parenterals, injectable and adds a several advantages over other having poor patient compliance, anaphylaxis, and some other

Transcription

1 1 INTRODUCTION 1.1. Buccal drug delivery system Buccal drug delivery is a favorable route compare to parenterals, injectable and adds a several advantages over other routes1. The parenteral route offers excellent bioavailability, similarly having poor patient compliance, anaphylaxis, and some other infections. Peroral route posses some inconvenience to patients. Hence for the immediate release of medication and for instant release at desire location in which the drug is absorbed distributer and easily metabolized. This limitation leads to the development of alternative routes of administration. Buccal mucosa has absorptive function and offers many benefits like avoidance of first pass effect, which is a non invasive route, increase in bioavailability, a rapid action is possible and reduce side effects2,3. Buccal, sublingual, palatal and gingival 4 regions shows effective drug delivery in oral cavity. Buccal and sublingual route of drug delivery are most widely in which local and systemic effects are treated. The permeability of oral mucosa denotes the physical nature of the tissues. The permeable part is sublingual mucosa and buccal mucosa is thinner part and in which there is a high blood flow and surface area; it is a feasible site when a rapid onset of action is desired. For the treatment of acute disorders sublingual route is a preferred one; however its surface washed with saliva which makes formulations in the oral cavity hard in nature.

2 2 Buccal drug delivery system is well accepted because it is having several advantages. Buccal areas offer a control release system which is having immobile surface. The buccal layer is tolerate to potential allergens and has capability of preventing damage compare to other mucosal tissues. In treatment of the local or systemic therapies, buccal mucosa favors a useful measure by overcoming drawbacks and as convenient route for the administration. This type of route is well vascularized draining to the heart unswervingly via the internal jugular vein. In chronic systemic therapies, buccal drug delivery acts as potential site and chemical modification due to salivary production and its composition. There is a chance of drug loss at site of absorption in case of the oral route and for some dosage form salivary scavenging is constant with in oral cavity which make difficult for retaining to an extensive duration at the site to enhance the absorption. Bioadhesive polymers have prolonged contact time with the tissues and can notably maintain the performance of several drugs6. The controlled drug delivery products have high patient compliance and a low cost with enhanced bioavailability. Advantages 1. It is richly vascularised and additional reachable administration and removal of formulations. 2. Patient accessibility is high. 3. Retentive dosage forms are suitable for administration. 4. Improves bioavailability by eliminating first pass metabolism. for

3 3 5. Surface of buccal mucosa achieves a fast cellular recovery. 6. Low enzyme activity. 7. Non-invasive method of drug administration. 8. Ability to incorporate permeation enhancer in the formulation. Disadvantages 1. Buccal membrane has low permeability. 2. Small surface area (170 cm2). 3. Continuous secretion of saliva results in following dilution of the drug. 4. Inconvenience route of drug administration when the patient is swallowing or taking. Limitations 1. There is a chance of swallowing and the effect of salivary scavenging. 2. Protective characteristics of buccal mucosa. 3. Relatively small absorption area Anatomy of oral mucosa Buccal cavity is a component of mouth in which lips and cheeks are anteriorly bounded and teeth, gums bounded posteriorly and medially. The buccal glands are positioned between the mucous membrane and buccinator muscle. The thickness of buccal mucosa is having uneven texture and about µm7 and buccal epithelium return time at 5-6 days8. The non-keratinised stratified squamous

4 4 epithelium lines the buccal mucosa and having µ and surface area of about 50.2 cm Structure The oral mucosa consists of three distinctive layers. They are epithelium, basement membrane and connective tissues. Buccal cavity is lined with epithelium; supported by basement membrane which intern supported by connective tissues. In underlying tissues, protective layer is epithelium which is divided in to9,10 (a) Surface which is non-keratinised lining of soft palate, tongue surface, lips and vestibule. (b) Hard palate and other non flexible regions keratinized epithelium present in oral cavity. Fig: 1.1. Cross-section of buccal mucosa

