11 CONTROLLED DRUG DELIVERY SYSTEMS.pptx

Different delivery systems in pharma

1. Controlled Drug delivery systems

2. Content Introduction Terminology/ Definitions Rationale Advantages Disadvantages Selection of drug candidates Approaches to design controlled release formulations based on Diffusion, Dissolution, and ion exchange principles Physicochemical and biological properties of drugs relevant to controlled release formulations

3. Content Polymers: a. Introduction b. Classification c. Properties d. Advantages and application of polymers in formulation of controlled release drug delivery systems

4. Syllabus as per GTU NDDS Practice school Industrial Pharmacy II

5. Introduction https://www.youtube.com/watch?v=e8xH_HXISus

6. Introduction Conventional drug therapy typically involves the periodic dosing of a therapeutic agent that has been formulated in a manner to ensure its stability, activity and bioavailability. For most of the drugs, conventional methods of formulation are quite effective

7. Disadvantages of conventional therapy Require frequent dosing to maintain therapeutic levels in body Patient compliance is poor due to increased frequency of dosing Some drugs are unstable and toxic and have a narrow therapeutic range, exhibit extreme solubility problems, require localization to a particular site in the body or require strict compliance for long-term use. In such cases a method of continuous administration of drug is desirable to maintain fixed plasma drug levels.

8. Introduction: Goal /Rationale in designing Sustained or controlled drug delivery systems: To reduce the frequency of dosing To increase the effectiveness of drug by localization at the site of action Reduce the dose required Provide uniform drug delivery

9. What is an ideal drug delivery system? It should release the drug at a rate dictated by the needs of the body over the period of treatment Deliver the drug a constant rate and maintain constant plasma drug levels It should deliver the drug entity at the site of action i.e. to specific receptors, tumor cells or specific tissues of the body No drug delivery system is able to achieve these goals

10. Terminology: Modified release delivery systems may be divided conveniently in to four categories. A) Delayed release B) Sustained release i ) Controlled release ii) Extended release C) Site specific delivery systems D) Receptor targeted systems

11. Delayed release systems These systems are those that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Examples of delayed release systems include repeat action tablets and capsules and enteric-coated tablets where timed release is achieved by a barrier coating They maintain the drug within the dosage form for some time before drug release. The release rate is not altered and does not result in sustained delivery once drug release has begun

12. Repeat action dosage form Repeat action tablets are sustained release in which multiple doses of drug are contained within a dosage form and each dose is released at a periodic interval

13. Sustained release dosage form Sustained release dosage form constitutes any dosage form that provides medication over an extended period of time. It maintains therapeutic blood levels or tissues over an extended period of time. However there is no control over the rate at which drug is released.

14. Controlled release dosage form It is a therapeutic system that is able to control the drug release in the target tissue and provide actual therapeutic control for a prolonged period of time. This is usually accomplished by attempting to obtain zero order release from the dosage form Zero order release indicates that drug release is independent of the amount of drug in the dosage form e.g. Osmotic delivery systems.

15. Extended Release: Pharmaceutical dosage forms that release the drug slower than normal manner at predetermined rate & necessarily reduce the dosage frequency by two folds.

16. Site specific and targeted delivery systems Site specific delivery systems: These systems refer to targeting of a drug directly to a certain biological location. In this case the target is adjacent to or in the diseased organ or tissue.

17. Receptor targeting systems: These systems refer to targeting of a drug directly to a certain biological location. In this case the target is the particular receptor for a drug within an organ or tissue.

18. Differences between sustained and controlled drug delivery system Sustained release dosage form Constitutes dosage form that provides medication over extended period of time SRDF generally do not attain zero order release kinetics Usually do not contain mechanisms to promote localization of the drug at active site. Controlled release dosage form Constitutes dosage form that maintains constant drug levels in blood or tissue Maintains constant drug levels in the blood target tissue usually by releasing the drug in a zero order pattern. Controlled dosage forms contain methods to promote localization of the drug at active site.

19. Potential advantages and disadvantages of sustained release dosage forms Advantages: Reduction in frequency of drug administration Improved patient compliance Reduction in drug level fluctuation in blood Reduction in total drug usage when compared with conventional therapy Reduction in drug accumulation with chronic therapy Reduction in drug toxicity (local/systemic) Stabilization of medical condition (because of more uniform drug levels)

20. Disadvantages: Delay in onset of drug action Possibility of dose dumping in the case of a poor formulation strategy Increased potential for first pass metabolism Greater dependence on GI residence time of dosage form Possibility of less accurate dose adjustment in some cases Cost per unit dose is higher when compared with conventional doses Not all drugs are suitable for formulating into SR dosage form

21. Characteristics That May Make A Drug Unsuitable For Control release Dosage Form Short elimination half-life Long elimination half-life Narrow therapeutic index Poor absorption Active absorption Low or slow absorption Extensive first pass effect

