IntroductionControlled drug delivery systems that are intended todeliver drugs at predetermined rates for predefined periods of time, have beenused to control the shortcomings of conventional drug formulations. In somecases drug has to be delivered in response to ph in the body, Infact it wouldbe desirable if the drug could be administered in a manner that preciselymatches the physiological needs at proper times at the specified target sites.The range of fluids in various sections in the GIT may provide environmentalstimuli for responsive drug release ph. Stimuli-responsive polymers are one ofthe most important excipients in in DDS and pharmaceutical formulations. Theseare designed to produce specific and desired PH concentration activatedresponse according to body physiological environment variations.PH sensitive drug delivery systems (PSDDS) deliver the drugat specific time as per the pathophysiological need of the body and givesimproved patient compliance and therapeutic efficacy that is why it is gainingimportance.  PolymersAll the Ph sensitivepolymers consist of pendant acidic (carboxylic acid and sulfonic acids) andbasic (ammonium salts) groups that either accept or release protons in responseto changes in environment PH.

The polymers having large number of ionizablegroups are called polyelectrolytesThe charge density of the polymers is dependant on the PHand ionic concentration of the outer solution (in which the polymer isexposed). Swelling or de-swelling of the polymer can be caused by altering theph of the solution.1.      Poly-acidic polymers are unswollen at the low phas the acidic groups will be protonated and thus unionized.2.

      With increasing ph polyacidic polymers are goingto swell3.      In polybasic polymers with decreasing phionization of basic group is going to increase4.       Derivativesof acrylic acid are most commonly used ph sensitive polymers.Methodologies for PHSensitive Drug DeliveryProperties of PHSensitive Hydrogel Hydrogels comprises of cross linked polyelectrolytes thathave big differences in swelling properties depending upon the environmental PH.The pendant acidic or basic groups on polyelectrolytes undergo ionizationhowever it is difficult due to electrostatic effects exerted by other adjacentionized groups, this makes the apparent dissociation constant (ka) differentfrom that of corresponding monoacid or monobase. ionizable groups presence  on polymer chains results in swelling of thehydrogels. The swelling of the polyelectrolyte hydrogels happens due to theelectrostatic repulsion among charges that are present on the polymer chain ,the degree of swelling can be influenced by any condition that reduceelectrostatic repulsion such as ph, ionic strength and type of counter ions.

The swelling and ph responsiveness of polyelectrolyte hydrogels can be balancedby using the neutral comonomers such as 2-hydroxyethyl methacrylate and methylmethacrylate. Different comonomers provide different hydrophobicity to thepolymer chain, as a result different ph sensitive behaviour is shown.ExampleHydrogels made up ofpoly methacrylic acid grafted with poly ethylene glycol have unique Phsensitive properties. the acidic protons of carboxylic acid of PMA at low PHinteract with ether oxygen of PEG through hydrogen bonding resulting inshrinkage of hydrogels. At high PH the carboxylic groups of PMA become ionized,the resulting complexation results in swelling of the hydrogels.Applications of phsensitive hydrogelsControlled drugdeliveryPH Sensitivehydrogels have been most frequently used to develop controlled releaseformulations for oral administration. The ph in stomach (<3) is quitedifferent from neutral ph in the intestine and that difference is large enoughto generate ph sensitive behaviour of polyelectrolyte hydrogels.

Forpolycationic hydrogel the swelling is minimum at neutral ph, thus minimizingthe drug release from hydrogels. This property has been used to stop therelease of foul-tasting drugs in the neutral ph environment of the mouth. Polycationic hydrogels that are in the form of semi-IPN have been used for the drugdelivery in stomach. Semi-IPN of cross-linked chitosan and PEO have shown moreswelling under acidic conditions (in stomach).

This type of hydrogels would beideal for localized delivery of antibiotics such as amoxicillin andmetronidazole in the stomach for the treatment of Helicobacter Pylori.Hydrogels that are made up of PPA and PMA can be used to develop formulations thatrelease drug in the neutral ph environment.Hydrogels comprising  of poly anion (PPA) crosslinked withazoaromatic crosslinkers were developed for colon-specific drug delivery.Swelling of such hydrogels in the stomach is minimal hence the drug release isalso minimized. The degree of swelling increases as hydrogels is passed downthe intestinal tract due to increasing ph leading to the ionization ofcarboxylic groups. the azoaromatic crosslinks of hydrogels can be degraded onlyin the colon by azo-reductase produced by the microbial flora of the colon. Thedegradation kinetics and pattern can be controlled by cross-linking density.

