INSITU DRUG DELIVERY

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IN-SITU DRUG DELIVERY: 

IN-SITU DRUG DELIVERY BY MAHESH P 2 nd SEMESTER M.PHARM PHARMACEUTICS 1

INTRODUCTION: 

Insitu drug delivery systems are in sol form before administration in the body, but once administered undergo gelation insitu to form gel. The formation of gels depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation , from which the drug gets released in a sustained and controlled manner INTRODUCTION 2

ADVANTAGES OF INSITU DELIVERY: 

ease of application, localized delivery for a site-specific action, prolonged delivery periods, decreased body drug dosage with concurrent reduction in possible undesirable side effects common to most forms of systemic delivery, Improved patient compliance and comfort. ADVANTAGES OF INSITU DELIVERY 3

APPROACHES TO INSITU DRUG DELIVERY: 

Physiological stimuli (e.g., temperature and pH ) P hysical changes in biomaterials (e.g., solvent exchange and swelling ) C hemical reactions (e.g. Enzymatic, chemical and photo-initiated polymerization ). APPROACHES TO INSITU DRUG DELIVERY 4

In situ formation based on physiological stimuli: : 

Thermally trigged system transitions from sol-gel is triggered by increase or decrease in temperature 3 strategies: Negatively thermosensitive (poly N- isopropylacrylamide ) Positively thermosensitive (poly acrylicacid , polyacrylicamide ) Thermally reversible( pluronics , tetronics ) In situ formation based on physiological stimuli: 5

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All the pH-sensitive polymers contain pendant acidic or basic groups that either accept or release protons in response to changes in environmental pH . Swelling of hydrogel increases as the external pH increases in the case of weakly acidic (anionic) groups, but decreases if polymer contains weakly basic (cationic) groups Eg : PAA, polyvinylacetate diethylaminoacetate (sol at pH 4 but gel at nuetral pH), PEG+PMA etc pH triggered systems 6

In situ formation based on physical mechanism : 

Swelling In situ formation may also occur when material absorbs water from surrounding environment and expand to occur desired space myverol 18-99 (glycerol mono- oleate ), which is polar lipid that swells in water to form lyotropic liquid crystalline phase structures. It has some Bioadhesive properties and can be degraded invivo by enzymatic action In situ formation based on physical mechanism 7

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This method involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or solidification of polymer matrix. N methyl pyrrolidone (NMP) Diffusion 8

In situ formation based on chemical reactions: 

Ionic crosslinking Polymers may undergo phase transition in presence of various ions k-carrageenan forms rigid, brittle gels in reply of small amount of K +, i-carrageenan forms elastic gels mainly in the presence of Ca2 + Gelrite ® is an anionic polysaccharide that undergoes in situ gelling in the presence of mono- and divalent cations , including Ca2+, Mg2+, K+ and Na +. Alginic acid undergoes gelation in presence of divalent/polyvalent cations e. g. Ca2+ due to the interaction with gulcuronic acid block in alginate In situ formation based on chemical reactions 9

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an enzymatic process operates efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators . Cationic pH-sensitive polymers containing immobilized insulin and glucose oxidase can swell in response to blood glucose level releasing the entrapped insulin in a pulsatile fashion Enzymatic cross-linking 10

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A solution of monomers or reactive macromer and initiator can be injected into a tissues site and the application of electromagnetic radiation used to form gel . acrylate polymerizable functional groups are typically used as monomers and macromers because they rapidly undergo photo- polymerisation in the presence of suitable photo initiator. 2,2 dimethoxy-2-phenyl acetophenone for UV systems Camphorquinone for vis systems Photo- polymerisation 11

POLYMERS USED IN INSITU GEL: 

POLYMERS USED IN INSITU GEL & 12

NATURAL: 

