PH Sensitive Drug
Controlled drug delivery systems that are considered
to deliver drugs at predetermined rates for predefined periods of time, have
been used to control the limitations of conventional drug formulations. In some
cases drug has to be delivered in response to pH in the body, in fact it would
be advantageous if the drug could be administered in a manner that precisely
matches the physiological needs at proper times at the specified target sites.
The range of fluids in various sections in the GIT may provide environmental
stimuli that are responsive to drug release ph. Stimuli-responsive polymers are
one of the most important excipients in in DDS and pharmaceutical formulations.
These are designed to produce specific and desired PH concentration activated
response according to body physiological environment variations.
PH sensitive drug delivery systems (PSDDS) deliver the
drug at specific time as per the pathophysiological need of the body and gives
improved patient compliance and therapeutic efficacy that is why it is gaining
All the PH sensitive polymers consist of pendant
acidic (carboxylic acid and sulfonic acids) and basic (ammonium salts) groups that
either accept or release protons in response to changes in environment PH. The
polymers having large number of ionizable groups are called polyelectrolytes
The charge density of the polymers is dependent on the
PH and ionic concentration of the outer solution (in which the polymer is
introduced). Swelling or de-swelling of the polymer can be caused by altering
the pH of the solution.
low pH Poly-acidic polymers are un-swollen as the acidic groups will be
protonated and thus unionized.
increasing pH poly-acidic polymers are going to swell
polybasic polymers with decreasing pH ionization of basic group is going to
of acrylic acid are most commonly used pH sensitive polymers.
Methodologies for PH Sensitive Drug Delivery
Properties of PH Sensitive Hydrogel
Hydrogels comprises of cross linked polyelectrolytes
that have large differences in swelling properties depending upon the
environmental PH. The pendant acidic or basic groups on polyelectrolytes
experience ionization however it is difficult due to electrostatic effects
exerted by other adjacent ionized groups, making the apparent dissociation
constant (ka) different from that of corresponding monoacid or monobase ionizable
groups presence on polymer chains results in swelling of the hydrogels. The
swelling of the polyelectrolyte hydrogels happens due to the electrostatic
repulsion among charges that are present on the polymer chain , the extent of
swelling can be influenced by any condition that lessen electrostatic repulsion
such as pH, ionic strength and type of counter ions. The swelling and pH
responsiveness of polyelectrolyte hydrogels can be balanced by using the
neutral comonomers such as 2-hydroxyethyl methacrylate and methyl methacrylate.
Different comonomers provide different hydrophobicity
to the polymer chain, as a result different pH sensitive behaviour is shown.
Hydrogels made up of poly methacrylic acid attached
with poly ethylene glycol have unique PH sensitive properties. The acidic
protons of carboxylic acid of PMA at low PH interact with ether oxygen of PEG
through hydrogen bonding resulting in condensation of hydrogels. At high PH the
carboxylic groups of PMA become ionized, the resulting complexation results in
swelling of the hydrogels.
Applications of pH sensitive hydrogels
Controlled drug delivery
PH Sensitive hydrogels are usually used to develop
controlled release formulations for oral administration. The pH in stomach
(<3) is quite different from neutral pH in the intestine and that difference is large enough to generate pH sensitive behaviour of polyelectrolyte hydrogels. For poly-cationic hydrogel the swelling is minimum at neutral pH, thus minimizing the drug release from hydrogels. This property has been used to stop 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 the drug delivery in stomach. Semi-IPN of cross-linked chitosan and PEO have shown more swelling under acidic conditions (in stomach). This type of hydrogels would be ideal for localized delivery of antibiotics such as amoxicillin and metronidazole in the stomach for the treatment of Helicobacter Pylori. Hydrogels that are made up of PPA and PMA can be used to develop formulations that release drug in the neutral pH environment. Hydrogels comprising of poly anion (PPA) crosslinked with azo-aromatic cross-linkers were developed for colon-specific drug delivery. Swelling of such hydrogels in the stomach is minimal hence the drug release is also minimized. The degree of swelling increases as hydrogels is passed down the intestinal tract due to increasing pH leading to the ionization of carboxylic groups. The azo-aromatic crosslinks of hydrogels can be degraded only in the colon by azo-reductase produced by the microbial flora of the colon. The degradation kinetics and pattern can be controlled by cross-linking density. Super porous hydrogels for delivery of drug in the alkaline pH were formulated involving acrylamide and methacrylic acid by free radical polymerization. They are swelled only in the basic pH and showed very fast swelling kinetics. Super porous hydrogels are developed as gastroretentive drug delivery system as they swell only in acidic pH and are highly sensitive. Hydrogels that are responsive to both temperature and