5 5 The epithelial cells originating from the basal cells mature, change their shape, and increase in size while moving towards the surface. The basement membrane acts as mechanical support for the epithelium and forms a distinctive layer between the connective tissues and the epithelium. The underlying connective tissues provide many of the mechanical properties of oral mucosa. The non keratinized tissue is a part of buccal epithelium which is penetrated by connective tissues that are tall and conical in form. These tissues, which are also referred to as the lamina propria, consisting collagen fibers, smooth muscles, blood vessels and an underneath film of connective tissues. Lamina propria is followed by the sub mucosa (Fig 1). The external carotid artery supplies to the oral mucosa. The main sources of blood supply to the lining of the cheek in the buccal cavity are derived from the buccal artery, some terminal branches of the facial artery, the posterior alveolar artery, and the infra orbital artery Permeability The oral mucosal epithelium is somewhat leaky and intermediate between that of the epidermis and intestinal mucosa. Buccal mucosal having times greater permeability 11 than skin and different regions having difference in permeability of oral cavity because of its diverse structures and functions of the oral mucosa 12,13. The relative thickness and degree of keratinization of the tissues

6 6 precedes the ranking. Both the sublingual mucosa and buccal mucosa are non-keratinized, however they differ in thickness. The buccal mucosa is thicker than the sublingual mucosa and the palatal mucosa is intermediate in thickness but keratinized. The permeability of the oral mucosa is in the decreasing order14 sublingual >buccal > palatal Environment The intercellular ground substance surrounds the oral epithelium known as mucus which envelops the complete oral cavity. Mucus gives protection to the cells under by bounding to the apical cell surface15. Mucus primarily consists of about 95 99% water, 0.5 5% of water insoluble glycoproteins and several other components in small quantities, such as free proteins (1%), enzymes, electrolytes, and nucleic acids16. Mucus looks like a visco-elastic hydrogel. Mucus composition can vary based on the origin of the mucus secretion in the body17. At physiological ph, the mucus network carries a negative charge due to the presence of sialic acid and sulfate residues. Mucus plays a major role in mucoadhesion by forming a strong cohesive gel structure which attached to the epithelial cell surface as a gelatinous layer18. Depending on the flow rate the ph of saliva ranges from 5.5 to 7. At high flow rates, the ph is proportional to the concentration of sodium and bicarbonate. The daily salivary volume of secretion is between 0.5 to 2 liters and plays a major role to hydrate oral mucosal

7 7 dosage forms19. The chief reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is rich environment of water in the oral cavity Barriers to penetration across buccal mucosa About quarter to one third of the epithelium consists of barrier which is mainly useful for penetration. The barriers which retard the rate and extent of drug absorption through the buccal mucosa are, Membrane coating granules Basement membrane Mucus Saliva Membrane coating granules Membrane coating granules20,21 are which extrudes into the intercellular region of both keratinized and non-keratinized oral epithelium and are responsible for preventing the transmucosal penetration. The component of the membrane coating granules is different in keratinized and non-keratinized epithelia22. Basement membrane The superficial layers of the oral epithelium represent the primary barrier to the entry of substances from the exterior; the basement membrane also plays a role in limiting the passage of materials across the junction between epithelium and connective tissue. The charge on the constituents of the basal lamina may limit the rate of penetration of lipophilic compounds that can traverse the

8 8 superficial epithelial barrier relatively easily 23. The molecular weight of the permeant molecule and its reactivity with the barrier as well as the structural and functional factors of the barrier influences the barrier function of basal lamina24. Mucus Mucus is having mainly of water where mucins and inorganic salts are present25. Mucin chiefly includes glycosylated proteins having oligosaccharide chains26. These are responsible for gel like character of mucus. The composition of mucin are 70 80% carbohydrate, 12 25% protein and 5% ester sulphate 27,28. The sugar coating layer responsible for withstanding of water and acting against proteolysis, this is very essential for the barrier properties of mucosa29. Saliva The mucosal surface has a salivary coating estimated to be 70 μm thick, which act as unstirred layer. Saliva consists of high molecular weight mucin named MG1 which maintains hydration, provides secretory lubrication, concentrate immunoglobulin s and protective limit molecules such the attachment as of microorganisms by binding to the surface of oral cavity 30. The constant flow of saliva within the oral cavity makes it very difficult for drugs to be retained for a significant amount of time in order to facilitate absorption at this site. The intercellular spaces act as a major source for permeation of hydrophilic compounds, and major

