1. 1

2. Drug delivery systems  Definition: They are systems for the delivery of drugs to target sites of pharmacological actions.  They play an important role in controlling the pharmacological effect of the drug as it can influence: a)The pharmacokinetic profile of the drug b)The rate of drug release c)The site and duration of drug action and subsequently the side- effect profile.  An optimal drug delivery system ensures that the active drug is available at the site of action for the correct time and duration. 2

3. Drug delivery systems onset Duration 3

4. Differentiating drug delivery systems according to their mechanism of drug release I- Immediate release Drug is released immediately after administration II- Modified release Drug release only occurs some time after the administration or for a prolonged period of time or to a specific target in the body.  Modified release systems can be classified as: a) Delayed release b) Extended release c) Targeted release 4

5. I- IMMEDIATE RELEASE   The drug is released immediately or at least as quickly as possible after administration.  This is useful if a fast onset of action is required for therapeutic reasons (such as tablets containing a painkiller).  Immediate release dosage forms  release the drug at  a first-order kinetics profile i.e, the drug is released initially very quickly  the highest plasma level (C max ) in a short time (t max ). Then, the drug is distributed throughout the body and elimination of the drug occurs following first-order kinetics. 5

6. I- IMMEDIATE RELEASE 6

7. II- Modified release   Drug release only occurs some time after the administration or for a prolonged period of time or to a specific target in the body. Delayed release Extended releaseTargeted release Modified release systems 7

8.   A dosage form designed to ‎ release the drug at a time other than immediately ‎ after administration.  The delay may be time ‎ based or based on the influence of environmental conditions, like G.I.T. pH. ‎  The delay of drug release  by coating the dosage form with specific polymers that show no or limited solubility in the parts of the G.I.T. in which release is to be avoided but then release the drug quickly in the segments of the G.I.T where dissolution of the drug is desired. A) DELAYED RELEASE DOSAGE FORMS 8

9. Lag time 9

10. (N.B) Polymer films are also used in the formulation of immediate- release dosage forms. The reasons for this include: a- Facilitating swallowing of the dosage form b- Masking taste and odor c- Facilitating identification of the dosage form d- Enhancing the appearance of the dosage form e- Protecting the dosage form against environmental conditions (e.g. light and moisture). f- Protecting the dosage forms from breaking or abrasion during packaging or handling.  however, such coats are dissolved quickly in the stomach and do not interfere with the release of the drug. 10

11.  Enteric-coated dosage forms  prevent drug release until the small intestine is reached.  The reasons for enteric coating are: a- To protect the drug from degradation by the acidity of stomach e.g. Azole-type proton pump inhibitors (omeprazole and pentoprazole) and antibiotics (erythromycin and penicillins) b- To prevent gastric mucosa irritation by irritant drugs such as aspirin and some NSAID such as naproxen. c- For drugs locally acting in the small intestine and a high drug conc. in this part of G.I.T is desired such as anthelmintics. d- For drugs that are absorbed only in the small intestine. I- Small intestine-specific delivery (enteric-coated) 11

12. Mechanism of enteric coatings The pH in the stomach  1.5 - 2 in the fasted state  4-5 in the fed state. In the small intestine  the pH between 6 (in the duodenum) and 6.5 - 7 (in the jejunum and ileum).  If a polymer is insoluble polymer at pH 5 but soluble above pH 5  pH-triggered release (i.e. pH-controlled release) in the small intestine. I- Small intestine-specific delivery (enteric-coated) 12

13.   Polymers used for enteric coating include:  cellulose derivatives such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose acetate phthalate (HPMCAP)  Polyvinyl derivatives such as poly(vinyl acetate phthalate) (PVAP)  Poly(methacrylate) derivatives such as Eudragit L which dissolves at pH 5.5-6 and Eudragit S which dissolves at pH 6.5  Shellac or fatty or waxy materials such as beeswax and carnuba wax. I- Small intestine-specific delivery (enteric-coated) 13

14. Advantages 1- For drugs (e.g. peptides and proteins)  pH conditions in the colon are more favorable than in the stomach. 2- For the treatment of local (e.g. colorectal cancer) and systemic diseases. Disadvantages 1- Absorption from the colon will lead to drug transport to the liver via the portal vein  degradation via hepatic first-pass effect. 2- The conc. of micro-organisms in the colon is very high  induce pre-systemic drug metabolism by these micro-organisms. II- Colon-specific drug delivery 14