pH can be made simply combining ionisable and hydrophobic functional groups to the same hydrogels. When a small amount of anionic monomer such as acrylic acid is mixed in a thermos-reversible polymer, the LCST of the hydrogel depends on the ionization of pendant carboxyl groups. As the pH of the medium increases above the pka of carboxyl groups of the polyanions, the LCST shifts to higher temperatures due to the increased hydrophilicity and charge repulsion. Terpolymer hydrogels consisting of NIPPAAm, acrylic acid and 2-hydroxyethyl methacrylate were prepared for the pulsatile delivery of streptokinase and heparin as a function of stepwise pH and temperature changes. Other Applications PH sensitive hydrogels are helpful in making biosensors and permeation switches, the pH sensitive hydrogels are filled with enzymes that change the local microenvironment inside the hydrogels. One of the enzymes that is used in this process is glucose oxidase that convert glucose into gluconic acid. The formation of gluconic acid lowers the local pH, hence affecting the swelling of pH sensitive hydrogels. Limitations and Improvements Non-biodegradability is one of the limitations of pH sensitive polymers. Because of this reason polymers made up of non-biodegradable polymers are discharged from body after use. The non-biodegradability is not a complication in certain applications such as in oral drug delivery but it becomes a serious limitation in other applications such as the development of implantable drug, attention has been focused on the development of biodegradable, pH sensitive hydrogels based on peptides, proteins and polysaccharides. Dextran was activated with 4-aminobutyric acid for crosslinking with 1, 10 diaminodecane and also combined with carboxylic groups. The modified dextran hydrogels showed a faster and higher extent of swelling at high pH conditions and changing the pH between 7 and 2 resulted in cyclic swelling- de-swelling. It is observed that the dextran hydrogels may not be actually biodegradable, since the body or certain sites may not have the enzyme to degrade dextran molecules. The natural polysaccharides are not usually biodegradable in human body. Synthetic polypeptides are also used in the synthesis of biodegradable hydrogels because of their more structured arrangement and less versatile amino acid residues than those derived from the natural proteins. Poly aspartic acid, poly L-lysine and poly glutamic acid are the examples of synthetic polypeptide hydrogels. Enteric coated systems Enteric-coated formulations are suitable vehicles to improve the release of active substances such that release at specific target areas in the gastrointestinal tract and preventing its release in stomach. The major purpose of enteric coating is the protection of drugs that are sensitive or unstable at acidic ph. This is particularly important for drugs such as enzymes and proteins because these macromolecules are immediately hydrolyzed and inactivated in acidic medium. Macrolide antibiotics such as erythromycin are rapidly degenerated by gastric juices. Acidic drugs like NSAID's are also enteric coated to prevent local irritation of the mucosa. Another purpose of enteric coating is drug targeting as in case of 5-aminosalicylic acid or the prodrugs sulfasalazine. In these cases, enteric coating is administered such that the drug concentration is increased in the lower parts of the GI Tract. Although the use of enteric coating to improve modified drug release is known for long but it has always been criticized as to its true value of providing protection and targeted release of coated active agents. Dosage Forms In general, film coated dosage forms can be divided into two forms multiple unit and single unit dosage forms. Single unit dosage form contains tablets, film coated capsules and other forms. Multiple units contains granules, capsules, pellets and compressed film coated particles. Drug in enteric coated form can produce aqueous dispersions and suspensions. The enteric coated time clock system comprising of tablet core that is coated with a mixture of hydrophobic material and surfactant that is applied as an aqueous dispersion. The drug release from the core is occurring at a predetermined lag time. The lag time is insensitive of GI PH and depends on the thickness of hydrophobic layer. Tablets Tablets can be easily enteric coated and a wide variety of products are in the market for example naproxen, acetyl salicylic acid , diclofenac they have increased bioavailability , improved patient compliance and the formulation stability due to coating process. Capsules Extra precautions are required during coating as capsule shells become brittle during storage. To ensure proper coating of the capsule 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 showed good stability. Multiple units A widely used method of producing multiple units has been the formulation of sachets containing film coated granules. Capsules filled with enteric coated particles is of common use. In addition to the flexible polymers for coating, suitable larger sized fillers-binders and stable strong pellet cores are also considered for the enteric dosage form designs. Only methacrylic acid copolymers seem to have these properties necessary to produce these dosage forms. Example: Small microcapsules of ibuprofen were film coated with cellulose acetate phthalate and dispersed in