PECTIN NATURAL 13

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Pectins are polysaccharides, in which the polymer backbone mainly comprises α-(1-4)-D galacturonic acid residues. Low methoxypectins (degree of esterification <50%) readily form gel it is water soluble. Sodium citrate may be added to the pectin solution to form a complex with most of calcium ions added in the formulation. The potential of an orally administered in situ gelling pectin formulation for the sustained delivery of Paracetamol has been reported , Wataru K, Yasuhiro K, Miyazaki S, Attwood D. Drug Develop Ind Pharm 2004;30:593-9. 14

xyloglucan: 

xyloglucan 15

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Xyloglucan is a polysaccharide derived from tamarind seeds and is composed of a (1-4)-β-D- glucan backbone chain , which has (1-6)-α-D xylose branches that are partially substituted by (1-2)- β-D- galactoxylose . When xyloglucan is partially degraded by β- galactosidase , the resultant product exhibits thermally reversible gelation by the lateral stacking of the rod like chains Its potential application in oral delivery exploits the slow gelation time Xyloglucan gels have been used for oral, intraperitoneal, ocular and rectal drug delivery 16

Xanthan gum: 

Xanthan gum 17

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Xanthan gum is a high molecular weight extra cellular polysaccharide produced by the fermentation of the gram-negative bacterium Xanthomonas campestris structure of this naturally produced cellulose derivative contains a cellulosic backbone ( β- D-glucose residues) and a trisaccharide side chain of β- D-mannose- β- D- glucuronicacid - α- D-mannose 18

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19 GELLANGUM

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Gellan gum is an anionic deacetylated exocellular polysaccharide secreted by Pseudomonas elodea with a tetrasaccharide repeating unit of one α-L- rhamnose , one β-D- glucuronic acid and two β-D- glucuronic acid residues gelation is temperature dependent or cations induced . This gelation involves the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by complexation with cations and hydrogen bonding with water 20

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21 CHITOSAN

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Chitosan is a biodegradable, thermosensitive , polycationic polymer obtained by alkaline deacetylation of chitin, a natural component of shrimp and crab shell . remains dissolved in aqueous solutions up to a pH of 6.2 Neutralization of chitosan aqueous solution to a pH exceeding 6.2 leads to the formation of a hydrated gel 22

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23 CARBOPOL

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pH dependent polymer, which stays in solution form at acidic pH but forms a low viscosity gel at alkaline pH . For example indomethacin occular drug delivery has been formulated for uveitis Sustained release for 8h was observed A pH induced in-situ precipitating polymeric system (an aqueous solution of carbopol -HPMC system) was designed and developed by Ismail et al . for plasmid DNA delivery . 24

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Poloxamers or pluronic are the series of commercially available difunctional triblock copolymers of non-ionic nature . They comprise of a central block of relatively hydrophobic polypropylene oxide surrounded on both sides by the blocks of relatively hydrophilic poly ethylene oxide . Pluronics or Poloxamers also undergo in situ gelation by temperature change . They are triblock copolymers consisting of poly( oxyethylene ) and poly( oxypropylene ) units that undergo changes in solubility with change in environment temperature. Pluronic ™ F 127. A 25-40% aqueous solution of this material will gel at about body temperature, and drug release from such a gel occurs over a period of up to one week PLURONIC F-127 25

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26 Miyazaki, et al (5, 28,45 ). Indomethacin , anticancer agents, (adriamycin,5 flurouracil ), and mitomycin C in PF127. PF-127 is a good vehicle for topical and rectal administration of Indomethacin and excellent for sustained–release of mitomycin . Wang, et al (52 ). In vitro and in vivo skin absorption of capsaicin and nonivamide from hydrogels. Moderate correlation between in vitro skin permeation and in vivo erythema responses of topically applied capsaicin and nonivamide . Kattan , et al (53 ). Effect of four terpene enhancers on the percutaneous permeation of ketoprofen . The highest increase in the ketoprofen permeation was observed using limonene followed by nerolidol , fenchone , and thymol Chi, et al (54 ). Anti-inflammatory and analgesic transdermal gel. Prolonged anti-inflammatory and analgesic activities

SYNTHETIC POLYMERS: 

