Rajiv Gandhi University of Health Sciences



RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

4th ‘T’ Block, Jayanagar, BANGALORE – 560 041

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

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|1. |Name of the Candidate |ABDUL RAHMAN |

| |and Address: |S/o ABDUL KHALIQUE |

| | |House no-17 sector 11 |

| | |Aashiyana , VIKAS NAGAR |

| | |Lucknow 226022 |

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|2. |Name of the Institution: |Al-Ameen College of Pharmacy, |

| | |Hosur Road, Bangalore – 560 027. |

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|3. |Course of Study and Subject: |M. Pharm – Pharmaceutics |

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|4. |Date of Admission: |04-06-2012 |

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|5. |Title of the Topic: |

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| |“Formulation and evaluation of self-assembled vesicular nanoparticle system for the combination of Pilocarpine HCl and Timolol |

| |maleate” |

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|6.0 |Brief resume of the intended work: |

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| |6.1 – Need for the study: |

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| |Glaucoma is a condition that causes damage to the eye's optic nerve and gets worse over time. It's associated with a buildup of |

| |pressure inside the eye. This increase in pressure can happen when eye fluid isn't circulating normally in the front part of the eye. |

| |Normally, this fluid, called aqueous humor, flows out of the eye through a mesh-like channel. If this channel becomes blocked, fluid |

| |builds up, causing glaucoma. Less common causes of glaucoma include a blunt or chemical injury to the eye, severe eye infection, |

| |blockage of blood vessels in the eye, inflammatory conditions of the eye. Glaucoma usually occurs in both eyes, but it may involve |

| |each eye to a different extent. If damage to the optic nerve from high eye pressure continues, glaucoma will cause permanent loss of |

| |vision. People over the age of 40 and having health problems such as diabetes are at risk for glaucoma. |

| |There are two main types of glaucoma, the most common one is Open-angle glaucoma in which the structures of the eye appear normal, but|

| |fluid in the eye does not flow properly through the drain of the eye, called the trabecular meshwork. And the less common one is |

| |Angle-closure glaucoma which shows a sudden build-up of pressure in the eye. Drainage may be poor because the angle between the iris |

| |and the cornea (where a drainage channel for the eye is located) is too narrow.1 |

| |Worldwide, Glaucoma is a major cause of blindness (second-leading cause). Between 67 million and 105 million people are estimated to |

| |have glaucoma worldwide2. In the United States alone, approximately 3 million people have glaucoma, although only half of them are |

| |aware of their condition. Glaucoma affects one in 200 people aged 50 and younger, and one in 10 over the age of eighty3. In India |

| |approximately 11.2 million persons aged 40 years and older are found with glaucoma. Primary open angle glaucoma is estimated to affect|

| |6.48 million persons. The estimated number with primary angle-closure glaucoma is 2.54 million.4 |

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| |Normally, IOP should be below 21 mmHg. If the IOP is higher than 30 mmHg, the risk of vision loss from glaucoma is 40 times greater |

| |than someone with intraocular pressure of 15 mmHg or lower. So the clinical treatment includes the drugs which have the property to |

| |reduce IOP. |

| |Timolol, a non-selective β-adrenergic antagonists reduce IOP by decreasing aqueous humor production.The most likely action is by |

| |decreasing the secretion of aqueous humor5. Timolol is categorized as BCS Class I 6 having bioavailability of about 60%, protein |

| |binding 10%, water solubility of 2.74 mg/ml. It is having 2.5-5 hour half-life and 201.5-202.5 oC melting points.5 Pilocarpine has |

| |been used in the treatment of chronic open-angle glaucoma and acute angle-closure glaucoma. It acts on a subtype of muscarinic |

| |receptor (M3) found on the iris sphincter muscle, causing the muscle to contract and engage in miosis. Pilocarpine also acts on the |

| |ciliary muscle and causes it to contract. When the ciliary muscle contracts, it opens the trabecular meshwork through increased |

| |tension on the scleral spur. This action facilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure.7 |

