Controlled Drug Delivery Systems: Current Status and Future Directions

Abstract

The drug delivery system enables the release of the active pharmaceutical ingredient to achieve a desired therapeutic response. Conventional drug delivery systems (tablets, capsules, syrups, ointments, etc.) suffer from poor bioavailability and fluctuations in plasma drug level and are unable to achieve sustained release. Without an efficient delivery mechanism, the whole therapeutic process can be rendered useless. Moreover, the drug has to be delivered at a specified controlled rate and at the target site as precisely as possible to achieve maximum efficacy and safety. Controlled drug delivery systems are developed to combat the problems associated with conventional drug delivery. There has been a tremendous evolution in controlled drug delivery systems from the past two decades ranging from macro scale and nano scale to intelligent targeted delivery. The initial part of this review provides a basic understanding of drug delivery systems with an emphasis on the pharmacokinetics of the drug. It also discusses the conventional drug delivery systems and their limitations. Further, controlled drug delivery systems are discussed in detail with the design considerations, classifications and drawings. In addition, nano-drug delivery, targeted and smart drug delivery using stimuli-responsive and intelligent biomaterials is discussed with recent key findings. The paper concludes with the challenges faced and future directions in controlled drug delivery.

Keywords: controlled release dosage forms; intelligent biomaterials; nano-drug delivery; pharmacokinetics; smart and stimuli-responsive delivery.

Figure 1

Dosage form composition.

Figure 2

BCS Classification of drugs.

Figure 3

Various routes of drug administration.

Figure 4

Classification of conventional dosage forms.

Figure 5

Classification of solid dosage forms.

Figure 6

Solid unit dosage forms: (a) Tablets, (b) Effervescent tablets, (c) Chewable tablets, (d) Pills, (e) Hard-gelatine capsules, (f) Soft-gelatine capsules, (g) Lozenges. (h). Granules.

Figure 7

Semisolid dosage forms.

Figure 8

(a) Types of transdermal patches, (b) Transdermal patch applied on skin, (c) First commercially available Scopolamine transdermal patch (reproduced from [21] with permission from Perrigo, licensed under Creative Commons Attribution (CC BY 4.0) license).

Figure 9

Sterile and non-sterile liquid dosage forms.

Figure 10

Pharmacokinetic phases of a drug: 1. Absorption, 2. Distribution, 3. Metabolism, 4. Excretion.

Figure 11

Schematic of transport of drug through the plasma membrane by passive transport and active transport (reproduced from [34] with permission from the OpenStax, (part of Rice University, which is a 501(c)(3) nonprofit) and [35] licensed under Creative Commons Attribution (CC BY 4.0) international license).

Figure 12

Schematic of barriers to drug distributions (a) Plasma protein binding, (b) Anatomical barriers.

Figure 13

Schematic of drug metabolism in the liver as well as the cells.

Figure 14

Schematic illustration of drug excretion from the body by kidneys, liver, skin and airways.

Figure 15

Schematic of factors accountable for the reduction in bioavailability.

Figure 16

Drug plasma levels and release profiles.

Figure 17

Schematic of drug safety-therapeutic index.

Figure 18

Plasma drug levels with time after administering (a) Single conventional dose, (b) Multiple doses, (c) Increased single dose.

Figure 19

Limitations of Conventional drug delivery systems.

Figure 20

A typical bolus of (a) Conventional DDS; (b) Controlled DDS.

Figure 21

Medical Rationale behind controlled release drug delivery systems (CRDDS).

Figure 22

General design considerations of controlled release drug delivery systems (CRDDSs).

Figure 23

Dissolution-controlled delivery systems.

Figure 24

Schematic of diffusion-controlled delivery systems.

Figure 25

Membrane-controlled drug delivery systems.

Figure 26

Monolithic/matrix-controlled drug delivery systems.

Figure 27

Schematic of osmotic pressure-controlled drug delivery system.

Figure 28

Example of osmotically controlled drug delivery systems (reproduced from [58,59,60] with permission from Pfizer Laboratories Div Pfizer Inc., Johnson & Johnson Consumer Inc. 2019 and Bayer licensed under Creative Commons Attribution (CC BY 4.0) license).

Figure 29

Schematic of mechanism of drug release from the swelling-controlled drug delivery systems.

Figure 30

Schematic of bulk erosion and surface erosion.

Figure 31

Polymer-drug conjugate systems.

Figure 32

Some common examples of nanocarriers in controlled drug delivery.

Figure 33

pH-responsive drug release of Tamoxifen from chitosan nanoparticles (adapted from [147] with copyright permission from Marine Drugs, MDPI licensed under Creative Commons Attribution (CC BY 4.0) license).

Figure 34

Enzyme-responsive drug release from doxorubicin loaded PEG lipid-GLFG peptide liposome designed as a cathepsin B cleavable peptide linker to hydrolyse and release drugs specifically in tumour cells (reproduced from [151] with permission from Polymers, MDPI licensed under Creative Commons Attribution (CC BY 4.0) license).

Figure 35

Green laser light induced nanogels (reproduced from [156] with permission from Polymers, MDPI licensed under Creative Commons Attribution (CC BY 4.0) license).

Figure 36

Thermo-responsive drug release by PNIPAM hydrogel (reproduced from [160] with permission from the Royal Society of Chemistry).

Figure 37

Ultrasound triggered release from microbubbles by mechanical effects by acoustic cavitation and thermal effects by acoustic radiation (reproduced from [167] with permission from Fluids, MDPI licensed under Creative Commons Attribution (CC BY 4.0) license).

Figure 38

Molecular Imprinting polymers synthesis protocol (reproduced from [176] with permission from Sensors, MDPI licensed under Creative Commons Attribution (CC BY 4.0) license).