15.   Colon-specific delivery can be achieved by 3 different strategies: a- Enzyme-triggered release by using either pro-drugs or polymers b- Time-controlled release by using suitable polymers c- pH controlled release by using suitable polymers II- Colon-specific drug delivery 15

16. a- Enzyme-triggered release  Enzyme-triggered drug release exploits micro-organisms present in the colon to release drug by: 1- converting pro-drugs to the parent drug 2- digesting polymer coatings on solid dosage forms (N.B) Care must be taken when antibiotics are administered  antibiotics may affect colon micoflora  adversely affect the release of the drug. II- Colon-specific drug delivery 16

17. a- Enzyme-triggered release 1- Pro-drug for enzyme-triggered release EX: The pro-drug of sulfasalazine (used in the ttt. of Crohn's disease and inflammation of the colon). The azo group ( -N=N-) in sulfasalazine is cleaved in the colon by bacterial diazoreductases into sulfapyridine and the active drug 5- aminosalicylic acid. + II- Colon-specific drug delivery SulfasalazineSulfapyridine5-aminosalicylic acid diazoreductase 17

18. a- Enzyme-triggered release 2- Polymers for enzyme-triggered release  Natural and semi-synthetic polysaccharides (e.g. chitosan, pectin, inulin, cyclodextrins and xylan)  These polymers are not digested in the upper parts of G.I.T but degraded by microflora in the colon. II- Colon-specific drug delivery 18

19. b- pH controlled release  Polymer coatings that dissolve at pH 7  used to trigger release in the colon. e.g. Poly(methacrylate) derivatives such as Eudragit FS 30D.  Unlike Eudragit L and S used for enteric coating, the ratio of the free carboxyl gps : ester groups in Eudragit FS 30D  1:10  the polymer dissolves at a pH of 7. II- Colon-specific drug delivery 19

20. c- Time-controlled release  By double coating of a dosage form with an outer enteric coat & inner coat of a slow-release polymer  promote release in the colon.  The outer polymer prevents drug release in the stomach and the inner coat will retard release of the drug  drug is released in the colon.  In this case drug release is not affected by pH, but depends on the nature and thickness of the inner coat. e.g. Eudracol system II- Colon-specific drug delivery 20

21.  A dosage ‎ form that allows for the drug to be released over prolonged period  the frequency of dosing can be reduced.  Extended release can be achieved by using 1. Sustained release dosage forms 2. Controlled release dosage forms. ‎ 1. Sustained-release dosage forms  They maintain the rate of drug release over a sustained period.  Sustained-release can be achieved by use of polymers through a) Coat granules or tablets  reservoir systems b) Form a matrix in which the drug is dissolved or dispersed  matrix systems. B) Extended Release dosage forms 21

22. 1. Sustained Release dosage forms 22

23. 2. Controlled Release dosage forms  A dosage form in which a drug is released from the delivery system in a planned, predictable, and slower than normal manner. 23

24. Differences between sustained & Controlled release D.F  Controlled-release systems are designed to lead to predictably constant plasma concentrations  attain control over the drug plasma concentration, not just release of the drug from the dosage form.  Sustained-release dosage forms are restricted to oral dosage forms whilst controlled-release systems are used in a variety of administration routes, including transdermal, oral and vaginal administration. 24

25. Rationale for extended release pharmaceuticals 1. Drugs with short t 1/2  require multiple daily dosing to achieve the desired therapeutic results.  Multiple daily dosing  inconvenient & result in missed doses and noncompliance with the regimen.  Multiple daily dosing  therapeutic blood level peaks and valleys a) If doses are administered too frequently  reach MTC of drug  toxic side effects. b) If doses are missed  sub-therapeutic drug blood levels  no benefit to the patient. 25

26. By contrast, 1. Extended release formulations  taken only once or twice daily. 2. Extended release formulations   the time drug plasma concentration is within the therapeutic range   fluctuations (peaks and troughs) in the drug plasma concentration   side effects and  patient compliance., ‎ Rationale for extended release pharmaceuticals 26

27. Advantages of extended-release pharmaceuticals 1. Less fluctuation in drug ‎ blood levels 2. Reduction in dosing frequency   convenience & patient compliance. 3. Reduction in adverse side effects, because of fewer blood level peaks above MTC 4. Reduction in overall health ‎ care costs Although  initial cost of extended release dosage forms, overall cost of treatment may be less (WHY???) because of enhanced therapeutic benefit,  side effects,  time for health care personnel to ‎ monitor patients. ‎ 27