9 9 transport barrier for lipophilic compounds is the cell membrane which is lipophilic in nature. Due to a low partition coefficient it is difficult to permeate through the cell membrane 31, Drug transport mechanisms The main mechanisms involved for the penetration of various substances include simple diffusion (paracellular and transcellular), carrier mediated transport and endocytosis 33. The convey of drugs across the buccal mucosa follows the mechanism involved in passive diffusion; although it has been reported that carrier mediated transport plays a small role upto some extent. Depending on the physicochemical properties of the molecule and the type of tissue being traversed rate of penetration may vary and leads to the suggestion that materials uses one or more of the following routes simultaneously to cross the barrier region in the process of absorption which depends on the physicochemical properties of the diffusant 34, but one route is predominant over the other. i. Passive diffusion a. Transcellular or intracellular route b. Paracellular or intercellular route ii. Carrier mediated transport iii. Endocytosis The transport of drugs across buccal epithelium may follow different pathways but their selection depends upon the nature of the permeant, i.e. the overall molecular geometry, lipophilicity and charge.

10 10 Most of the compounds diffuse through the buccal mucosa by passive diffusion or simple Fickian diffusion 35. Under sink condition, the flux of drug passing through the membrane for paracellular route can be written as36 Where, Dp is diffusion coefficient, hp is path length, cd is concentration in donar compartment έ is paracellular route area. In transcellular route under sink conditions flux of drug can be given as follows37,38, Where, Kc is partition coefficient, Dc is the diffusion coefficient and hc is the path length. The permeation across buccal epithelium via carrier mediated diffusion provided by the substances like Glucose, monocarboxylic acids, salicylic acid and nicotinic acid 39. The enzyme inhibitors are used as mucoadhesive agents for protein and peptide delivery Enhancement of buccal transport The buccal mucosa exhibits insufficient permeability depending on physicochemical characters of the drug and represents a major limitation in the development of a transmucosal drug delivery system41. Also, the limited absorptive area and the short exposure time, due to the washing effect of saliva can decrease absorption efficiency even more. Permeation enhancers are used to permeate the

11 11 drugs across epithelial barriers. However, proper penetration enhancers are used to improve the drug permeability42. Ideal permeation enhancers should have the following properties Safest and non-toxic nature Pharmacologically and chemically inert and non irritant. Should be non-allergenic Classification of permeation enhancers 43 a) Chelators: sodium salicylate, methoxy salicylates, EDTA, citric acid. b) Surfactants: SLS, Polyoxyethylene-9-laurylether, cetyltrimethyl ammonium bromide, Benzalkonium chloride. c) Bile salts: sodium glycocholate, sodium tauro cholate, sodium deoxy cholate, sodium tauro deoxycholate. d) Fatty acids: phosphatidylcholine, oleic acid, propylene glycol, methyl oleate. e) Inclusion complexes: cyclodextrins. f) Others: polysorbate 80, sulfoxides, aprotinin, azone, cyclodextrin, dextran sulfate, menthol and various alkyl glycosides. g) Thiolated polymers: chitosan thiobutylamide, chitosan cysteine, chitosan -4- thioglycholic acid Mechanisms of action Changing mucus rheology The drug absorption is affected by forming viscoelastic layer by the mucus of varying thickness44. Further, the absorption is hindered

12 12 by saliva covering the mucus layers. So permeation enhancers are used to increase the absorption, they act by reducing the viscosity of the mucus and saliva which overcomes this barrier Fluidity of lipid bilayer membrane Intracellular route favors the buccal mucosa to show mechanism of action for the drug absorption and lipid at protein components interacts with some enhancers to disturb the intracellular lipid packaging Acting on the components at tight junctions Some enhancers act on desmosomes, a major component at the tight junctions there by increases drug absorption By overcoming the enzymatic barrier Some of the substances overcome the enzymatic barrier by inhibiting the various peptidases and proteases present within buccal mucosa. In addition, enzymatic activity is indirectly affected by the changes in membrane fluidity Increasing the thermodynamic activity of drugs Some enhancers may alter the partition coefficient by increase the solubility of drug. Better absorption is achieved by increased thermodynamic activity. The intracellular lipid penetration is followed for permeability of drugs by which surfactants like cationic, anionic, nonionic, bile salts increases and calcium ion interference is mainly due to which chelates, phospholipid fluidity increases with the help of

