In situ gel drug delivery system

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Hardik patel * Chirag Baladhiya , Paresh Desai, Parth Joshi Department of Pharmaceutics,sem.II Atmiya institute of pharmacy, Rajkot IN SITU GEL DRUG DELIVERY


In situ is a Latin phrase which translated literally as ' In position ‘ In situ gel is drug delivery systems that are in sol form before administration in the body, but once administered, undergo gelation in situ, to form a gel . Introduction Administration route for in situ gel oral, ocular, rectal, vaginal, injectable and intraperitoneal routes. IN SITU GEL DRUG DELIVERY 2

Advantages of in situ forming polymeric delivery systems:

Advantages of in situ forming polymeric delivery systems ease of administration Improved local bioavailability Reduced dose concentration Reduced dosing frequency, improved patient compliance and comfort. Its production is less complex and thus lowers the investment and manufacturing cost. IN SITU GEL DRUG DELIVERY 3

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Formulation 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. Various biodegradable polymers that are used for the formulation of in situ gels include gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly(DL lactic acid), poly(DL-lactide-co- glycolide) and poly- caprolactone . IN SITU GEL DRUG DELIVERY 4


APPROACHES OF IN SITU GEL DRUG DELIVERY Mechanisms used for triggering the in situ gel formation of biomaterials Physiological stimuli Physical changes in biomaterials Chemical reactions IN SITU GEL DRUG DELIVERY 5 (e.g., temperature and pH) (e.g., solvent exchange and swelling) (e.g., enzymatic, chemical and photo-initiated polymerization)

In situ formation based on physiological stimuli:

In situ formation based on physiological stimuli Thermally trigged system Temperature-sensitive hydrogels are classified into IN SITU GEL DRUG DELIVERY 6 Negatively thermosensitive Positively thermosensitive Thermally reversible gels (1, 3)

Positively thermosensitive:

Positively thermosensitive A positive temperature sensitive hydrogel has an upper critical solution temperature (UCST), such hydrogel contracts upon cooling below the UCST. E.g. poly(acrylic acid) (PAA) polyacrylamide ( PAAm ) poly( acrylamide -co-butyl methacrylate ) The most commonly used thermoreversible gels are prepared from poly(ethylene oxide)- b -poly(propylene oxide)- b -poly(ethylene oxide) ( Pluronics ®, Tetronics ®, poloxamer ) . IN SITU GEL DRUG DELIVERY 7

Negatively thermosensitive:

Negatively thermosensitive Negative temperature-sensitive hydrogels have a lower critical solution temperature (LCST) and contract upon heating above the LCST E.g. Poly(N- isopropylacrylamide )[ PNIPAAm ] water soluble at low LCST hydrophobic above LCST IN SITU GEL DRUG DELIVERY 8

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Polymer Phase transition temperature in aqueous solution LCST behaviour PNIPAM 30–34 °C Poly(N,N-diethylacrylamide) 32–34 °C Poly(methyl vinyl ether) 37 °C Poly(N-vinylcaprolactam) 30–50 °C (a) PEO-b-PPO 20–85 °C Poly(GVGVP) 28–30 °C UCST behaviour PAAm/PAAc IPN 25 °C (a) Strongly dependent on MW and concentration IN SITU GEL DRUG DELIVERY 9 above this temperature sol convert to gel form below this temperature sol convert to gel form

pH triggered systems :

pH triggered systems With increases external pH, Swelling of hydrogel increases if polymer contains weakly acidic (anionic) groups , decreases if polymer contains weakly basic (cationic) groups E.g. poly ( acrylic acid) (PAA) ( Carbopol ®, carbomer ) cellulose acetate phthalate(CAP) latex, polymethacrilic acid(PMMA) polyethylene glycol (PEG) pseudolatexes IN SITU GEL DRUG DELIVERY 10

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IN SITU GEL DRUG DELIVERY 11 Polyvinylacetal diethylaminoacetate (AEA) Solutions with a low viscosity at pH 4 Hydrogel at neutral pH condition Cellulose acetate phthalate (CAP) Solutions at pH 4.5 coagulation at pH 7.4 by the tear fluid

In situ formation based on physical mechanism :

In situ formation based on physical mechanism IN SITU GEL DRUG DELIVERY 12 Swelling Diffusion Myverol (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. 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) has been shown to be useful solvent for such system .

