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Paper Coordinator
Content Reviewer
Dr. Vijaya Khader Dr. MC Varadaraj
Principal Investigator
Dr. Vijaya Khader
Former Dean, Acharya N G Ranga Agricultural University
Content Writer
Prof. Farhan J Ahmad
Jamia Hamdard, New Delhi Paper No: 05 Product Development 1
Module No: 19 Polymers as excipients for novel drug delivery applications Part 2
Development Team
Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
Prof Roop K. Khar
BSAIP, Faridabad
Prof. Dharmendra.C.Saxena SLIET, Longowal Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi
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IntroductionWith the emergence of novel and effective drugs, increased importance is being placed upon the ways by which these drugs are being delivered to the body. Conventional drug delivery methods result in a peak in plasma drug concentrations, followed by a plateau and finally a decline. As a result, these methods of drug delivery may lead to toxic plasma drug concentrations or ineffective plasma levels.
Even though sustained and controlled release devices are advantageous, they maintain the drug within the desired therapeutic range with just a single dose, they reduce dose frequency, they allow localized drug delivery, they prevent degradation of drug by the body, and ultimately improve patient compliance but they remain insensitive to the changing metabolic states of the body. Mechanisms capable of responding to these physiological variations must be provided in order to synchronize drug release profiles with changing physiological conditions. Ideally, a drug delivery system should respond to physiological requirements, sense the changes and alter the drug-release profile accordingly.
Similar to living systems that can nonlinearly respond to external applied stimuli/signals, polymers can undergo drastic changes in chemical or physical properties to adapt to the surrounding environment which made them unique materials for a wide of applications including drug delivery, imaging, theranostic and tissue engineering. Such polymers are called as ‘smart’ polymers, ‘stimuli-responsive’
polymers, ‘environmental-sensitive’ polymers or ‘intelligent’ polymers. The distinguishing characteristic of these stimuli-responsive polymers is their ability to undergo rapid changes in their microstructure from a hydrophilic to a hydrophobic state in response to an external stimulus. The macroscopic changes that occur are reversible; therefore the system is capable of returning to its initial state when the stimulus is removed. Common stimuli that drive these changes are temperature, pH, light, electric field and bio responses.
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Responses to these stimuli may be manifested as changes in shape, surface characteristics, solubility, hydrophilic-hydrophobic balance, formation of an intricate molecular assembly or a sol-to-gel transition.Based on these changes the polymers are classified into three categories:
(1). Coil-to-globule transition of linear polymer chain in solution
Polymers under this category undergo a reversible collapse upon the application of an external stimulus.
For phase transition to occur a delicate balance between hydrophilic and hydrophobic proportion is required in the molecular structure of the polymer. With increasing hydrophobicity, the soluble polymer is precipitated out of solution and forms a totally different insoluble phase. This conversion is achieved either due to neutralization of the electric charges that are present on the polymeric network or because of reduction in the number of hydrogen bonds that the polymer forms with water.
(2). Swelling/ deswelling of covalently cross-linked hydrogels
Investigations into stimuli-responsive polymers have often been focused to a large extent on hydrogels that swell in aqueous media. These hydrogels may respond rapidly to physical and chemical stimuli resulting in changes in swelling behavior due to change in polymer – polymer or water – polymer interactions. These hydrogels may be synthesized in the conventional manner to result in hydrogels with
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small pore sizes or they may be synthesized by various other approaches to result in macroporous hydrogels for different applications.(3). Micellization or self-assembly of amphiphilic block copolymers
Phase separation of stimuli-responsive polymers occurs only when a sharp conformational change of a macromolecule occurs. This change must be accompanied with a drastic increase in hydrophobicity triggered by a small change in the environment. When a polymer reversibly swells or collapses on a surface it converts the interface from hydrophilic to hydrophobic and vice versa. This occurs when the
‘collapsed’ hydrophobic macromolecules aggregate and form a separate phase. The ‘intelligent’
polymers do not aggregate but the conformational transition from a hydrophilic to a hydrophobic state renders the surface hydrophobic. The surface is hydrophilic when the polymer is in its expanded soluble state and hydrophobic when in its collapsed insoluble state.
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Critical attributes of a smart polymer for drug delivery should include: Biocompatibility and biodegradability;
Sustained or controlled release profile;
High drug loading capacity;
Lack of detrimental properties such as toxicity, immunogenicity and carcinogenicity;
Ability to undergo modification with ease; and
Excellent stability profile.
