Formulation and Evaluation of Anti Emetic Patch Comprising On Dan Set Ron Hydro Chloride

FORMULATION AND EVALUATION OF ANTIEMETIC PATCH COMPRISING ONDANSETRON HYDROCHLORIDE
Dissertation
Submitted to KLE University, Belgaum, Karnataka In partial fulfillment of the requirement for the award of the degree of
Master of Pharmacy In Pharmaceutics

By Miss. PRAMEELA KIRAN SURYADEVARA B.Pharm Under the guidance of DR. BASAVARAJ K. NANJWADE PhD
DEPARTMENT OF PHARMACEUTICS, JN MEDICAL COLLEGE, BELGAUM-590010, KARNATAKA, INDIA
MAY-2010
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KLE UNIVERSITY, BELGAUM, KARNATAKA
Declaration Declaration by the Candidate

I hereby declare that this dissertation entitled
FORMULATION AND EVALUATION OF ANTIEMETIC PATCH COMPRISING OF ONDANSETRON HYDROCHLORIDE is a
bonafide and genuine research work carried out by me under the guidance of Dr. B.K. NANJWADE, Associate Professor, Department Belgaum. of Pharmaceutics, JN Medical College,
Date:
Miss. PRAMEELA KIRAN SURYADEVARA B.Pharm Dept. of Pharmaceutics, Place: Belgaum. JN Medical College, Belgaum 590 010, Karnataka.
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Certificate by the Guide

I hereby declare that this dissertation entitled
FORMULATION AND EVALUATION OF ANTIEMETIC PATCH COMPRISING OF ONDANSETRON HYDROCHLORIDE is a
bonafide research work done by MISS. KIRAN SURYADEVARA in partial fulfillment of the requirement for the degree of Master of Pharmacy in Pharmaceutics.
Date: Place: Belgaum.
Dr. B. K. NANJWADE PhD Professor, Dept. of Pharmaceutics, JN Medical College, Belgaum 590 010, Karnataka.
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Endorsement By The HOD, Principal/ Head of The Institution

This is to certify that the dissertation entitled
FORMULATION AND EVALUATION OF ANTIEMETIC PATCH COMPRISING OF ONDANSETRON HYDROCHLORIDE is a bonafide research work done by Miss. KIRAN SURYADEVARA in partial fulfillment of the requirement for the degree of Master of Pharmacy in Pharmaceutics, under the guidance of Dr. B. K. NANJWADE, Professor, Department of Pharmaceutics, JN Medical College, Belgaum.
MRS. R. S. MASAREDDY M.PHARM Associate Professor & Head, Dept. of Pharmaceutics, JN Medical College, Belgaum 590 010. Karnataka
DR. V. D. PATIL MD, DCH Principal, JN Medical College, Belgaum 590 010, Karnataka.
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Copyright Declaration by the Candidate

I hereby declare that the KLE University, Belgaum, Karnataka shall have the rights to preserve, use and disseminate this dissertation/thesis in print or electronic format for academic/research purpose.
Miss. PRAMEELA KIRAN S B.Pharm Dept. of Pharmaceutics, JN Medical College, Belgaum 590 010, Karnataka.
J.N. Medical College, KLE University, Belgaum, Karnataka

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Affectionately D edicated
to
My Family
The family is a haven in this world
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Acknowledgement
The Almighty, has been bestowing us with his blessings throughout our life. I thank thou force for all that he has done for me and my friends. We all are his disciples. Words are few to express the feeling of thanks and gratitude to the following persons. I would like to grab the opportunity to thank my guide
Dr. B.K. Nanjwade (prof) KLE University, Belgaum, for his immense support for the project. Sir you been a great support for me, enlightening my path of education and knowledge. Thanks for your unparalleled and excellent guidance, continuous encouragement for my project. It is a great pleasure and honour to thank Chancellor, Vice-Chancellor, Dr. V.D. Patil(principal) , Dr. F.V. Manvi, Dr. P.V. Patil (Cont of Examination) , Prof A.D. Taranalli and Dr. Pramod HJ (Pharmacognosy) of KLE University, for such a temple of education that they provided. I would like to thank all the teaching and non-teahing staff of the KLEs Womens College of Pharmacy, Belgaum, for their support. I would like to thank Yellapa and Gajanan for their support during the project. I owe my thanks to the whole staff of Library.
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I would like to cast a vote of thanks to my friends and batchmates Sushmitha, Venkatlaxmi, Anu, Sank ,Mohite, Vishwas, Eshwar, Amol, Bhushan, Rajesh, Ritesh, Ayaz, Jatin, Ketan, Dhaval, Suhas, Chirag, Kemy, Rucha and Vishal for their kind support throughout my project. My gratitude goes to my seniors Chakridhar and Kotishwar for their guidance during the project. A very special thanks to all my juniors Bhavya Shanthi, Swathi, Hima, Nirmala Devi, Haritha, Kishori, Alok, Navik and Vedprakash for making my stay a pleasant one in Belgaum. Thanks to my friends who always care for me Raghu Ram, Rahul, Raghu Kumar, Guru Prasad, Chandna, Srinivas, Prem and Anurupa. A heartily and warm thanks to Mac R. Kella for supporting me throughout my project and studies. This dissertation is dedicated to my family, for without their blessings nothing would have been possible. My sisters and jijus have been a driving force behind me for my accomplishments and achievements. Thanks a lot for everything that you have been doing for me. A special thanks to my Maternal Uncles V. Ashok Vardhan and Mr. V. S. Prasad.
KIRAN SURYADEVARA
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LIST OF ABBREVIATIONS
EC FT-IR gm HPMC ml PBS pKa PVA PVP RH t t max g
Ethyl Cellulose Fourier transform Infrared spectroscopy Grams Hydroxy Propyl Methyl Cellulose Milli-litres Phosphate buffer solution Dissociation constant Polyvinyl alcohol Poly Vinyl Pyrrolidone Relative Humidity Elimination half-life Time to attain peak concentration Micrograms
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ABSTRACT
The skin can be used as the site for drug administration for continuous transdermal drug infusion into the systemic circulation. For the continuous diffusion/penetration of the drugs through the intact skin surface membrane-moderated systems, matrix dispersion type systems, adhesive diffusion controlled systems and micro reservoir systems have been developed. Various penetration enhancers are used for the drug diffusion through skin. In matrix dispersion type systems, the drug is dispersed in the solvent along with the polymers and solvent allowed to evaporate forming a homogeneous drug-polymer matrix. Matrix type systems were developed in the present study. In the present work, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising of Ondansetron-HCl with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent evaporation technique. The physicochemical compatibility of the drug and the polymers was studied by infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the in-vitro permeation studies using rat skin. On the basis of results obtained form the in-vitro study and physical evaluation the patches containing hydrophilic polymers i.e. polyvinyl alcohol and poly vinyl pyrrolidone, with oleic acid as the penetration enhancer(5%) were considered as suitable for large scale manufacturing with a backing layer and a suitable adhesive membrane. Keywords: Transdermal drug delivery, penetration enhancers, hydrophilic and hydrophobic polymers, Ondansetron HCl.
CONTENTS
SL. NO. 1. 2. 3. 4. 5. 6. 7. 8. TITLE INTRODUCTION RESEARCH OBJECTIVES REVIEW OF LITERATURE METHODOLOGY RESULTS AND DISCUSSION CONCLUSION SUMMARY BIBLIOGRAPHY PAGE NO. 1 28 31 53 64 86 87 89
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LIST OF TABLES
Sr. No. 1. 2. 3. 4. 5. 6. 7. 8. Title of Table Regional variation in water permeability of stratum corneum Examples of marketed transdermal drug delivery system List of chemicals used with grade and supplier List of Instruments used Formulation table of Ondansetron HCl Patches Standard calibration curve of Ondansetron HCl Solubility data for Ondansetron HCl Physicochemical evaluation data of Ondansetron HCl Transdermal patches Ex-vivo diffusion study of OND 1 Ex-vivo diffusion study of OND 2 Ex-vivo diffusion study of OND 3 Ex-vivo diffusion study of OND 4 Ex-vivo diffusion study of OND 5 Ex-vivo diffusion study of OND 6 Data for regression Page No. 9 27 53 54 57 67 67 68
9. 10. 11. 12. 13. 14. 15.
69 70 71 72 73 74 75
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LIST OF FIGURES
Sl. No. 1 2 3 4 5 6. 7. 8. 9. 10. 11. Title of Figure Comparative graphs of conventional, sustained- and controlled release delivery systems. Structure of skin A multilayer skin model showing sequence of Transdermal permeation of drug for systemic delivery The microstructure of stratum corneum Routes for drug permeation Epidermal routes for drug permeation Action of penetration enhancers Cross-sectional view of polymer membrane permeation-controlled TDD systems Cross-sectional view of polymer matrix diffusion-controlled TDD Systems Cross-sectional view of a drug reservoir gradient-controlled TDD system Cross-sectional view of a drug microreservoir dissolution-controlled TDD system Assembly for % elongation kesary Chein diffusion cell UV spectrum for Ondanstron HCl Calibration curve of Ondansetron HCl Ex vivo diffusion study of OND F1 Ex vivo diffusion study of OND F2 Ex-vivo diffusion study of OND F3 Ex-vivo diffusion study of OND F4 Ex-vivo diffusion study of OND F5 Page No. 1 6 9 10 11 11 15 20 22 23 24
12. 13. 14. 15. 16. 17. 18. 19. 20.
60 62 76 76 77 77 78 78 79
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21. 22. 23. 24. 25. 26. 27. 28. 29 30
Ex-vivo diffusion study of OND F6 Higuchis plot for OND F1 Higuchis plot for OND F2 Higuchis plot for OND F3 Higuchis plot for OND F4 Higuchis plot for OND F5 Higuchis plot for OND F6 Formulated patches IR spectra of OND F1 IR spectra of OND pure drug
79 80 80 81 81 82 82 83 84 85
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Chapter 1
Introduction
INTRODUCTION Controlled drug delivery

Treatments of acute and chronic diseases have been accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. These dosage forms are known to provide a prompt release of drug. But recently several technical advancements have been done and resulted in new techniques for drug delivery. These techniques are capable of controlling the rate of drug release. The term-controlled release has a meaning that goes beyond scope of sustained release. The release of drug ingredients from a controlled release drug delivery advances at a rate profile that is not only predictable kinetically, but also reproducible from one unit to another1. The difference between sustained release and controlled release is shown by fig.1.
Figure. 1: Comparative graphs of conventional, sustained- and controlled release delivery systems.
The classification of controlled drug delivery can be given as follows. Dept of Pharmaceutics, KLE University, Belgaum 1
Chapter 1 1. Rate-preprogrammed drug delivery systems 2. Activation-modulated drug delivery systems 3. Feedback-regulated drug delivery systems 4. Site-targeting drug delivery systems
Introduction
Out of these classes first class contains new drug delivery systems as transdermal delivery, intra uterine delivery, ocular inserts, and sub dermal implants. The transdermal drug delivery has advantage to deliver medicines via skin to systemic circulation at a predetermined rate and maintain therapeutic concentration for prolong period of time.
Transdermal drug delivery: An Introduction