In situ formation based on chemical reactions:

In situ formation based on chemical reactions Following chemical reaction cause gelation IN SITU GEL DRUG DELIVERY 13 Enzymatic cross-linking Ionic crosslinking Photo-initiated processes

Ionic crosslinking:

Ionic crosslinking K- carrageenan forms rigid, brittle gels in presence of K + . I- carrageenan forms soft, elastic gels in presence of Ca 2+ . Gellan gum ( Gelrite ®) undergoes in situ gelling in the presence of mono- and divalent cations , including Ca 2+ , Mg 2+ , K + and Na + . Alginic acid undergoes gelation in presence of divalent/polyvalent cations . IN SITU GEL DRUG DELIVERY 14

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Helix formation by hydrogen bonding Chemical (covalent) cross linking Physical (non-covalent) cross linking e.g. carrageenansagar e.g. Alginates IN SITU GEL DRUG DELIVERY 15 Chelation of cation (.)

Enzymatic cross-linking:

Enzymatic cross-linking 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. Adjusting the amount of enzyme also provides a convenient mechanism for controlling the rate of gel formation, which allows the mixtures to be injected before gel formation. IN SITU GEL DRUG DELIVERY 16


Photo- polymerisation 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 . long wavelength ultraviolet and visible wavelengths are used. Short wavelength ultraviolet is not used because it has limited penetration of tissue and biologically harmful . Initiator 2,2 dimethoxy-2-phenyl acetophenone in ultraviolet light systems Camphorquinone and ethyl eosin in visible light systems. IN SITU GEL DRUG DELIVERY 17

Polymer used for in situ gel formulation:

Polymer used for in situ gel formulation Pectin ( an orally administered in situ gelling pectin formulation of Paracetamol ) Xyloglucan ( used for oral, ocular and rectal drug delivery) Gellan gum [ Gelrite TM or Kelcogel TM ] (an orally administered in situ gelling gellan formulation of theophylline ) Alginic acid ( for ophthalmic formulations ) Xanthum gum Chitosan Carbopol IN SITU GEL DRUG DELIVERY 18

Classification of In situ polymeric systems :

Classification of In situ polymeric systems IN SITU GEL DRUG DELIVERY 19


Oral-delivery Pectin, xyloglucan and gellan gum are used for in situ forming oral drug delivery systems. An orally administered in situ gelling pectin formulation for the sustained delivery of paracetamol has been reported. Main advantage of using pectin for these formulations is that it is water soluble, so organic solvents are not necessary in the formulation. IN SITU GEL DRUG DELIVERY 20

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In situ gelling gellan formulation as vehicle for oral delivery of theophylline is reported. The formulation consisted of gellan solution with calcium chloride and sodium citrate complex. When administered orally, the calcium ions are released in acidic environment of stomach leading to gelation of gellan thus forming a gel in situ. IN SITU GEL DRUG DELIVERY 21

Ocular- delivery:

Ocular- delivery Polymer used :- Gellan gum, alginic acid and xyloglucan Drug used for Ocular in situ drug delivery:- Antimicrobial agents, antiinflammatory agents and autonomic drugs used to relieve intraocular tension in glaucoma. IN SITU GEL DRUG DELIVERY 22

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Conventional delivery systems often result in poor bioavailability and therapeutic response because high tear fluids turn over and dynamics cause rapid elimination of the drug from the eye . So, to overcome bioavailability problems, ophthalmic in situ gels were developed. Drug release from these in situ gels is prolonged due to longer precorneal contact times of the viscous gels compared with conventional eye drops. IN SITU GEL DRUG DELIVERY 23