The major benefits of using smart polymer-based drug delivery systems includes:
Drug could be released at the target site in the desired manner
Maintenance of desired therapeutic concentration
Prolonged release of incorporated drug
Reduced dosing frequency
Reduced side effects
Patient compliance
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TEMPERATURE RESPONSIVE POLYMERSTemperature has been widely investigated as a stimulant for responsive polymer systems owing to its ease of modulation and applicability in drug delivery applications. Temperature sensitive polymers called as thermo sensitive polymers undergo abrupt change in their structure and solubility in response to a small change in temperature.
Thermo sensitive polymers are characterized by presence of lower critical solution temperature (LCST) or upper critical solution temperature (UCST). Lower critical solution temperature is the temperature above which the polymeric monophasic system becomes hydrophobic and insoluble, leading to phase separation, whereas below the LCST the polymers are soluble. This phase transition stems from the hydrophilic/hydrophobic balance of polymer chains, which is modulated by recurrent establishment and disruption of intra- and inter-molecular electrostatic and hydrophobic interactions. Below the LCST, water molecules exist in an ordered state in the local environment of polymer chains. As temperature rises above the LCST, polymer-polymer hydrophobic interactions dominate, polymer chains collapse and water molecules are released to the bulk, resulting in a net entropic gain for the polymer/solvent system.
As for example, PNIPAAm, has been thoroughly investigated for its ability to undergo a reversible, negative temperature-dependent phase transition. Below its LCST which is 32°C, PNIPAAm exists as a hydrophilic coil, whereas above LCST, PNIPAAm chains collapse sharply into a hydrophobic globule.
In contrast to this, polymers that exhibit positive temperature-dependent swelling behavior, i.e., a globule-to-coil transition with increasing temperature, possess an UCST.
For pharmaceutical applications, LCST systems are preferred over UCST systems because high temperatures for UCST systems are unfavorable for heat-labile drugs and biomolecules.
An aqueous thermo sensitive polymeric solution exhibits temperature-dependent and reversible sol–gel transitions near body temperature that control the rate of release of incorporated drug along with maintaining physicochemical stability and biological activity. This phenomenon is generally governed by the ratio of hydrophilic to lipophilic moieties on the polymer chain and is an energy-driven
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phenomenon which depends on the free energy of mixing or the enthalpy or entropy of the system. For drug delivery applications, it may be desirable to shift the critical temperature for volume phase transition to a specific temperature range. This can be accomplished through the inclusion of hydrophilic or hydrophobic moieties in the polymer chain. Usually polymers with a larger hydrophobic hydration area possess stronger hydrophobic interactive forces and undergo collapse at a lower temperature.Conversely, increasing the hydrophilic content of the polymer chain will increase the LCST.
LCST temperature (32°C) of NIPAAM can be shifted to body temperature by formulating with surfactants or additives. This makes poly (NIPAAM) an excellent carrier for in situ drug delivery.
Thermo responsive polymers are attractive candidates for in situ implants in which thermo reversible gelation is exploited for the facile implantation of solid drug-depot preparations. In these systems, a liquid drug/polymer solution is injected into a target site at ambient temperature. As the solution temperature warms to body temperature, the polymer gels, which entraps the drug in the physically cross- linked matrix. Diffusion of the drug from the solid gel allows for sustained-release formulations.
In a reported study, using temperature-responsive chitosan grafted with PEG delivery of protein bovine serum albumin was sustained for approximately 70 hours. Further, crosslinking of gel with genipin resulted in prolongation of release of BSA for up to 40 days. Thermo responsive polymers also play role in targeting drugs to inflammatory sites and cancer cells since these sites have slightly higher temperature compared to rest of body.
The thermo sensitive polymers can be categorized into four types:
(a) Polymers exhibiting phase transition at LCST such as PNIPAAm, poly(N-vinylcaprolactam) poly(vinyl methyl ether), poly(dimethylamino ethyl methacrylate), poly(N-vinyl isobutyl amide) and Pluronics.
(b) Amphiphilic block polymers such as polyoxyethylene and polyoxypropylene (PEO-PPO-PEO).
(c) Thermo sensitive polysaccharides include cellulose derivatives, like, ethyl cellulose, ethyl hydroxyethyl cellulose (EHC), hydroxyethyl cellulose (HEC) and certain natural polysaccharides, including agarose, carrageenan, amylose, amylopectin and gellan gum.