The idea of delivering drugs through skin is old, as the use is reported back in 16th century B.C. The husk of castor oil plant in water was placed on an aching head2. Today the transdermal drug delivery is well accepted for delivering drug to systemic circulation. Until recently, the use of transdermal patches for pharmaceuticals has been limited because only a few drugs have proven effective delivered through the skin typically cardiac drugs such as nitroglycerin and hormones such as estrogen. A skin patch uses a special membrane to control the rate at which the liquid drug contained in the reservoir within the patch can pass through the skin and into the bloodstream. The basic components of any transdermal delivery system include the drug(s) dissolved or dispersed in a reservoir or inert polymer matrix; an outer backing film of paper, plastic, or foil; and a pressure-sensitive adhesive that anchors the patch to the skin. The adhesive is covered by a release liner, which needs to be peeled off before applying the patch to the skin. Drugs administered via skin patches include scopolamine, nicotine, estrogen, nitroglycerin, and lidocaine (Table 2).
Dept of Pharmaceutics, KLE University, Belgaum
Chapter 1
Introduction
Non-medicated patch markets include thermal and cold patches, nutrient patches, skin care patches (a category that consists of two major sub-categories therapeutic and cosmetic), aroma patches, weight loss patches, and patches that measure sunlight exposure. Transdermal drug delivery has many advantages over conventional drug delivery and can be discussed as follows.
Advantages2, 3, 4, 5
1. They can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity, and drug interactions with food, drink, and other orally administered drugs. 2. They can substitute for oral administration of medication when that route is unsuitable, as with vomiting and diarrhea. 3. They avoid the first-pass effect, that is, the initial pass of s drug substance through the systemic and portal circulation following gastrointestinal absorption, possibly avoiding the deactivation by digestive and liver enzymes. 4. They are noninvasive, avoiding the inconvenience of parenteral therapy. 5. They provide extended therapy with a single application, improving compliance over other dosage forms requiring more frequent dose administration. 6. The activity of a drugs having s short half-life is extended through the reservoir of drug in the therapeutic delivery system and its controlled release. 7. Drug therapy may be terminated rapidly by removal of the application from the surface of the skin. 8. They are easily and rapidly identified in emergencies (e.g., unresponsive, unconscious, or comatose patient) because of their physical presence, features, and identifying markings.
Chapter 1 9. They are used for drugs with narrow therapeutic window.
Introduction
At the same time transdermal drug delivery has few disadvantages that are limiting the use of transdermal delivery. Disadvantages 3, 4, 6 1. Only relatively potent drugs are suitable candidates for transdermal delivery because of the natural limits of drug entry imposed by the skins impermeability. 2. Some patients develop contact dermatitis at the site of application from one or more of the system components, necessitating discontinuation. 3. The delivery system cannot be used for drugs requiring high blood levels. 4. The use of transdermal delivery may be uneconomic. For better understanding of transdermal drug delivery, the structure of skin should be briefly discussed along with penetration through skin and permeation pathways.
Structure of skin 1, 4, 7, 8
The skin, the heaviest single organ of the body, combines with the mucosal lining of the respiratory, digestive, and urogenital tracts to form a capsule which separates the internal body structures from external environment. For an average 70 kg human with skin surface area of 1.8 m2, a typical square centimeter covers 10 hair follicles, 12 nerves, 15 sebaceous glands, 100 sweat glands, and 3 blood vessels with 92 cm total length. The skin has several functions, which can be summarized as follows.
Functions of skin4, 9
1. Protection from invasion by microbes, chemicals, physical agents (e.g. mild trauma, UV light), and dehydration. 2. Reflex action due to sensory nerves to stimuli 3. Regulation of body temperature regulate body temperature about 36.8C (98.4F)
Chapter 1 with variation of 0.5C to 0.75C.
Introduction
4. Formation of vitamin D fatty substance present in skin, 7- dehydrocholesterol, in presence of UV light from sun is converted to vitamin D. 5. Absorption absorbs some drug with low molecular weight as well as toxic chemicals like mercury. 6. Excretion excretes sodium chloride in sweat, urea when kidney function is impaired, and aromatic substances (e.g. garlic and other spices) Now, its important to understand the detailed structure of skin so as to understand the concept related to permeation of drug.
Anatomy and Physiology7, 8

Human skin comprises of three distinct but mutually dependent tissues. A) The stratified, a vascular, cellular epidermis, B) Underlying dermis of connective tissues, and C) Hypodermis. 1. Epidermis The multilayered envelop of the epidermis varies in thickness, depending on cell size and number of cell layers, ranging from 0.8 mm on palms and soles down to 0.06 mm on the eyelids. Stratum corneum and the remainder of the epidermis so called viable epidermis cover a major area of skin.
Chapter 1
Introduction
Figure . 2: Structure of skin i) Stratum corneum This is the outermost layer of skin also called as horney layer. It is approximately 10mm thick when dry but swells to several times this thickness when fully hydrated. It contains 10 to 25 layers of parallel to the skin surface lying dead, keratinized cells, called corneocytes. It is flexible but relatively impermeable. The stratum corneum is the principal barrier for penetration. The barrier nature of the horney layer depends critically on its constituents: 75-80%proteins, 5-15%lipids, and5-10%ondansetron material on a dry weight basis. Protein fraction predominantly contains alpha-keratin (70%) with some beta keratin (10%) and cell envelope (5%). Lipid constituents vary with body site (neutral lipids, sphingolipids, polar lipids, cholesterol). Phospholipids are largely absent, a unique feature of mammalian membrane. The architecture of horney layer may be modeled as a wall-like structure.
Chapter 1
Introduction
In this model, the keratinized cells function as a protein bricks embedded in lipid mortar. The lipids are arranged in a multiple bi layers, and it has been suggested that there is sufficient amphipilic material in the lipid fraction, such as polar free fatty acids and cholesterol, to maintain a bi layer form. ii) Viable epidermis This is situated beneath the stratum corneum and varies in thickness from 0.06mm on the eyelids to 0.8mm on the palms. Going inwards, it consists of various layers as stratum lucidum, stratum granulosum, stratum spinosum, and the stratum basale. In the basale layer, mitosis of the cells constantly renews the epidermis and this proliferation compensates the loss of dead horney cells from the skin surface. As the cells produced by the basale layer move outward, they alter morphologically and histochemically, undergoing keratinization to form the outermost layer of stratum corneum. 1. Dermis Dermis is 3 to 5mm thick layer and is composed of a matrix of connective tissue, which contains blood vessels, lymph vessels, and nerves. The cutaneous blood supply has essential function in regulation of body temperature. It also provides nutrients and oxygen to the skin, while removing toxins and waste products. Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for most molecules penetrating the skin barrier. The blood supply thus keeps the dermal concentration of a permeate very low, and the resulting concentration difference across the epidermis provides the essential driving force for transdermal permeation.
Chapter 1 2. Hypodermis
Introduction
The hypodermis or subcutaneous fat tissue supports the dermis and epidermis. It serves as a fat storage area. This layer helps to regulate temperature, provides nutritional support and mechanic protection. It carries principal blood vessels and nerves to skin and may contain sensory pressure organs. For transdermal drug delivery drug has to penetrate through all these three layers and reach into systemic circulation while in case of topical drug delivery only penetration through stratum corneum is essential and then retention of drug in skin layers is desired.
Fundamentals of skin permeation9

Until the last century the skin was supposed to be impermeable with exception to gases. However, in the current century the study indicated the permeability to lipid soluble drugs like electrolytes. Also it was recognized that various layers of skin are not equally permeable i.e. epidermis is less permeable than dermis. After a large controversy, all doubts about stratum corneum permeability was removed and using isotopic tracers, it was suggested that stratum corneum greatly hamper permeation. A. Stratum corneum as skin permeation barrier The average human skin contains 40-70 hair follicles and 200-250 sweat ducts per square centimeter. Especially water-soluble substances pass faster through these ducts; still these ducts dont contribute much for skin permeation. Therefore, most neutral molecules pass through stratum corneum by passive diffusion. Thus, the stratum corneum acts as a passive, but not inert, diffusion medium. Series of steps in sequence: 1. Sorption of a penetrant molecule on surface layer of stratum corneum. 2. Diffusion through it and viable epidermis, and finally 3. The molecule is taken up into the microcirculation for systemic distribution.
Chapter 1
Introduction
Table 1: Regional variation in water permeability of stratum corneum Sr. No. 1 2 3 4 5 6 7 8 Abdomen Volar forearm Back Forehead Scrotum Back of hand Palm Plantar 15 16 10.5 13 5 49 400 600 Skin Region Thicknes (m) Permeation (mg/cm2/hr) 0.34 0.31 0.29 0.85 1.70 0.56 1.14 3.90 Diffusivity (cm2/sec x 1010) 6.0 5.9 3.5 12.9 7.4 32.3 535 930
Figure. 3: A multilayer skin model showing sequence of Transdermal permeation of drug for systemic delivery
Chapter 1 B. Intracellular verses transcellular diffusion
Introduction
Figure. 4: The microstructure of stratum corneum Intracellular regions in stratum corneum are filled with lipid rich amorphous material. In dry stratum corneum intracellular volume may be 5% to 1% in fully hydrated stratum corneum. C. Permeation pathways1.4 Percutaenous absorption involves passive diffusion of the substances through the skin. A molecule may use two diffusional routes to penetrate normal intact skin, the appendageal route and the epidermal route (Fig.5). 1. Appendageal route Appendageal route comprises transport via sweat glands and hair follicles with their associated sebaceous glands (shown as no.1&3 in fig.5). These routes circumvent penetration through the stratum corneum and are therefore known as shunt routes. This route is considered to be of minor importance because of its relatively small area, approximately 0.1 % of the total skin area.
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Chapter 1
Introduction
Figure. 5: Routes for drug permeation 2. Epidermal route (shown as no.2 in fig.5) For drugs, which mainly cross-intact horney layer, two potential micro routes of entry exists, the transcellular (intracellular) and intercellular pathways. (Fig.6)
Fig. 6: Epidermal routes for drug permeation
i) TranscellularDept of Pharmaceutics, KLE University, Belgaum 11
Chapter 1
Introduction
Transcellular pathway means transport of molecules across epithelial cellular membrane. These include passive transport of small molecules, active transport of ionic and polar compounds, and endocytosis and transcytosis of macromolecules. ii) ParacellularParacellular pathway means transport of molecules around or between the cells. Tight junctions or similar situations exist between the cells. The principal pathway taken by a permeant is decided mainly by the partition coefficient (log k). Hydrophilic drugs partition preferentially into the intracellular domains, whereas lipophilic permeants (o/w log k >2) traverse the stratum corneum via the intercellular route. Most permeants permeate the stratum corneum by both routes. However, the tortuous intercellular pathway is widely considered to provide the principal route and major barrier to the permeation of most drugs.
Factors influencing transdermal drug delivery4