13 13 fatty acids and interaction of ions on mucosa with the help of positive and negative charges Mucoadhesive polymers Polymer is a generic term used to describe a very long molecule consisting of structural units and repeating units of monomers connected by covalent chemical bonds. Polymers act as adhesive component bioadhesive formulations. These formulations are often water soluble and forms strong interaction by attracting water from the biological surface. When hydrated with water these polymers form viscous liquids and allow long retention time on the mucosal surfaces leading to the formation of adhesive interactions. Bioadhesive polymers should possess certain physicochemical features including hydrophilicity, viscoelastic properties, flexibility for interpenetration with mucus and epithelial tissue Ideal characteristics 1. Shows better spreading, wetting, swelling, solubility and biodegradability characters. 2. Should have biocompatible ph and possess good visco-elastic properties. 3. Should attach rapidly to buccal mucosa and hold adequate mechanical strength. 4. Have wide bioadhesive ranges of peel, tensile and shear strengths. 5. The polymers are not having high cost and easily available.

14 Bioadhesive nature in both anhydrous and hydrous condition. Should posse s penetration enhancement properties by inhibiting local enzyme. 8. It exhibit satisfactory stability. 9. The molecular weight is optimum. 10. Should not help in progress of secondary illness like dental caries Classification mucoadhesive polymers9 a) Based on source Natural: e.g. Agarose, chitosan, gelatin, Hyaluronic acid, and gums. Synthetic: e.g. Cellulose derivatives like CMC, SCMC, HEC, HPC, MC, Thiolated CMC and HPMC. Based on aqueous solubility Water soluble: e.g. CP, HEC, HPC, HPMC, SCMC, sodium alginate. Water insoluble: e.g. Chitosan and EC. b) Based on charge Cationic: e.g. Chitosan, Dimethylaminoethyl (DEAE), Dextran, Anionic: e.g. CP, Carboxy methyl cellulose, Na alginate, Sodium carboxy methyl cellulose, xanthan gum. Non-ionic: e.g. Hydroxy propyl cellulose, Poly ethylene oxide, Polyvinyl alcohol, Polyvinyl pyrrolidone. c) Based on potential bioadhesive forces Covalent bond: e.g. Cyanoacrylate. Hydrogen bond: e.g. Acrylates, CP, PVA

15 15 Electro-static interaction: e.g.chitosan Formulation design Buccoadhesive formulations with the size 1 3 cm2 and a daily dose of 25 mg or less are convenient19. The general considerations in buccal dosage form design includes Pharmaceutical considerations. Physiological considerations. Pathological considerations. Pharmacological considerations. Pharmaceutical considerations The release of core from the dosage form can be retarded by its solubility in saliva. The absorption of weakly water soluble drugs can be increased by solubilizing the drug in Cyclodextrin and administered via buccal route. The physicochemical characteristics, morphological characters of the drug all influence the desirable drug release and absorption48.in case of dosage forms, for enhancing the effectiveness and acceptability, some excipients are incorporated. Various permeation enhancers increase permeability of buccal mucosa49. Enzyme inhibitors may be included in the dosage forms to prevent enzyme degradation and ph modifiers may be included in order to temporarily modulate the microenvironment at the application site for better drug absorption.

16 16 Physiological considerations Challenges of drug delivery to the oral cavity are Constant flow of saliva and mobility of tissues. The residence time of drugs in the oral cavity is typically short, in the range of <5 10 min50. The problem is mainly overcome by use of buccal formulation. The device size is 13 cm and daily dose of 25 mg in case of buccal delivery and ellipsoid shape favors to be more acceptable and thickness is usually limited to few mm for buccal formulation 52. Pathological considerations Thickness of epithelium is affected mainly with many diseases in which the barrier of mucosa results in alteration. Mucus properties are influenced with some diseases, hence in pathologic conditions which complicate bio adhesive device to be retention and at site of application. Pharmacological aspects In case of systemic circulation buccal dosage form is designed and in local therapy of oral mucosa. The dosage form is affected mainly due to drug characteristics, target site of action and at the treated site9. Ideal properties of novel buccal drug delivery systems Should release the drug in a controlled fashion Unidirectional way of drug release towards the mucosa. Should facilitate the rate and extent of drug absorption. Should not cause any irritation or inconvenience to the patient.

