Drug delivery barriers

By Abdallah Muhammed Youssof, M.sc.
Department of pharmaceutics, college of pharmacy, King Saud University

1. Drug Transport Obstacles Prepared by: Abdallah M. Youssof PhD Student, College of Pharmacy, KSU [email protected]

2. 2 “And of Knowledge, you (mankind) have been given only a little.”

3. Content I. Objectives II. Introduction III. Drug Barriers IV. Physiological Barriers V . Biochemical Barriers VI. Chemical and Physicochemical Barriers VII. Methods to Overcome Drug Barriers VIII. Conclusion IX. Questions 3

4. I. Objectives By the end of this lecture you will be able to: 1. Realize the impact of drug barriers on the therapeutic efficacy 2. Identify the main barriers encountered in drug transport 3. Understand the clinical importance of P-glycoproteins 4. Answer related MCQs 4

5. I. Introduction From many years researchers and scientists are working a lot on the drug discovery. Many of the potent drugs have been yet discovered but still the given drug dose not reach the site of action, especially the drugs given orally because of barriers present in body and due to drug properties. And this problem also persist with biological products like peptides, proteins etc. 5

6. II. Types of Drug Barriers 6

7. III. Physiological Barriers A. Blood B rain B arrier (BBB): is a membrane that controls the passage of substances from the blood into the central nervous system. It is not an absolute barrier but is a site that is less permeable to more hydrophilic substances than are most other areas of the body; (98% of small Mwt drugs and 100% of large Mwt drugs, mainly peptides and proteins, developed for CNS pathologies don’t readily cross the BBB). Excludes ionized substances. Active transport mechanisms 7

8. III. Physiological Barriers B. Intestinal epithelium : is a single cell layer , largest and most important barrier against the external environment. Weak acids and bases will be absorbed by simple diffusion to a greater extent in the part of the GI tract in which they exist in the most lipid-soluble (non-ionized) form H ydrophilic substances will be transported to the liver by the portal vein. Highly hydrophilic substances may be absorbed through transporters ( xenobiotics with similar structures to endogenous substrates). 8

9. III. Physiological Barriers C. Blood Ocular B arrier: is a barrier created by endothelium of capillaries of the retina and iris. (Barrier to MOST molecules EXCEPT lipophilic molecules) N.B. Passage of molecules results in inflammation & injury Example of drugs that can penetrate barrier: • Antibiotics: Ciprofloxacin – chloramphenicol • NSAID – SAID Example of drugs that can NOT penetrate barrier: • Fluorescine dye (So, it is used to test integrity of retinal circulation) • Drugs that bound to plasma proteins 9

10. III. Physiological Barriers D. Skin : The physical barrier is mainly located in the stratum corneum and consists of protein-enriched cells and lipid enriched intercellular domains. 10

11. IV. Biochemical Barriers A. Metabolizing enzymes : In the lumen of stomach, a mixture of hydrochloric acid and proteolytic pepsins is the first metabolic barrier and the enzymes of the upper small intestine act as second barrier . B. Transporter and efflux pump : Substrate can be transported through the brush border membrane in a carrier-mediated and pH-dependent manner. P-glycoprotein ( P- gp ) is a known MRP(multi resistance protein) that serves as an efflux pump. 11

12. IV. Biochemical Barriers P-glycoprotein Multidrug resistance protein 1 ( MDR1) Transport various molecules, including xenobiotic , across cell membrane Extensively distributed and expressed throughout the body 12

13. IV. Biochemical Barriers 13 Site of Transportation Function Liver – Bile Elimination Kidney - Urine Excretion Placenta – Maternal blood Protect fetal from drug exposure Intestine – Intestinal lumen Reduce drug absorption into the blood Brain – Blood Monitor drug access to the brain Function of P-glycoprotein

14. IV. Biochemical Barriers Role of P- gp is significant in tumor cells. Expression of P- gp in tumor cells reduces the accessibility of cytotoxic drugs by eliminating them in various pathways. Hence, P- gp may act as a major barrier to effective drug treatments. Over expression of P- gp limits the treatment for cancer , AIDS, Alzheimer’s and epilepsy. 14 Clinical Importance of P-glycoprotein

15. IV. Biochemical Barriers 15

16. IV. Biochemical Barriers 16

17. V. Chemical Barriers Hydrogen B onding P otential A hydrogen bond is the attractive force between the hydrogen attached to an electronegative atom of one molecule and an electronegative atom of a different molecule. Hydrogen bonding is a key contributor to the specificity of intramolecular and intermolecular interactions in biological system. 17

18. VI. Physicochemical Properties of Drugs Physicochemical properties of drug are also important determinants in the passage of drugs via the para-cellular path. The physicochemical properties such as solubility, ionization, lipophilicity , permeability , etc. are important for determination of drug action. 18