Aliphatic polyesters such as poly (lactic acid), poly (glycolic acid), poly ( lactide - coglycolide ), poly ( decalactone ), poly ε- caprolactone These polymers are mainly used for the injectable in situ formulations . Another type of synthetic polymeric system includes the in situ cross linked system, where the polymers form cross linked networks by means of free radical reactions that may occur by means of light ( photopolymerizablesystems ) or heat( thermosettingsystems ). SYNTHETIC POLYMERS 27

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Thermosetting polymers are other type of synthetic polymers Sol- gel transition is called as curing Curing mainly involves the formation of covalent cross links between polymer chains to form a macromolecular network Eg : co polymer of DL lactide with poly caprolactone for prosthetic implants 28

APPLICABILITY OF IN SITU POLYMERIC DRUG DELIVERY SYSTEM : 

APPLICABILITY OF IN SITU POLYMERIC DRUG DELIVERY SYSTEM 29

ORAL DELIVERY : 

Pectin, xyloglucan and gellan gum are the natural polymers used for in situ forming oral drug delivery systems. pectin is water soluble Xyloglucan forms thermally reversible gels on warming to body temperature. slow gelation time (several minutes) that would allow in situ gelation in the stomach following the oral administration of chilled xyloglucan solution. ORAL DELIVERY 30

OCCULAR DELIVERY : 

The following characteristics are required to optimize ocular drug delivery systems. A good corneal penetration. A prolonged contact time with corneal tissue. Simplicity of installation for the patient. A non- irritative and comfortable form (the viscous solution should not provoke lachrymation and reflex blinking). Appropriate rheological properties and concentration OCCULAR DELIVERY 31

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These systems have the advantages : Prolonged drug release Reduced systemic side effects Reduced number of applications Better patient compliance. Generally more comfortable than insoluble or soluble insertion. Less blurred vision as compared to ointment 32

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gellan gum (temp and ionic), alginic acid(ionic crosslinking) and xyloglucan are most commonly used polymers Drug release from these in situ gels is prolonged due to longer precorneal contact times of the viscous gels compared with conventional eye drops 33

NASAL DRUG DELIVERY : 

. Gellan gum and xanthan gum were used as in situ gel forming polymers An in situ gel system for nasal delivery of mometasone furoate was developed and evaluated for its efficacy for the treatment of allergic rhinitis Wu et al. designed a new thermosensitive hydrogel by simply mixing N-[(2-hydroxy-3-methyltrimethylammonium)propyl]chitosan chloride and poly (ethylene glycol) with a small amount of α-β- glycerophosphate ; for nasal delivery of insulin NASAL DRUG DELIVERY 34

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The formulation was in solution form at room temperature that transformed to a gel form when kept at 37°. Animal experiments demonstrated hydrogel formulation to decrease the blood-glucose concentration by 40-50% of the initial values for 4-5 h after administration with no apparent cytotoxicity. 35

RECTAL & VAGINAL DELIVERY : 

Miyazaki et al . investigated the use of xyloglucan based thermoreversible gels for rectal drug delivery of indomethacin. Administration of indomethacin loaded xyloglucan based systems to rabbits indicated broad drug absorption peak and a longer drug residence time as compared to that resulting after the administration of commercial suppository . For a better therapeutic efficacy and patient compliance, mucoadhesive , thermosensitive , prolonged release vaginal gel incorporating clotrimazole - β- cyclodextrin complex was formulated for the treatment of vaginitis . RECTAL & VAGINAL DELIVERY 36

EVALUATION AND CHARACTERIZATIONS OF IN SITU GEL SYSTEM: 

Clarity Texture analysis Sol-Gel transition temperature and gelling time Gel-Strength Viscosity and rheology Fourier transform infra-red spectroscopy and T hermal analysis In-vitro drug release studies Histopathological studies EVALUATION AND CHARACTERIZATIONS OF IN SITU GEL SYSTEM 37

Texture analysis : 