(d) Artificial polypeptides comprise of elastin-like polymer (ELP) or silk-elastin-like block copolymers (SELPs)
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The major advantage of thermo sensitive polymeric systems is the avoidance of toxic organic solvents, the ability to deliver both hydrophilic and lipophilic drugs, reduced systemic side effects, site-specific drug delivery, and sustained release properties.PH RESPONSIVE POLYMERS
Physiological pH varies systematically in the body, particularly along the GI tract, where stomach has a pH of 1 to 3, followed by duodenum with pH value 5-6, followed by small intestine with pH ranging from 6.2 to 7.0 and colon with pH ranging from 7.0 to 7.5. Physiological pH also change among cellular compartments with endosomes, lysosomes and Golgi complex exhibiting pH values in range of 5.0 to 6.8, 4.5 to 5.5 and 6.2 to 6.4, respectively. Also, it is well known that inflamed or diseased tissues exhibit different pH than normal tissue. Tumors have been reported to produce acidic conditions (pH ~ 6.5) in the extracellular milieu. Thus, it is no surprise that scientists and engineers have devoted considerable effort toward the rational design of polymers capable of exploiting these pH variations to selectively deliver valuable therapeutics to specific intracellular or extracellular sites of action. By judicious materials selection and careful engineering of molecular architecture, pH-responsive polymer delivery systems can be developed to give well-controlled pH response and drug release.
All pH-sensitive polymers consist of pendant acidic or basic group that can either accept or release a proton in response to changes in environmental pH.
pH sensitive polymers are classified into two types: weak polyacids and weak polybases.
Weak polyacids:
Weak polyacids accept protons at low pH and release protons at neutral and high pH. As the environmental pH changes, the pendant acidic group undergoes ionisation at specific pH. This rapid change in net charge of the attached group causes alteration in the molecular structure of the polymeric chain. This transition to expanded state is mediated by the osmotic pressure exerted by mobile counter ions neutralized by network charges.
Poly (acrylic acid) and poly (methacrylic acid) are commonly used pH-responsive polyacids. The carboxyl group of Poly (acrylic acid) and poly (methacrylic acid) remains in the unionized state in the
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acidic pH environment of stomach and get ionized in the alkaline environment of small intestine releasing the drug molecule.pH-Sensitive polymers containing a sulphonamide group are another example of polyacid polymers in which he hydrogen atom of the amide nitrogen is readily ionized to form polyacids.
Weak polybases:
Polybases bearing an attached amino group are the most representative polybasic group. Polycationic polymers, such as, chitosan, poly(lysine), poly(N,N-dimethylaminoethyl methacrylate), poly(vinylamine), poly(N,N-diakyl aminoethyl methacrylates), and poly(ethylenimine) exhibit a different behaviour in different pH environment. The amine groups of these polycationic polymers exist in the unionized form. In neutral or alkaline pH, keeps the drug intact in the carrier structure and when the pH value is reduced to less than the pKa, they become ionized leading to the swelling of polymer due to electrostatic repulsion of the neighbouring positively charged groups and hence releasing the drug to the environment.
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LIGHT-SENSITIVE POLYMERSA light-sensitive polymer undergoes a phase transition in response to exposure to light. The major advantages of light-sensitive polymers are that they are water soluble, biocompatible and biodegradable and their capacity for instantaneous transition from sol to gel, making light-responsive polymers important for various engineering and biomedical applications. Light-responsive polymers are very attractive for triggering drug release because of the ability to control the spatial and temporal triggering of the release. This means that the encapsulated drug can be released or active after irradiation with a light source from outside the body. The light sensitive polymers can be classified on the basis of the wavelength of light that triggers the phase transition:
UV light-sensitive polymers
Visible light-sensitive polymers
Infrared-sensitive polymers UV-sensitive polymers
Polymer gels containing a leuco-derivative molecule, bis(4-dimethylamino) phenyl methyl leucocyanide, undergo phase transition behavior in response to UV light. Triphenylmethane-leuco derivatives dissociate into ion-pairs such as triphenylmethyl cations upon UV irradiation. At a fixed temperature these hydrogels swell discontinuously due to increased osmotic pressure in response to UV irradiation but shrink when the stimulus is removed. Increased osmotic pressure within the gel was due to cyanide ions formed by UV irradiation.