water before administering, plasma levels didn't differ from the conventional enteric coated tablet as expected. PH sensitive gels Many poly-anionic materials are pH sensitive and the extent of swelling of such polymers can be changed by changing ph. An application of such technology is used in the development of biomimetic secretary granules for drug delivery system. The polymer network, containing biological mediators such as histamine exist in a collapsed state as a result of internal pH and ionic content that is maintained by the lipid surrounding the membrane. Histamine release from granule is initiated by the fusion of the granule with the cell membrane revealing the poly-anionic internal matrix to the extracellular environment. Hence the change in pH and ionic strength results in ion exchange and swelling of the poly-anionic network that causes the release of mediators Application The use of this system in conjunction with temperature sensitive lipids provide potential to target drugs to the areas of inflammation or to reach site specific, pulsatile drug delivery through the localized external application of ultrasound or heating to distort the lipid bilayers. PH-Sensitive Liposomes PH-Sensitive liposomes are stable at physiological pH, under acidic conditions they destabilize leaking to the release of their aqueous contents. In addition, they appear to destabilize or combine with the membranes of endosomes in which they are internalized allowing even macromolecular liposomes contents to enter the cytoplasm. Following binding to cells, liposomes are internalized through the endocytotic pathway. Liposomes are retained in early endosomes that mature into late endosomes. The potential of pH sensitive liposomes lies in their ability to undergo destabilization at this stage thus preventing their degradation at the lysosomal level and therefore increasing access to nuclear targets. Applications Hyper-branched poly glycidal (HPG) derivatives were formulated as a new type of pH sensitive polymer used in modification of liposomes. They showed stronger interaction with the membrane than the linear polymers show. Thus liposomes modified with HPG derivatives show better results. PH sensitive nanoparticles Particles in the size range of 40-120nm are translocated both transcellularly and paracellularly. In addition to enhancing drug bioavailability, particulate oral drug delivery systems can protect reactive macromolecules from stomach acid and first pass effect in the GIT. The use of pH sensitive polymers like hydroxypropyl methyl cellulose phthalate for encapsulating proteins or antigens for oral administration, these particles are matrix-type dispersed systems. At a specific pH highly dispersed drugs release within the GIT close to the absorption window of the drug thus increasing the probability to maximum absorption and to minimize first pass metabolism. Methods to prepare polymeric nanoparticles are ionic gelation, solvent evaporation, salting-out/emulsification diffusion and polymerization. Application PH-Sensitive nanoparticles are used for antitumor evaluation Advantages Following are the advantages 1. Drug directly available at the target site 2. Decreased dose to be administered 3. reduced side effects 4. Improved drug utilization 5. enhance patient compliance 6. Lower daily cost to the patient due to fewer dosage units are required by the patient in therapy 7. Mucosa protection from irritating drugs 8. Extensive drug pass metabolism for prevention of drug loss Example of Novel Drugs Example 1 PH-sensitive hydrogels comprises of polyethylene glycol and methacrylic acid (MAA) macromonomer (PEGMEMA) entrapping diliazem HCL were synthesized inside soft gelatine capsules for use as a new dosage form for oral drug administration. For the assessment of their swelling and release behaviour in two media, different monomers were used: at pH 7 stimulating the higher ph environment of the intestine while at low pH stimulating the acid ph of the stomach. DIL-HCL release and swelling both processes are dependent on PH and composition of monomer. Hydrogels with intermediate formations showed diminished DIL·HCl release at pH 1.2. Similar shaped release profiles were found for the four hydrogels compositions at pH 7. At this neutral pH slow protonation of the carboxylate groups of MAA led to the swelling front and a dry core that is detected by MRI. As a result of this swelling, release curves displayed a long period of zero order kinetics. So, this shows that the system could be a suitable candidate for developing a zero order release dosage form for oral administration of DIL-HCL. The processes of dissolution and swelling were analysed by different mathematical approaches. Example 2 The development of a novel colon-specific drug delivery system with methacrylate derivatives of 5-ASA using properties of drug release and PH sensitive swelling. 5-ASA film coated tablets were developed for colon specific delivery. During this method 5-ASA core tablets were initially made then coated with dispersion containing Eudragit RS and dessterrifed pectin, polygalacturonicacidor its sodium and potassium salts. Negligible drug release occurred during the first five hours where the coated tablets were in small intestine and stomach. After that, 5-ASA release from coated tablets happened linearly as a function of time because of the action of pectinolytic enzymes.