17 17 Should not interfere with the normal functions such as talking, drinking etc Approaches of buccal drug delivery system Non-attached drug delivery systems This includes Fast dissolving tablet dosage forms, Chewing gum formulations and Micro-porous hollow fibers. Bio-adhesive drug delivery systems a) Solid buccal adhesive dosage forms. b) Semi solid buccal adhesive dosage forms. c) Liquid buccal adhesive dosage forms. Liposome Delivery of proteins and peptides Non-attached drug delivery systems The local physiological environment greatly affects the nonattached drug delivery system, e.g. the presence of saliva and the intake of foods and liquids41. Bio-adhesive drug delivery systems a) Solid buccal adhesive dosage forms Dry formulations achieve bio-adhesion via dehydration of the local mucosal surface. Buccal tablets Buccal tablets are small, flat and oval in shape with a diameter of approximately 5 8 mm. The direct compression technique is most widely used for preparation of buccal tablets; other techniques like

18 18 wet granulation can also be employed. These tablets stick to the buccal mucosa in presence of saliva. They are designed to release the drug either unidirectional, targeting buccal mucosa or multidirectional in to the saliva53. Microspheres, microcapsules, micro particles The local irritation caused by microspheres54,55 or microcapsules56 or micro particles57 at the site of adhesion is less and provide comfortable sensation of a foreign object within the oral cavity. Wafers Wafer is a drug delivery system with surface layers possessing adhesive properties58. Lozenges Bioadhesive lozenge offers prolonged drug release with improved patient compliance compared to Conventional lozenges, thus avoiding multiple daily dose59. b) Semi-solid buccal adhesive dosage forms. Gels Bioadhesive polymers forming gels which form cross linked polyacrylic acid used in which mucosal surfaces are fixed to provide the release in control manner for extensive period of time and drug at the absorption site. Bioadhesive polymers forming gels are of limited use for drugs with narrow therapeutic window due to their inability to deliver a measured dose of drug to the site 60.

19 19 Buccal patches Patches are laminates consists of drug-containing reservoir layer and an impermeable backing layer. Drug is released in a controlled manner from the drug-containing reservoir layer, and a bioadhesive surface for mucosal attachment 61. Buccal adhesive Patches can be prepared by two methods, Solvent casting technique and Direct milling method. In solvent casting technique, the solvent is evaporated by casting the solution of the drug and polymer onto a backing layer sheet and the patches were punched in intermediate sheet. In method like direct milling in which the constituents of formulation forms desire thickness by proper mixing, by which the desired shapes are cut and punched out in case of patches. Backing layer acts as protective layer which is impermeable and is applied to control the prevention of drug loss and direction of drug release during the administration. Buccal films These are the most recently developed dosage form which meant for buccal administration. Buccal films 62 have more flexibility and comfort when compared with adhesive tablets. So, buccal films are preferred instead of adhesive tablets. In addition to these, they have saliva which removes and wash easy and short residence time on mucosa of oral gels. The wound surface is protected mainly by films, when the drugs are administered orally for local delivery and treat the disease more effectively by reducing the pain. An ideal film should be

20 20 soft, elastic, flexible and posses adequate strength to withstand breakage due to stress from mouth movements. It should retain in the mouth to produce desired action with good bioadhesive strength. Swelling of film should not be too extensive in order to prevent discomfort. Solvent casting method is widely used for the preparation of buccal films. In solvent mixture, drug and polymer(s) are dissolved. The solution made in to film and dried, a liner or a backing layer are used to finally laminate. The salivary diffusion in to drug layer is avoided by the backing layer; there is a reduction in the drug loss and by enhancing adhesion time in oral cavity. The main disadvantage with solvent casting technique is time consuming, long processing and some concerns with the environment by the usage of different type of solvents. Hot-melt extrusion method is used to overcome the drawbacks. c) Liquid buccal adhesive dosage forms Liquids used to coat buccal surface are viscous and serve as either protective agents or as drug vehicles for delivery of drug on to the mucosal surface. Recently, pharmaceutically acceptable polymers were used to improve the viscosity of products to aid their maintenance in the oral cavity. Lubrication can be provided by treating dry mouth with artificial saliva solutions and to retain the drug on mucosal surfaces. This solution consists of SCMC as bioadhesive polymer.

