Intelligent or stimuli-sensitive polymers

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Chapter: Pharmaceutical Drugs and Dosage: Pharmaceutical polymers

The terms intelligent, stimuli-sensitive, or stimuli-responsive polymers refer to polymers that exhibit relatively large and sharp changes in physical or chemical properties in response to a small change in the environment, such as pH and temperature.


Intelligent or stimuli-sensitive polymers

The terms intelligent, stimuli-sensitive, or stimuli-responsive polymers refer to polymers that exhibit relatively large and sharp changes in physical or chemical properties in response to a small change in the environment, such as pH and temperature. Changes in the environment that affect polymer properties are termed stimuli, while the resulting changes in the polymer and the system (such as dissolved state of the polymer in a sol-vent) are termed the responses. The mechanistic basis of changes in the physical properties of stimuli-responsive polymers is generally a modifi-cation in the structure of the polymer in solution. For example, water-soluble polymers and copolymers can undergo conformational change or phase transition in response to environmental stimuli. These changes may exhibit as swelling, change in solubility and conformation of poly-mer matrix or chain, or polymer precipitation. When a soluble polymer is stimulated to precipitate, it will be selectively removed from the solution. When such polymers are grafted or coated onto a solid support, then one may reversibly change the water adsorption into the polymer-coated surface of the solid, thus changing the wettability of the surface. When a


Figure 11.6 Schematic representations of stimuli-sensitive polymers in solutions, on surface, and as hydrogels.

hydrogel is stimulated to collapse, it shrinks in size, squeezes out water from its pores, turns opaque, and becomes stiffer. Figure 11.6 shows the schematic representations of stimuli-sensitive polymers in solutions, on surface, and as hydrogels.

The stimuli responsiveness of the stimuli-sensitive polymers originates in the bulk and surface chemistry and the architecture of these organic compounds. Physicochemical properties of organic compounds are a result of their surface chemistry (i.e., elemental and functional group compo-sition) and architecture (i.e., surface exposure of functional groups and molecular domains). The surface exposure or display of functional groups could be different within the different forms of the same molecule. For small molecules, this is exemplified by the existence of different crystalline forms (polymorphism) and different morphologies of the same crystalline form. These result in different surface properties (such as solubility and dissolution rate) and bulk properties (such as powder adhesion) of crys-tals, depending on the differences in the functional groups and molecular domains exposed on the surface.1 For large molecules, this is exemplified by protein structure where surface exposure of functional groups of a peptide chain can lead to a protein being hydrophilic and globular or hydropho-bic and membrane-embedded, with many potential secondary and tertiary structure possibilities.

In addition to the changes in these physicochemical properties, for rela-tively large-molecular-weight organic compounds (such as polymers and proteins), the sheer multitude of functional groups and presence of molecu-lar domains (such as hydrophobic regions) impart special characteristics to the interactions of these molecules with the external environment. These interactions include solute–solute and solute–solvent interactions in the dissolved state. Such interactions are responsible for phenomena such as micellization and swelling/collapse of a cross-linked scaffold.

At a molecular level, stimuli responsiveness of polymers is typically based on changes in polymer–polymer and polymer–solvent interac-tions. For example, polymers that bear multiple ionizable weakly acidic or weakly basic functional groups undergo ionization as a function of pH, resulting in changes in the strength and extent of polymer interactions with the solvent. Polymer structure, number and positioning of the func-tional groups, and the strength of their interactions determine the macro-scopic response of the polymer system to the environmental stimulus. For example, some polymeric systems can undergo reversible or irreversible phase transformation from a single-phase solution to biphasic precipitated or aggregated state. However, certain polymer solutions may display gell-ing or micellization without physical phase separation. In addition, colloi-dal or biphasic polymeric systems that contain cross-linked polymers can show polymer swelling or shrinkage with changes in the type and strength of polymer–solvent interactions.