| |Pilocarpine is having water solubility of 1000 mg/ml and its half-life is 0.76. 8 Studies have shown that combination of both the |

| |drugs have most effective and significant decrease in intraocular pressure when compared to lowering effect of individual drugs. It is|

| |known to administer into the eye simultaneously a β-blocker and pilocarpine in the form of an eye drop combination formulation which |

| |is buffered to a pH of 6.0 to 6.8. The use of a combination formulation rather than administering the two drugs separately has the |

| |advantage of additional beneficial therapeutic effects and also improved patient compliance.9 |

| |Amongst the various routes of drug delivery, the field of ocular drug delivery is one of the most interesting and challenging |

| |endeavors facing the pharmaceutical scientist as they need to overcome the very important additional barrier represented by the |

| |cornea, which is the main entrance to the inner eye. The area of contact of the drug with the cornea is restricted to approximately 2 |

| |cm. This small fraction of drug in contact with the cornea is then confronted with the very restrictive sub-barriers such as the |

| |epithelium, the stroma and the endothelium. Both the first and the last barrier, but particularly the first, limit the absorption to |

| |water soluble substances, due to the existence of tight junctions between the |

| |epithelial cells. The stroma, with high water content, limits the absorption of lipophilic drugs. As a result of the above mentioned |

| |processes, typically less than 1-5% of the instilled dose reaches the aqueous humour. This extremely low "ocular bioavailability" |

| |often implies the necessity of frequent dose administration, a situation that may lead to a significant systemic absorption and the |

| |corresponding side effects.10 |

| |As previously mentioned, the eye defence mechanisms represent the main limitation to the use of liquid formulations for ophthalmic |

| |therapy. Within this context, nanoparticles offer great possibilities of increasing the amount of drug at the anterior chamber of the |

| |eye, while spacing the dose administration. Nano systems have been one of the most studied colloidal systems with the objective of |

| |improving the targeting of drugs to organs and increase in drug bioavailability across biological membranes including the corneal |

| |epithelium by augmenting ocular residence time, reducing the nasolacrimal clearance.11 |

| |These colloidal Nano systems includes liposomes, niosomes, cubosomes, micro emulsions, Nano emulsion etc. and are having the advantage|

| |of higher drug loading capacity and higher stability11. Most of these self-assembled systems like liposomes and cubosomes(Nano sized) |

| |have been extensively investigated as ocular drug delivery vehicles for over a decade because they offer the potential benefits of |

| |controlled release and protection from metabolic processess.12 |

| |Cubosomes are self-assembled liquid crystalline particles of certain surfactant with proper ratio of water with a microstructure that |

| |provides unique properties of practical interest. |

| |The structure generally maintains the efficacy; stability of actives such as vitamins and proteins. Cubosomes are thermodynamically |

| |stable; lasting indefinitely. Cubic phase of cubosomes is attractive for controlled release because of its small pore size (5—10 nm); |

| |its ability to solubilize hydrophobic, hydrophilic, and amphiphilic molecules; and its biodegradability by simple enzyme action. Cubic|

| |phase is strongly bio adhesive and is thought to be a penetration enhancer with excellent compatibility with topical and mucosal |

| |deposition and delivery of active ingredients. Compared to liposomes or vesicles, cubosomes possess much higher bilayer |

| |area-to-particle volume ratios as well as higher viscous resistance to rupture.13 |

| |Thus by using the combination of timolol and pilocarpine in these self-assembled Nano delivery systems would help us in attaining |

| |increased ocular bioavailability and more controlled action , thus reducing intra ocular pressure to a greater extent. |

| |REVIEW OF LITERATURE |

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| |Matthias C. Grieshaber et al. reported that Glaucoma, the most common optic neuropathy (GON) is characterized by the loss of retinal |

| |ganglion cells and their axons, but the main risk factor is an intraocular pressure (IOP) that exceeds the tolerance of the ONH. Among|

| |the multiple risk factors, an increased intraocular pressure (IOP) is of utmost importance. IOP reduction is also the most frequent |