Superporous hydrogelsfor delivery of drug in the alkaline ph were formulated employing acrylamideand methacrylic acid by free radical polymerization. These swelled only in thebasic ph and showed very fast swelling kinetics. Superporous hydrogels havebeen developed as gastroretentive drug delivery system as they swell only inacidic ph and are highly sensitive.Hydrogels that areresponsive to both temperature and ph can be made simply incorporatingionisable and hydrophobic functional groups to the same hydrogels. When a smallamount of anionic monomer such as acrylic acid is incorporated in athermoreversible polymer, the LCST of the hydrogel depends on the ionization ofpendant carboxyl groups. As the ph of the medium increases above the pka ofcarboxyl groups of the polyanions, the LCST shifts to higher temperatures dueto the increased hydrophilicity and charge repulsion.

Terpolymer hydrogelscontaining NIPPAAm, acrylic acid and 2-hydroxyethyl methacrylate were preparedfor the pulsatile delivery of streptokinase and heparin as a function ofstepwise ph and temperature changes.OtherApplications Phsensitive hydrogels have been used in making biosensors and permeationswitches, the ph sensitive hydrogels for these applications are loaded withenzymes that change the local microenvironment inside the hydrogels. One of theenzymes used is glucose oxidase that transforms glucose into gluconic acid. Theformation of gluconic acid lowers the local ph, thus affecting the swelling ofph sensitive hydrogels.Limitationsand ImprovementsOne of thelimitations of synthetic ph sensitive polymers is non-biodegradability.

Forthis reason polymers made up of non-biodegradable polymers are removed frombody after use. The non-biodegradability is not a problem in certainapplications such as in oral drug delivery but it becomes a serious limitationin other applications such as the development of implantable drug attention hasbeen focused on the development of biodegradable, ph sensitive hydrogels basedon peptides, proteins and polysaccharides.Dextran wasactivated with 4-aminobutyric acid for crosslinking with 1, 10 diaminodecaneand also grafted with carboxylic groups. The modified dextran hydrogels showeda faster and higher degree of swelling at high ph conditions and changing theph between 7 and 2 resulted in cyclic swelling-deswelling. It is noted that thedextran hydrogels may not be exactly biodegradable, since the body or certainsites in body may not have the enzyme to degrade dextran molecules. The naturalpolysaccharides are not usually biodegradable in human body.Syntheticpolypeptides are also used in the synthesis of biodegradable hydrogels becauseof their more regular arrangement and less versatile amino acid residues thanthose derived from the natural proteins.

Example of such synthetic polypeptidehydrogels include poly aspartic acid poly L-lysine and poly glutamic acid.Entericcoated systemsEnteric-coatedformulations are suitable vehicles to modify the release of active substancessuch that release at specific target areas in the gastrointestinal tract andpreventing its release in stomach. The major aim of enteric coating is theprotection of drugs that are sensitive or unstable at acidic ph.

This isparticularly important for drugs such as enzymes and proteins because thesemacromolecules are rapidly hydrolyzed and inactivated in acidic medium.Macrolide antibiotics such as erythromycin are rapidly degraded by gastricjuices. Acidic drugs like NSAID’s are also enteric coated to prevent localirritation of the mucosa.Anotherpurpose of enteric coating is drug targeting as in case of 5-aminosalicylicacid or the prodrugs sulfasalazine. In these cases, enteric coating is appliedsuch that the drug concentration is increased in the lower parts of the GITract.

Although the use of enteric coating to achieve modified drug release isknown for long but it has always been criticized as to its true value ofproviding protection and targeted release of coated active agents.DosageFormsIn general,film coated dosage forms can be divided into two forms multiple unit and singleunit dosage forms. Single unit dosage form contains tablets, film coatedcapsules and other forms.

Multiple units contains granules, capsules, pelletsand compressed film coated particles.It’s beenreported that drug in enteric coated form can produce aqueous dispersions and suspensions.The enteric coated time clock system comprising of tablet core that is coatedwith a mixture of hydrophobic material and surfactant that is applied as an aqueousdispersion. The drug release from the core is occurring at a predetermined lagtime. The lag time is insensitive of GI PH and depends on the thickness of hydrophobiclayer.

TabletsTablets canbe easily enteric coated and a wide variety of products are in the market forexample naproxen, acetyl salicylic acid , diclofenac they have increasedbioavailability , improved patient compliance and the formulation stability dueto coating process.CapsulesExtra precautionsare required during coating as capsule shells become brittle during storage. Toensure proper coating of the capsule closure the thickness of the film coatinglayer has to be increased.

Enteric coating of hard gelatine capsules containingacetaminophen showed good stability. Soft gelatine capsules containing thintransparent film coating also showed good stability.MultipleunitsA widelyused method of producing multiple units has been the formulation of sachets containingfilm coated granules. Capsules filled with enteric coated particles is of commonuse. In addition to the flexible polymers for coating, suitable larger sizedfillers-binders and stable strong pellet cores are also considered for the entericdosage form designs.

