure: A programmable |

| |drug delivery system. J Cont Rel. 2009;136(2):125-131. |

| |Jonathan Sutch CD, Alistar Ross C, Walter K, Richard Bowtell W, Ross Mac Rae J, Howard Stevens NE et al. Investigating the coating dependent |

| |release mechanism of a pulsatile capsule using NMR microscopy. J Cont Rel. 2003;92(3):341-347. |

| |Stevens HNE, Clive WG, Peter WG, Binns JS, Steve WR. Evaluation of pulsincap to provide regional delivery of dofetilide to the human GI tract. Int|

| |J Pharm. 2002;236(1,2):27-34. |

| |Pankaj P, Pankaj S, Mayur S, Sumit P. Development and evaluation for tablet in capsule of nifedipine and atenolol. Int J pharm and Bio Sci. |

| |2011;1(4):468-473. |

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| | |

| |Meena R, Kumar B, Suriya TNK, Senthamarai R. Development and evaluation of pulsatile drug delivery system for lornoxicam. Int J Pharm W Res. |

| |2011;2(2):1-15. |

| |Nitin S, Sanjula B, Alka A, Javed A. Site specific chronotherapeutic drug delivery systems. Rec . Pate . on Dru. Del. and Form. 2009;3(1):64-70. |

| |Ananthanayaki R, Bairiagaiah G. A review on recent advances in oral pulsatile drug delivery. J Adv Pharm sci. 2011;1(1):132-145. |

| |Mahajan AN1 ,Pancholi SS2. Formulation and evaluation of timed delayed capsule device for chronotherapeutic delivery of terbutaline sulphate. ARS |

| |Pharm. 2010;50(4):215-223. |

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|9 |SIGNATURE OF THE CANDIDATE | |

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|10 |REMARKS OF THE GUIDE |Recommended for Dissertation work |

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|11 |NAME AND DESIGNATION OF | |

| | | |

| |11.1 GUIDE |Mr. B.V.BASAVARAJ, M.Pharm., ACCR |

| | |Asst. Professor, |

| | |Dept. of Pharmaceutics, |

| | |M.S.Ramaiah College of Pharmacy, |

| | |Bangalore-560054. |

| | | |

| |11.2 SIGNATURE | |

| | | |

| |11.3 CO-GUIDE |Not applicable |

| | | |

| |11.4 SIGNATURE |Not applicable |

| | | |

| |11.5 HEAD OF THE DEPT. |Dr. S.BHARATH, M.Pharm., Ph.D., ACCR |

| | |Professor and Head, |

| | |Dept. of Pharmaceutics |

| | |M.S.Ramaiah College of Pharmacy, |

| | |Bangalore-560 054. |

| | | |

| |11.6 SIGNATURE | |

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|12 |REMARKS OF THE PRINCIPAL |Forwarded and Recommended for favorable consideration |

| | | |

| |12.1 SIGNATURE | |

| | | |

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