22. Criteria for selection of drug for Sustained or controlled drug delivery a) Desirable half-life. b) High therapeutic index c) Small dose d) Desirable absorption and solubility characteristics . e) Desirable absorption window. f) First past clearance

23. Biological factors influencing Selection of drug for controlled drug delivery: Biological Half life Drugs having a t ½ and 8 hours are ideally suited for CRDDS. If the t ½ is less than 1 hour the dose size required to be incorporated for a 12 hour or 24 hour duration dosage form may be too large. If the t ½ is >8hrs there is usually no need for a CRDDS since it itself gives sustained effect. Ideally, the drug should have half-life of three to four hours for formulating as CRDDS. Drugs like furosemide and levodopa having half life < 2hrs are poor candidates for sustained release formulations Compounds with biological half life >8hrs are not used in CRDDS e.g. Digoxin , warfarin , phenytoin

24. Absorption Purpose of formulating a SR system : to control the rate at which drug is released from the dosage form In SR systems, the rate of drug release << than rate of absorption. Transit time in GIT is 8-12 hrs which corresponds to a maximum half life for absorption between 3-4hrs which corresponds to an absorption rate constant of 0.17 to 0.23h -1 to give 80 to 95% absorption over this time period. The release rate of the drug from the SR dosage form should be equivalent to absorption rate constant. Drugs having absorption rate constant < 0.17 to 0.23h -1 are poor candidates for sustained delivery

25. Desirable absorption and solubility characteristics Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into sustained release formulations is therefore unrealistic and may reduce overall absorption efficiency. Desirable absorption window : Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the ‘absorption window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as sustained release dosage form are unsuitable

26. High therapeutic index: Drugs with low therapeutic index are unsuitable for incorporation in sustained release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg . Digitoxin .

27. Metabolism Drugs that are metabolized before absorption either in the lumen or tissue of intestine show decreased bioavailability from sustained release dosage forms Most enzymes are saturable. As drug is released at a slower rate to these regions less total drug is present to the enzymes, allowing all the drug to be metabolized. E.g. Aloprenolol is more extensively metabolized in intestinal wall when given as a sustained release dosage form.

28. First pass clearance: As discussed earlier in disadvantages of sustained delivery system, delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in sustained release forms.

29. Physicochemical factors Small dose: If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for sustained release is seriously undermined. This is chiefly because the size of a unit dose sustained release formulation would become too big, to administer without difficulty.

30. Solubility Compounds with low solubility( <0.01mg/ml) are inherently sustained release since their release over the time course of dosage form in GI tract is limited by dissolution of the drug. e.g. Digoxin , griseofulvin , salicylamide . The lower limit of solubility of a drug to be formulated as sustained release system has been reported to be 0.1mg/ml

31. Partition coefficient Drug administered by oral route Crosses several biological membranes Biological membranes are lipidic Therefore partition coefficient becomes imp in effectiveness of membrane barrier penetration

32. Partition coefficient PC is the ratio of drug in oil phase to adjacent aqueous phase Compounds with high PC are predominantly lipid soluble and have low aqueous solubility Can persist in lipid membranes for long periods Compounds with low PC have difficulty in penetrating the membranes, resulting in poor bioavailability

33. Stability Orally administered drugs can be subjected to both acid base hydrolysis and enzymatic degradation. For drugs that are unstable in stomach , systems that prolong delivery over the entire course of GI tract are beneficial. Even delayed release systems are beneficial. Compounds unstable in intestinal fluids may show decreased bioavailability when administered in sustained release dosage form.

34. Approaches for oral sustained and controlled release products Dissolution controlled release systems: Reservoir type Matrix type 2. Diffusion controlled release systems: Reservoir type Matrix type 3. Diffusion and Dissolution controlled systems 4. Ion exchange resins 5. Osmotically controlled release 6. pH independent formulations 7. Low density approach

35. 37 DISSOLUTION CONTROLLED SYSTEMS A drug with a slow dissolution rate is inherently sustained and for those drugs with high water solubility, one can decrease dissolution through appropriate salt or derivative formation. In dissolution controlled systems, the rate controlling step is dissolution. The drug is embedded in a slowly dissolving erodible matrix or by coating with slowly dissolving substances. They are of two types : Encapsulation dissolution controlled system Matrix dissolution controlled system

36. 38 ENCAPSULATION DISSOLUTION CONTROLLED SYSTEMS :- The drug particles are coated or encapsulated by microencapsulation techniques with slowly dissolving materials like cellulose, polyethylene glycols, poly methacrylates , waxes etc. The dissolution rate of coat depends upon the solubility and thickness of the coating.

37. ENCAPSULATION DISSOLUTION CONTROLLED SYSTEMS Reservoir type: Drug is coated with a given thickness of coating, which is slowly dissolves in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats as shown in figure, a pulsed delivery can be achieved. If the outer layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can be quickly established with pulsed intervals.