The effective transdermal drug delivery can be formulated by considering three factors as Drug, Skin, and the vehicles. So the factors affecting can be divided in to classes as biological factors and physicochemical factors. A. Biological factors Skin condition Acids and alkalis; many solvents like chloroform, methanol damage the skin cells and promote penetration. Diseased state of patient alters the skin conditions. The intact skin is better barrier but the above mentioned conditions affect penetration. Skin age The young skin is more permeable than older. Children are more sensitive for skin absorption of toxins. Thus, skin age is one of the factors affecting penetration of drug in TDDSs.
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Chapter 1
Introduction
Blood supply Changes in peripheral circulation can affect transdermal absorption. Regional skin site Thickness of skin, nature of stratum corneum, and density of appendages vary site to site. These factors affect significantly penetration. Skin metabolism Skin metabolizes steroids, hormones, chemical carcinogens and some drugs. So skin metabolism determines efficacy of drug permeated through the skin. Species differences The skin thickness, density of appendages, and keratinization of skin vary species to species, so affects the penetration.
B. Physicochemical factors Skin hydration In contact with water the permeability of skin increases significantly. Hydration is most important factor increasing the permeation of skin. So use of humectants is done in transdermal delivery. Temperature and pH The permeation of drug increase ten folds with temperature variation. The diffusion coefficient decreases as temperature falls. Weak acids and weak bases dissociate depending on the pH and pKa or pKb values. The proportion of unionized drug determines the drug concentration in skin. Thus, temperature and pH are important factors affecting drug penetration. Diffusion coefficient Penetration of drug depends on diffusion coefficient of drug. At a constant temperature the diffusion coefficient of drug depends on properties of drug, diffusion medium and interaction between them. Drug concentration the flux is proportional to the concentration gradient across the barrier and concentration gradient will be higher if the concentration of drug will be more across the barrier.
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Chapter 1
Introduction
Partition coefficient The optimal K, partition coefficient is required for good action. Drugs with high K are not ready to leave the lipid portion of skin. Also, drugs with low K will not be permeated. Molecular size and shape Drug absorption is inversely related to molecular weight; small molecules penetrate faster than large ones. Because of partition coefficient domination, the effect of molecular size is not known. Ideal molecular properties for transdermal delivery4, 6 From the above considerations we can conclude with some observations that can be termed as ideal molecular properties for drug penetration. They are as follows. The partition coefficient will be high if the molecular weight is less than 600 daltons. An adequate solubility in lipid and water is necessary for better penetration of drug. (1mg/ml) Optimum partition coefficient is required for good therapeutic action Low melting point of drug is desired. (<200C) The pH of the saturated solution should be in between 5 to 9. The potent drug with dose of 10-15 mg/day is desired.
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Chapter 1
Introduction
Penetration Enhancers3, 4
Figure. 7: Action of penetration enhancers If the skin absorbs high concentrations of organic solvents such as DMSO, ethanol, or propylene glycol, the resulting medium (skin/solvent) may have an increased partition coefficient for the therapeutic agent of interest. Chemical enhancers By definition, a chemical skin permeation enhancer increases skin permeability by reversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance. Among the alterations are increase in hydration of stratum corneum, a change in the structure of the lipids and lipoproteins in the intracellular channels through the solvent action or denaturation, or both. Some drugs have inherent capacity to permeate the skin without chemical enhancers. However when this is not case, chemical permeation enhancers are useful in transdermal drug delivery. More than 275 chemical compounds have been cited in the literature as skin penetration enhancers; they include acetone, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide (DMSO), ethanol, oleic acid, propylene glycol, and polyethylene glycol and sodium lauryl sulphate.
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Chapter 1
Introduction
The selection of a permeation enhancer should be based not only on its efficacy in enhancing skin permeation but also on its physicochemical and biologic compatibility with the systems other components. Methods are provided for enhancing the permeability of skin or mucosal tissue to topical or transdermal application of local anesthetic agents minimizing the skin damage, irritation or sensitization. The permeation enhancer can be an inorganic or organic base10. The possibility of applying a highly lipophilic drug, the anti estrogen AE (log P=5.82), transdermally by polyacrylate-based matrix TDS was checked and in-vitro release as well as in-vitro permeation of AE through excised skin of hairless mice was found to be independent of concentrations of both drug and enhancers. Therefore, the permeation of this highly lipophilic drug seems to be limited by the stratum corneum barrier function. In contrast, the transdermal permeation of the enhancers was dependent on the TDS composition. Increase in enhancer content resulted in a higher permeation of enhancers, whereas skin pretreatment did not11. The synthesis of alkyldisiloxanes containing sugar moiety with various alkyl chain lengths was developed a penetration enhancer, which was expected to show a low irritation to the skin12. Iontophoresis and Sonophoresis In addition to chemical means, some physical methods are being used to enhance transdermal drug delivery and penetration, as, iontophoresis and sonophoresis. Iontophoresis is delivery of charged chemical compound across the skin membrane using electrical field. A number of drugs have been the subjects of iontophoretic studies; they include Lidocaine, Dexamethasone, amino acids, peptides
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Chapter 1
Introduction
and insulin, verapamil and propranolol. There is particular interest to develop alternative routes for biologically active peptides. At present peptides are delivered by injection because of their rapid metabolism and poor absorption after oral delivery. They are poorly absorbed by transdermal route because of large molecular size an ionic character and general impermeability of the skin. However, iontophoresisenhanced transdermal drug delivery has shown some promise as a mean of peptide and protein administration. Sonophoresis, or high frequency ultrasound, is also being studied as a means to enhance transdermal drug delivery. Among the agents examined are hydrocortisone, Lidocaine, and salicylic acid in formulations such as gels, creams, and lotions. It is thought that high frequency ultrasound can influence the integrity of the stratum corneum and thus affects its permeability. The transfer of sotalol and salicylate was measured varying the salt (NaCl) concentration in the donor and receiver compartments. It appears that osmotic pressure and ion exchange make a significant contribution to the flux enhancement by the diffusion potential13. Iontophoresis and enhancers were performed to enhance percutaneous absorption of enoxacin so as to compare the enhancement between these two enhancing methods. The cationic surfactant of benzalkonium chloride showed the highest enhancing activity for enoxacin for all pH values of buffer vehicles. The enhancement factor of sodium lauryl sulfate showed a dose-dependent property between the ranges of 0.1% to 3.0% concentration. Nonionic surfactant of Polysorbate 80 did not exhibit any enhancing effect on the percutaneous absorption of enoxacin. The highest enhancement factor of iontophoretic delivery was observed at pH 5.0 solutions of anodal iontophoresis for cationic enoxacin. The cathodal iontophoresis of
17
Chapter 1
Introduction
negative molecules and anodal iontophoresis of neutral molecules showed lower enhancing effect for enoxacin. The skin residuals of enoxacin after iontophoresis showed both tremendous and current density-dependent amounts for cationic enoxacin. This suggested local skin and soft tissue infections might be treated by this physical enhancement method. Combination of benzalkonium chloride and iontophoresis exerted a synergistic effect for anionic enoxacin in pH 10.0, which was possibly due to the shielding of negative charge in skin and the water molecules carried by chloride14. The effect of current, its magnitude and penetration enhancers (propylene glycol/oleic acid) on the transdermal flux of AZT (Zidovudine) across hairless mouse skin was studied and the results were compared. The in vitro iontophoretic flux from AZT solution increased to about 5-40 fold that obtained by passive diffusion, depending on the magnitude of current density. When the donor side was karaya gum matrix, instead of solution, the flux enhancement effect by iontophoresis was much smaller. Incorporation of penetration enhancers into the matrix increased the passive flux 2-50 fold, depending on the amount of penetration enhancers in the matrix. These enhancers worked synergistically with iontophoresis in the transdermal transport: a much larger flux than that expected from a simple additive effect was observed. Electrical resistance data from our previous work is utilized to further discuss this synergistic effect15. The effect of various liposome formulations on the iontophoretic transport of enoxacin through excised rat skin was studied16. The effect of terpenes/Ethyl alcohol combination in comparison to Ethyl alcohol and neat terpene on transdermal iontophoretic permeation of insulin was done and found higher than the individual effect17.
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Chapter 1 Electroporation
Introduction
Skin electroporation has recently been shown to increase transdermal transport of small-size drugs as well as considerably larger molecules by up to 4 orders of magnitude in vitro. Nevertheless, no in vivo studies have proven that high-voltage pulses can induce therapeutic plasma levels of drug. Thus, the study of the potential of skin electroporation in transdermal delivery of fentanyl was done in vivo18. The transdermal transport of timolol through human stratum corneum was studied in three compartment diffusion cells. The electrodes, buffer composition and pulse conditions were optimized to study the effect of skin electroporation to achieve therapeutic fluxes of timolol. Electroporation enhanced the transdermal transport of timolol by 1-2 orders of magnitude as compared to passive diffusion. Therapeutic fluxes of timolol (>50 microg/cm2/h) through human stratum corneum were achieved by electroporation19. Oral delivery of buprenorphine, a synthetic opiate analgesic, is less efficient due to low absorption and large first-pass metabolism. While transdermal delivery of buprenorphine is expected to avoid the first-pass effect and thereby be more bioavailable, use of electrical enhancement i.e. the electrically assisted transdermal delivery of buprenorphine could provide better programmability20.
Technologies for developing transdermal drug delivery systems1, 9

The technologies can be classified in four basic approaches. A Polymer membrane partition-controlled TDD systems: In this type of systems, the drug reservoir is sandwiched between a drugimpermeable backing laminate and a rate controlling polymeric membrane. (Fig.8)
19
Chapter 1
Introduction
Figure. 8: Cross-sectional view of polymer membrane permeation-controlled TDD systems The drug is allowed to permeate only through the rate controlling membrane. The drug solids are homogeneously dispersed in a solid polymer matrix, suspended in an unleachable, viscous liquid medium e.g. silicone fluid, to form a paste like suspension, or dissolved in a releasable solvent e.g. alkyl alcohol, to form a clear drug solution. The rate controlling membrane can be either a microporous or a nonporous polymeric membrane e.g. ethylene-vinyl acetate copolymer, with specific drug permeability. On the external surface of the polymeric membrane a thin layer of drugcompatible, hypoallergenic pressure sensitive adhesive polymer e.g. silicone adhesive, may be applied to provide intimate contact of TDD system with the skin surface. Varying the composition of drug reservoir formulation and the permeability coefficient and thickness of rate controlling membrane can alter the drug release rate. E.g. Some FDA approved systems Transderm-Nitro for angina pectoris, TransdermScop for motion sickness, Catapres-TTS system for hypertension. The intrinsic rate of drug release from this type of TDD system is defined by
20
Chapter 1 where, CR is drug concentration in reservoir compartment;
Introduction
Km / r the partition coefficient for the interfacial partitioning of drug from the reservoir to the membrane Ka / m the partition coefficient for the interfacial partitioning of drug from membrane to adhesive Da diffusion coefficient in rate controlling membrane Dm diffusion coefficient in adhesive layer ha thickness of rate controlling membrane hm thickness of adhesive layer B Polymer matrix diffusion-controlled TDD systems In this system, the drug reservoir is formed by homogeneously dispersing the drug solids in a hydrophilic or lipophilic polymer matrix, and then the medicated polymer formed is molded into medicated disks with defined surface area and thickness. This drug reservoir containing polymer disk is then mounted on occlusive base plate in a compartment fabricated from a drug-impermeable plastic backing. Instead of coating adhesive polymer directly on the surface of medicated disk, it is applied along the circumference of the patch to form a strip of adhesive rim surrounding the medicated disk. E.g. Nitro-Dur system and NTS system for angina pectoris.
21
Chapter 1
Introduction
Figure. 9: Cross-sectional view of polymer matrix diffusion-controlled TDD systems. The rate of release from polymer matrix drug dispersion-type is
Where, Ld is drug loading dose initially dispersed in polymer matrix CP is solubility of drug in polymer matrix DP is diffusivity of drug in polymer matrix Only drug is dissolved in polymer matrix can release, CP is practically equal to CR. Alternately, the polymer matrix drug dispersion-type TDD system can be fabricated by directly dispersing drug in a pressure-sensitive adhesive polymer, e.g. polyacrylate, and then coating the drug-dispersed adhesive polymer by solvent casting or hot melt onto a flat sheet of a drug-impermeable backing laminate to form a single layer of drug reservoir.this yields a thinner patch. E.g. Minitran system, Nitro-Dur II system for angina pectoris.
C. Drug reservoir gradient-controlled TDD systems: Polymer matrix drug dispersion-type TDD systems can be modified to have the drug loading level varied in an incremental manner, forming a gradient of drug reservoir along the diffusional path across the multi laminate adhesive layers. The drug release from this type of drug reservoir gradient- controlled TDD systems can be expressed by
22
Chapter 1
Introduction
In this system the thickness of diffusional path through which drug molecules diffuse increases with time, i.e. ha (t). The drug loading level in the multi laminate adhesive layer is designed to increase proportionally i.e. Ld (ha) so as to compensate time dependent increase n diffusional path as a result of drug depletion due to release. Thus, theoretically this should increase a more constant drug release profile. E.g. Deponit system containing nitroglycerine for angina pectoris.
Figure. 10: Cross-sectional view of a drug reservoir gradient-controlled TDD system.
D. Microreservoir dissolution-controlled TDD systems: A hybrid of reservoir- and matrix dispersion-type drug delivery systems, which contains dug reservoir formed by first suspending the drug solids in an aqueous solution of water-miscible drug solubilizer e.g. propylene glycol, then homogeneously dispersing the drug suspension, with controlled aqueous solubility, in a lipophilic
23
Chapter 1
Introduction
polymer, by high shear mechanical force, to form thousands of unleachable microscopic drug reservoirs.
Figure. 11 : Cross-sectional view of a drug microreservoir dissolution-controlled TDD system. E.g. Nitrodisk system for angina pectoris. The rate of drug release from this system is defined by
Components of a Transdermal Patch3