| |goal for glaucoma therapy.14 |

| |Treatment of glaucoma by lowering intraocular pressure can slow the deterioration of visual fields, hence the glaucomatous process. |

| |Intraocular pressure can be lowered with medication, usually eye drops.2 |

| |Several different classes of medications are used to treat glaucoma, with several different medications in each class like |

| |Prostaglandin analogs, beta-adrenergic receptor antagonists, Alpha2-adrenergic agonists, Miotic agents, Carbonic anhydrase inhibitors.|

| |Reduction of IOP of at least 30% is needed to induce a favorable alteration in the course of glaucoma. Drugs are available with the |

| |potency to induce reductions of IOP of 30% or more like Pilocarpine, Timolol, Brimonidine, Betaxolol, Latanoprost, Bimatoprost etc.3 |

| |Since the introduction in 1979 of timolol eye drops as a twice daily treatment for glaucoma, it has been the experience of many |

| |clinicians that in between 10% and 32% of patients the intraocular pressure (IOP) is not adequately controlled even with 0.5% timolol |

| |twice daily. In over half of these it is found possible to gain control by adding pilocarpine to the regimen. In time, probably due to|

| |progression of the disease process a few more experience loss of IOP control and require additional therapy. Now, with the present |

| |invention, there is provided a combination therapy for elevated intraocular pressure and glaucoma comprising twice a day topical |

| |ocular administration of a timolol and pilocarpine which results in a smooth, well controlled reduced intraocular pressure.9 |

| |Patric T S. investigated that Cubosomes, are self-assembled nanostructured particles that can be formed in aqueous lipid and |

| |surfactant systems. Of the many liquid crystalline structures self-assembled from aqueous surfactant systems, bicontinuous |

| |cubic phases possess a special status. Cubic phases are composed of contorted bilayers.15 |

| |Philip F. J et.al reported that the cubic phases are unique in that they possess very high solid-like viscosities because of their |

| |intriguing bicontinuous structures.16 |

| |Thandaki M et al. reported that bicontinuous cubic phases consist of two separate, continuous but nonintersecting hydrophilic regions |

| |divided by a lipid bilayer in to a periodic minimal surface with zero curvature. The bi continuous nature of such cubic phases |

| |differentiates them from the so-called micellar or discontinuous cubic containing micelles packed in cubic symmetry. Cubosomes are |

| |thermodynamically stable; lasting indefinitely. Colloidal dispersions of cubosomes can be stabilized by the addition of polymers. They|

| |also possess the potential for controlled delivery of actives, where diffusion is governed by the tortuous diffusion of the active |

| |through the “regular” channel structure of the cubic phase. Cubosomes possess a sufficient average degree of molecular orientation |

| |order to characterize by structural symmetry, and often form in aqueous surfactant system at relatively high amphiphile |

| |concentrations.17 |

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| |The production of cubosomes entails two distinct technologies Top-Down Technique: Top-down approach begins with a suitable starting |

| |material and then sculpts the functionality from the material, second is Bottom-Up Technique which involves first formation of the |

| |nanostructure building blocks and then assembles them into the final material. It is more recently developed technique of cubosomes |

| |formation, allowing cubosomes to form and crystallize from precursors on the molecular length scale. The scientists have investigated |

| |that the production of cubosomes can be done by aqueous dispersions of lipid based lyotropic liquid crystalline phases. Dispersion of |

| |the nanoparticles produced in the cubosomes formation can be done by several techniques like Sonication, High pressure homogenization,|

| |Spontaneous emulsification, Spray drying.18 |

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| |Great efforts have been made over the past two decades to develop novel ophthalmic drug delivery systems, including liposomes, micro |

| |emulsions and nanoparticles. Cubosomes, as dispersed colloidal particles of cubic phase liquid crystals, have stimulated significant |

| |research interest as controlled-release drug delivery system. They are commonly prepared from a glycerol monooleate (GMO)-water |

| |mixture |

| |through high-pressure emulsification, using poloxamer 407 as a stabilizer. Flurbiprofen-loaded cubosomes were prepared using hot and |

| |high-pressure homogenization and the results shown that cubosomes can reduce ocular irritancy and improve bioavailability.19 |