21 21 Liposomes Drugs which are encapsulated in liposome formulations have been investigated for buccal administration. Applications of liposome formulation in buccal delivery resulted in a decrease of systemic and an increase of local, drug concentration. Peptides can be entrapped within the liposome The transport of hydrophilic substances to the layer of the epithelium through liposome formulations can be limited. Poly methyl methacrylate is a hydrophilic polymer and found to be the most appropriate mucoadhesive ointment for local application in the oral cavity since the liposomes were shown to be more stable in this polymer. The performance of less effective liposome peptide delivery systems can be improved by incorporation of protease inhibitors. Delivery of proteins and peptides The buccal drug delivery systems avoids pre systemic (or) hepatic first-pass metabolism, acidity and protease activity come across in the gastrointestinal tract hence provide as potential important site for controlled delivery of macromolecular therapeutic agents, such as peptides and protein drugs66. Another attractive advantage is its tolerance (in comparison with the nasal mucosa and skin) to potential sensitizers.

22 DRUG PROFILE Famotidine Generic name Famotidine Class H2 receptor antagonist67 Structural formula Fig: 1.2. Structure of Famotidine Chemical name Propanimidamide, N-(aminosulfonyl)-3[[[2[diaminomethylene) amino]-4-thiazolyl] methyl] thio]-[1-amino-3-[[[2-[diaminomethylene) amino]-4-[thiazolyl]-methyl] thio] propylidene] sulfamide68. Molecular formula C8H15N7O2S3 Molecular weight Description It occurs as yellowish white or white crystalline powder. Melting point 1630C and1640c.

23 23 Solubility Freely soluble in dimethyl formamide and in glacial acetic acid, practically insoluble in ether and in ethyl acetate, slightly soluble in methanol, water and in dehydrated alcohol, it gets dissolved in dilute mineral acids. Standards Famotidine contains not less than 98.5% and not more than 101.0% of C8H15N7O2S3 calculated on dried basis. Heavy metals : Not more than 0.001%. Sulphated Ash : Not more than 0.1%, determined for 1.0 g. Loss on drying Dry it at a pressure between 1 and 5 mmhg at 80 oc for 5 h, it loses not more than 0.5% of its weight. Pharmacological profile69 Famotidine is antihistamine drugs particularly serve as H2receptor antagonist. Inhibition of gastric secretion is the primary clinical importance. The volume of gastric secretion and acid concentration are suppressed by Famotidine, changes in pepsin secretion are proportional to volume output. Mechanism of action H2 receptor antagonists inhibit acid production by reversibly competes the binding of H2 receptors with histamine on the baso lateral membrane of parietal cells. It competitively inhibits the actions

24 24 of histamine at all H2 receptors but their main clinical use is as inhibition of gastric acid secretion. Pharmacokinetic parameters of Famotidine 69 Bio availability 40 45% Plasma half life 2.5 to 4 h Plasma protein binding 15 20% Peak plasma concentration (Cmax) 1 to 3 h Renal excretion 65 70% Metabolic excretion 30 35%. Renal clearance ml/min. Approximate duration of therapeutic effect 12 h Drug interactions It does not inhibit hepatic microsomal enzyme CytP450 system and hence it does not interact with the drugs which are substrates for CytP450 systems like Caffeine, Phenytoin, Warfarin, Quinidine, etc. Food Interactions Alcohol intake should be avoided. Intake of caffeine should be limited. Slight increase in the product's bioavailability is seen when reacts with meal. Adverse effects Famotidine when administered intravenously, low incidence of adverse effects is seen (< 3%) it causes diarrhoea, dizziness, fatigue, muscle pain, transient rashes, hypergastrinemia, less common side

25 25 effects affecting the CNS include (confusion, delirium, hallucinations, slurred speech and headaches), teratogenicity not associated and used during pregnancy. Therapeutic uses 1. Healing of gastric and duodenal ulcers is the major therapeutic indication. 2. Treatment is not complicated for treating GERD. 3. Stress ulcers can be treated Prophylactically. 4. Famotidine when given along with antibiotics useful for the treatment of infection caused with Helicobacter pylori i.e. in the treatment of Gastritis. Dosage and administration70 Duodenal Ulcer and Benign Gastric Ulcer 40 mg once at bedtime (or) 20 mg twice a day Gastro Esophageal Reflux Disease (GERD) 20 mg twice a day up to 6 weeks Orally Disintegrating Tablets Famotidine tablets can be replaced by orally disintegrating tablets with same dose.