The main components to a transdermal patch are: 1. Release Liner Protects the patch during storage. The liner is removed prior to use. 2. Drug reservoir The most important part of TDDS is drug reservoir. It consists of drug particles dissolved or dispersed in the matrix.
24
Chapter 1
Introduction
To make the drug soluble, use of solvents and co solvents is done. The effect of solvent and co solvent should be considered while doing selection. The effect of various vehicles on the in vitro permeation of melatonin across porcine skin. Flux values of melatonin with Labrasol, propylene glycol and mineral oil were significantly lower than that of water (P<0.001). In general, vehicles with high melatonin solubility showed low permeability coefficient values. The flux had no correlation to the solubility data, suggesting that high solubility values do not translate to high drug permeation21. 3. Adhesive Serves to adhere the components of the patch together along with adhering the patch to the skin. The adhesive must posses sufficient adhesion property so that the TDDS should remain in place for a long time. Pressure sensitive adhesives are commonly used for transdermal patch to hold the skin. Commonly used adhesives are silicone adhesives, poly iso butylenes adhesives, and poly acrylate based adhesives. 4. Membrane Membrane controls the release of the drug from the reservoir and multi-layer patches. It may or may not contain rate-controlling membrane. It should be flexible enough not to split or crack on bending or stretching. Some of rate-controlling membranes are polyethylene sheets, ethylene vinyl acetate co-polymer, and cellulose acetate. 5. Backing Protects the patch from the outer environment. The backing layer should be impermeable to drug and penetration enhancers. It serves a function of holding the entire system and protects drug reservoir from atmosphere. The commonly used backing materials are polyesters, aluminized polyethylene terepthalate, and siliconized polyethylene terepthhalate.
25
Chapter 1
Introduction
General clinical considerations in the use of TDDS3

The patient should be advised of the following general guidelines. The patient should be advised of the importance of using the recommended site and rotating locations within the site. Rotating locations is important to allow the skin to regain its normal permeability and to prevent skin irritation. 1. TDDSs should be applied to clean, dry skin relatively free of hair and not oily, inflamed, irritated, broken, or callused. Wet or moist skin can accelerate drug permeation beyond ondansetron time. Oily skin can impair the adhesion of patch. If
hair is present at the site, it should be carefully cut, not wet shaved, nor should a depilatory agent be used, since later can remove stratum corneum and affect the rate and extent of drug permeation. 2. Use of skin lotion should be avoided at the application site, because lotions affect the hydration of skin and can alter partition coefficient of drug. 3. Cutting should not physically alter TDDSs, since this destroys integrity of the system. 4. The protecting backing should be removed with care not to touch fingertips. The TDDS should be pressed firmly against skin site with the heel of hand for about 10 seconds.
26
Chapter 1
Introduction
Table. 2: Examples of marketed transdermal drug delivery system3 Sr. No. 1. 2. 3. 4. 5. 6. Clonidine Estradiol Fentanyl Nicotine Testosterone Nicotine Catapres-TTS (Boehringer Ingelheim) Vivelle (Novartis) Duragesic (Janssen) Prosstep (Lederie) Testoderm (Alza) Habitrol (Novartis Consumer) Nicoderm CQ (Smithkline Beecham 7. Nicotine Consumer) 8. Nitroglycerine Transderm-Nitro (Novartis) Transderm-Scop 9. Scopolamine (Novartis Consumer) Therapeutic agent Marketed name (company)
27
Chapter 2
Objective of Study
OBJECTIVE OF STUDY
At present, the most common form of delivery of drugs is the oral route. While this has the notable advantage of easy administration, it also has significant drawbacks namely poor bioavailability due to hepatic metabolism (first pass) and the tendency to produce rapid blood level spikes (both high and low), leading to a need for high and/or frequent dosing, which can be both cost prohibitive and inconvenient. To overcome these difficulties there is a need for the development of new drug delivery system; which will improve the therapeutic efficacy and safety of drugs by more precise (i.e. site specific), spatial and temporal placement within the body thereby reducing both the size and number of doses. One of the methods most often utilized has been transdermal drug delivery meaning transport of therapeutic substances through the skin for systemic effect. Closely related is percutaneous delivery, which is transport into target tissues, with an attempt to avoid systemic effects. Ondansetron Hcl is an anti nauseant and antiemetic agent indicated for the prevention of nausea and vomiting associated with moderately-emetogenic cancer chemotherapy and for the prevention of postoperative nausea and vomiting. The chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine, and that the released serotonin then activates 5-HT3 receptors located on vagal efferents to initiate the vomiting reflex. Therefore Ondansetron HCl works by blocking the reception of serotonin at these 5-HT3 receptors.
28
Chapter 2
Objective of Study
Ondansetron HCl has the half-life of 5-6 hours. Its total bioavailability in the body is 60% due to first pass metabolism. The total dose of Ondansetron HCl is 24mg daily. Transdermal administration of drugs that undergo first pass metabolism can improve the bioavailability and reduce the dosing frequency compared with the oral route. A number of drug molecules have been developed in the transdermal drug delivery system. Some of the potential advantages of transdermal drug delivery system include: Avoidance of the first pass metabolism Elimination of gastrointestinal irritation Reduce dosing frequency Rapid termination of the drug action
Hence in present work, an attempt is been made to provide a transdermal drug delivery system using water soluble and water insoluble polymers with model drug as Ondansetron HCl. Objective of the Study: Preparation of matrix transdermal patches by using combination of appropriate polymers. To study the effect of varying concentration of polymers on in vitro drug release.
29
Chapter 2
Objective of Study
To study the effect of permeation enhancers on in vitro drug release. Characterization of prepared matrix transdermal patches for the following parameters. A. Thickness Using screw gauge. B. Weight variation By using digital weighing balance C. Drug content uniformity By using ultraviolet spectrophotometer D. Tensile strength Using pulley system E. % Elongation Using pulley system F. Folding endurance Using appropriate method suggested in the article G. Moisture content Using dessicator and digital weighing balance H. In-vitro drug permeation study Using Keshary-chein diffusion cell
30
Chapter 3
Review of Literature
DRUG PROFILE
Ondansetron Hydrochloride Dihydrate22 Proprietary name: Zofran; Zophren. IUPAC Name: 1,2,3,9-Tetrahydro9methyl3-[(2methyl1H-imidazol1
yl)methyl] 4Hcarbazol 4one hydrochloride dehydrate Molecular formula: C18H19N3O,HCl,2H2O Molecular weight: 365.9 CAS No 99614014 Structure:
Description A white crystalline solid from water/isopropanol with m.p. 178.5 to 179.5. It is soluble in aqueous solutions but solubility decreases with pH >5.7. Dissociation Constant. Hydrochloride dihydrate; pKa7.4. Ultraviolet Spectrum. Aqueous acid (pH 2.8)210, 248, 266, 310 nm.
Dept. Of Pharmaceutics, KLE University, Belgaum
31
Chapter 3
Standard UV visible Spectrum of Ondansetron HCl Mass Spectrum Principal ions at m/z: 96, 293, 198, 211, 143, 183, 55, 115.
Standard mass spectrum of Ondansteron HCl Bioavailability 60% (young healthy subjects), 65% (elderly); 85% (patients with cancer) and 100% (severe hepatic impairment). Halflife 3 h (young healthy subjects), 5 h (elderly) and 15 to 32 h (severe hepatic impairment). Volume of distribution Approx. 140 to 160 L; also reported as 1.3 to 2.9 L/kg. 3.05 L/kg (mild liver disease); 3.36 L/kg (moderate); 3.86 L/kg (severe); 2.5 L/kg (healthy individuals).
32
Chapter 3 Clearance
16.6 L/h (patients with mild liver disease); 15.9 L/h (moderate liver disease); 11.6 L/h (severe); 28.3 L/h (healthy volunteers). Distribution in blood Blood:plasma ratio is 0.83. It distributes into erythrocytes and circulates bound within. Protein binding 70 to 75%. Dose Adult: 8 mg (orally) before treatment followed by 8 mg every 12 h. 16 mg daily (by rectum administration) or 32 mg (intravenously). Children: 5 mg/m2 (intravenously) immediately before treatment and then 4 mg orally every 12 h. Alternatively, 100 g/kg (maximum 4 mg) (over 2 years old). Uses and Administration Ondansetron is a 5-HT3 antagonist (5-HT3-receptor antagonist) with antiemetic activity. It is used in the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy. It is also used for the prevention and treatment of postoperative nausea and vomiting. For the management of nausea and vomiting, and the important role of 5-HT3 antagonists. Ondansetron is given by intramuscular or slow intravenous injection as the hydrochloride, by mouth as the hydrochloride or base, or rectally as the base. Doses are expressed in terms of the base. Ondansetron hydrochloride 4.99 mg is approximately equivalent to 4 mg of ondansetron base.
33
Chapter 3
For highly emetogenic chemotherapy the following dose schedules appear to be equally effective in preventing acute emesis: a single dose of 8 mg by slow intravenous or intramuscular injection immediately before treatment or 8 mg by slow intravenous or intramuscular injection immediately before treatment, either followed by a continuous intravenous infusion of 1 mg/hour for up to 24 hours, or by a further two doses of 8 mg two to four hours apart or a single dose of 32 mg given by intravenous infusion over at least 15 minutes immediately before treatment or a 16-mg suppository rectally, given 1 to 2 hours before treatment The efficacy of ondansetron in highly emetogenic chemotherapy may be enhanced by intravenous administration of dexamethasone sodium phosphate 20 mg before chemotherapy. For preventing acute emesis with less emetogenic chemotherapy and radiotherapy: 8 mg may be given as a slow intravenous or intramuscular injection immediately before treatment or 16 mg rectally can be given 1 to 2 hours before treatment or 8 mg can be given by mouth 1 to 2 hours before treatment followed by 8 mg 12 hours later. Drug class Antiemetic
34
Chapter 3
Polymer Profile23 Ethyl Cellulose:

Nonproprietary Names BP: Ethylcellulose PhEur: Ethylcellulosum USPNF: Ethylcellulose Synonyms Aquacoat ECD; Aqualon; Ethocel; Surelease. Structure
Molecular formula (C12H23O5)n CAS Registry Number: 9004-57-3 Functional Category: Coating agent; flavoring fixatives; tablet binder; tablet filler; viscosity-increasing agent. Applications in Pharmaceutical Formulation or Technology Ethyl cellulose is widely used in oral and topical pharmaceutical formulations. Ethyl cellulose coatings are used to modify the release of a drug, to mask an unpleasant
35
Chapter 3
taste, or to improve the stability of a formulation. Ethyl cellulose, dissolved in an organic solvent or solvent mixture, can be used on its own to produce water-insoluble films. Higher-viscosity ethyl cellulose grades tend to produce stronger and more durable films. Ethyl cellulose films may be modified to alter their solubility, by the addition of hypromellose or a plasticizer. Ethyl cellulose has also been used as an agent for delivering therapeutics agents from oral appliances. In topical formulations, ethyl cellulose is used as a thickening agent in creams, lotions, or gels, provided an appropriate solvent is used. Description Ethyl cellulose is a tasteless, free-flowing, white to light tan-coloured powder. Typical Properties Density (Bulk): 0.4 g/cm3 Moisture content: ethyl cellulose absorbs very little water from humid air or during immersion, and that small amount evaporates readily. Solubility: ethyl cellulose is practically insoluble in water, propylene glycol, and glycerin. Ethyl cellulose that contains less than 46.5% of ethoxyl groups is freely soluble in chloroform, methyl acetate, and tetrahydrofuran, and in mixtures of aromatic hydrocarbons with ethanol (95%). Specific Gravity: 1.12-1.15 g/cm3 Viscosity: the viscosity of ethyl cellulose is measured typically at 25C using 5%v/v ethyl cellulose dissolved in a solvent blend of 80% toluene: 20% ethanol. The Viscosity of an ethyl
36
Chapter 3
cellulose solution increases with an increase in ethyl cellulose concentration; e.g., the viscosity of a 5% w/v solution of Ethocel standard 10 premiums is 9 11 mPa s. In addition, no pharmaceutical grades of ethyl cellulose that differ in their ethoxyl content and degree of polymerization are available. Stability and Storage Conditions Ethyl cellulose is a stable, slightly hygroscopic material. It is chemically resistant to alkalis, both dilute and concentrated, and to salt solutions, although it is more sensitive to acidic materials than are cellulose esters. Ethyl cellulose should be stored at a temperature not exceeding 32C in a dry area from all sources of heat. It should not be stored next to peroxides or other oxidizing agents.
37
Chapter 3
Poly Vinyl Pyrrolidone

Nonproprietary Names: BP: povidone JP: povidone PhEur: polyvidonum USP: povidone Synonyms: E1201:kollidon; plasdone; poly[1-(2-oxo-1-poyrrolidinyl)ethylene]; Polyvidone; polyvinyl pyrrolidone;PVP; 1-vinyl 2-pyrrolidinone polymers. Chemical Name: 1-ethenyl-2-pyrrolidinone homopolymer Empirical Formula: (c6H9NO)n Molecular Weight: 2500-3000000 Functional Category: Disintegrant; dissolution aid; suspending agent; tablet binder. Description: Povidone occurs as a fine, white to creamy-white colored, and almost odorless, hygroscopic powder. Povidone with K values equal to (or) lower than 30 are manufactured by spray-drying and exist as spheres. Povidone with K-90 and higher K-values povidones are manufactured by drum drying and exist as plates. Typical properties: Acidity/alkalinity : pH=3.0-7.0(s%w/v aqueous solution) Denstiy(bulk) : 0.409g/cm3 Density(tapped) : 0.508g/cm3 Density(true) : 1.180g/cm3
38
Chapter 3 Flow ability: 20g/s for povidone k-15, 16g/s for povidone k-29/32, Melting point: softens at 150 c
Moisture content: povidone is very hygroscopic, significant amounts of moisture being absorbed at low relative humilities. Particle size distribution: Kollidon 25/30:90% >50um, 50% >100um, 5% > 200um; kollidon 90: 90 % >200um, 95% >250um. Solubility: Freely soluble in acids, chloroform, ethanol(95%), ketones, methanol and water; practically insoluble in ether, hydrocarbons and mineral oil. In water, the
concentration of solution is limited Only by the viscosity of the resulting solution, which is a function of the K value. Viscosity (dynamic):The viscosity of aqueous povidone solution depends on both the concentration and the molecular weight of the polymer employed. Stability and storage conditions: Povidone darkens to some extend on heating at 150 c, with a reduction in aqueous solubility. It is stable to a short cycle of heat exposure around 110-130 c; steam sterilization of an aqueous solution does not alter its properties. Aqueous solution are susceptible to mold growth and consequently require the addition of suitable preservatives. Povidone may be stored under ordinary conditions without undergoing decomposition or degradation. However, since the powder is hygroscopic, it should be stored in an airtight container in a cool and dry place.
39
Chapter 3 Incompatibilities:
Povidone is compatible in solution with a wide range of inorganic salts, natural and synthetic resins and other chemicals. It forms molecular adduct in solution with sulfathiazole, compounds. Safety: Povidone is widely used as a excipient, particularly in oral tablets and solutions. When consumed orally, povidone may be regarded as essentially nontoxic since it is not absorbed from the gastrointestinal tract or mucous membranes. Povidone additionally has no irritant effect on the skin and cause no sensitization. Comments: the molecular adduct formation properties of povidone may be used advantageously in solution, slow release solid-dosage forms, and parenteral formulation. Perhaps the best-known example of povidone complex formation is povidone-iodine, which is used as topical disinfectant. Application in pharmaceutical formulation or technology: In tableting, pvp solutions are used as binder in wet-granulation processes. It is used as a solubilizer in oral and parenteral formulation and has been shown to forms. It may also be used as coating agent. It is usedas suspending, stabilizing or viscocity-increasing agent in a number of topical and oral suspension and solution. (10-25%) (5%) (2-10%) (5%) enhance dissolution of poorly soluble drugs from solid-dosage sodium salicylate, salicylic acid, Phenobarbital, tannin and other
Used as: carrier for drug Dispersing agent Eye drops Suspending agent
40
Chapter 3
Polymethacrylates:
Synonyms: Eudragit Functional category: Film former, binder Chemical names: Copolymers synthesized from dimethylaminoethyl methacrylate and other neutral methacrylate esters. CAS registry number: none Molecular weight: 100,000 Description: Eudragit RL is a co-polymer of acrylic and methacrylic acid esters containing ammonium groups, available as 12.5% ready to use solution in isopropanol and acetone (60:40). Colorless, clear to cloudy granules with a faint amine like odour. Density: 12.5;0.825 g/cm3 Solubility: Soluble in isopropanol and ethanol in combination with acetone or methacrylate chloride, also in methanol, chloroform and glycerol monethyl ether. Insoluble in petroleum ether or light petroleum. Viscosity: 5 to 15 cps. Stability and storage conditions: Dry powder forms appear to be stable at room temperature. Dispersions are stable for about 1 year after manufacturing and stored at room temperature in tight containers.
Dept. Of Pharmaceutics, KLE University, Belgaum 41
Chapter 3 Incompatibilities:
Incompatibilities occur with acid and/or alkaline conditions depending upon which polymer is being used. Applications: Binder Eudragit E (concentration between 5 and 20%) Film former: Eudragit forms water insoluble film coats for delayed release products.
42
Chapter 3
Polyvinyl alcohol
Nonproprietary Names PhEur: Poly(vinylis acetas) USP: Polyvinyl alcohol Synonyms Airvol; Alcotex; Elvanol; Gelvatol; Gohsenol; Lemol; Mowiol; Polyvinol; PVA; vinyl alcohol polymer. Chemical Name and CAS Registry Number Ethenol, homopolymer [9002-89-5] Empirical Formula and Molecular Weight (C2H4O)n, 20 000200 000. Structural Formula
Functional Category Coating agent; lubricant; stabilizing agent; viscosity-increasing agent. Applications in Pharmaceutical Formulation or Technology Polyvinyl alcohol is used primarily in topical pharmaceutical and ophthalmic formulations. Use Emulsions Ophthalmic formulations Topical lotions Concentration (%) 0.5 0.253.00 2.5
43
Chapter 3 Description
Polyvinyl alcohol occurs as an odorless, white to cream-colored granular powder. Typical Properties Melting point: 228C for fully hydrolyzed grades; 180190C for partially hydrolyzed grades. Solubility: Soluble in water; slightly soluble in ethanol (95%); insoluble in organic solvents. Dissolution requires dispersion (wetting) of the solid in water at room temperature followed by heating the mixture to about 90C for approximately 5 minutes. Mixing should be continued while the heated solution is cooled to room temperature. Stability and Storage Conditions Polyvinyl alcohol is stable when stored in a tightly sealed container in a cool, dry place. Aqueous solutions are stable in corrosion-resistant sealed containers. Preservatives may be added to the solution if extended storage is required. Polyvinyl alcohol undergoes slow degradation at 100C and rapid degradation at 200C; it is stable on exposure to light. Incompatibilities Polyvinyl alcohol undergoes reactions typical of a compound with secondary hydroxy groups, such as esterification. It decomposes in strong acids, and softens or dissolves in weak acids and alkalis. It is incompatible at high concentration with inorganic salts, especially sulfates and phosphates; precipitation of polyvinyl alcohol 5% w/v can be caused by phosphates. Gelling of polyvinyl alcohol solution may occur if borax is present.
44
Chapter 3
Plasticizer review Di butyl phthalate24

Synonyms: butyl phthalate; DBP Structure:
Chemical name: Dibutyl benzene 1,2-dicarboxylate Empirical formulation: Molecular weight: Description: Density: Boiling point: Refractive index: C16H22O4 278.3 A clear, colorless some what viscous 1.045 g/cm3 at 20c 3300 1.492-1.495
Solubility: very soluble in ethanol, ether acetone, benzene, miscible with ethanol ether and most other organic solvents.
45
Chapter 3
Propylene Glycol
Nonproprietary Names BP: Propylene Glycol JP: Propylene Glycol PhEur: PropylenGlycolum USP: Propylene Glycol Synonyms 1,2 Dihydroxypropane; E1520; 2-hydroxypropranol; methyl ethylene glycol; propane-1, 2-diol. Chemical Name and CAS Registry Number 1,2- propanediol [57-55-6] (-)-1,2- propanediol [4254-14-2] (+)-1,2- propanediol [4254-15-3] Empirical Formula:C3 H8 O2 Molecular Weight: 76.08 Structure:
Functional Category Antimicrobial preservatives; disinfectant; humectant; plactisizer; solvent; stabilizer for vitamins; water-miscible co-solvent.
46
Chapter 3 Applications in Pharmaceutical Formulation or Technology
Propylene Glycol has become widely used as solvent, extractant, and preservative in a variety of parenteral pharmaceutical formulations. It is a better solvent than glycerin and dissolves a wide variety of materials, such as corticosteroids, phenols, sulfa drugs, barbiturates, vitamins (A and D), mostly alkaloids, and many local anesthetics. As an antiseptic it is similar to ethanol, and against molds it is similar to glycerin and only slightly less effective than ethanol. Propylene Glycol is commonly used as a plasticizer in aqueous film-coating formulations. Propylene Glycol is also used in cosmetics and in the food industry as a carrier for emulsifiers and as a vehicle for flavors in preference to ethanol, since its lack of volatility provides a more uniform flavor.
Description Propylene glycol is a clear, colorless, viscous, practically odorless liquid with a sweet, slightly acrid taste resembling that of glycerin. Typical Properties: Boiling point: 188C Density: 1.038 g/cm3 at 20C Melting point: -59C Osmolarity: a 2.0%v/v aqueous solution is iso-osmotic with serum. Refractive index: 1.4324 Solubility: miscible with acetone, chloroform, ethanol (95%), glycerin, and water; soluble at 1 in 6 parts of ether; not miscible with light mineral oil or fixed oils, but will dissolve some essential oils. Viscosity (dynamic): 58.1-mPa s (58.1 CP) at 20C.
47
Chapter 3 Stability and Storage Conditions:
At cool temperatures, propylene glycol is stable in a well-closed container, but at high temperatures, in the open, it tends to oxidize, giving rise to products such as propionaldehyde, lactic acid, pyruvic acid, and acetic acid. Propylene glycol is chemically stable when mixed with ethanol (95%), glycerin, or water; aqueous solutions may be protected from light, in a cool, dry place. Sterilized by autoclaving. Propylene glycol is hygroscopic and should be stored in a well-closed container.
48
Chapter 3
Permeation enhancers Oleic acid25

Synonyms: Structure: (9Z)-octadecenoic acid
CAS number: 112-80-1
Empirical formula: C18H34O2 Appearance formulation: pale yellow or oily liquid with lard-like odor
Density: 0.895 g/ mL Boling point: 3600c
Solubility: soluble in methanol, chloroform, insoluble in water.
Uses: Oleic acid may hinder the progression of ALD, or adrenoleukodystrophy, a fatal disease that affects the brain and adrenal glands.
Oleic acid is also the most abundant fatty acid in human adipose tissue.
49
Chapter 3
Review of work done on Drug