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| |Ocular diseases are usually treated with topical application of drug solutions (eye drops). The potential in ocular drug delivery is |

| |limited by rapid clearance from the precorneal region, as the same rapid drainage has been observed as for aqueous eye drops. In order|

| |to enhance adherence to the corneal/conjunctival surface, dispersion of the vesicular systems like liposomes, cubosomes, |

| |transferosomes etc. into mucoadhesive gels has been proposed. Dexamethazone cubosomes particles were produced by fragmenting a cubic |

| |crystalline phase of monoolein and water in the presence of stabilizer Poloxamer 407.The results of In vitro corneal penetration and |

| |Preocular retention shown that cubosomes increases the pre ocular retention and ocular bioavailability.20 |

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| |Cubosomes are the liquid crystalline cubic nanoparticles share features from both liquids and crystalline substances having cavities |

| |which can accommodate both lipophilic and hydrophilic drugs. Cubosomes were prepared by using poloxamer and glyceryl monooleate |

| |employing rotary evaporator. A novel approach was made for vitiligo therapy by incorporating piperine in cubosomes. Ex-vivo permeation|

| |and deposition studies were conducted by indigenously fabricated diffusion cell and the results clearly shown that cubosomes could |

| |achieve better tissue drug bioavailability at target site.21 |

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| |OBJECTIVE OF STUDY |

| |To formulate and evaluate the self-assembled vesicular nanoparticle system for the combination of pilocarpine hcl and timolol maleate.|

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| |SPECIFIC OBJECTIVES |

| |Improving pre-ocular retention and ocular bioavailability. |

| |Controlled release of the drug. |

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| |7.0 Materials and Methods |

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| |7.1 Source of Data: |

| |I. Review of Literature from |

| |a. Journals - such as |

| |Science Direct. |

| |Scopus. |

| |J-Gate@HELINET |

| |PubMed. |

| |International Journal of Pharmaceutical Sciences and Nanotechnology. |

| |International Journal of Drug Development & Research. |

| |International journal of pharmaceutics. |

| |European Journal of Pharmaceutics and Biopharmaceutics. |

| |International Journal of Pharmacy and Pharmaceutical Sciences. |

| |International Journal of Pharmaceutical Sciences. |

| |b. Internet Browsing. |

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| |- Method of collection of data: |

| |From Literature |

| |Laboratory based studies including: |

| |Preformulation studies |

| |Standardization of method for simultaneous estimation of pilocarpine and timolol. |

| |Determination of solubility profile, partition coefficient, IR of pure drug. |

| |Evaluation of drug excipients interaction. |

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| |Preparation of self-assembled nanoparticles of pilocarpine and timolol by suitable methods using different polymers and lipids. |

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| |Optimization of formulation variables. |

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| |Optimization of formulation methods like micronizing, hot-melt,high pressure homogenization. |

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| |Evaluation of self assembled nanosystem – |

| |Particle size |

| |Zeta potential measurement |

| |Drug encapsulation efficiency |

| |Morphological and structure studies |

| |SEM |

| |DSC |

| |X-ray diffraction |

| |Stability studies |

| |Cryo-TEM |

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| |In-vitro drug release profile of the developed self-assembled nanoparticles of pilocarpine and timolol. |

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| |In-vivo studies. |

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| |- Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, Please |

| |describe briefly. |

| |YES, the study is to be done on albino rabbits |

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| |– Has ethical clearance been obtained from your Institution in case of 7.3? |

| |Applied for clearance |

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| |Bibliography |

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| |Ivan G, Franzco, Francs (April 2003) 'Relationship between Intraocular pressure and preservation of visual field in glaucoma', SURVEY |

| |OF OPHTHALMOLOGY, ELSEVIER, VOLUME 48, pp. [Online]. Available at: (Accessed:22 |

| |Dec 2012 ). |

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| |URL: |

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| |George R, Ve RS, Vijaya L. Glaucoma in India: estimated burden of disease. J Glaucoma. 2010 Aug;19(6):391-7. |