Nasal -drug delivery system:

Nasal -drug delivery system In-situ gel was found to inhibit the increase in nasal symptoms in treatment of allergic rhinitis as compared to marketed formulation nasonex ( mometasone furoate suspension 0.05%). for nasal delivery of insulin- The formulation was in solution form at room temperature that transformed to a gel form when kept at 37 o C. Nasal in situ drug delivery system is suitable for protein and peptide drug delivery through nasal route. IN SITU GEL DRUG DELIVERY 24

Rectal and vaginal -delivery:

Rectal and vaginal -delivery Miyazaki et al. investigated the use of xyloglucan based thermo reversible gels for rectal drug delivery of indomethacin. They observe that in situ gel has broad drug absorption peak and a longer drug residence time as compared to 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 IN SITU GEL DRUG DELIVERY 25

Injectable-Drug Delivery Systems:

Injectable-Drug Delivery Systems A novel, injectable, thermosensitive in situ gelling hydrogel was developed for tumor treatment. This hydrogel consisted of drug loaded chitosan solution neutralized with β- glycerophosphate. IN SITU GEL DRUG DELIVERY 26


COMMERCIAL FORMULATIONS OF IN-SITU POLYMERIC SYSTEMS Timoptic -XE It is a timolol maleate ophthalmic gel formulation of Merck and Co. Inc. , supplied as a sterile, isotonic, buffered, aqueous gel forming solution of timolol maleate . Dosage strengths 0.25% and 0.5% in market . (Each ml of Timoptic -XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate ). pH of solution is approximately 7.0 Inactive ingredients include gellan gum, tromethamine , mannitol , and water for injection and the preservative used is benzododecinium bromide 0.012%. IN SITU GEL DRUG DELIVERY 27

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Regel is one of the Macromed's proprietary drug delivery system and based on triblock copolymer, composed of poly ( lactide -co- glycolide ), poly (ethylene glycol), poly( lactide -co- glycolide ). It is a thermally reversible gelling polymers developed for parenteral delivery that offers a range of gelation temperature, degradation rates and release characteristics as a function of molecular weight, degree of hydrophobicity and polymer concentration. IN SITU GEL DRUG DELIVERY 28

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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. hGHD-1 is a novel injectable depot formulation of human growth hormone (hGH) utilizing Macromed's Regel drug delivery system for treatment of patients with hGHdeficiency IN SITU GEL DRUG DELIVERY 29


EVALUATION OF IN SITU GEL Viscosity and rheology Measured 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 arised during their administration by the patient, especially during parenteral and ocular administration. Clarity The clarity of formulated solutions determined by visual inspection under black and white background. IN SITU GEL DRUG DELIVERY 30

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Texture analysis Firmness, consistency and cohesiveness of formulation are assessed using texture analyzer which 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. IN SITU GEL DRUG DELIVERY 31

Determination of mucoadhesive Force:

Determination of mucoadhesive Force IN SITU GEL DRUG DELIVERY 32 Mucoadhesive force was the minimum weight required to detach two vials.

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sol-gel transition temperature may be defined as that temperature at which the phase transition from sol meniscus to gel meniscus is occurred. 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. IN SITU GEL DRUG DELIVERY 33 solution Gel Sol-Gel transition temperature & gelling time


Gel-Strength This parameter can be evaluated using a rheometer . Method: 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. IN SITU GEL DRUG DELIVERY 34 Weight Probe Mess cylinder Poloxamer gel

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Thermogravimetric analysis can be conducted for in situ forming polymeric systems to quantitate the percentage of water in hydrogel. Differential scanning calorimetry is used to observe if there are any changes in thermograms as compared with the pure ingredients used thus indicating the interactions . IN SITU GEL DRUG DELIVERY 35

