In-situ Gels and Hydrogels

In-situ Gels and Hydrogels

Introduction:2

Hydrogels are crosslinked polymer networks that absorb substantial amounts of aqueous solutions.

These crosslinks provide the network structure and

physical integrity.

Hydrogels can contain over 99.9% water.

The high water content of the materials contributes to

their biocompatibility.

What is a Hydrogel?Three-dimensional networks of hydrophilic polymer chains that do not dissolve but can swell in water.Cross-links produced through:Chemical reaction to form covalent bondsEntanglement of polymersHydrogen bonding and van der Walls forces

PropertiesBoth solid like and liquid like propertieshigh biocompatibilityEnvironmental stimuli respondent (temperature, pH, light, specific molecules)Ideal for controlled drug delivery

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Advantages Of Hydrogels

Adaptable targeting system, allowing great flexibility for many different drugs.

Offers more accurate drug placement.

Creating a more precise response and fewer side effects.

Non-toxic and biocompatible, raising the level of bio-safety for the patient.

Absence of Phagocytosis by macrophages.

Advantages of HydrogelsEnvironment can protect cells and other substances (i.e. drugs, proteins, and peptides)

Timed release of growth factors and other nutrients to ensure proper tissue growth

Good transport properties

Biocompatible

Can be injected

Easy to modify

Disadvantages of Hydrogels Low mechanical strength

Hard to handle

Difficult to load

Sterilization

Because of these qualities it gained different names like intelligent gels or smart hydrogels. The smartness of any material is the key to its ability to receive, transmit or process a stimulus, and respond by producing a useful effect. 8Hydrogels are smart or intelligent in the sense that they can recognize the predominant stimuli and respond by displaying changes in their physical or chemical behavior, resulting in the release of entrapped drug in a controlled manner.

9Some hydrogels undergo continuous or discontinuous changes in swelling that are mediated by external stimuli such as changes in pH, temperature, ionic strength, solvent type, electric and magnetic elds, light, and the presence of chelating species.

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Hydrogel : Swellable Polymeric Materials Hydrogels are three dimensional networks of hydrophilic polymers.

Extremely absorbent and possess a degree of flexibility very similar to natural tissue . Drug encapsulated in a hydrogel matrix is only released after contact with organ-or tumor-specific molecules (e.g. surface proteins).

The majority of stimuli responsive hydrogels were created using conventional (traditional) methods of synthesis of a relatively small number of synthetic polymers, especially (meth) acrylate derivatives and their copolymers. 12Classification- various criteria for the classification of hydrogelsOriginNaturalSyntheticWater content or degree of swellingLow swellingMedium swellingHigh swellingSuperabsorbentPorosityNonporousMicroporousMacroporousSuperporousCross-linkingChemical (covalent bonding)Physical (noncovalent bonding)BiodegradabilityBiodegradableNondegradable13

Classification Of Hydrogels:

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Types of Hydrogel Polymers Natural Polymers Dextran, Chitosan, Collagen, Dextran Sulfate

AdvantagesGenerally have high biocompatibilityIntrinsic cellular interactionsBiodegradableCell controlled degradabilityLow toxicity byproducts

DisadvantagesMechanical StrengthBatch variationAnimal derived materials may pass on virusesTypes of Hydrogel Polymers Synthetic Polymers PEG-PLA-PEG, Poly (vinyl alcohol)

AdvantagesPrecise control and mass producedCan be tailored to give a wide range of properties (can be designed to meet specific needs)Low immunogenecity Minimize risk of biological pathogens or contaminants

DisadvantagesLow biodegradabilityCan include toxic substances

Combination of natural and syntheticCollagen-acrylate, P (PEG-co-peptides)

Properties of HydrogelsSwelling properties influenced by changes in the environment pH, temperature, ionic strength, solvent composition, pressure, and electrical potential

Can be biodegradable, bioerodible, and bioabsorbable

Can degrade in controlled fashion

Properties of HydrogelsPore Size

Fabrication techniques

Shape and surface/volume ratio

H2O content

Strength

Swelling activationProperties and Structures of HydrogelsRs = (Ws-Wd) / WdRs = swelling ratioWs = weight of swollen hydrogelsWd = weight of dried hydrogels

