Controlled drug delivery systems that are consideredto deliver drugs at predetermined rates for predefined periods of time, havebeen used to control the limitations of conventional drug formulations. In somecases drug has to be delivered in response to pH in the body, in fact it wouldbe advantageous 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 that are responsive to drug release ph. Stimuli-responsive polymers areone of the most important excipients in in DDS and pharmaceutical formulations.These are designed to produce specific and desired PH concentration activatedresponse according to body physiological environment variations.PH sensitive drug delivery systems (PSDDS) deliver thedrug at 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 sensitive polymers consist of pendantacidic (carboxylic acid and sulfonic acids) and basic (ammonium salts) groups thateither accept or release protons in response to changes in environment PH. Thepolymers having large number of ionizable groups are called polyelectrolytesThe charge density of the polymers is dependent on thePH and ionic concentration of the outer solution (in which the polymer isintroduced). Swelling or de-swelling of the polymer can be caused by alteringthe pH of the solution.1. Atlow pH Poly-acidic polymers are un-swollen as the acidic groups will beprotonated and thus unionized.2. Withincreasing pH poly-acidic polymers are going to swell3.
Inpolybasic polymers with decreasing pH ionization of basic group is going toincrease4. Derivativesof acrylic acid are most commonly used pH sensitive polymers.Methodologies for PH Sensitive Drug DeliveryProperties of PH Sensitive Hydrogel Hydrogels comprises of cross linked polyelectrolytesthat have large differences in swelling properties depending upon theenvironmental PH.
The pendant acidic or basic groups on polyelectrolytesexperience ionization however it is difficult due to electrostatic effectsexerted by other adjacent ionized groups, making the apparent dissociationconstant (ka) different from that of corresponding monoacid or monobase ionizablegroups presence on polymer chains results in swelling of the hydrogels. Theswelling of the polyelectrolyte hydrogels happens due to the electrostaticrepulsion among charges that are present on the polymer chain , the extent ofswelling can be influenced by any condition that lessen electrostatic repulsionsuch as pH, ionic strength and type of counter ions. The swelling and pHresponsiveness of polyelectrolyte hydrogels can be balanced by using theneutral comonomers such as 2-hydroxyethyl methacrylate and methyl methacrylate.Different comonomers provide different hydrophobicityto the polymer chain, as a result different pH sensitive behaviour is shown.ExampleHydrogels made up of poly methacrylic acid attachedwith poly ethylene glycol have unique PH sensitive properties.
The acidicprotons of carboxylic acid of PMA at low PH interact with ether oxygen of PEGthrough hydrogen bonding resulting in condensation of hydrogels. At high PH thecarboxylic groups of PMA become ionized, the resulting complexation results inswelling of the hydrogels.Applications of pH sensitive hydrogelsControlled drug deliveryPH Sensitive hydrogels are usually used to developcontrolled release formulations for oral administration.
The pH in stomach(<3) is quite different from neutral pH in the intestine and that differenceis large enough to generate pH sensitive behaviour of polyelectrolytehydrogels. For poly-cationic hydrogel the swelling is minimum at neutral pH,thus minimizing the drug release from hydrogels. This property has been used tostop the release of foul-tasting drugs in the neutral pH environment of the mouth.
Poly cationic hydrogels that are in the form of semi-IPN have been used for thedrug delivery in stomach. Semi-IPN of cross-linked chitosan and PEO have shownmore swelling under acidic conditions (in stomach). This type of hydrogelswould be ideal 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) crosslinkedwith azo-aromatic cross-linkers were developed for colon-specific drugdelivery.
Swelling of such hydrogels in the stomach is minimal hence the drugrelease is also minimized. The degree of swelling increases as hydrogels ispassed down the intestinal tract due to increasing pH leading to the ionizationof carboxylic groups. The azo-aromatic crosslinks of hydrogels can be degradedonly in the colon by azo-reductase produced by the microbial flora of thecolon. The degradation kinetics and pattern can be controlled by cross-linkingdensity.Super porous hydrogels for delivery of drug in thealkaline pH were formulated involving acrylamide and methacrylic acid by freeradical polymerization. They are swelled only in the basic pH and showed veryfast swelling kinetics.