Visible light-sensitive polymers
Visible light-sensitive hydrogels are prepared by incorporating photosensitive molecules or chromophores such as trisodium salt of copper chlorophyllin to thermosensitive polymer. When light of appropriate wavelength is applied, the chromophore absorbs light which is then dissipated locally as heat, increasing the temperature of the hydrogel, leading to alteration of the swelling behavior of the thermosensitive hydrogel. The temperature increase directly depends on the intensity of light and chromophore concentration. Another example of visible light-responsive hydrogels for temporal drug delivery is cross linked hyalouronic acid hydrogel that undergoes photosensitized degradation in the
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presence of methylene blue. Visible light-sensitive polymers are comparatively preferred over UV light- sensitive polymers because of their safety and ease of use.Infrared light- sensitive polymers
Another activation mechanism is the use of infrared light which can elicit a response in hydrogels in the absence of chromophores. The method is advantageous since water readily absorbs infrared radiation.
When hydrogels without chromophores are irradiated by infrared the volume phase transition along with gel bending was observed, while the relaxation of the gel to its original form after irradiation was terminated followed.
Limitations of light-sensitive polymers include inconsistent response due to the leaching of noncovalently-bound chromophores during swelling or contraction of the system, and a slow response of hydrogel towards the stimulus. Dark toxicity is also one of the drawbacks of light-responsive polymeric systems.
ELECTRIC FIELD-SENSITIVE POLYMERS
Electric field-sensitive polymers change their physical properties in response to a small change in electric current. Most polymers that exhibit electro-sensitive behavior are polyelectrolytes i.e. contain a relatively high number of ionizable groups and they are pH-responsive as well. These polyelectrolytes undergo deformation under an electric field due to anisotropic swelling or deswelling as the charged ions move towards the cathode or anode. Greatest stress is felt by the region surrounding the anode and smaller stress near the vicinity of the cathode. This stress gradient contributes to the anisotropic gel deformation under an electric field. Electro-responsive polymers transform electric energy into mechanical energy and had shown wide application in the field of sustained and targeted drug delivery. The electric current causes a change in pH which leads to disruption of hydrogen bonding between polymer chains, causing bending or degradation of the polymer chain leading to drug release. The mechanisms involved in drug release are electrophoresis of charged drug, diffusion, forced convection of drug out of the gel and liberation of drug upon erosion of electro-erodible polymers.
Gel bending or degradation due to electric field stimulus depends on a number of factors such as:
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Position of the gel relative to the electrodes
Applied voltage
Osmotic pressure
Thickness or shape of the gel
Naturally occurring polymers such as chitosan, alginate and hyalouronic acid are commonly employed to prepare electro-responsive materials. Synthetic polymers such as vinyl alcohol, acrylonitrile, allyl amine, methacrylic acid and vinylacrylic acid are also used. Combination of natural and synthetic polymers are also employed for electro-responsive materials.
One of the applications of electrosensitive polymers includes the delivery of edrophonium hydrochloride and hydrocortisone in a pulsatile manner using the polymer poly(2-acrylamido-2-methylpropane sulphonic acid-co-n-butylmethacrylate). Control of drug release was achieved by varying the intensity of electric stimulation.
The major constraint that has to be considered in this type of drug delivery system is the critical selection of electric current which can cause drug release without stimulating the nerve endings in the surrounding tissue.
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BIORESPONSIVE POLYMERSBiologically responsive polymer systems are increasingly important in various biomedical applications.
The major advantage of bioresponsive polymers is that they can respond to the stimuli that are inherently present in the natural system. Bioresponsive polymeric systems mainly arise from common functional groups that are known to interact with biologically relevant species, and in other instances the synthetic polymer is conjugated to a biological component.
Glucose responsive polymer:
The working of bio responsive polymer is shown by taking example of glucose responsive polymers.
Glucose responsive polymers have the ability to mimic normal endogenous insulin secretion which minimizes diabetic complications and can release the bioactive compound in a controlled manner. These are sugar-sensitive and show variability in response to the presence of glucose. These polymers have garnered considerable attention because of their application in both glucose-sensing and insulin-delivery applications.
Type 1: Works on the principle of enzymatic oxidation of glucose by glucose oxidase
This delivery system consist of insulin entrapped in poly (acrylic acid) polymer conjugated with the GOx system. Glucose sensitivity occurs by the response of the polymer toward the byproducts that result from the enzymatic oxidation of glucose. Glucose oxidase oxidizes glucose resulting in the formation of gluconic acid and H2O2. As the blood glucose level is increased glucose is converted into gluconic acid which causes the reduction of pH and protonation of PAA carboxylate moieties. The protonation of PAA polymer causes the release of insulin.