Swelling property is influenced by:type and composition of monomersother environmental factors such as :temperature, pH, ionic strengthcross-linking

Mechanical strength and permeabilityCross-linking and/or copolymerization with hydrophobic comonomers density, mechanical strength, swelling property19How theyre made.Can cross link polymers via:HeatPressure Chemical reactionPhotopolymeriziationUse light UV, visibleRadiationElectron beamsGama rays X-rays

How theyre made.Radical chain reaction used to form cross linksCrosslinkersAcrylate, double bond forms radical

Hydrogel FabricationChemical hydrogelsPhysical hydrogels Hydrogen bonding hydrophobic interaction crystallinity stereocomplex formation ionic complexation Covalently crosslinkedNoncovalently crosslinkedThermoset hydrogelsThermoplastic hydrogelsVolume phase transition Sol-gel phase transition Reliable shape stability and memoryLimited shape stability and memory22Hydrogel FabricationPhysical crosslinking Ionic hydrogel

Chemical and Physical crosslinking

Cross-linking without chemical reactionionic interaction, hydrogen bonding, antigen-antibody interaction, supramolecular association23Hydrogel Fabrication+MonomerCrosslinkerVinyl group-containing water-soluble polymers CopolymerizationPolymerizationHydrogel networkChemical crosslinkingPolymerization of water soluble monomers in the presence of bi- or multifunctional cross-linking agentor24Applications of Hydrogels in Drug Delivery - Benefits of controlled drug delivery more effective therapies with reduced side effects the maintenance of effective drug concentration levels in the blood patients convenience as medicines hence increased patient compliance

- Release mechanisms of drug molecules : diffusion, dissolution, osmosis, ion exchange25Applications of Hydrogels in Drug Delivery Environment-Sensitive Hydrogels respond to environmental change : temperature, pH, specific molecule reversible volume phase transition or sol-gel phase transition intelligent or smart hydrogel Drug-loaded gelChange in pH for gel swellingDrug release through the swollen networkDrug release by the squeezing actionChange in temperature for gel collapse2627

Hydrogel can be delivered by any of the following routsApplications of Hydrogels Soft contact lensesPills/capsulesBioadhesive carriersImplant coatingsTransdermal drug deliveryElectrophoresis gelsWound healingChromatographic packaging material Applications of Hydrogels in Drug Delivery - Benefits of controlled drug delivery more effective therapies with reduced side effects the maintenance of effective drug concentration levels in the blood patients convenience as medicines hence increased patient compliance

- Release mechanisms of drug molecules : diffusion, dissolution, osmosis, ion exchange29Applications of Hydrogels in Drug Delivery - Diffusion controlled Drug Delivery(1) Polymer matrixWater-insolublePolymer matrices(2) Reservoir systemtimeWater-insolublePolymer membranetime30Applications of Hydrogels in Drug Delivery Environment-Sensitive Hydrogels respond to environmental change : temperature, pH, specific molecule reversible volume phase transition or sol-gel phase transition intelligent or smart hydrogel Drug-loaded gelChange in pH for gel swellingDrug release through the swollen networkDrug release by the squeezing actionChange in temperature for gel collapse31UsesBiomaterial, coatings for medical devices, contact lensesBiologically compatibleDrug deliveryDegradable, swelling propertiesMany other biological applicationsDevelop human tissuesFood- Jello