The firmness, consistency and cohesiveness of formulation are assessed using texture analyzer mainly indicates the syringeability of sol so the formulation can be easily administered in-vivo . Higher values of adhesiveness of gels are needed to maintain an intimate contact with surfaces like tissues . Texture analysis 38

Sol-Gel transition temperature and gelling time : 

the sol-gel transition temperature may be defined as that temperature at which the phase transition of sol meniscus is first noted when kept in a sample tube at a specific temperature and then heated at a specified rate Gel formation is indicated by a lack of movement of meniscus on tilting the tube. Gelling time is the time for first detection of gelation Sol-Gel transition temperature and gelling time 39

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Gel strength This parameter can be evaluated using a rheometer This gel containing beaker is raised at a certain rate, so pushing a probe slowly through the gel . The changes in the load on the probe can be measured as a function of depth of immersion of the probe below the gel surface 40

In-vitro drug release studies: 

For the in situ gel formulations to be administered by oral, ocular or rectal routes, the drug release studies are carried out by using the plastic dialysis cell The cell is made up of two half cells, donor compartment and a receptor compartment. Both half cells are separated with the help of cellulose membrane In-vitro drug release studies 41

Fourier transform infra-red spectroscopy and thermal analysis: 

During gelation process, the nature of interacting forces can be evaluated using this technique by employing potassium bromide pellet method Thermo-gravimetric analysis can be conducted for in situ forming polymeric systems to quantitate the percentage of water in hydrogel Fourier transform infra-red spectroscopy and thermal analysis 42

Viscosity and rheology: 

Viscosity and rheological properties of in situ forming drug delivery systems may be assesses using Brookfield rheometer or some other type of viscometers such as Ostwald's viscometer . the viscosity of these formulations should be such that no difficulties are envisaged during their administration by the patient, especially during parenteral and ocular administration. Viscosity and rheology 43

COMMERCIAL FORMULATIONS OF IN-SITU POLYMERIC SYSTEMS: 

Timoptic -XE: sterile, isotonic, buffered , aqueous gel forming solution of timolol maleate, Merck and Co. Inc . Regel:depot-technology : Oncogel is a frozen formulation of paclitaxel in Regel . It is a free flowing liquid below room temperature which upon injection forms a gel in-situ in response to body temperature . Cytoryn : This is one of the Macromed's products, which is a novel , peritumoral , injectable depot formulation of interleukin-2 (IL-2) for cancer immunotherapy COMMERCIAL FORMULATIONS OF IN-SITU POLYMERIC SYSTEMS 44

conclusion: 

Patient compliance offered by insitu drug delivery Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable . Variuos advantages over conventional dosage forms conclusion 45

REFERENCE: 

Indian Journal of Pharmaceutical Sciences In Situ Forming Polymeric Drug Delivery Systems M . Madan , * A. Bajaj, S. Lewis, 1 N. Udupa, 1 and J. A. Baig 2 C . U. Shah College of Pharmacy, S. N. D.T. Women's University, Mumbai-400 049, India, May-Jun ; 71(3): 242–251 . In-Situ gel: New trends in Controlled and Sustained Drug Delivery System Nirmal H.B.*, Bakliwal S.R., Pawar S.P. P.S.G.V.P.M’s College of Pharmacy, Shahada , Nandurbar-425409, Maharashtra, India. Vol.2, No.2, pp 1398-1408, April-June 2010 REFERENCE 46

PowerPoint Presentation: 

. Wataru K, Yasuhiro K, Miyazaki S, Attwood D. In situ gelling pectin formulations for oral sustained delivery of paracetamol . Drug Develop Ind Pharm. 2004;30:593–9 . Kawasaki N, Ohkura R, Miyazaki S, Uno Y, Sugimoto S, Attwood D. Thermally reversible xyloglucan gels as vehicles for oral drug delivery. Int J Pharm. 1999;181:227–34. In-Situ Gelling System: A Review * Harnish Patel1, Priyanka Patel2, Tushar Brahmbhatt1 and Mayur Suthar , J. Chem. Pharm. Res., 2011, 3(6):217-221 47