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Type 2: Works on the principle of specific binding of lectin with glucoseThis system utilizes the unique carbohydrate binding properties of lectin for the fabrication of a glucose- sensitive system. Concanavalin A (Con A) is a lectin possessing four binding sites and has been used frequently in insulin-modulated drug delivery. In this type of system the insulin moiety is chemically modified by introducing a functional group (or glucose molecule) and then attached to a carrier or support through specific interactions which can only be interrupted by the glucose itself. The glycosylated insulin-Con A complex exploits the competitive binding behaviour of Con A with glucose and glycosylated insulin. The free glucose molecule causes the displacement of glycosylated Con A-insulin conjugates within the surrounding tissues and are bioactive.
Type 3: Reversible covalent bond formation with phenylboronic acid moieties
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Polymers with phenylboronic group forms gel with molecules such as diglucosylhexadiamine due to complex formation between the pendant phenylborate and hydroxyl groups. As the glucose concentration increases, the crosslinking density of the gel decreases and as a result insulin is released from the eroded gel. The glucose exchange reaction is reversible and reformation of the gel occurs as a result of borate–polyol crosslinking.
In spite of these advantages, the major limitations of these systems are their short response time and possible non-biocompatibility.
BIOADHESIVE/ MUCOADHESIVE POLYMERS
Bioadhesion is defined as a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological membrane and the polymers, which allows the polymer to adhere to the biological surface for an extended period of time. Mucoadhesion specifically represents adhesion of the polymers with the surface of the mucosal layer made up of mucus secreted by the goblet cells. It lines the visceral organs, which are exposed to the external environment. The main components of mucus are water and mucin (an anionic polyelectrolyte), with minor quantities of proteins, lipids and mucopolysaccharides.
The adhesion of delivery systems to mucus has been explored for:
(1) Improved retention time of the active agent at the desired location thus improving bioavailability.
(2) The use of specific bioadhesive molecules allows for possible targeting of particular sites or tissues, for example the ocular surface, GI tract etc.
(3) Sustained drug release combined with increased residence time may lead to lower administration frequency.
(4) Avoidance of first-pass metabolism.
(5) Reduction of dose-related side effects due to drug localization at the disease site.
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Polymers used in mucosal delivery system may be of natural or synthetic origin. In this section we will briefly discuss theories of mucoadhesion, factors affecting mucoadhesion, and some of the common classes of mucoadhesive polymers.Theories of Mucoadhesion
Electronic theory: According to electronic theory transfer of electrons amongst the surface of the polymer and mucosa results in the formation of an electrical double layer thereby giving rise to attractive forces.
Wetting theory: According to this theory mucoadhesion develops between polymer and the mucosal surface if the polymer in liquid system is in intimate contact with mucosal surface and if sufficiently spreads over the surface of mucosa.
Adsorption theory: According to this theory the mucoadhesion develops between polymer and the mucosal surface owing to presence of intermolecular forces, viz., hydrogen bonding and Van der Waals forces.
Diffusion theory: This theory assumes that the polymer chains present on the polymer undergoes diffusion across the mucosal surface forming a networked structure and mucoadhesion.
Mechanical theory: According to this theory mucoadhesion develops due to diffusion of the liquid adhesives into the micro-cracks and irregularities present on the substrate surface thereby forming an interlocked structure.
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Cohesive theory: According to this theory the phenomena of bioadhesion are mainly due to the intermolecular interactions amongst like-molecules.Factors affecting mucoadhesion of polymer:
The mucoadhesive property of a polymer can be tailored by changing the parameters which alter the interaction among the polymer and the mucosal layer. In this section we will study the parameters which can tailor the mucoadhesive property of the polymers.
Molecular weight: Generally, the interpenetration of polymer molecules is favored by low-molecular- weight polymers, whereas entanglements are favored at higher molecular weights. Thus, mucoadhesiveness of a polymer increases with the increase in the molecular mass of the polymer chain.
Polymers with molecular mass greater than 100 kDa possess adequate mucoadhesive property. As an example, PEG of 20 kDa molecular mass does not exhibit mucoadhesion, whereas PEG of 200 kDa exhibit mucoadhesion and PEG of 400 kDa exhibit excellent mucoadhesion. Similarly, dextrans of 200 kDa, poly(acrylic acid) of around 750 kDa and poly(ethylene oxide) of 4000 kDa showed good mucoadhesive properties.