Basic difference in gel and hydrogelBoth gels and hydrogels might be similar chemically, but they are physically distinct. D. Jordan suitably described gels as The colloidal condition, the gel, is one which is easier to recognize than to defineTechnically, gels are semi-solid systems comprising small amounts of solid, dispersed in relatively large amounts of liquid, having more solid-like than liquid-like character. Sometimes, hydrogels are also described as aqueous gels because of the prefix hydro. 33Although the term hydrogel implies a material already swollen in water, while in a true sense hydrogel is a cross-linked network of hydrophilic polymers. They possess the ability to absorb large amounts of water and swell, while maintaining their three-dimensional (3D) structure. 34hydrogels display swelling in aqueous media for the same reasons that an analogous linear polymer dissolves in water to form an ordinary polymer solution. Thus, the feature central to the functioning of a hydrogel is its inherent cross-linking.Conventional gels can also develop small levels of cross-links as a result of a gain in energy under the influence of shear forces, but these are reversible35Because of the above quality hydrogels is a polymer network, these polymers produce systems that extend a range of rigidities, beginning with a sol and increasing to jelly, gel and hydrogel. Thus, hydrogel, sometimes referred to as xerogel, is a more rigid form of gel3636Environmental FactorTypical polymersMain Mechanism

ApplicationsTemperaturePNIPAAm, PDEAAm, PEO-PPO block copolymersCompetition between hydrophobic interaction and hydrogen bondingOn/off drug release, squeezing devicepHPolyelectrolytes, PAA, PDEAEMIonization of polymer chains upon pH changepH-dependent oral drug deliveryGlucose

pH-sensitive hydrogels; Concanavalin A-grafted polymers; polymers containing phenylborate groups

pH change caused by glucose oxidase; reversible interaction between glucose-containing polymers and Concanavalin A; reversible solgel transformationSelf-regulated insulin delivery

Electric signal

Polyelectrolytes (pH-sensitive)Reversible swelling or deswelling in the presence of electric fieldActuator, artificial muscle, on off drug releaseLight

Copolymer of PNIPAAm and light sensitive chromophore, such as triphenylmethane and leuco derivativesTemperature change via the incorporated photosensitive molecules; dissociation into ion pairs by UV irradiationOptical switches, ophthalmic drug delivery

AntigenSemi-IPN with grafted antibodies or antigensCompetition between polymer-grafted antigen and free antigenModulated drug release in the presence of a specific antigen; sensor for immunoassay and antigen Environmental-Sensitive Hydrogels used for Drug Delivery37Specific applications of Hydrogels in Oral Drug Delivery

38SummaryHydrogels have played role in the development of various controlled-release formulationbiocompatible and increasing the solubility of poorly soluble drugHydrogels with novel properties will continue to play important role in drug delivery smart hydrogels and new controlled-release formulation39In Situ GelIt is a drug delivery system which is in a solution form before the administration in the body but it converts in to a gel form after the administration.

There are various routes such as oral, ocular, vaginal, rectal, I/V , intraperitoneal etc40AdvantagesEase of administrationImproved local bioavailabilityReduced dose concentrationReduced dosing frequencyImproved patient compliance and comfortSimple formulation and manufacturing so less investment and cost 41There are various factors such as Temp. modulation, pH change, presence of ions, UV irradiation, solvent exchange and from which drug release in a sustained manner Various biodegradable polymers used are: Gellan gum Poloxamer Pectin Chitosan Poly(DL lactic acid) Poly(DL lactide-co-glycolide) Poly-caprolactone Alginic acid Xyloglucan42APPROACHES OF IN SITU GEL DRUG DELIVERYThere are certain broadly defined mechanisms used for triggering the in situ gel formation of biomaterials: Physiological stimuli (e.g., temperature and pH), Physical mechnism-changes in biomaterials (e.g., swelling and solvent exchange-Diffusion ), Chemical reactions (e.g. ionic, enzymatic, and photo-initiated polymerization)43In situ formation based on Physiological stimuliThermally triggered systems Temperature-sensitive hydrogels are probably the most commonly studied class of environment sensitive polymer systems in drug delivery research. The use of biomaterial whose transitions from sol-gel is triggered by increase in temperature, is an attractive way to approach in-situ formation. The ideal critical temperature range for such system is ambient and physiologic temperature, such that clinical manipulation is facilitated and no external source of heat other than that of body is required for triggering gelation. A useful system should be tailorable to account for small differences in local temperature, such as might be encountered in appendages at the surface of skin or in the oral cavityThey are classified into Positively thermosensitive Negatively thermosensitive Thermally reversible gels44Positively thermosensitiveA positive temp sensitive hydrogel is having upper critical solution temperature(UCST), such hydrogels contracts upon cooling below this UCST Ex. Poly(acrylic acid)(PAA), Poly(acrylamide) (PAAm), Poly(acrylamideco- butyl methacrylate).