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In-vitro drug release studies The drug release studies are carried out by using the plastic dialysis cell which is made up of two half cells, donor compartment and a receptor compartment . Both half cells are separated with the help of cellulose membrane. Sol form of formulation is placed in donor compartment. The assembled cell is then shaken horizontally in an incubator. The total volume of the receptor solution can be removed at intervals and replaced with the fresh media. This receptor solution is analyzed for the drug release using analytical technique. IN SITU GEL DRUG DELIVERY 36

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For injectable in situ gels The formulation is placed into vials containing receptor media and placed on a shaker water bath at required temperature and oscillations rate. Samples are withdrawn periodically and analyzed. IN SITU GEL DRUG DELIVERY 37

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IN SITU GEL DRUG DELIVERY 38 Drug Polymer used Route of administration Results Theophylline Gellan gum Oral Four – five fold increase of bioavailability in rats and three fold in rabbits as compared to comercial oral formulation Doxorubicine Human serum albumin and tartric acid derivative Injectable Sustained delivery of anti cancer drug for a long period app. A00 h. Paracetamol and Ambroxol Pectin Oral Sustained oral delivery Metoclopramide hydrochloride Poloxamer 407 and polyethylene glycol Nasal Ease of administration, accuracy of dosing, prolonged nasal residence and improved drug bioavailability Cinnarizine 4% of sodium alginate with 0.5% of calcium carbonate Oral Formulation having sustained drug action for 12 hours. Summary of some reported study investigating the sustained release by in situ gel

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IN SITU GEL DRUG DELIVERY 39 Drug Polymer used Route of administration Results Sumatriptan Pluronic F127 (PF127) and Carbopol 934P Nasal prolonging nasal residence time and increase nasal absorption Timolol Maleate Carbopol and Chitosan Ocular Therapeutically efficacious and showed a diffusion controlled type of release behaviour over 24 h periods. clarithromycin and metronidazole benzoate Sodium alginate and CaCO 3 Oral Sustained oral delivery Itraconazole (1%w/w). Polaxamer with carbopol 934 oral topical gels ( mucoadhesive buccal gel) increase in Buccal residence time and patient comfort Salbutamol Sulphate carbopol 934 and HPMC nasal sustained release and higher bioavailability.

Possible Questions:

Possible Questions IN SITU GEL DRUG DELIVERY 40 Classify in situ gel drug delivery system according to their route of administration and discuss which type of polymer used in each route of drug delivery system. Discuss mechanisms involving for triggering the in situ gel formation of biomaterials and advantages of in situ gel drug delivery system. Brief note on evalution parameter of in situ gel formulation. ? ? ?


References M madan, A bajaj, S lewis, N udupa , JA baig, review article : in situ forming polymeric drug delivery systems , . Int J Pharm sci, 2009; vol.7 ; 3: 242-251 Nirmal H.B.*, Bakliwal S.R., Pawar S.P., In-Situ gel: New trends in Controlled and Sustained Drug Delivery System, Int J Pharm Tech Research, 2010; ISSN : 0974-4304 ; Vol.2, No.2:1398-1408. Peppas na, langer r. New challenges in biomaterials. Science 1994;263:1715-20. Ni Y, Kenneth MY. In-situ gel formation of pectin. 2004. United States Patent 6777000. IN SITU GEL DRUG DELIVERY 41

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Zhidong l, jaiwei l, shufang n, hui l, pingtian d, weisan p. Study of an alginate/HPMC based in situ gelling ophthalmic delivery system for gatifloxacin. Int J pharm 2006;315:12-7. Al-tahami k, singh j. Smart polymer based delivery systems for peptides and proteins. Recent pat drug deliv formul 2007;1:66-71. 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. Miyazaki S, Suzuki S, Kawasaki N, Endo K, Takahashi A, Attwood D. In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride. Int J Pharm 2001;229:29-36. IN SITU GEL DRUG DELIVERY 42

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