26 POLYMER PROFILES HYDROXY PROPYL METHYL CELLULOSE (HPMC) 71 Nonproprietary Names BP: Hypromellose, JP: Hydroxypropylmethylcellulose, PhEur: Hypromellosum, USP: Hypromellose Synonyms Methocel, methyl cellulose propylene glycol ether, methyl hydroxyl propy lcellulose. Structural formula Where R is H, CH3 or [CH3CH (OH) CH2] Fig: 1.3. Structure of HPMC Molecular weight Description It is an odorless and tasteless, white or creamy white colored fibrous powder. Solubility It is soluble in cold water and forming a viscous colloidal solution, soluble in mixtures of ethanol and dichloromethane,

27 27 mixtures of methanol and dichloromethane. It is practically insoluble in chloroform, 95% ethanol and ether. Viscosity HPMC 2% w/v aqueous solutions viscosities measured at 20ºC. HPMC grades K4M, K15M, K100M having viscosity of 4000, and cps respectively. Typical properties of HPMC Glass transition temperature ºC Density (bulk) g/cm3 Density (tapped) g/cm3 Density (true) g/cm3 Specific gravity 1.26 Melting point ºC. Functional Category HPMC posses a wide variety of functional categories such as rate controlling polymer for sustained release, film former, coating agent, stabilizing agent, viscosity-increasing agent, suspending agent and tablet binder CARBOPOL71 Nonproprietary Names BP: Carbopols,, PhEur: Carbopola, USPNF: Carbopol. Synonyms Acritamer, poly acrylic acid polymer, carbopol, carboxy poly methylene, acrylic acid, carboxyvinyl polymer.

28 28 Structural formula Acrylic acid monomer unit in carbopol resins. Fig: 1.4. Structure of Carbopol Acrylic acid monomer is the repeating monomer unit in carbopol polymer. The monomer unit is shown above. Allyl sucrose or allyl pentaerythritol are the cross linked polymer chains in carbopol. Molecular Weight Description Carbopols are colorless, fluffy, acidic, hygroscopic powders with a slight characteristic odor. Solubility It is soluble in water after neutralization in ethanol (95%) and glycerin. Carbopols merely swell to a remarkable extent but do not dissolve. Viscosity Carbopols forms low viscosity colloidal dispersions which are acidic in nature and forms viscous gels when gets neutralized.

29 29 Typical properties of Carbopol Glass transition temperature ºC Density (bulk) g/cm3 Density (tapped) 1.4 g/cm3 Specific gravity 1.41 Melting point 260ºC Functional Category Bioadhesive, emulsifying and release modifying agent, viscosity promoters, tablet binder and suspending agent POLY VINYL PYRROLIDONE (PVP) 71 Nonproprietary Names USP: Povidone, BP: Povidone, JP: Povidone, PhEur: Povidonum Synonyms Plasdone, Kollidon, polyvidone, poly vinyl pyrrolidone and 1vinyl-2-pyrrolidinone polymer Structural formula Fig: 1.5. Structure of PVP

30 30 Molecular Weight , 00,000 Description Povidone exists as a fine, white to creamy white colored, odorless, hygroscopic in nature. Moisture content Povidone at low relative humidity absorbs significant amounts of moisture and is very hygroscopic. Solubility It is freely soluble in water, methanol, ethanol (95%) and acids. Viscosity Both the concentration and the molecular weight of the polymer employed influence the viscosity of aqueous povidone solutions. Typical properties of PVP Density (bulk) g/cm3 Density (tapped) 1.4 g/cm3 Density (true) g/cm3 Melting point Softens at 150 ºC. Functional category PVP serves as tablet binder, suspending agent, film forming agent, disintegrating agent, dissolution aid.