Negatively thermosensitiveIt has lower critical solution temperature(LCST), contracts upon heating above LCSTEx. poly(N-isopropylacrylamide) (PNIPAAm) PNIPAAm is a water soluble polymer at its low LCST, but hydrophobic above LCST, which result on precipitation of PNIPAAm from the solution at the LCST.45Mostly used Thermo reversible gels are prepared from Pluronics andTetronics Pluronics are poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPOPEO) triblock co-polymer that are fluid at low temperature, but forms thermo responsible gel when heated as a consequences of a disorder-order transition in micelle packing which makes these polymers suitable for in situ gelation.46pH triggered systemsAll the pH-sensitive polymers contain pendant acidic or basic groups that either accept or release protons in response to changes in environmental pH .The polymers with a large number of ionizable groups are known as polyelectrolytes. 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 The most of anionic pH-sensitive polymers are based on PAA,Carbopol- carbomer or its derivative Likewise polyvinyl acetal diethylaminoacetate (AEA) solutions with a low viscosity at pH 4 form hydrogel at neutral pH conditionAnother ex. Are PMMA, PEG, CAP latex, Pseudolatex etc..47IN SITU FORMATION BASED ON PHYSICAL MECHANISMSwelling In situ formation may also occur when material absorbs water from surrounding environment and expand to cover desired space. One such substance is Myverol 18- 99 (glycerol monooleate), 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.Solvent exchange-DiffusionThis 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.48IN SITU FORMATION BASED ON CHEMICAL REACTIONSFollowing chemical reaction cause gelation Ionic crosslinking Enzymatic cross-linking Photo-polymerization49Ionic crosslinkingPolymers may undergo phase transition in presence of various ions. Some of the polysaccharides fall into the class of ion-sensitive ones. While K-carrageenan forms rigid, brittle gels in reply of small amount of K +, i-carrageenan forms elastic gels mainly in the presence of Ca2+. Gellan gum commercially available as Gelrite is an anionic polysaccharide that undergoes in situ gelling in the presence of mono- and divalent cations, including Ca2+, Mg2+, K+ and Na+. Gelation of the low-methoxy pectins can be caused by divalent cations, especially Ca2+. Likewise, alginic acid undergoes gelation in presence of divalent/polyvalent cations e. g. Ca 2+due to the interaction with guluronic acid block in alginate chain 50Enzymatic cross-linkingIn situ formation catalysed by natural enzymes has not been investigated widely but seems to have some advantages over chemical and photochemical approaches. For example, an enzymatic process operates efficiently under physiologic conditions without need for potentially harmful chemicals such as monomers and initiators. Intelligent stimuli-responsive delivery systems using hydrogels that can release insulin have been investigated. 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.51PHOTO-POLYMERIZATIONPhoto-polymerization is commonly used for in situ formation of biomaterials. 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 gelAcrylate or similar polymerizable functional groups are typically used as the polymerizable groups on the individual monomers and macromers because they rapidly undergo photo-polymerisation in the presence of suitable photoinitiator (2,2 dimethoxy-2-phenylacetophenone, is often used as the initiator for ultraviolet photo-polymerization, where as camphorquinone and ethyl eosin initiators are often used in visible light systems) 52PHOTO-POLYMERIZATIONTypically long wavelength ultraviolet and visible wavelengths are usedShort wavelength ultraviolet is not used often because it has limited penetration of tissue and biologically harmfulPhotopolymerizable systems when introduced to the desired site via injection get photocured in situ with the help of fiber optic cables and then release the drug for prolonged period of time. The photo-reactions provide rapid polymerization rates at physiological temperature. Furthermore, the systems are easily placed in complex shaped volumes leading to an implant formation.