Gattani SG et al. formulated transdermal films of ondansetron HCl by using different hydrophilic and lipophilic polymers. In vitro results obtained showed that hydrophilic polymers had higher release than the lipophilic and hydrophilic-lipophilic combinations. Permeation enhancers like oleic acid, limonene were found to give favorable permeation enhancement26. H.S. Gwak, I.S. Oh and I.K. Chun found feasibility of developing an Ondansetron transdermal system using Duro-Tak 87-2100 and Duro-Tak 87-2196 as pressure sensitive adhesives (PSA). Effect of vehicles, propylene glycol monocaprylate (PGMC)-diethylene glycol monoethyl ether (DGME)-propylene glycol (PG) cosolvents with 3% oleic acid, was studied & found that DGME in PGMC-DGME cosolvent system decreased release rate as its concentration was increased. Also as amount of PSAs increased, the permeation flux was decreased. Overall fluxes from PSAs were significantly lower compared to those obtained from solution formulations. Lag time decreased significantly from 5.14 3.31 hr to 0.31 0.12 hr as PG increased from 40% to 60%27. H.S. Gwak, I.S. Oh and I.K. Chun studied effect of vehicles and penetration enhancers on transdermal delivery of Ondansetron across dorsal hairless mouse skin. Among vehicles used, water and ethanol showed high permeation fluxes as 48.2 23.7 & 41.9 17.9 g/cm2/hr. respectively. The highest flux was achieved at 40% of DGME combinations with PGMC & ethanol (80:20) and PGMC & PG (60:40) increased permeation by six- & two-fold respectively, compared to PGMC alone28.
50
Chapter 3
Review of Literature Review of work done on Polymers
Calpena A C, Blanes C, Moreno J, Obach R, Domenech J studied comparative in vitro study of transdermal absorption of antiemetics that was used in treatment of nauseas and their use in patients receiving oncogenic treatment with chemotherapy. They studied permeation parameters of antiemetics in order to predict their potential therapeutic formulation in TDD29. Agrawal SS et al. developed matrix type transdermal patches of atenolol and metoprolol using polymers like polyvinyl pyrrolidone, cellulose acetate phthalate, hydroxyl propyl methyl cellulose. The results obtained showed drug release from the formulation containing PVP and HPMC was for 48 hour and it caused no irritation on the skin30. Sankar V et al. investigated ethyl cellulose films for the permeation of the nifedipine drug through the film by using castor oil and glycerol as the plasticizers. It was found that the drug release from the patches containing the glycerol as the plasticizer was more than that from the one containing castor oil31. Gattani SG et al. investigated transdermal films of chlorpheniramine maleate using different polymer combinations and concluded that hydrophilic polymer showed higher release than the lipophilic and hydrophilic-lipophilic combination32. Manvi FV et al. Formulated transdermal films of ketotifen fumarate using combination of eudragit L100: hydroxypropylmethylcellulose and ethyl cellulose: hydroxypropylmethylcellulose as polymers along with permeation enhancers such as ethyl sulfoxide and propylene glycol. Polyethylene glycol was used as a plasticizer. It was found that there was decrease in drug release rate from EL100:HPMC films in comparison to EC:HPMC was found, due to the hydrophobic nature of the polymer33.
Dept. Of Pharmaceutics, KLE University, Belgaum 51
Chapter 3
Saxena M et al. prepared transdermal patches of metoclopramide hydrochloride using polyvinyl alcohol and polyvinylpyrrolidone. The combination of PVA:PVP in the ratio 1:4 containing 20 mg of drug showed the required sustained release effect34. Ubaidulla U et al. developed a matrix-type transdermal therapeutic system containing carvedilol with different ratios of hydrophilic and hydrophobic polymeric combinations by the solvent evaporation technique and reported that the developed transdermal patches increased the efficacy of carvedilol for the therapy of hypertension by using different polymer ratios35.
52
Chapter 4
Methodology
METHODOLOGY
Materials: The following materials of Pharma grade or the best possible Laboratory Reagent were used as supplied by the manufacturer. Table 3: List of chemicals used with grade and supplier Sr. No. 1. 2. 3. Ondansetron Hcl Polyvinyl Pyrrolidone Ethyl Cellulose Pharma Grade LR Pharma Grade Sun rise Pharma Hi-media pharma Colorcon Goa Evonik Pharma 4. Eudragit LR Germany 5. Chloroform LR Merck Ltd., Mumbai Ranbaxy fine chemicals 6. Oleic acid LR Ltd., New Delhi. Ranbaxy Fine 7. Dibutyl Phthalate LR Chemicals Ltd., New Delhi. Rankem, fine chemicals 8. Methanol LR Limited, Mumbai 9. Poly Vinyl Alcohol LR Hi-media pharma Materials Used Grade Manufacturer
53
Chapter 4 Table 4: List of Instruments used Sr. No. Instrument
Methodology
Manufacturer
Shimadzu Corporation, 1. Double beam UV Visible Spectrometer Japan. Spectrum one, Perkin 2. FTIR 200 Spectrometer Elmer, USA. Remi Equipments, 3. Magnetic Stirrer 2MLH Mumbai, India. Bhanu Scientific 4. Keshry diffusion cell Instruments Co., Bangalore. 5. Electronic Balance Petit Bhanu scientific 6. Distillation Assembly Instruments Co., Bangalore
54
Chapter 4 METHODS: Preformulation studies:
Methodology
Preformulation testing is the first step in the rationale development of dosage forms of a drug. It can be defined as an investigation of physical and chemical properties of drug substance, alone and when in combined with excipients. The overall objective of the preformulation testing is to generate information useful to the formulator in developing stable and bio availability dosage forms which can be mass produced. The goals of preformulation studies are: To establish the necessary physicochemical characteristics of a new drug substance. To determine its kinetic release rate profile. To establish its compatibility with different excipients. Hence, preformulation studies on the obtained sample of drug include colour, taste, solubility analysis, melting point determination and compatibility studies. Characterization of Ondansetron Hydrochloride: A. Melting point determination: The melting point of Ondansetron hydrochloride was determined by using melting point apparatus. B. Spectroscopic studies: a. IR spectrum interpretation: The infrared spectrum of the pure Ondansetron Hydrochloride sample was recorded and the spectral analysis was done. The dry sample of drug was directly placed after mixing and triturating with dry potassium bromide.
55
Chapter 4 b. UV spectroscopy36: I. Determination of max
Methodology
A 10mg of Ondansetron Hydrochloride was accurately weighed and was first dissolved in 35ml methanol solution. The solution was then diluted using phosphate buffer (pH- 7.4) to 100 ml. UV spectrum was recorded in the wavelength range 200600 nm. II. Preparation of calibration curve for Ondansetron hydrochloride A standard curve was prepared by dissolving 10 mg of Ondansetron hydrochloride in 50ml of methanol. It was further diluted with phosphate buffer pH 7.4 to get solutions in concentration range of 4 to 16 g /ml. The absorbances of these solutions were determined spectrophotometrically at 305 nm. C. Determination of solubility of ondansetron hydrochloride37 The ondansetron hydrochloride has very low aqueous solubility. Its solubility is not reported in any official book, so determination of solubility is important. The solubility was determined in distilled water and phosphate buffer pH 7.4. The procedure can be detailed as follows. Saturated solution of o Ondansetron hydrochloride prepared using 10 ml. of distilled water/ phosphate buffer pH 7.4 in 25 ml volumetric flasks in triplicate. Precaution was taken so that the drug remains in medium in excess. Then by using mechanical shaker, the flasks were shaken for 48 hours. The sampling was done on 24th & 48th hour. The sample withdrawn (1 ml after filtration) was diluted with appropriate medium and analyzed by using UV spectrophotometer at 305 nm and 303.5 nm for phosphate buffer and distilled water respectively.
56
Chapter 4 FORMULATION OF TRANSDERMAL PATCHES34, 35 Preparation of blank patches:
Methodology
Polymers of single or in combination were accurately weighed and dissolved in respective solvent and then casted in a Petri-dish with mercury as the plain surface. The films were allowed to dry overnight at room temperature. Formulation of Drug Incorporated Transdermal Patches: The matrix-type transdermal patches containing Ondansetron Hcl were prepared using different ratios of ethyl cellulose, Polyvinyl pryrrolidone, Eudragit and polyvinyl alcohol. The polymers in different ratios were dissolved in the respective solvents. Then the drug was added slowly in the polymeric solution and stirred on the magnetic stirrer to obtain a uniform solution. Di-n-butyl phthalate and propylene glycol were used as plasticizers. Oleic acid was used as the penetration enhancer. Then the solution was poured on the Petri dish having surface area of 78.5 cm2 and dried at the room temperature. Then the patches were cut into 2x2 cm2 patches. Drug incorporated for each 2x2 cm2 patch was 14.5 mg. the formulation table is given in table no. 5. Table 5: Formulation table of Ondansetron Hcl Patches Formulation Polymer Polymer Polymer Plasticizer Oleic Solvent acid PG (10%) PG (10%) DBP (5%) OND-4 7:3 DBP (5%) OND-5 8:2 DBP (5%) OND-6 5:5 DBP (5%) Dept of Pharmaceutics, KLE University, Belgaum 57 10% Chloroform 10% Chloroform 10% Acetone 10% 10% 10% Water Water Acetone
PVA:PVP RLPM:RSPM EC:PVP OND-1 OND-2 OND-3 5:5 3:7 5:5 -
Chapter 4 D. Evaluations of films a. Physical evaluations 1. Thickness39
Methodology
The thickness of films was measured by digital Vernier calipers with least count 0.001mm. The thickness uniformity was measured at five different sites and average of five readings was taken with standard deviation. 2. Moisture uptake35 The percent moisture absorption test was carried out to check the physical stability and integrity of the films at high humid conditions. In the present study the moisture absorption capacities of the films were determined in the following manner. The films were placed in the dessicator containing saturated solution of aluminium chloride, keeping the humidity inside the dessicator at 79.5 % R.H. After 3 days the films were taken and weighed the percentage moisture absorption of the films was found. 3. Tensile Strength40 The tensile strength was determined by the apparatus designed as shown in fig 13 . The instrument was designed such that it had horizontal wooden platform with fixed scale and attachments for two clips that holds transdermal patch under test. Out of the two clips one was fixed and other was movable. Weights were hanged to one end of pulley and the other end of pulley was attached with movable clip. The wooden platform was such fitted that it would not dislocate while the test is running. Three strips of patch were cut having 2cm length and 2cm breadth. The thickness and breadth of strips were noted at three sites and average value was taken for calculation. The rate of change of stress was kept constant with the increment of 0.5g per 2
58
Chapter 4
Methodology
minutes. The elongation was observed and the total weights taken were used for calculation. The tensile strength was calculated by using following formula.
where, S = tensile stress in 980 dynes/cm2 m = mass in grams g = acceleration due to gravity (980 dynes/cm2) b = breadth of strip in centimeters t = thickness of strip in centimeters The strain is change resulting in size of strip after the force was applied to its original size. Therefore, the strain can be given as,
Where, L = length after force was applied L0 = original length
59
Chapter 4
Methodology
Figure 12: Assembly for % elongation 4. Percent elongation The percent elongation at break was measured by formula given below.
where, L = length after force was applied L0 = original length 5. Folding endurance41 Using an apparatus designed in laboratory, folding endurance test for films was performed. The disintegration apparatus was modified as a folding endurance apparatus. The apparatus consists of two clamps for holding the film. Out of two clamps, one clamp was fixed while other was moving. The clamps were able to move 5cm distance from each other at speed of 30 rpm. The film was attached in such a way Dept of Pharmaceutics, KLE University, Belgaum 60
Chapter 4
Methodology
that when clamps were at maximum distance the film will be slightly stretched. The apparatus was put on and allowed to run until film broke into two pieces. The foldings were counted by rpm. 6. Drug content42 The patch of area 2x2 cm2 was cut and dissolved in distilled water. Then solvent ethanol and dichloromethane, to make polymer soluble, were added to the mixture and the remaining volume was made up with distilled water to 100ml in 100ml volumetric flask. Then 1 ml was withdrawn from the solution and diluted to 10ml. The absorbance of the solution was taken at 303.5nm and concentration was calculated. By correcting dilution factor, the drug content was calculated. 7. Weight variation34 The three disks of 2*2 cm2was cut and weighed on electronic balance for weight variation test. The test was done to check the uniformity of weight and thus check the batch- to- batch variation. D. Diffusion studies43 Preparation of skin A full thickness of skin was excised from dorsal site of dead rat and skin was washed with water. The fatty tissue layer was removed by using nails of fingers. The outer portion with hairs was applied with depilatory and allowed to dry. With the help of wet cotton the hairs were scrubbed and washed with normal saline solution. The skin was kept in normal saline solution in refrigerator until skin was used for diffusion study. Prior to use, the skin was allowed to equilibrate with room temperature. Then skin was mounted between donor and receptor compartment of cell. The skin was clamped in such a way that the dermal side will be in contact with receptor medium.
61
Chapter 4 Diffusion cell
Methodology
The diffusion studies were done to get an idea of permeation of drug through barrier from the transdermal system. In vitro studies are also done for TDDS development. Usually, two types of diffusion cells are used as horizontal and vertical. The Franz and Keshary Chien (K-C) type of diffusion cells are of horizontal type of cells. In this work, K-C type of diffusion cell was used. Diffusion cells generally comprise two compartments, one containing the active Compartment (donor compartment) and the other containing receptor solution (receptor compartment), separated by barrier i.e. rat abdominal skin. The cell consisted of sampling port and temperature maintaining jacket. The outlet and inlet was connected with latex tube so the jacket had stagnant water inside and heat was provided by hot plate. The stainless steel pin was used to stir the receptor solution using magnetic stirrer. The rat abdominal skin was placed on receptor compartment and both compartments held tight by clamps.
Figure 13: Kesary Chein diffusion cell Dept of Pharmaceutics, KLE University, Belgaum 62
Chapter 4 Method
Methodology
Phosphate buffer pH 7.4 was used as receptor solution. The volume of diffusion cell was 10 ml and stirred with bent stainless steel pin. The temperature was maintained at 37 1C with the help of hot plate. The diffusion was carried out for 10 hours and 1 ml sample was withdrawn at an interval of 1 hour. The same volume of phosphate buffer pH 7.4 was added to receptor compartment to maintain sink conditions and the samples were analyzed at 305.5nm. Other designs of diffusion cells that are in existence include Valia-Chien (V-C) cell, Ghannam-Chien (G-C) cell, Jhawer-Lord (J-L) Rotating disc system, etc.
63
Chapter 5
Results and Discussion
RESULTS AND DISCUSSION