pH-responsive polymers

Polymers that bear ionizable functional groups can undergo reversible (e.g., by hydration) or irreversible (e.g., by hydrolysis) changes in response to changes in the environmental pH. Hydration can lead to reversible poly-mer swelling and deswelling or collapse. Hydrolysis, on the other hand, can lead to irreversible polymer-chain degradation or breakage, result-ing in changes in the overall molecular weight and monomer content of the polymer. The reversible pH-sensitive polymers are typically polyelec-trolytes that contain a multiple weakly acidic or weakly basic (ionizable) functional groups, whose ionization status can change in response to the environmental pH. The weak acid, HA, is ionized at basic pH to H+ and A, while the weak base, B, is ionized at acidic pH to BH+. In the ionized state, increased polymer–water interaction through hydrogen and electro-static bond interactions leads to higher proportion of polymer-associated water of hydration. In addition, electrostatic repulsion between functional groups bearing the same charge on the polymer backbone can lead to polymer-chain expansion. In the unionized state, weak dipole–dipole and hydrophobic interactions within and between the polymer chains can lead to polymer collapse, solvent exclusion, and reduced hydrodynamic volume, eventually causing polymer aggregation or precipitation.

Changes in polymer properties, such as water solubility, water absorp-tion, and polymer degradation by hydrolysis, as a function of solution pH can be utilized in various ways. For example:

·           Sustained drug delivery can be achieved by forming a well-mixed matrix or a core–shell structure of a water-soluble drug in a water-insoluble polymer that degrades in the appropriate pH environment. Hydrolytic degradation of the polymer leads to slow and sustained drug release.

·           pH-triggered drug release in the target tissue can be achieved using polymers linked to drugs through hydrolyzable functional groups. For example, polymeric prodrugs of 5-amino salicylic acid (5-ASA) such as methacryloyloxyethyl-5-amino salicylate (MOES) and N-methacryloylaminoethyl-5-amino salicylamide (MAES) utilize hydrolyzable ester linkages that release the drug in the colon on cleav-age of the biodegradable linkers.

·           Tumor tissue targeting of a cytotoxic drug can be achieved by cova-lent conjugation with or entrapment in the drug delivery system com-posed of a pH-sensitive polymer. Tumor tissues have a slightly lower pH compared to nontumor tissues. The polymers that show signifi-cant change in their physicochemical properties as a result of decrease in the environmental pH, usually due to the ionization of basic func-tional groups, can be utilized for targeted drug delivery to the tumors.

·           Intracellular drug release in specific organelles or regions of the cell can be achieved based on the mechanism of cellular uptake and the pH-responsive properties of the polymer utilized in a drug deliv-ery system. The pH responsiveness of polymers has been utilized in nonviral gene and antisense drug delivery by utilizing polycationic polymers, such as poly(ethyleneimine) (PEI), poly(l-lysine) (PLL), and poly(l-histidine) (PLH). These polymers possess multiple amine func-tional groups that are cationically (positively) charged and ionized at acidic pH but unionized at basic and neutral pH. On cellular uptake through the endosomal pathway, as the pH of the endosomes becomes more and more acidic toward lysosomal pH, the ionization of these polymers leads to water retention and increase in osmotic pressure of the endosomal vesicles, causing their disruption. These carriers, then, are able to release the drug cargo intracellularly before the endosomes become the lysosomes.

·           Enteric- and colon-targeted oral drug delivery can be achieved by coating a drug delivery system using a polymer that exhibits pH-dependent solubility or degradation. Gastrointestinal (GI) fluid’s pH changes progressively from acidic to basic from the stomach through the intestines to the colon. The changes in the GI fluid’s pH can be utilized to release a drug at a particular physiological location in the GI tract. In particular, dosage forms of drugs that are sensitive to the acidic environment of the stomach, or whose release in the stom-ach is otherwise undesirable, can be coated with a polymer that would be insoluble at the acidic stomach pH and soluble at the basic intes-tinal pH. Such polymers are known as enteric polymers, and such a coating on the dosage form is termed enteric coating. Enteric poly-mers are exemplified by methacrylic acid polymer (Eudragit® L100), methyl methacrylate polymer (Eudragit® S100), CAP, HPMCP, and carboxymethyl ethylcellulose etc.