53Polymers used in In situ drug delivery Gellan gum Poloxamer Pectin Chitosan Poly(DL lactic acid) Poly(DL lactide-co-glycolide) Poly-caprolactone Alginic acid Xyloglucan54Synthetic polymersSynthetic polymers are popular choice mainly for parenteral preparations. The trend in drug delivery technology has been towards biodegradable polymers such as poly (lactic acid), poly (glycolic acid), poly (lactide- coglycolide), poly (decalactone), poly -caprolactone have been the subject of the most extensive recent investigationsThe feasibility of lactide/glycolide polymers as excipients for the controlled release of bioactive agents is well proven. These materials have been subjected to extensive animal and human trials without evidence of any harmful side effects.55Synthetic polymersThermosetting systems are in the sol form when initially constituted, but upon heating , they set into their final shape. This sol-gel transition is known as curing. But if this cured polymer is heated further, it may lead to degradation of the polymer. Curing mainly involves the formation of covalent cross links between polymer chains to form a macromolecular network An important example of thermosensitive polymer is poly-(N-isopropyl acrylamide)-poly (NIPAAM), which is used for the formation of in situ gels. The polymers such as poly(DL-lactide), poly(DL-lactide-co- glycolide) and poly(DL-lactide-co- -caprolactone) form solvent-removal precipitating polymeric systems.

56Classification Of In Situ Drug DeliveryIn situ gel forming systems have been classified in two categories as below: Based on Mechanism of Gelation Based on Route of Administration Based on Mechanism of Gelation a) pH Sensitive Gel b) Gel Sensitive to electrical current c) Thermosensitive Gel d) Enzyme Sensitive e) Presence of Ions Based on Route of Administration (Applicability of In Situ Drug Delivery System) a) In situ forming polymeric systems for oral administration b) In situ forming polymeric systems for ocular delivery c) In situ forming polymeric systems for rectal and vaginal delivery d) In situ forming injectable drug delivery systems e) In situ forming nasal drug delivery systems 57Applicability Of In Situ Drug Delivery System inIn situ forming polymeric systems for Oral administration.In situ forming polymeric systems for Ocular drug delivery.In situ forming polymeric systems for Rectal and Vaginal delivery.In situ forming Injectable drug delivery systems.In situ forming Nasal drug delivery systems.58EVALUATION AND CHARACTERIZATIONOF IN SITU GEL / HYDROGEL SYSTEM1.Clarity The clarity of formulated solutions determined by visual inspection under black and white background 2.Viscosity and rheology The viscosity and rheological properties of the polymeric formulations, either in solution or in gel made with artificial tissue fluid (depending upon the route of administrations) were determined with Brookfield rheometer or some other type of viscometers such as Ostwalds viscometer.No difficulties are envisaged during their administration by the patient, especially during parenteral and ocular administration.593.Determination of Mucoadhesive forceModified balance method or TensilometerGel Strength This parameter can be evaluated using a rheometer. Depending on the mechanism of the gelling of gelling agent used, a specified amount of gel is prepared in a beaker, from the sol form . 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.604.Sol-gel Transition Temperature And Gelling TimeFor in situ gel forming systems incorporating thermoreversible polymers, 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 as defined above.615.Texture analysisThe 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.Fourier transform infra-red spectroscopy and thermal analysisDuring gelation process, the nature of interacting forces can be evaluated using this technique by employing potassium bromide pellet method. 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. Thermogravimetric analysis can be conducted for in situ forming polymeric systems to quantitate the percentage of water in hydrogel626.In Vitro Drug Release StudiesFor 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. The sol form of the formulation is placed in the 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.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 analyzed63COMMERCIAL FORMULATIONS OF IN SITUPOLYMERIC SYSTEMSTimoptic-XEReGel:depot technologyCytoryn TM64CONCLUSIONThe primary requirement of a successful controlled release product focuses on increasing patient compliance which the in situ gels offer. Exploitation of polymeric in- situ gels for controlled release of various drugs provides a number of advantages over conventional dosage forms. Sustained and prolonged release of the drug, good stability and biocompatibility characteristics make the in situ gel dosage forms very reliable.Use of biodegradable and water soluble polymers for the in situ gel formulations can make them more acceptable and excellent drug delivery systems.65