28. Disadvantages of extended-release pharmaceuticals 1. Loss of flexibility in adjusting the ‎ drug dose and/or dosage regimen. 2. A risk of ‎ sudden and total drug release (dose dumping), due to a failure of technology. ‎ 3. High cost of the formulation technology. 4. Difficulty to adopt all extended release formulations into the large scale production due to formulation complexity. 28

29. 1- They should exhibit neither very slow nor very fast ‎ rates of absorption and excretion.  Drugs with ‎ slow rates of absorption and excretion are inherently long- acting, and no need for extended release ‎ forms. 2- Drugs prepared in extended-release forms must have good aqueous ‎ solubility and maintain adequate residence time ‎ in G.I.T.  Drugs having a very low solubility are poor candidates for ER formulations since their absorption is controlled by their slow dissolution.  Drugs that are taken up by active transport processes are poor candidates for ER formulations, because the time/region for absorption is limited. 3. Drugs should not have a high degradation rate in the G.I.T. Drug candidates for ‎ extended-release products 29

30. 4- They are administered in relatively small doses. ‎  Drugs with large single doses are not ‎ suitable for ER because the tablet/ ‎ capsule needed to maintain a sustained ‎ therapeutic blood level of the drug would be too ‎ large for the patient to be swallow. ‎ 5- They are used in the ttt of chronic rather ‎ than acute conditions. 6- Drugs should have adequate t1/2  Drugs with very short t 1/2 (<1 hour)  large quantities of drug required for formulation  poor candidates for ‎ ER.  Drugs with a relatively long t 1/2 (>8 hours)  their biological effect is already sustained  are poor candidates for ER. 7- They possess a wide therapeutic index.  Drugs with ‎ very narrow therapeutic indices   risk ‎ of dose dumping  poor candidates for ER formulation. Drug candidates for ‎ extended-release products 30

31. Drug candidates for ‎ extended-release products 31

32. 1- Controlling ‎ access of biologic fluids to the drug through ‎ the use of barrier coatings. 2- Controlling drug ‎ diffusion rates from dosage forms. ‎ 3- Physicochemical reaction or interaction between the ‎ drug substance or its pharmaceutical barrier ‎ and site specific biologic fluids. ‎ Technologies for preparing a MR solid dosage ‎ forms 32

33.  The rate of drug release can be decreased by lowering the drug dissolution rate.  This can be achieved by increasing the drug particle size via: A) Incorporating the drug into a slowly dissolving matrix (matrix dissolution dosage forms) B) Coating the drug with a slowly dissolving film (encapsulated dissolution dosage forms) I- Dissolution-based sustained-release dosage forms 33

34. EX: Repeated action drug delivery system  The drug substance alone or loaded onto inert beads made of sugar or on ‎ microcrystalline cellulose spheres  coated with polymer such as hydroxypropylmethylcellulose (HPMC)  Sustained action.  whilst, others are not coated  immediate action.  These granules are then compressed into a tablet or filled into a hard gelatin capsule.  Upon ingestion, the drug is released over a prolonged period of time depending on the rate of the dissolution of the polymeric coat; the thicker the initial coat, the later the drug will be released. I- Dissolution-based sustained-release dosage forms 34

35.  Prolong the gastric residence time of dosage form in stomach.  This approach is useful especially: a- If drug absorption takes place in the stomach or the upper part of the small intestine (duodenum) b- For drugs exerting a local action in the stomach such as antacid and anti-peptic ulcer drugs c- For drugs with narrow absorption window.  Gastro-retentive systems can be divided into 1- Floating systems 2- Expandable systems 3- High-density systems II- Gastro-retentive drug delivery systems 35

36.  Principle: Dosage forms with densities of less than 1g/cm 3  float on gastric fluids  allow for an increased release time of drug before the system is emptied out into the small intestine.  These systems require the presence of sufficient fluid must be present in the stomach to support these systems. Floating Systems include: a) Hydrodynamically balanced systems (HBS) b) Effervescent systems 1- Floating systems 36