31 SODIUM CARBOXY METHYL CELLULOSE (SCMC) 71 Nonproprietary Names USP: Carboxy methyl cellulose sodium, JP: Carmellose sodium BP: Carmellose sodium, PhEur: Carmellosum natricum Synonyms Akucell, aquasorb, cellulose gum, sodium cellulose glycolate Structural Formula Fig: 1.6. Structure of SCMC Molecular Weight 90,000-7, 00,000 Description It occurs as odorless granular white powder. Solubility SCMC forms clear, colloidal solution with water at all temperatures and insoluble in acetone, ethanol, ether and toluene. Viscosity Aqueous 1% w/v solutions with viscosities of 5 13,000 cp and solutions were stable at ph 4 10.

32 32 Typical properties of SCMC Dissociation constant pka = 4.30 Bulk density 0.52g/cm3 Tapped density 0.78 g/cm3 Melting point 252 ºC. Functional category Suspending agent, stabilizing agent, viscosity promoters, coating agent, tablet binder, disintegrating agent ETHYL CELLULOSE (EC) 71 Non proprietary Names USPNF: Ethylcellulose, BP: Ethylcellulose, PhEur : Ethylcellulosum Synonyms Aqualon; surelease; Aqua coat ECD; Aqualon; E 462; Ethocel;. Structural Formula Fig: 1.7. Structure of EC Chemical name Cellulose ethyl ether Description White to light tan colored, tasteless and free flowing powder.

33 33 Moisture content During immersion or humid air, EC absorbs very little amount of water and that small amount evaporates readily. Solubility It is freely soluble in chloroform, ethanol (95%), ethyl acetate, methanol and toluene. It is insoluble in water. Viscosity The viscosity of 5% w/v ethyl cellulose dissolved in toluene and ethanol at the ratio of 80:20 were calculated at room temperature and this solution is proportional to concentration of ethyl cellulose. Typical properties of EC Glass transition temperature ºC Density (bulk) 0.4 g/cm3 Specific gravity g/cm3 Functional category Used as a tablet binder, tablet filler, viscosity promoters and coating agent SODIUM ALGINATE71 Non proprietary Names USPNF: Sodium alginate, BP: Sodium alginate, PhEur : Natrii alginas, Synonyms Algin, alginic acid, Kelcosol, Protanal.

34 34 Structural Formula Fig: 1.8. Structure of Sodium alginate Description It occurs as white to pale yellowish-brown colored powder of odorless and tasteless. Solubility Sodium alginate is soluble in water and slowly forming a viscous colloidal solution. Insoluble in 95% ethanol, ether, chloroform and ethanol/water mixtures, organic solvents and aqueous acidic solutions in which the ph is less than 3. Viscosity Sodium alginate is commercially available in various grades of varying viscosity. Typically, a 1% w/v aqueous solution, at 20 oc, will have a viscosity of CP. Functional category Tablet binder, Stabilizer, suspending agent, tablet and capsule disintegrating agent, viscosity promoters

35 POLYMETHACRYLATES (EUDRAGIT) 71 Non-proprietary Names BP: Methacrylic acid ethyl acrylate copolymer (1:1) BP: Ammonio methacrylate copolymer Synonyms Methacrylic acid and Polymeric methacrylate Chemical Name Poly (ethyl acrylate, methyl methacrylate, tri methyl ammonio ethyl methacrylate chloride) Structural Formula R3 R1 R3 R1 C CH2 C CH2 C CH2 C CH2 C O C O C O C O O O O O R2 R4 R2 R4 For Eudragit RL and RS 100 Fig: 1.9. Structure of Eudragit R1 = H, CH3, R2 = CH3, C2H5, R3 = CH3, R4 = CH2 CH2 N(CH3)3+ClMolecular Weight 100,000 and approximately 135,000 Description Eudragit RS and Eudragit RL also referred to as ammonio methacrylate copolymers. Both polymers are Cationic, non-

36 36 biodegradable,which are insoluble in water and films that are prepared from Eudragit RL shows free permeability in water and Eudragit RS formed films shows slight permeation with water. Solubility It is Soluble in acetone, alcohol and dichloromethane, and insoluble in water and petroleum ether. Viscosity Eudragit RS100 is less than15 mp. Functional category Film former, binder and diluent in tablet formulations