Super porous hydrogels are developed as gastroretentivedrug delivery system as they swell only in acidic pH and are highly sensitive.Hydrogels that are responsive to both temperature andpH can be made simply combining ionisable and hydrophobic functional groups tothe same hydrogels. When a small amount of anionic monomer such as acrylic acidis mixed in a thermos-reversible polymer, the LCST of the hydrogel depends onthe ionization of pendant carboxyl groups. As the pH of the medium increasesabove the pka of carboxyl groups of the polyanions, the LCST shifts to highertemperatures due to the increased hydrophilicity and charge repulsion.Terpolymer hydrogels consisting of NIPPAAm, acrylic acid and 2-hydroxyethylmethacrylate were prepared for the pulsatile delivery of streptokinase and heparinas a function of stepwise pH and temperature changes.Other Applications PH sensitive hydrogels are helpful in makingbiosensors and permeation switches, the pH sensitive hydrogels are filled withenzymes that change the local microenvironment inside the hydrogels. One of theenzymes that is used in this process is glucose oxidase that convert glucoseinto gluconic acid.
The formation of gluconic acid lowers the local pH, hence affectingthe swelling of pH sensitive hydrogels.Limitations and ImprovementsNon-biodegradability is one of the limitations of pHsensitive polymers. Because of this reason polymers made up ofnon-biodegradable polymers are discharged from body after use. The non-biodegradabilityis not a complication in certain applications such as in oral drug delivery butit becomes a serious limitation in other applications such as the developmentof implantable drug, attention has been focused on the development ofbiodegradable, pH sensitive hydrogels based on peptides, proteins andpolysaccharides.Dextran was activated with 4-aminobutyric acid forcrosslinking with 1, 10 diaminodecane and also combined with carboxylic groups.The modified dextran hydrogels showed a faster and higher extent of swelling athigh pH conditions and changing the pH between 7 and 2 resulted in cyclic swelling-de-swelling. Dextran hydrogels may not be actually biodegradable, since the bodyor certain sites may not have the enzyme to degrade dextran molecules.
Thenatural polysaccharides are not usually biodegradable in human body.Synthetic polypeptides are also used in the synthesisof biodegradable hydrogels because of their more structured arrangement andless versatile amino acid residues than those derived from the naturalproteins. Poly aspartic acid, poly L-lysine and poly glutamic acid are theexamples of synthetic polypeptide hydrogels.Enteric coated systemsEnteric-coated formulations are suitable vehicles toimprove the release of active substances such that release at specific targetareas in the gastrointestinal tract and preventing its release in stomach. Themajor purpose of enteric coating is the protection of drugs that are sensitiveor unstable at acidic ph. This is particularly important for drugs such asenzymes and proteins because these macromolecules are immediately hydrolyzedand inactivated in acidic medium.
Macrolide antibiotics such as erythromycinare rapidly degenerated by gastric juices. Acidic drugs like NSAID’s are alsoenteric coated to prevent local irritation of the mucosa.Another purpose of enteric coating is drug targetingas in case of 5-aminosalicylic acid or the prodrugs sulfasalazine. In these cases,enteric coating is administered such that the drug concentration is increasedin the lower parts of the GI Tract. Although the use of enteric coating toimprove modified drug release is known for long but it has always beencriticized as to its true value of providing protection and targeted release ofcoated active agents.Dosage FormsIn general, film coated dosage forms can be dividedinto two forms multiple unit and single unit dosage forms. Single unit dosageform contains tablets, film coated capsules and other forms. Multiple unitscontains granules, capsules, pellets and compressed film coated particles.
Drug in enteric coated form can produce aqueousdispersions and suspensions. The enteric coated time clock system comprising oftablet core that is coated with a mixture of hydrophobic material and surfactantthat is applied as an aqueous dispersion. The drug release from the core isoccurring at a predetermined lag time. The lag time is insensitive of GI PH anddepends on the thickness of hydrophobic layer.TabletsTablets can be easily enteric coated and a widevariety of products are in the market for example naproxen, acetyl salicylicacid , diclofenac they have increased bioavailability , improved patientcompliance and the formulation stability due to coating process.CapsulesExtra precautions are required during coating ascapsule shells become brittle during storage. To ensure proper coating of thecapsule closure the thickness of the film coating layer has to be increased.Enteric coating of hard gelatine capsules containing acetaminophen showed good stability.