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| |URL: |

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| |Yang Y, Faustino PJ, Volpe DA, Ellison CD, Lyon RC, Yu LX. Biopharmaceutics classification of selected beta-blockers: solubility and |

| |permeability class membership. Mol Pharm. 2007 Jul-Aug;4(4):608-14. |

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| |URL: |

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| |URL: |

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| |URL: |

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| |10. Alejandro S and Maria J. A (n.d.) 'Nanoparticular Carriers for Ocular Drug Delivery', in VLADIMIR P TORCHILIN (ed.) |

| |NANOPARTICULATES AS DRUG CARRIERS. 57 Shelton Street Covent Garden London WC2H 9HE: Imperial College Press,649. |

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| |11. Achouri D, Alhanout K, Piccerelle P, Andrieu V. Recent advances in ocular drug delivery. Drug Dev Ind Pharm. 2012 Nov 16 |

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| |12. Eljarrat E,Abraham J D 'Nanoparticles in ocular drug delivery', Nanoparticles for pharmaceutical application.367-9. |

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| |13. Garg G, Saraf S H , and Saraf S W. Cubosomes: An Overview. Biol. Pharm. Bull 2007;30(2):350-3 |

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| |14. Grieshaber M C, Flammer J. Is the medication used to achieve the target intraocular pressurein glaucoma therapy of relevance? – An|

| |exemplary analysis on the basis of two beta-blockers. Prog Retin Eye Res. 2010;79–93. |

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| |15. Patric T S. Progress in liquid crystalline dispersions: Cubosomes. Curr. Opin. Colloid Interface Sci. 5oct2005;274 – 9 |

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| |16. Philip F. J. Hoyng, MD and Yoshi Kitazawa. Medical Treatment of Normal Tension Glaucoma. Surv Ophthalmol.2002 Aug; 47(Suppl |

| |1):S116–S124. |

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| |17. Thandaki M, Kumari SP,Prabha SK. Overview of cubosomes: a nanoparticle. IJRPC 2011;1(3). |

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| |18. Prashar D and Sharma D. Cubosomes: A Sustained Drug Delivery Carrier. Asian J. Res. Pharm. Sci. 2011;1(3):59-62. |

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| |19. Shun Han et.al. Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high |

| |bioavailability. APS 2010;990–8. |

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| |20. Li Gan et al. Self-assembled liquid crystalline nanoparticles as a novel ophthalmic delivery system for dexamethasone: Improving |

| |preocular retention and ocular bioavailability. Int J of Pharmaceutics 2010;396:179–87. |

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| |21. Vinod K.R et al. A novel approach of piperine incorporated cubosomal preperationa for vitiligo therapy.Bioeqiv.Availab. |

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|9 |Signature of the candidate: | |

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| | |(ABDUL RAHMAN) |

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|10 |Remarks of the Guide: |Recommended for Approval |

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|11 |Name and Designation of: | |

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| | |Mrs. PREETI KARWA |

| |11.1 Institutional Guide: |Assistant Professor |

| | |Department of Pharmaceutics, |

| | |Al-Ameen College of Pharmacy, |

| | |Bangalore- 560027 |

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| |11.2 Signature: | |

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| | |Dr. (Mrs.) V. KUSUM DEVI |

| |11.3 Head of the Department: |Professor and Head, |

| | |Department of Pharmaceutics, |

| | |Al-Ameen College of Pharmacy, |

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| |11.4 Signature: | |

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|12 | | |

| |12.1 Remarks of the Chairman and Principal: |Forwarded to the University for scrutiny |

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| |12.2 Signature: | |

| | |Prof. B. G. SHIVANANDA |

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| | |Principal |

| | |Al-Ameen College of Pharmacy, |

| | |Hosur Road, Bangalore – 560 027. |

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