Polymer chain: It is generally accepted that increase in polymer chain length increases the mucoadhesive property of the polymer. Not only chain length but also flexibility of polymer chain plays
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important role in mucoadhesion. Flexible polymeric chains helps in the better entanglement to the mucosal layer. Thus, tethering of long flexible chains onto the polymer matrices is an excellent way to improve their mucoadhesive property. This phenomenon has been utilized to develop tethered PEG–poly(acrylic acid) hydrogels with improved mucoadhesive properties. The flexibility of the polymer chains is affected by hydration of the polymer network and the cross-linking. The lower the cross-link density, the higher the flexibility and hydration rate; the larger the surface area of the polymer, the better the mucoadhesion. Besides chain length and flexibility, spatial arrangement of the polymer chains is also important. As for example, despite a high molecular weight of 19,500 kDa for dextrans, they have adhesive strength similar to that of PEG, with a molecular weight of 200 kDa. The helical conformation of dextran may shield many adhesively active groups, primarily responsible for adhesion, unlike PEG polymers, which have a linear conformation
Functional groups: Formation of hydrogen bond between the functional groups of the polymers and mucosal layer also decides the fate of mucoadhesion. Usually, stronger the hydrogen bonding stronger is the adhesion. The ability of hydroxyl, carboxyl and amino groups to form strong hydrogen bonds results in improved mucoadhesion owing to presence of these functional groups. Polymers which have the ability to form strong hydrogen bonds include celluloses, starch, acrylic derivatives and poly(vinyl alcohol). The presence of charged functional groups in the polymer chain also has a marked effect on the strength of the mucoadhesion and anionic polyelectrolytes have been found to form stronger adhesion when compared with neutral polymers.
Polymer concentration: The polymer concentration also plays a substantial role in the process of mucoadhesion. At low concentrations, there is an inadequate and unstable interaction between the polymer and the mucosal layer resulting in weak mucoadhesion. However, for certain polymers, like poly(vinyl alcohol) and poly(vinyl pyrrolidone), solvent diffusion into the polymer network decreases at very high polymer concentration due to the formation of the highly coiled structure thereby limiting
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interpenetration of the polymer and mucin chains with the subsequent reduction in the mucoadhesive property.Physiological factors: Apart from the above-mentioned physico-chemical properties of the polymer, various physiological factors also play an important role in mucoadhesion. As mentioned previously, mucoadhesion is dependent on the ionization of functional groups which in turn depends upon the pH of the physiological site. Hence, change in the pH may play an important role in tailoring mucoadhesive property. As for example, chitosan, a cationic polyelectrolyte, exhibit profound mucoadhesion in neutral or alkaline medium. Not only pH nut also other factors such as duration of contact, fluid turnover, hydration and thickness of mucosal layer play an important role in governing the mucoadhesive properties of a polymer.
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Mucoadhesive polymersThe polymers that are commonly employed in the development of mucoadhesive drug delivery systems that adhere to mucin–epithelial surfaces may be suitably divided into two broad categories:
A) Non-specific (First generation) mucoadhesive polymers B) Specific (Second generation) mucoadhesive polymers
Non-specific (First generation) mucoadhesive polymers are classified as
Anionic polymers
Cationic polymers
Non-ionic polymers
Anionic polymers: Anionic polymers are widely employed mucoadhesive polymers for drug delivery due to their high mucoadhesive functionality and low toxicity. These polymers are characterized by the presence of sulphate and carboxyl functional groups that give rise to a net overall negative charge at pH values exceeding the pKa of the polymer. Typical examples include poly (acrylic acid) (PAA) and its derivatives, polycarbophil (Noveon), carbomer (Carbopol) and sodium carboxymethylcellulose (NaCMC). PAA and NaCMC are hydrophilic in nature and exerts their mucoadhesion by formation of strong hydrogen bonding interactions with mucin. PAA polymers are available in a wide range of molecular weights and are considered safe for oral use by the FDA. Polycarbophil is insoluble in aqueous media but has a high swelling capacity under neutral pH conditions, permitting high levels of entanglement within the mucus layer. Additionally its non-ionized carboxylic acid groups bind to the mucosal surfaces via hydrogen bonding interactions.
