Controlled drug delivery systems that are consideredto deliver drugs at predetermined rates for predefined timeframe, have beenutilized to control the limitations of conventional drug formulations.
In somecases drug has to be delivered in response to pH in the body, it would beinvaluable if the medication could be controlled in a way that correctlymatches the physiological needs at appropriate circumstances at the predefinedtarget sites. The scope of fluids in different sections in the GIT may offerenvironmental stimuli that are responsive to drug release ph. Stimuli-responsivepolymers are one of the most important excipients in in DDS and pharmaceuticalformulations. These are designed to produce specific and desired pHconcentration activated response according to body physiological environmentvariations.
PH sensitive drug delivery systems (PSDDS) supply thedrug at particular time according to the pathophysiological need of the bodyand gives enhanced patient compliance and therapeutic efficacy that is thereason it is gaining significance. PolymersAll the PH sensitive polymers consist of pendantacidic (carboxylic acid and sulfonic acids) and basic (ammonium salts) groupsthat either accept or discharge protons in response to changes in environmentalPH. The polymers having substantial number of ionizable groups are calledpolyelectrolytesThe charge density of the polymers is dependent on thePH and ionic concentration of the external solution (in which the polymer isintroduced). Swelling or de-swelling of the polymer can be caused by modifyingthe pH of the solution.
pHsensitive ionization of polyelectrolytes. Poly (acrylic acid) at the top andpoly (N, N-diethylaminoethyl methacrylate) bottom1. Atlow pH poly-acidic polymers are un-swollen as the acidic groups will beprotonated and hence unionized.2. Withincreasing pH poly-acidic polymers are going to swell3. Inpolybasic polymers with diminishing pH ionization of basic group is going toincrease4. Derivativesof acrylic acid are mostly used pH sensitive polymers.Methodologies for PH Sensitive Drug DeliveryProperties of PH Sensitive Hydrogel and MechanismHydrogels are made up of cross linked polyelectrolytesthat have large differences in swelling properties relying upon the environmentalscale of PH.
The pendant acidic or basic groups on polyelectrolytes experience ionizationhowever it is difficult due to electrostatic effects applied by differentadjacent ionized groups, creating the apparent dissociation constant (ka) completelydifferent from that of corresponding monoacid or monobase, ionizable groups thatare present on polymer chains leads to swelling of the hydrogels. The swellingof the polyelectrolyte hydrogels happens due to the electrostatic repulsion thatis among charges present on the polymer chain, the extent of swelling isaffected by means of any condition that lessen electrostatic repulsion such aspH, ionic strength and counter ions type. The swelling and pH responsiveness ofpolyelectrolyte hydrogels can be maintained by usage of neutral comonomers suchas 2-hydroxyethyl methacrylate and methyl methacrylate. Different hydrophobicity is provided by differentcomonomers to the polymer chain, as a result distinct pH sensitive behaviour isshown.ExampleHydrogels made up of poly methacrylic acid attachedwith poly ethylene glycol have special pH sensitive properties.
The acidicprotons of carboxylic acid of PMA at low pH interact with ether oxygen of PEGvia hydrogen bonding resulting in condensation of hydrogels. At high PH thecarboxylic groups of PMA become ionized, the resulting complexation ends up inswelling of the hydrogels.Applications of pH sensitive hydrogelsControlled drug deliveryPH Sensitive hydrogels are usually used to expandcontrolled release formulations for oral administration.
The pH in stomach(<3) is quite different from impartial pH in the intestine and that differenceis sufficient to generate pH sensitive behaviour of polyelectrolyte hydrogels.For poly-cationic hydrogel the swelling is minimum at neutral pH, as a result minimizingthe release of drug from hydrogels. This characteristic has been used to stopthe 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 kind of hydrogelswould be ideal for localized delivery of antibiotics such as amoxicillin and metronidazolein the stomach for Helicobacter Pylori treatment. Hydrogels that are made up ofPPA and PMA can be used to advance formulations that release drug in theneutral 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 so the drugrelease is also minimized.
The degree of swelling increases as hydrogels is passedalong the intestinal tract due to increasing pH leading to the ionization ofcarboxylic groups. The azo-aromatic crosslinks of hydrogels can be degradedonly in the colon by azo-reductase generated through the microbial flora of thecolon. The degradation kinetics and pattern can be controlled by cross-linkingdensity.Schematicillustration of oral colon-specific drug delivery using biodegradable and pH-sensitivehydrogels.Super porous hydrogels for transport of drug in thealkaline pH have been formulated involving acrylamide and methacrylic acid byfree radical polymerization. They are swelled only in the basic pH and have shownvery fast swelling kinetics. Super porous hydrogels are formulated as gastro-retentivedrug delivery system as they swell only in acidic pH and are exceptionallysensitive.
Schematicillustration of on-off release from a squeezing hydrogel device for drugdeliveryHydrogels that are responsive to both temperature andpH can be made simply by combining ionisable and hydrophobic functional groupsto the corresponding hydrogels. When a small quantity of anionic monomer suchas acrylic acid is mixed in a thermos-reversible polymer, the LCST of thehydrogel is dependent on the ionization of pendant carboxyl groups. As the pHof the medium increases above the pka of carboxyl groups of the polyanions, theLCST shifts to higher temperatures due to the increased hydrophilicity andcharge repulsion. Terpolymer hydrogels consisting of NIPPAAm, acrylic acid and2-hydroxyethyl methacrylate were formulated for the pulsatile delivery ofstreptokinase and heparin as a function of stepwise pH and temperature changes.