Soft gelatine capsules containing thin transparent film coating also showedgood stability.Multiple unitsA widely used method of producing multiple units hasbeen the formulation of sachets containing film coated granules. Capsulesfilled with enteric coated particles is of common use. In addition to theflexible polymers for coating, suitable larger sized fillers-binders and stablestrong pellet cores are also considered for the enteric dosage form designs.Only methacrylic acid copolymers seem to have these properties necessary toproduce these dosage forms.Example: Small microcapsules ofibuprofen were film coated with cellulose acetate phthalate and dispersed inwater before administering, plasma levels didn’t differ from the conventionalenteric coated tablet as expected.
PH sensitive gelsMany poly-anionic materials are pH sensitive and theextent of swelling of such polymers can be changed by changing ph. Anapplication of such technology is used in the development of biomimetic secretarygranules for drug delivery system.The polymer network, containing biological mediatorssuch as histamine exist in a collapsed state as a result of internal pH andionic content that is maintained by the lipid surrounding the membrane.Histamine release from granule is initiated by the fusion of the granule withthe cell membrane revealing the poly-anionic internal matrix to theextracellular environment. Hence the change in pH and ionic strength results inion exchange and swelling of the poly-anionic network that causes the releaseof mediators ApplicationThe use of this system in conjunction with temperaturesensitive lipids provide potential to target drugs to the areas of inflammationor to reach site specific, pulsatile drug delivery through the localizedexternal application of ultrasound or heating to distort the lipid bilayers. PH-Sensitive LiposomesPH-Sensitive liposomes are stable at physiological pH,under acidic conditions they destabilize leaking to the release of theiraqueous contents. In addition, they appear to destabilize or combine with themembranes of endosomes in which they are internalized allowing evenmacromolecular liposomes contents to enter the cytoplasm.
Following binding tocells, liposomes are internalized through the endocytotic pathway. Liposomesare retained in early endosomes that mature into late endosomes. The potentialof pH sensitive liposomes lies in their ability to undergo destabilization atthis stage thus preventing their degradation at the lysosomal level andtherefore increasing access to nuclear targets.ApplicationsHyper-branched poly glycidal (HPG) derivatives wereformulated as a new type of pH sensitive polymer used in modification ofliposomes. They showed stronger interaction with the membrane than the linearpolymers show. Thus liposomes modified with HPG derivatives show betterresults.
PH sensitive nanoparticlesParticles in the size range of 40-120nm aretranslocated both transcellularly and paracellularly. In addition to enhancingdrug bioavailability, particulate oral drug delivery systems can protect reactivemacromolecules from stomach acid and first pass effect in the GIT. The use of pHsensitive polymers like hydroxypropyl methyl cellulose phthalate forencapsulating proteins or antigens for oral administration, these particles arematrix-type dispersed systems. At a specific pH highly dispersed drugs releasewithin the GIT close to the absorption window of the drug thus increasing theprobability to maximum absorption and to minimize first pass metabolism.Methods to prepare polymeric nanoparticles are ionic gelation, solventevaporation, salting-out/emulsification diffusion and polymerization. ApplicationPH-Sensitive nanoparticles are used for antitumorevaluationAdvantages Following are the advantages1. Drugdirectly available at the target site2. Decreaseddose to be administered3.
reducedside effects4. Improveddrug utilization5. enhancepatient compliance6. Lowerdaily cost to the patient due to fewer dosage units are required by the patientin therapy7. Mucosaprotection from irritating drugs8.
Extensivedrug pass metabolism for prevention of drug loss Example of Novel DrugsExample 1PH-sensitive hydrogels comprises of polyethyleneglycol and methacrylic acid (MAA) macromonomer (PEGMEMA) entrapping diliazemHCL were synthesized inside soft gelatine capsules for use as a new dosage formfor oral drug administration. For the assessment 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. DIL-HCLrelease and swelling both processes are dependent on PH and composition ofmonomer.
Hydrogels with intermediate formations 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 isdetected by MRI. As a result of this swelling, release curves displayed 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 processes of dissolution and swelling wereanalysed by different mathematical approaches.Example 2The development of a novel colon-specific drug delivery system usingmethacrylate derivatives of 5-ASA using properties of drug release and PHsensitive swelling. 5-ASA film coated tablets were developed for colon specificdelivery. During this process 5-ASA core tablets were initially made thencoated with dispersion containing Eudragit RS and dessterrifed pectin,polygalacturonicacidor its sodium and potassium salts. During the first fivehours negligible drug release occurred where the coated tablets were in smallintestine and stomach. After that, 5-ASA release from coated tablets releasedlinearly as a function of time because of pectinolytic enzymes action.