37. Principle: The drug is encapsulated in a hard gelatin capsule together with a gel-forming hydrophilic polymer such as HPMC or CMC.  After administration  capsule shell disintegrates  hydrophilic polymer forms a hydrated boundary layer  drug is released by diffusion through hydrated boundary layer  Finally, the polymer slowly erodes and the drug is completely released.  The hydrated boundary layer also entraps air in the inside  The overall density of the system lower than that of the gastric fluid  Float in gastric fluid.  Lipophilic excipients (e.g. vegetable oils) may be added  slow down water uptake and erosion and also to reduce the density of the system. a) Hydrodynamically balanced systems (HBS) 37

38. a) Hydrodynamically balanced systems (HBS) 38

39. Principle: By using effervescent substances (bicarbonate or carbonate) in the formulation.  When ingested, gastric acid + HCO 3 - or CO 3 2-  CO 2, which remains entrapped in the dosage form and provide the necessary buoyancy. b) Effervescent systems 39

40. Principle:  In these systems, hydrogels having a pore size of more than 100 μm (so-called super-porous hydrogels) are used.  The swelling of such super-porous hydrogels is so faster (occurs in seconds to minutes) and swelling ratio of over 100 can be achieved  After administration  the swollen systems become too large to pass through the pylorus  retained in the stomach for a prolonged time. 2- Swelling and expandable gastro-retentive DDS 40

41. a) Muco-adhesive dosage forms  Muco-adhesive polymers such as poly(acrylic acid), and chitosan  allowing the sticking of the dosage form onto the mucus of the gastric wall   gastric retention Disadvantage: due to the rapid turnover of the mucus in the stomach, the application of these system was limited. b) Magnetic dosage forms  Magnetic materials such as ferric oxide is included  held in the stomach by an external magnet Disadvantage: this approach requires a precise positioning of the external magnet and is assumed to have no patient compliance. 3- High-density systems 41

42.  In theses systems, the polymer itself should not dissolve, but should allow the drug to diffuse through the polymer membrane/matrix to outside. Diffusion-based sustained-release dosage forms can be divided into A) Polymer membrane (reservoir) system B) Polymer matrix systems III- Diffusion-based sustained-release dosage forms 42

43. Characters 1- The drug is present in the core of the dosage form (termed the reservoir) and is surrounded by an inert polymeric membrane (film). 2- The release of the drug occurs by diffusion of drug molecules through the film. 3- The release profile usually follows zero-order kinetics. 4- Factors controlling drug release through the film include a) Nature of the drug and the polymer film b) The permeability of the drug across the polymer film c) The polymer film thickness. 5- To ensure a sustained release, membrane integrity must be maintained. A) Polymer membrane (Reservoir) system 43

44. Advantages 1- Reservoir systems lead to a near-zero-order release of drugs  allow the release of the drug for a sustained period of time Disadvantages 1- If the polymeric membrane is not dissolved/degraded after passage through G.I.T.  the dosage form will appear in the stool of the patient  who might assume that the drug has not been absorbed. 2- If such systems are used for administration routes other than oral route  they must be removed from the body after the drug is released. 3- If the polymeric coat is faulty  dose dumping may occur. A) Polymer membrane (Reservoir) system 44

45. Polymers used Ethylcellulose (EC) and Eudragit RS or RL A) Polymer membrane (Reservoir) system  The presence of the quaternary ammonium group gives the polymer the necessary polarity to allow water and drug diffusion after administration.  Eudragit RS sustains drug release for longer time than Eudragit RL. Eudragit RL contains double the amount of quaternary ammonium groups as Eudragit RS. 45

46. Characters 1- The drug is dispersed in a lipidic or polymeric material which acts as the release matrix. 2- Release from matrix systems is controlled by diffusion throughout the polymer matrix. 3- Polymer matrix systems can either be: a)Homogenous: the drug is partly dissolved and evenly distributed in the polymer matrix b) Porous: the matrix contains an additional soluble polymer which after administration dissolves quickly  leaving pores in the release matrix 4- Drug release from matrix systems does not follow zero-order kinetics instead the system shows a linear release of the drug as a function of the square root of time. (Higauchi order) B) Polymer matrix systems 46

47. Advantage 1- They are less expensive than reservoir systems. 2- There is no risk of dose dumping. Polymers used a- Hydrophobic matrix formers such as poly(ethylene), poly(propylene) and ethylcellulose (EC). b- Hydrophilic matrix formers such as MC, HPC, HPMC, Eudragit NE 40D B) Polymer matrix systems 47

