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-
i. Ionizable groups with solubility and/or conformational changes in
response to environmental pH.
ii. Acid sensitivity bonds that cleave to release molecules anchored
into the backbone.
• pH-responsive hydrogels can be classified as
i. Anionic
ii. 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.

13. This Photo by Unknown Author is licensed under CC BY-SA