Thermosensitive polymers

Thermosensitive polymers show changes in physicochemical properties with pharmaceutically and physiologically relevant changes in tempera-ture. An aqueous polymer solution might show phase transition above or below a certain temperature, called the critical solution temperature (CST). Solutions may exhibit upper or lower CST, depending on their temperature. Solutions that exhibit upper CST (UCST) are monophasic and isotropic above a certain temperature (but biphasic below that temperature), while solutions that exhibit a lower CST (LCST) are monophasic below a certain temperature (and biphasic above that temperature). The CST is also known as the cloud point, since phase separation occurs at this temperature, lead-ing to cloudy appearance of the solution.

Injectable depot formulations, tissue engineering, and temperature-induced tumor drug delivery exemplify biopharmaceutical applications of thermoresponsive polymers. Temperature-responsive biodegradable poly-mers that show sol–gel transition between room temperature and physi-ological temperature can be utilized to prepare a drug formulation as a solution that precipitates or forms a gel on injection. The in vivo gel serves as a drug reservoir for sustained or controlled drug release over a period of time. Injectable gel-forming polymers are exemplified by block copo-lymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). Commercially available injectable polymers that undergo sol–gel transition include BST-Gel® (BioSyntech) and ReGel® (Macromed) etc.


Other stimuli-responsive polymers

Light-responsive polymers can be designed to respond to either visible or ultraviolet (UV) light. This behavior is typically exhibited in a polymer solution or hydrogel. Hydrophilic polymers can form hydrogels in water, which are three-dimensional polymer chain networks with unique physical properties such as higher viscosity and reduced fluidity than liquid water or dilute polymer solutions. The mechanism of stimuli responsiveness of light-responsive hydrogels may involve chemical bond cleavage with the higher-energy UV irradiation or may involve energy transfer to the polymer network with lower-energy visible radiation.

Electrically responsive polymers respond to the application of electrical field for triggering or controlling drug release. These allow user control over the amplitude of current, duration of impulses, and the time interval between electrical impulses. Drug delivery systems that respond to elec-trical signal are typically polyelectrolyte polymers with multiple ionizable functional groups. The application of electric field aligns the dipoles in polar or charged molecules, resulting in a change in the polymer conforma-tion. This conformational change could involve polymer swelling, shrink-age, or a change in shape. A small change in the electric potential across a polyelectrolyte gel can lead to significant (up to several 100-fold) reversible change in the volume of the gel.

Magnetically responsive drug delivery systems have been used to target the location of drug release to a particular tissue and/or trigger the drug release from a system based on the application of an exter-nal magnetic field. This is usually accomplished by the incorporation of ferromagnetic micro- or nanoparticles in the drug delivery system. Magnetically responsive drug delivery systems might require exposure to strong magnetic fields for prolonged period of time. This exposure is likely to generate localized heating, which could be a part of the drug-release mechanism. For example, Katagiri et al. showed drug release from magnetically responsive lipid bilayer capsules prepared with mag-netite, iron (II, III) oxide (Fe3O4), nanoparticles. The lipid bilayer was deposited on top of the magnetite nanoparticles. On application of alter-nating magnetic field, heating of the magnetite resulted in phase transi-tion of the bilayer membrane, leading to release of the drug incorporated in the bilayers.

Ultrasound-responsive drug delivery systems commonly use ultrasound as a permeation enhancer through biological membranes such as skin, lungs, intestinal wall, and blood vessels. The use of ultrasound for increas-ing transdermal drug delivery is known as sonophoresis or phonophore-sis. Ultrasound increases skin permeability through formation of bubbles caused by acoustic cavitation. The use of ultrasound for drug delivery can be based on energy transfer from the ultrasonic waves, leading to chemical degradation of the polymer.

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