Cationic polymers: Among presently explored cationic polymer systems, chitosan is gaining increasing importance due to its good biocompatibility, biodegradability and favorable toxicological properties.
Whereas anionic polymer bind to mucus via hydrogen bonds chitosan exhibit its mucoadhesion via ionic interactions between primary amino functional groups and the sialic acid and sulphonic acid substructures of mucus. The linearity of chitosan molecules also ensures sufficient chain flexibility for interpenetration. Chitosan not only provide improved drug delivery via mucoadhesion it also enhance drug absorption opening of tight junctions between mucosal cells.
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Non-ionic polymers: Non-ionic polymers such as hydroxypropyl methyl cellulose, methyl cellulose, poly(vinyl alcohol) and poly(vinyl pyrrolidone), also exhibit mucoadhesion however their mucoadhesive properties are weak as compared to ionic counterparts and they have limited use in mucoadhesive drug delivery systems.B) Specific (Second generation) mucoadhesive polymers
The major disadvantage of using non-specific mucoadhesive polymers is that adhesion may occur at sites other than those intended. Unlike, non-specific polymers, second-generation polymers binds directly to mucosal surfaces the phenomena termed as cytoadhesives. Further as surface protein and carbohydrate composition at target sites vary regionally, more accurate drug delivery may be achievable. Examples of this class of polymers include thiolated polymers and lectin based polymers.
Thiolated Polymers: Thiolated polymers or thiomers are second-generation mucoadhesive polymers derived from hydrophilic polymers such as polyacrylates, chitosan or deacetylated gellan gum. The presence of free thiol groups in these polymer helps to bind with cysteine-rich sub-domains of mucin through formation of disulphide linkages, leading to increased residence time and improved bioavailability. Whilst first-generation mucoadhesive platforms are facilitated via non-covalent secondary interactions, the covalent bonding mechanisms involved in second-generation systems lead to interactions that are less susceptible to changes in pH or ionic strength. Examples of thiolated polymers include poly(acrylic acid)–cysteine, poly(acrylic acid)–homocysteine, sodium carboxymethylcellulose–
cysteine, chitosan–thioglycolic acid, chitosan–thioethylamidine, alginate–cysteine and poly(methacrylic acid)– cysteine.
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Lectin-Based Polymers: Lectins are proteins found in animal, microorganisms and plants, which have the ability to reversibly bind with specific carbohydrate / sugar residues. Their specific affinity towards sugar or carbohydrate provides them with specific cytoadhesive property. After initial mucosal cell- binding, lectins can either remain on the cell surface or possibly become internalized via a process of endocytosis. Such systems could offer dual functions including targeted attachment and controlled drug delivery via active cell-mediated drug uptake. Lectins extracted from legumes have been extensively explored to develop targeted delivery systems. Lectins extracted from soybean and peanut have shown specific binding to the mucosa. The wheat germ agglutinin has been also explored for oral and aerosol delivery systems due to its capability to bind to the intestinal and alveolar epithelium. Although lectins offer significant advantages in relation to site targeting, many are toxic or immunogenic, and the effects of repeated lectin exposure are largely unknown. It is also feasible that lectin-induced antibodies could block subsequent adhesive interactions between mucosal epithelial cell surfaces and lectin delivery vehicles. Moreover, such antibodies may also render individuals susceptible to systemic anaphylaxis on subsequent exposure.23
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POLYMERS INHIBITING ACTION OF ENZYMESThe polymers with enzyme-inhibiting properties include sodium alginate, chitosan citrate, polyacrylic acid, carboxymethyl cellulose and copolymers of poly(methacrylic acid) and poly(ethylene glycol) and starch.
The inhibition of enzyme is due to:
a) binding of polymer to the Ca2+ and Zn2+ ions, which are the key components for thermodynamic enzyme stability
b) enzyme–polymer interaction reducing the free enzyme concentration.
c) reduction in the pH value below the optimal level required for the enzyme activity.
Thiolated polycarbophil-cysteine, which binds to the Zn2+ ions in the enzyme carboxypeptidase A and B and aminopeptidase structure and inhibits them.
Chitosan itself is a weak enzyme-inhibitor but its conjugation with an enzyme-inhibitor likes Bowman-Birk inhibitor leads to enzyme-inhibition.
EDTA immobilized on chitosan prevents the secretion of Zn-dependent peptidases.
The trypsin-inhibitor when attached to soybean polyacrylate, improves its trypsin- and chymotrypsin-inhibiting properties.