Six formulations of Ondansetron HCl transdermal patches were formulated using different polymer ratios, the composition of which is shown in table 5. The prepared formulations are shown in figure. the formulations are subjected to evaluation parameters like thickness, drug content, folding endurance, tensile strength, % elongation, % moisture absorption, IR studies, ex-vivo permeation studies. A. Preformulation studies a. Melting point determination: The melting points were found to be in the range of 178 to 179C. The reported melting point is 178.5 to 179.5C. b. Spectroscopic Studies: 1. The spectra showed no incompatibility between the polymer and Ondansetron HCl drug. The spectra of the formulation F1 and the pure drug is given in the spectra 1 and 2 respectively. 2. Determination of max The spectrum obtained is shown in the figure 14. The peak showed in the figure is much similar to the reported peak. 3. Calibration curve of Ondansetron HCl The absorbance values obtained, are shown in table 6. Using concentration and absorbance data, a beer and lamberts plot was obtained. The plot is given the figure 15.
Dept of Pharmaceutics, KLE University, Belgaum 64
Chapter 5 c. Solubility determination
The solubility of ondansetron hydrochloride was determined and found very less as 78.94 g/ml in phosphate buffer. The solubility in distilled water was found more than that in phosphate buffer. The solubility data was shown in table 7. B. Physical evaluation: 1. Thickness: The thickness of the films varied from 0.025 to 0.048 mm. The values obtained for all the formulations is given in the table 8. 2. Moisture uptake: The formulation OND 5 (EC:PVP 8:2) showed lowest percent moisture absorption than other formulations. This might be because of the low water permeability of ethyl cellulose polymer. The values for the moisture uptake has been given in the table 8. 3. Tensile strength: The tensile strength was found to be in the range of 0.75 to 0.58. The formulation OND 1 showed the best tensile strength. The values for all the patches is tabulated in the table 8. 4. % Elongation: The % elongation was found to be in the range of. The formulation OND 1 showed minimum % elongation among all the other patches 15.25 to 30.5 %. The results obtained for all the formulations is tabulated in the table 8. 5. Folding Endurance: The folding endurance was found to be in the range of 72 1 to 79 2. The values for all six formulations is given in the table. This data revealed that the patches had good mechanical strength along with flexibility 8.
Dept of Pharmaceutics, KLE University, Belgaum 65
Chapter 5 6. Weight variation:
The weight variation was to be in the range of 65.24 1.2 to 67.05 1.8. The values for all the formulations is tabulated in the table 8. 7. Drug content: The drug content was in the range of 92.41 to 95.9 %. The values are given in the table 8. C. Diffusion study: The rat skin was used to carry out the study. The formulation OND 1 (PVA:PVP ; 5:5) showed drug diffusion for 10 hours upto 76.69 %. The % drug diffusion for six formulations is given in the table 9, 10, 11, 12, 13 and14 along with the Higuchis plot. The regression for Higuhis plot for all the formulations is given in table 15. The plot for the diffusion study for all the formulations is given in the figures 16, 17, 18, 19, 20 and 21 respectively. The Higuchis plot for all the formulations is given in the figures 22, 23, 24, 25, 26 and 27 respectively.
66
Chapter 5
Results and Discussion Table 6: Standard calibration curve of Ondansetron HCl Sr. No. 1 2 3 4 5 6 7 8 Concentration (g/ml) 0 4
0.277
Absorbance 0
6
0.361
8
0.482
10
0.58
12
0.6
14
0.823
16
0.928
Table 7: Solubility data for Ondansetron HCl Solubility medium Time duration 24 hours Distilled water 48 hours 24 hours Buffer pH 7.4 48 hours Solubility (g/ml) 55.03 4.25 76.94 0.93 78.5 1.48 93.13 1.89
67
Chapter 5
Table 8: Physicochemical evaluation data of Ondansetron HCl Transdermal patches Weight % elongation variation content SD SD endurance strength (mg) SD 65.24 1.2 62.50 1.8 67.05 1.8 66.55 1.8 66.89 1.9 65.05 1.6 94.16 0.6 93.66 0.5 95.9 0.4 77 1 72 1 71 0.9 95.03 0.2 79 2 94.28 0.5 76 1 0.73 0.68 0.70 0.61 0.58 92.41 0.1 78 2 0.75 15.25 % 20.54 % 22.89 % 23.86 % 30.5 % 29.56 % 4.5 % 4.8 % 5.07 % 5.18 % 3.5 % 3.9 % % drug Folding Tensile % moisture absorption
Formulation
Thickness
code
(mm)
SD
OND 1
0.036 1.2
OND 2
0.032 1.5
OND 3
0.045 1.8
OND 4
0.048 1.3
OND 5
0.025 1.4
OND 6
0.029 1.6
68
Chapter 5
Results and Discussion Table 9: Ex-vivo diffusion study of OND 1
Ex-vivo drug diffusion Time (h) % CDR
Higuchis plot Square root of time % CDR
1 2 3 4 5 6 7 8 9 10
15.46 21.10 28.10 34.02 39.85 47.21 57.23 64.04 69.71 76.69
1 1.41 1.73 2 2.23 2.44 2.64 2.82 3 3.16
15.46 21.10 28.10 34.02 39.85 47.21 57.23 64.04 69.71 76.69
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Chapter 5
1 2 3 4 5 6 7 8 9 10
12.70 17.74 22.88 29.18 33.99 41.40 47.78 54.20 60.21 65.52
1 1.41 1.73 2 2.23 2.44 2.64 2.82 3 3.16
12.70 17.74 22.88 29.18 33.99 41.40 47.78 54.20 60.21 65.52
70
Chapter 5
1 2 3 4 5 6 7 8 9 10
8.74 12.11 15.07 19.88 23.96 27.24 32.74 36.90 40.57 47.40
1 1.41 1.73 2 2.23 2.44 2.64 2.82 3 3.16
8.74 12.11 15.07 19.88 23.96 27.24 32.74 36.90 40.57 47.40
71
Chapter 5
1 2 3 4 5 6 7 8 9 10
8.40 11.76 14.55 18.92 23.17 26.78 30.95 36.13 40.65 46.46
1 1.41 1.73 2 2.23 2.44 2.64 2.82 3 3.16
8.40 11.76 14.55 18.92 23.17 26.78 30.95 36.13 40.65 46.46
72
Chapter 5
1 2 3 4 5 6 7 8 9 10
10.53 13.24 16.46 19.88 23.89 28.67 34.35 40.24 46.34 52.69
1 1.41 1.73 2 2.23 2.44 2.64 2.82 3 3.16
10.53 13.24 16.46 19.88 23.89 28.67 34.35 40.24 46.34 52.69
73
Chapter 5
1 2 3 4 5 6 7 8 9 10
11.20 13.91 16.71 20.34 24.50 28.17 33.37 39.46 45.85 51.13
1 1.41 1.73 2 2.23 2.44 2.64 2.82 3 3.16
11.20 13.91 16.71 20.34 24.50 28.17 33.37 39.46 45.85 51.13
74
Chapter 5 Table 15: Data for regression Formulation code OND 1 OND 2 OND 3 OND 4 OND 5 OND 6
Regression for Higuchis plot 0.983 0.984 0.977 0.975 0.960 0.960
75
Chapter 5
Results and Discussion Figure 14: UV spectrum for Ondanstron HCl
Figure 15: Calibration curve of Ondansetron HCl
76
Chapter 5
Results and Discussion Figure 16: Ex vivo diffusion study of OND F1
Figure 17: Ex vivo diffusion study of OND F2
77
Chapter 5
Results and Discussion Figure 18: Ex vivo diffusion study of OND F3
78
Chapter 5
79
Chapter 5
Results and Discussion Figure 22: Higuchis plot for OND 1
Figure 23: Higuchis plot for OND 2
80
Chapter 5
81
Chapter 5
82
Chapter 5
Results and Discussion Plate 1: Formulated Ondansetron HCl patches
F1
F2
F3
F4
F5
F6
83
Chapter 5 Spectra 1: IR spectra of OND F1
84
Chapter 5
Spectra 2: IR of pure drug
85
Chapter 6
Conclusion
CONCLUSION
Ondansetron HCl, an anti-emetic drug has been selected which has half-life of 5-6 hrs, the drug undergoes first pass metabolism. Hence in the present work, an attempt has been made to provide transdermal drug delivery using water soluble and water insoluble polymers with Ondansetron HCl as the model drug. IR study shows that there is no incompatibility between drug and polymers. The transdermal patches were prepared using solvent casting method using combination of EC, PVP, PVA and Eudragit in various ratios using Dibutyl phthalate and propylene glycol as plasticizers and oleic acid as a permeation enhancer. The formulation OND 1 (PVA:PVP ; 5:5) shows optimum difusion in concentration independent manner. The above formulation gave a maximum drug diffusion of 76.69% over a period of 10 hours. Higuchis plot for the formulation revealed that the predominant mechanism of drug release is diffusion. However; from Peppas plot the n value for OND F1 was found to be 0.721, thus indicating non-fickian diffusion. As an extension of this work pharmacokinetic studies, in-vivo studies on higher animals and controlled clinical studies on human beings can be carried out in future.
86
Chapter 7
Summary
SUMMARY
In this work an attempt was made to formulate and evaluate TDDS for sustained release Ondansetron HCl by solvent casting method. Low molecular weight, good permeability and shorter half-life of Ondansetron HCl made it a suitable drug candidate for the development of transdermal patches. The main objective of formulating the transdermal system was to prolong the drug release time, reduce the frequency of administration and to improve patient compliance. The compatibility parameters characterization was done by IR method. Six formulations were prepared using different polymers in different ratios and combinations, along with plasticizers and penetration enhancer. Mercury was used as a substrate for pouring the polymeric solution. The films were evaluated for uniformity of thickness, weight variation, drug content, folding endurance, tensile strength, % elongation, % moisture absorption and ex-vivo diffusion studies using kesary chein diffusion cell. The weight variation was found in the range of 65.24 to 67.05. Thickness variation was found to be between 0.025 to 0.048 mm. Tensile strength was found to be between 0.58 to 0.75 for 2 x 2 cm2 patches. The % moisture absorption for all the formulations was in the range of 3.9 to 5.18%. The formulation OND F1 showed the % moisture absorption of 4.5 %. The ex-vivo diffusion study was carried out in phosphate buffer pH 7.4 for 10 hours.
Dept Of Pharmaceutics, KLE University, Belgaum
87
Chapter 7 Rat skin was used for the diffusion study. The formulation OND 1 showed the best diffusion through the skin. It showed the diffusion of 76.69%.
Summary
The formulations followed the Higuchis model for the drug diffusion study. Since the formulations follow Higuchis model, thus they indicate diffusion mechanism. The peppas plot showed the n value of 0.721 for formulation OND F1, thus indicating non-fickian diffusion. There is scope for the further study and development of the Ondansetron HCl transdermal patches.
Dept Of Pharmaceutics, KLE University, Belgaum
88
Chapter 8
Bibliography
BIBLIOGRAPHY
1. Chien Y.W. Novel Drug Delivery Systems, 2nd Edition, Drugs And Pharmaceutical Sciences, Volume-50, Marcel Dekker, Inc. 2. Finnin B C, Morgan T M, Trasndermal penetration. J Pharm Sci. Oct 1999;88 (10):955-958. 3. Allen L V, Popovich N G, Ansel H C, Ansels Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Edition, Lippincott Williams & wilkins, 2005:298315. 4. Barry B. Transdermal Drug Delivery. In Ed: Aulton M E, Pharmaceutics: The Science of Dosage Form Design, Churchill Livingston. 2002:499-533 5. Cleary G W, Transdermal controlled release systems. Medical Applications of Controlled Release. 1:203-251. 6. Vyas S P, Khar R K, Controlled Drug Delivery: Concepts and Advances, Vallabh Prakashan, 1st Edition. 2002:411-447. 7. Tortora G, Grabowski S. The Integumentary system. In: Principles of Anatomy and Physiology. 9th edition. John Wiley and Sons Inc. 150-151. 8. Wilson K J W, Waugh A. Eds, Ross And Wilson: Anatomy And Physiology In Health And Illness, 8th Edition, Churchill Livingstone. 1996:360-366. 9. Barry B W; Dermatological Formulations: Percutaneous Absorption, Drugs and pharmaceutical sciences, Volume 18, MARCEL DEKKER, INC. 1983:1-39. 10. United States Patent: 6,673,363 Issued: January 6, 2004 Title: Transdermal and topical administration of local anesthetic agents using basic enhancers Inventors: Luo; Eric C. (Plano, TX); Gricenko; Nicole T. (San Diego, CA); Hsu; Tsung-Min (San Diego, CA)
89
Chapter 8
Bibliography
11. Funke AP, Gunther C, Muller RH, Lipp R. In-vitro release and transdermal fluxes of a highly lipophilic drug and of enhancers from matrix TDS. J Control Release. 2002 Jul;18;82(1):63-70. 12. Akimoto T, Nagase Y. Novel transdermal drug penetration enhancer: synthesis and enhancing effect of alkyldisiloxane compounds containing glucopyranosyl group. J Control Release. 2003 Mar 7;88(2):243-52. 13. Hirvonen J, Murtomaki L, Kontturi K. Effect of diffusion potential, osmosis and ionexchange on transdermal drug delivery: theory and experiments. J Control Release. 1998 Dec 4;56(1-3):33-9. 14. Fang JY, Lin HH, Chen HI, Tsai YH. Development and evaluation on transdermal delivery of enoxacin via chemical enhancers and physical iontophoresis. J Control Release. 1998 Aug 14;54(3):293-304. 15. Oh SY, Jeong SY, Park TG, Lee JH. Enhanced transdermal delivery of AZT (Zidovudine) using iontophoresis and penetration enhancer. J Control Release. 1998 Feb 12;51(2-3):161-8. 16. Fang JY, Sung KC, Lin HH, Fang CL. Transdermal iontophoretic delivery of enoxacin from various liposome-encapsulated formulations. J Control Release. 1999 Jun 28;60(1):1-10. 17. Pillai O, Panchagnula R. Transdermal iontophoresis of insulin. V. Effect of terpenes. J Control Release. 2003 Mar 7;88(2):287-96. 18. Vanbever R, Langers G, Montmayeur S, Preat V. Transdermal delivery of fentanyl: rapid onset of analgesia using skin electroporation. J Control Release. 1998 Jan 2;50(1-3):225- 35. 19. Denet AR, Preat V. Transdermal delivery of timolol by electroporation through human skinJ Control Release. 2003 Mar 7;88(2):253-62.
90
Chapter 8
Bibliography
20. Bose S, Ravis WR, Lin YJ, Zhang L, Hofmann GA, Banga AK. Electricallyassisted transdermal delivery of buprenorphine. J Control Release. 2001 Jun 15;73(2-3):197 203. 21. Kikwai L, Kanikkannan N, Babu RJ, Singh M. Effect of vehicles on the transdermal delivery of melatonin across porcine skin in vitro. J Control Release. 2002 Oct 4;83(2):307-11. 22. http://medical-dictionary.thefreedictionary.com/ondansetron+hydrochloride. 23. Handbook of pharmaceutical excipients. USA: American pharmaceutical association; 1986. 24. http//en.wikipedia.org/wiki/dibutyl_pthalate. 25. http//en.wikipedia.org/wiki/oleic_acid. 26. Gattani SG, Gaud RS, Chaturvedi SC. Formulation and evaluation of transdermal films of ondansetron hydrochloride. Indian Drugs. 2006;43(3):245-9. 27. Gwak H S, Oh IS, Chun I K, In-vitro percutaneous absorption of ondansetron hydrochloride from pressure-sensitive adhesive matrices through hairless mouse skin, Arch Pharm Res, 26 (8), 2003, 644-8. 28. Gwak H S, Oh IS, Chun I K, transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers, Drug Dev Ind Pharm, 30, (2), Feb 2004, 187-94. 29. Calpena A C, Blanes C, Moreno J, Obach R, Domenech J, A comparative in vitro study of transdermal absorption of antiemetics, J Pharm Sci, 83 (1), 1994, 29-33. 30. Agrawal SS, Munjal P. Permeation studies of atenololand metoprolol tartarate form three different polymer matrices for transdermal delivery. Ind J Pharm Sci. 2007: 535-9.
91
Chapter 8
Bibliography
31. Sankar V, Sivanand V, Ravichandran V. Design and evaluation of nifedipine transdermal patches. Ind J Pharm Sci. 2003;65(5):510-5. 32. Gattani SG, Gaud RS, Chaturvedi SC. Formulation and evaluation of transdermal films of chlorpheniramine maleate. Indian Drugs. 2007;44(1):27-33. 33. Manvi FV, Dandagi PM, Gadad AP. Formulation of a transdermal drug delivery system of ketotifen fumarate. Ind J Pharm Sci. 2003;65(3):239-43. 34. Saxena M, Mutalik S, Reddy MS. Formulation and evaluation of transdermal patches of metoclopramide hydrochloride. Ind drugs. 2006;43(9):740-5. 35. Ubaidulla U, Reddy MV, Ruckmani K. Transdermal therapeutic system of Carvedilol : effect of hydrophilic and hydrophobic matrix on in vitro and in Vivo characteristics. AAPS Pharmsci Tech. 2007;8(1):Article 2. 36. Patra S, Choudhury A. A, Kar R. K and Barik B. B. Spectrophotometric method Ondansetron HCl. Ind J. Pharm. Sci. 2007; 69(6): 840-1. 37. Murthy S N, Sateesh M, Hamsa V, Drug release from terbutaline sulphate transdermal films across human cadaver skin, Indain J Pharm Sci. 59(2);75-76. 38. M. Aqil and Asgar Ali. Monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate: in vitro characterization. European Journal of Pharmaceutics and Biopharmaceutics. 2002;54:161164. 39. Murthy S N, Shoba Rani, Hiremath R, Formulation and evaluation of controlled release transdermal patches of theophylline-salbutamol sulphate, Drug Dev Ind Pharm, Online published 30/09/2001, 1057-62. 40. Evaluation of free films. Indian drugs. 1985; 23(1):45-7. 41. www.priory.com/pharmmol/transdermal/pdf.
92
Chapter 8
Bibliography
42. Prashant M, satturwar S, Fulzele V and avinash K. dorle evaluation of polymerized rosin for the formulation and development transdermal drug delivery systems. AAPS Pharmscitech. 2005; 6(4):48-53. 43. Carmelo Puglia and Francesco Bonina. Effect of Polyunsaturated Fatty Acids and some conventional Penetration Enhancers on Transdermal Delivery of Atenolol. Drug Delivery. 2008; 15: 107112.
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Formulation and Evaluation of Anti Emetic Patch Comprising On Dan Set Ron Hydro Chloride

