P h activated drug delivery systems

m.pharm unit 2 rate controlled drug delivery systems- pH activated drug delivery sytems- nanoparticles, hydrogels, microspheres, microgels

1. pH- Activated Drug Delivery Systems MEHAK AGGARWAL M.Pharm Himachal Institute of Pharmacy

2. CONTENT Introduction Hydrogels Nanoparticles Microspheres Microgels

3. INTRODUCTION The pH- responsive carriers for oral drug delivery have been proven to enhance the stability of drug delivery in stomach and to achieve controlled release in intestines. Drugs release from pH- responsive hydrogels/microspheres, after the materials swelling and dissolution at specific pH. Drug molecules can cross the mucosal layer followed by a submucosal and areolar cell barrier where they interact with a plethora of transport pathways including paracellular or transcellular pathway or transcytosis pathway to enter systemic circulation.

4. HYDROGELS Hydrogels posses a diversity of tunable features of the bulk structure that can be tailored for a specific therapeutic. Cross-linked hydrogel networks enable to protect drugs from hostile environment, such as low pH and enzymes in the stomach. Drugs release from pH-responsive hydrogels after the material swelling at specific Ph. Mesh size of swollen network affects the physical properties of hydrogel such as- degradation, diffusion of captured molecules and mechanical strength. Mesh size of hydrogels in swollen state may range from 5 to 100 nm and can be optimized for sustained release of macromolecules based on their hydrodynamic radii.

5. There are two basic strategies for imparting pH-responsive behavior- Ionizable groups with solubility and/or conformational changes in response to environmental pH. Acid sensitivity bonds that cleave to release molecules anchored into the backbone. pH-responsive hydrogels can be classified as Anionic Cationic

6. i. Anionic Hydrogels Anionic hydrogels are ionized, at a pH above the pKa of the polymer network. Intestinal drug delivery systems protect drugs from gastric degradation and denaturation at low pH and release drugs in specific locations, such as upper small intestine and colon, further in the GI tract by taking advantage of pH-responsive anionic hydrogels. ii. Cationic Hydrogels Cationic hydrogels are ionized at a pH below the pKa of the polymer network. Cationic hydrogels are suited for drugs that release in stomach or intracellular environments. Drugs are protected by cationic polymers in the oral cavity (pH- 5.8-7.4), while releasing in stomach (pH- 1.0-3.5) in an oral delivery sytem .

7. NANOPARTICLES NPs have been extensively studied for oral delivery. NPs can protect encapsulated drugs from low PH environment, drug efflux pumps, and enzyme degradation due to their stability in the GI environment. Eudragits, that is poly (methacrylic acid-co-methyl acrylate) copolymers, are widely used for pH responsive NPs formulation. There are several types of Eudragits. Eudragit E100 is a cationic copolymer which dissolves in stomach, while Eudragit L100 and Eudragit $100 are anionic copolymers; separately dissolve at pH45.5 and pH47.0.

8. Eudragits copolymers were used to coat over layered double hydroxide (LDH) NPs. The LDHs used to immobilize drug molecules accelerate the dissolution of hydrophobic drugs significantly owing to increasing the drug surface area via highly dispersed drug molecules and decreasing the thickness of the diffusible layer via monolayer adsorption of the drug molecules in the LDH interlayers. The cationic polymer used for preparing pH-responsive NPs is primarily chitosan, which can increase the absorption of NPs by the intestinal epithelium. As the solubility of chitosan limits drugs delivery to the intestine, different derivatives of chitosan have been developed with favorable characteristics, such as improving functioning also in a higher PH. Inorganic pH-responsive NPs have advantages in terms of rich variety, biocompatibility, thermal stability, and easy control of size, structure and morphology.

9. The amphiphilic polymer is characterized by a hydrophilic outer shell containing a hydrophobic core, which permits encapsulation of hydrophobic chemotherapeutic agents. The polymer exists in cylindrical conformation at neutral pH within the body, and collapses to release its drug at an acidic pH.

10. MICROSPHERES Microspheres, derived from natural or synthetic materials, have been commonly studied for oral delivery of a wide variety of therapeutics. Limitation in the practical applications of microspheres is the relatively hydrophilic nature of most enteric coating materials with hydroxyl, carboxyl or other polar moieties, which frequently cause the microspheres to display low drug loading capacity for many hydrophobic drugs. Different from generally PH-responsive delivery systems, the pH-responsiveness of these microspheres is mainly dominated by carboxyl bearing compounds (CBC) molecules instead of carrier materials. These assembled microspheres have been proven to selectively release drug under intestinal conditions, with desirable scalability as well as excellent reconstitution capability, and may considerably improve the oral bioavailability of loaded therapeutics.

11. MICROGELS MGs are the microscopic hydrogels. pH-responsive microgels represent one of the major approaches for microgel-based delivery of biomacromolecular drugs. Stimuli-responsive MGs are smart drug delivery carriers and have the capability to incorporate and release their host molecule in response to stimuli (pH, ionic strength, temperature), for targeted drug delivery. pH-responsive polymers are generally fabricated by inserting pendant acidic or basic functional groups to the backbone of the polymer. These functional groups either accept or release protons in response to appropriate pH and changes in the ionic strength of surrounding aqueous media.

12. Veeranna B., Pramodkumar TM., Srujana N., Venkatesh MP., et al., (2011), pH sensitive drug delivery systems: a review, American journal of drug discovery and development, 1(1), 24-48. Yoshida T., Lai TC., Kwon GS., Sako K., (2013), pH and ion sensitive polymers for drug delivery, Expert opin drug deliv ., 10(11), 1497-1513. Jianyu L., Mooney DL., (2016), Designing hydrogels for controlled drug delivery, Nat rev mater., 1(12), 16071. Gao W., Chan J., Farokhzad OC., (2010), pH-responsive nanoparticles for drug delivery, mol pharm. 7(6), 1913-1920. Saini S., Kumar S., Choudhary M., Nitesh, (2018), Microspheres as controlled drug delivery system: an updated review, International journal of pharmaceutical sciences and research, 9(5), 1760-1768. Rashid Z., (2019), pH-responsive microgels: promising carriers for controlled drug delivery, intechopen .

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