Only methacrylic acid copolymers seem to have these propertiesnecessary to produce these dosage forms.Example :small microcapsules of ibuprofen were film coated with cellulose acetatephthalate and dispersed in water before administering , plasma levels didn’t differfrom the conventional enteric coated tablet as expected.Ph sensitivegelsMany polyanionicmaterials are ph sensitive and the extent of swelling of such polymers can bechanged by changing ph. An application of such technology is used in thedevelopment of biomimetic secretary granules for drug delivery system.The polymernetwork, containing biological mediators such as histamine exist in a collapsedstate as a result of internal ph and ionic content that is maintained by thelipid surrounding the membrane. Histamine release from granule is initiated bythe fusion of the granule with the cell membrane exposing the polyanionicinternal matrix to the extracellular environment.

Hence the change in ph andionic strength results in ion exchange and swelling of the polyanionic networkthat causes the release of mediators ApplicationThe use ofthis system in conjunction with temperature sensitive lipids provide potentialto target drugs to the areas of inflammation or to reach site specific,pulsatile drug delivery through the localized external application of ultrasoundor heating to distort the lipid bilayers. Ph-sensitiveliposomesPh sensitiveliposomes are stable at physiological ph, under acidic conditions they destabilizeleaking to the release of their aqueous contents. In addition, they appear todestabilize or fuse with the membranes of endosomes in which they areinternalized enabling even macromolecular liposomes contents to enter thecytoplasm. Following binding to cells, liposomes are internalized through theendocytotic pathway.

Liposomes are retained in early endosomes that mature intolate endosomes. The potential of ph sensitive liposomes lies in their abilityto undergo destabilization at this stage thus preventing their degradation atthe lysosomal level and consequently increasing access to nuclear targets.ApplicationsHyperbranched polyglycidal (HPG) derivatives were prepared as a new type of ph sensitive polymerused in modification of liposomes. They showed stronger interaction with themembrane than the linear polymers show. Thus liposomes modified with HPGderivatives show better results.PH sensitive nanoparticlesParticles in the sizerange of 40-120nm are translocated both transcellularly and paracellularly. In additionto enhancing drug bioavailability, particulate oral drug delivery systems canprotect labile macromolecules from stomach acid and first pass effect in theGIT. The use of ph sensitive polymers like hydroxypropyl methyl cellulosephthalate for encapsulating proteins or antigens for oral administration, theseparticles are matrix-type dispersed systems.

At a specific ph highly disperseddrugs release within the GIT close to the absorption window of the drug thusincreasing the probability to maximum absorption and to minimize first passmetabolism.ApplicationMethods to preparepolymeric nanoparticles are ionic gelation, solvent evaporation,salting-out/emulsification diffusion and polymerization. Advantages Following are theadvantages1.       Drug directly available at the target site2.       Decreased dose to be administered3.

       Decreased side effects4.       Improved drug utilization5.       Improved patient compliance6.       Lower daily cost to the patient due tofewer dosage units are required by the patient in therapy7.

       Protection of mucosa from irritating drugs8.       Drug loss is prevented by extensive drugpass metabolism   Example of noveldrugsPH-sensitive hydrogels based on polyethylene glycol andmethacrylic acid (MAA) macromonomer (PEGMEMA) entrapping diliazem HCL weresynthesized inside soft gelatin capsules for use as a new dosage form for oraladministration of drug. for the evaluation of their swelling and releasebehaviour in two media, different monomers were used:  at ph 7 stimulating the higher ph environmentof the intestine while at low ph stimulating the acid ph of the stomach.

Boththe processes DIL-HCL release and swelling are dependant on Ph and compositionof monomer. Hydrogels with intermediate compositions showed diminished DIL·HClrelease at pH 1.2. Similar shaped release profiles were found for the fourhydrogels compositions at ph 7. At this neutral ph slow protonation of thecarboxylate groups of MAA led to the swelling front and a dry core that isobserved by MRI. As a result of this swelling, release curves exhibited a longperiod of zero order kinetics. So, this shows that the system could be asuitable candidate for developing a zero order release dosage form for oraladministration of DIL-HCL.

The dissolution and swelling processes were analysedby different mathematical approaches.2) the development of a novel colon-specific drug delivery system withmethacrylate derivatives of 5-ASA using drug release properties and PHsensitive swelling. 5-ASA film coated tablets were prepared for colon specificdelivery. During this method 5-ASA core tablets were first prepared then coatedwith dispersion containing Eudragit RS and dessterrifed pectin,polygalacturonicacidor its sodium and potassium salts. Negligible drug releaseoccurred during the first five hours where the coated tablets were in smallintestine and stomach. After that, the release of 5-ASA from coated tabletsoccurred linearly as a function of time because of the action of pectinolyticenzymes. 


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