POLYMERS ENHANCING THE INTESTINAL EPITHELIUM PENETRATION:
Natural polymer like chitosan and synthetic polymer like carbomer are used to increase the penetration of biological molecules particularly proteins through the intestinal epithelium. These polymers bring about a decrease in transepithelial resistance mediated due to loosening of tight junctions between the epithelium cells. Cationic polymers, such as chitosan, may interact with negatively charged residues present on the cell surface, bringing about a conformational change in the membrane structure and
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proteins tightly bound to its surface. The thiolation of the mucoadhesive polymer further improves their permeability-enhancing properties, by inhibiting the action of the protein tyrosine phosphatase (PTP), which mediates closing of tight junctions through dephosphorylation of extracellular tyrosine group.This effect may also be attributed to the covalent binding of the polymer to cysteine residues.
EFFLUX PUMP-INHIBITING POLYMERS:
The bioavailability of several active pharmaceutical moiety is dependent on the activity of protein transporting those drugs. The drug transporter such as P-glycoprotein (Pgp) efflux the drug substance from the cells to the extracellular space via an active transport mechanism, thus preventing their accumulation inside the cell. Multifunctional polymers can be used to inhibit Pgp which would prevent their transport back to the intestinal lumen and will increase their bioavailability. Various natural polymers such as gellan gum, xanthan gum, sodium alginate, thiolated polycarbophil, thiolated chitosan and synthetic polymers including poloxamers, PEG, poly(caprolactone), poly(lactide), poly(D,L-lactide- co-glycolide) (PLGA) and polyoxylates, can be used to mediate efflux pump inhibiting activity.
The block copolymers of poloxamers can also be used to inhibit the activity of other transporters such as MRP (multidrug resistance proteins) and BCRP (breast cancer resistance proteins). This lead to an enhancement in bioavailability and improvement in therapeutic efficacy of several anticancer drugs like paclitaxel and doxorubicin.
The inhibition of the activity of an ATP-dependent pump is mediated by the nonspecific changes in lipids and protein conformation and their mobility. Furthermore, the drug sequestration in an acidic environment and detoxification is inhibited, with the participation of glutathione S transferase, due to the energy derived from the breakdown of ATP. The ATPase activity inhibition mediated by the copolymers causes the ATP deficit and hence a higher sensitivity of the cells to the applied treatment.
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Polymers as excipients for novel drug delivery applications Part 2
FATE OF SMART POLYMERSMost of the currently developed smart polymeric drug delivery systems and their applications have not yet made the clinical transition. In such a case, there are some critical points that have to be considered.
The most significant one is the potential cytotoxicity of smart polymers involved in the delivery of biomolecular drugs, such as peptides, proteins and nucleic acid drugs.
Another reason is the response time of the polymer; in majority of cases, it occurs on a reasonably slow time, and therefore fast-acting polymer systems are required.
Thermoresponsive polymeric drug delivery systems are well characterized and have proven useful for a wide range of applications. Unfortunately, most commonly used acrylamide or acrylic acid polymers are not hydrolytically degradable and often are associated with neurotoxicity. So these adverse effects limit the field of smart polymeric drug delivery.
Higher molecular weight smart polymers are more effective in reaching their cellular targets, but they are not biodegradable and not excreted, so they tend to accumulate in the body. This limit their clinical trials.
Research into smart drug delivery systems is predominantly focussed on cancer treatment and has attractive features such as physical or active targeting towards cancer cells and special protection of drug under circulation. But these do not show any clinical success until the drug delivery system can kill every last cancer cell. Some cancer cells undergo metastasis and are very difficult to kill. This challenging behavior represents a huge barrier to the clinical use of smart polymers.
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Polymers as excipients for novel drug delivery applications Part 2
CONCLUSIONWith the advancement of novel drug delivery systems, smart polymeric drug delivery systems provide a link between therapeutic need and drug delivery.
Various stimuli are utilized to attain the controlled and site-specific delivery of drug.
Smart polymeric drug delivery systems have wide applications in the field of oral drug delivery of biological drugs which are sensitive to both gastric acid and enteric enzymes and also in the field of smart diagnostics.
Inherent limitations of this drug delivery system are slow response times. While there are many exciting challenges facing this field, there are a number of opportunities for the development of smart polymeric drug delivery systems. Smart polymeric drug delivery systems have a very wide range of applications and are likely to have an exciting future.