19. VII. Methods to Overcome Drug Barriers 1.PHYSICAL METHODS External stimuli are applied to open the barrier it includes ultrasound, iontophoresis, stripping etc . Ultrasound, microwave or electromagnetic fields that can be used to open the blood brain barrier. Microwave irradiation facilitated central effects of domperidone by altering the permeability of blood brain barrier and enhancing the entry of drug into the CNS. 19

20. VII. Methods to Overcome Drug Barriers 1.PHYSICAL METHODS Stripping is a technique used to remove stratum corneum by application of adhesive tape or cyanoacrylate Glue. Iontophoresis and electroporation require electrical forces for drug delivery across stratum corneum . 20

21. VII. Methods to Overcome Drug Barriers 2. CHEMICAL METHOD Chemical method involves the use of chemicals to increase the permeability of the barrier. A large number of absorption enhancers have been studied, such as fatty acids, bile salts, enamine derivatives of phenylglycine , esters, ethers, salicylates. Mostly used blood brain barrier opening practice is via arterial injection of hyperosmolar solution (e.g. mannitol, arabinose ). Chemical enhancers for skin include the compounds that interact with the lipid matrix of the stratum corneum to alter its nanostructure and thereby increase permeability . 21

22. VII. Methods to Overcome Drug Barriers 2. CHEMICAL METHOD The most common chemical enhancer is water, which leads to hydration of the stratum corneum . Solvents , such as ethanol, methanol, chloroform and acetone, as well as detergents increases the permeability of stratum corneum . 22

23. VII. Methods to Overcome Drug Barriers 3. BIOCHEMICAL METHOD Biochemical method involves the biological molecule as permeability enhancer. A 45 kDa biological molecule zonula occludens toxin (Zot), an active tight junction modulator at the blood brain barrier. It also permits an enhanced transport of the therapeutic agents doxorubicin and paclitaxel. Magainin , a naturally occurring pore-forming peptide increase skin permeability by direct interaction with and disruption of stratum corneum lipids . 23

24. VII. Methods to Overcome Drug Barriers 4. DRUG DELIVERY BY FORMULATIONS COLLODIAL DRUG CARRIERS : include micelles, emulsions, liposomes and nanoparticles. BIODEGREDABLE NANOPARTICLES : formulated from poly (D,L- lactide -co- glycolide ) ( PLGA) are used for sustained and targeted delivery of different agents including plasmid DNA, proteins and peptides and low weight molecules . 24

25. VII. Methods to Overcome Drug Barriers 4. DRUG DELIVERY BY FORMULATIONS LIPOSOMES : Liposomes are small vesicles that are composed of unilamellar or multilamellar phospholipids bilayers surrounded by aqueous compartments. PRODRUG : The prodrug are used to overcome various barriers which can hinder drug delivery, including solubility. 25

26. VIII. Conclusions 26 The absorption of an orally administered drug depends on its passage through several barriers to deliver drug. The drug can pass either between or through the cells, depending on its physicochemical properties. Overcoming these barriers help in the development of improved drug delivery systems to treat different diseases conditions. Although many challenges exist in transporting the drug from different barriers, that’s why pharmaceutical scientists and medicinal chemists are overcoming them with new drug delivery system that enhance drug delivery.

27. V. Questions 27

28. 1. With respect to the BBB, Which of the following is/or true ? a. Limits the passage of approx. 100% of large molecular weight molecules b. Excludes ionized substances c. Active transport is considered d. All of the above 2. A Method (s) used to overcome the BBB? a. Ultrasound b. Microwave irradiation c. Both a and b d. Stripping 28

29. 3. For a drug to be passively transported through the GI tract, it requires to be a. Ionized and hydrophobic b. Non-ionized and hydrophilic c . Non-ionized and hydrophobic d. None of the above 4 . All of the following are true about the blood ocular barrier Except, a. Barrier to most molecules except hydrophilic molecules b . Barrier to most molecules except l ipophilic molecules c. NSAIDs can penetrate d . Drugs bound to plasma proteins can not penetrate 29

30. 5 . For transdermal drug delivery, which of the following is/are regarded as the major barrier (s)? a. Epidermis b. Stratum corneum c. Dermis d. None of the ab 6 . A naturally occurring pore-forming peptide increase skin permeability by direct interaction with and disruption of stratum corneum lipids? a. Magainin b. Zonula occludens toxin (Zot) c. All of the above d. None of the above 30

31. 7 . Mostly used blood brain barrier opening practice is a. A rterial injection of hyperosmolar solution b . Injection of mannitol c . Injection of arabinose d. All of the above 8. The permeability of skin barrier could be chemically enhanced using a. Iontophoresis b . Absorption enhancers such as bile salts c. Stripping d. None of the above 31

32. 9 . Regarding P-glycoprotein, which of the following is/are correct? a. Regarded as a Biochemical barrier b . Known as multidrug resistance protein 1 c . Overexpressed in tumor cells and d. All of the above 10. Drug delivery barriers could be overcome using advanced formulations such as a. Prodrugs b . Colloidal systems c. Nanoparticles d. All of the above 32

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