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FORMULATION AND EVALUATION OF ANTIEMETIC PATCH COMPRISING ONDANSETRON HYDROCHLORIDE

Master of Pharmacy In Pharmaceutics

DEPARTMENT OF PHARMACEUTICS, JN MEDICAL COLLEGE, BELGAUM-590010, KARNATAKA, INDIA

KLE UNIVERSITY, BELGAUM, KARNATAKA

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The family is a haven in this world

EC FT-IR gm HPMC ml PBS pKa PVA PVP RH t t max g

9. 10. 11. 12. 13. 14. 15.

12. 13. 14. 15. 16. 17. 18. 19. 20.

21. 22. 23. 24. 25. 26. 27. 28. 29 30

INTRODUCTION Controlled drug delivery

Transdermal drug delivery: An Introduction

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Chapter 1 with variation of 0.5C to 0.75C.

Anatomy and Physiology7, 8

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Fundamentals of skin permeation9

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Chapter 1 B. Intracellular verses transcellular diffusion

Dept of Pharmaceutics, KLE University, Belgaum

Fig. 6: Epidermal routes for drug permeation

i) TranscellularDept of Pharmaceutics, KLE University, Belgaum 11

Factors influencing transdermal drug delivery4

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Technologies for developing transdermal drug delivery systems1, 9

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Chapter 1 where, CR is drug concentration in reservoir compartment;

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Figure. 10: Cross-sectional view of a drug reservoir gradient-controlled TDD system.

Dept of Pharmaceutics, KLE University, Belgaum

Components of a Transdermal Patch3

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

General clinical considerations in the use of TDDS3

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept of Pharmaceutics, KLE University, Belgaum

Dept. Of Pharmaceutics, KLE University, Belgaum