48.  They are matrix systems in which the drug is not primarily released by diffusion or dissolution, but in which the erosion and/or degradation of the polymer is the rate-limiting step for drug release. Advantage: No "ghost matrix" will be formed as in the case of matrix systems with insoluble and non-degrading polymers. Disadvantage: It is difficult to control/predict the release kinetics of these systems.  Polymers used: poly(lactides) or copolymers of lactic and glycolic acid. IV- Bio-erodible sustained-release dosage forms Erosion of a polymer matrix is defined as the loss of polymer mass from the matrix. 48

49. A- Elementary osmotic pump  The system consists of a tablet core (drug + osmotic active agent) coated with a semi- permeable membrane in which a delivery orifice is drilled by a laser beam. V- Osmotic pressure-activated controlled DDS  The system ‎ operates on the principle of osmotic pressure.  When such a system is ingested  water from the G.I.T. diffuses in  the drug dissolves and is pushed out through the exit hole via the created osmotic pressure within the system. 49

50. A- Elementary osmotic pump  Drug release rate may be altered by a)Changing surface area b)Thickness or composition of the membrane c) Diameter of the release orifice. V- Osmotic pressure-activated controlled DDS  The drug release rate is not affected by GIT acidity, alkalinity, fed conditions, or gastrointestinal motility.  The system is not suitable for delivery of poorly soluble drugs. 50

51. B- Push-pull systems  They comprise one push layer ( which is drug-free but contains osmotic active agents and water-swellable polymers) and one or more drug layers. V- Osmotic pressure-activated controlled DDS  These multi-layered tablets are coated with a semi-permeable membrane into which a small orifice for drug release is drilled.  Upon ingestion  water from G.I.T. is drawn in  push layer swell  formation of a liquid suspension in the drug layers  The expanding push layer pushes the drug suspension out of the exit hole drilled into the drug layer 51

52. 52 Charged ions.

53. 53

54. 54

55.  Whilst controlling the rate of release of a drug from its delivery system can control plasma drug concentration levels, once released there is a little control over the distribution of the drug in the body.  Targeted release describes selective drug release at a specific body ‎ region, tissue, or site for drug ‎ action. ‎ Advantages: 1- Enhancing the activity of the drug and reduce its toxicity  improve its therapeutic profile. 2- Protecting the drug from inactivation before its reaches its target. C) Targeted-release dosage forms 55

56. Requirements of effective drug targeting system 1- There must be no non-specific interactions with biological components, tissue or organs other than the target site. 2- The targeting system should be non toxic. 3- The drug targeting system should not be cleared too quickly  allow the drug to interact with its physiological target. 4- It should retain the drug during transit to the target site i.e. no premature release. 5- The system should allow drug release at the target site. C) Targeted-release dosage forms 56

57. Candidates for drug targeting 1- Drugs with high total clearance are most appropriate for targeting since drug not retained at the target site will be cleared rapidly. 2- Highly toxic drugs such as chemotherapeutic agents  improve their therapeutic efficacy while significantly reducing the side effects C) Targeted-release dosage forms Targeted delivery systems consists mainly of a)Drug b) Carrier c) Targeting moiety 57

58. I- Passive targeting  Exploits the natural physiological conditions of the target organ to allow the preferential accumulation of drug carrier at the target site. Ex 1 : Local physiological conditions: The local pH or presence of specific enzymes within a target organ can be used to facilitate the release of the active drug from its carrier system. e.g. elevated enzyme levels at a target site can be used to release the active drug selectively from its pro-drug or carrier system. Types of drug targeting 58

59. I- Passive targeting Ex 2 : Enhanced permeability and retention (EPR) effect:  The integrity of the endothelial barrier at sites of inflammation or tumors is disrupted by the presence of endothelial gaps as large as 200-300 nm. Types of drug targeting  This leaky nature of blood vasculature can be exploited via EPR effect to target drug carriers passively to a sites of inflammation or tumors 59

60. II- Active targeting  Active targeting is based on ligand-receptor binding and takes advantage of elevated levels of such receptors at a target site. Ex 1 : Targeting via folate receptors Folate receptors are normally found at low levels in most tissues but these receptors are over-expressed in tumor tissues. Therefore, folate-targeted drug delivery systems are widely used for active targeting of tumor tissues over-expressing folate receptors. Types of drug targeting 60