38. ENCAPSULATION DISSOLUTION CONTROLLED SYSTEMS An alternative method is to administer the drug as a group of beads that have coating of different thickness. Since the beads have different coating thickness, their release occurs in a progressive manner. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be achieved from those with thicker coating.

39. 41

40. 42 MATRIX DISSOLUTION CONTROLLED SYSTEMS Matrix systems are also called as monoliths since the drug is homogeneously dispersed throughout a rate controlling medium. They employ waxes such as beeswax, carnauba wax, hydrogenated castor oil etc which control drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by altering the porosity of rate. The wax embedded drug is generally prepared by dispersing the drug in molten wax and congealing and granulating the same.

41. Matrix dissolution devices Matrix dissolution devices are prepared by compressing the drug with slowly dissolving carrier into tablet The drug release is determined by dissolution rate of the polymer Soluble drug Slowly dissolving matrix

42. 44 DIFFUSION CONTROLLED RELEASE SYSTEMS :- Diffusion systems are characterized by release rate of drug which is dependent on its diffusion through inert water insoluble membrane barrier. In this system the rate controlling step is not dissolution rate but the diffusion of dissolved drug through the polymeric barrier There are basically two types of diffusion devices : a) R eservoir diffusion systems b) Matrix diffusion systems

43. RESERVOIR DEVICE This system is hollow containing an inner core of drug. The water insoluble polymeric material surrounds drug reservoir. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media. The release drug from a reservoir device follows Ficks first law of diffusion. J = - D dc/ dx D = diffusion coefficient in area/ time dc/ dx = change of concentration 'c' with distance 'x'

44. 46 R eservoir diffusion system

45. Spherical type Slab type Drug delivery from typical reservoir devices

46. MATRIX DEVICES In this system a solid drug is dispersed homogeneously in an insoluble polymer matrix The rate of drug release is dependent on the rate of drug diffusion but not on the rate of dissolution According to Higuchi the drug release from the system is given by Q = D ἐ / T [2 A –Cs] Cst ½ Q = weight in gms of drug released per unit area of surface at time t D = Diffusion coefficient of drug in the release medium ἐ = porosity of the matrix Cs = solubility of drug in release medium T= Tortuosity of the matrix A = concentration of drug in the tablet, as gm/ ml

47. 50 MATRIX DIFFUSION SYSTEMS

48. 51 DISSOLUTION AND DIFFUSION CONTROLLED RELEASE SYSTEMS The drug core is encased in a partially soluble membrane. Pores are thus created due to dissolution of parts of the membrane which Permit entry of aqueous medium into the core and hence drug dissolution occurs Allow diffusion of dissolved drug out of the system. An example of obtaining such a coating is using a mixture of ethyl cellulose with poly vinyl pyrrolidone or methyl cellulose.

49. DRUG DELIVERY FROM COMBINATION OF DIFFUSION AND DISSOLUTION SYSTEM Insoluble membrane Entry of dissolution fluid Diffusion of dissolved drug Pore created by dissolution of soluble fraction membrane

50. 53 OSMOTICALLY CONTROLLED RELEASE SYSTEMS These systems are fabricated by encapsulating an osmotic drug core containing an osmotically active drug (or a combination of an osmotically inactive drug with an osmotically active salt eg NaCl ) within a semi permeable membrane made from biocompatible polymer, e.g. cellulose acetate. A gradient of osmotic pressure is they created, under which the drug solutes are continuously pumped out over a prolonged period of time through the delivery orifice.

51. Osmotically controlled systems A semi permeable membrane is placed around a tablet, particle or drug solution that allows transport of water into the tablet with eventual pumping of drug solution out of the tablet through a small delivery aperture in tablet coating. Two types of osmotically sustained systems are:- Type A contains an osmotic core with drug Type B contains the drug in flexible bag with osmotic core surrounding.

52. 55 This type of drug system dispenses drug solutes continuously at a zero order rate.

53. Drug in flexible bag with osmotic core surrounding

54. Altered density formulations: It is reasonable to expect that unless a delivery system remains in the vicinity of the absorption site until most, if not all of its drug contents isreleased , it would have limited utility. To this end, several approaches have been developed to prolong the residence time of drug delivery system in the gastrointestinal tract. High density approach In this approach the density of the pellets must exceed that of normal stomach content and should therefore be at least 1-4gm/cm 3 .

55. Altered density formulations: Low density approach: Globular shells which have an apparent density lower than that of gastric fluid can be used as a carrier of drug for sustained release purpose. They are known as floating systems.

56. pH– Independent formulations: The gastrointestinal tract present some unusual features for the oral route of drug administration with relatively brief transit time through the gastrointestinal tract, which constraint the length of prolongation, further the chemical environment throughout the length of gastrointestinal tract is constraint on dosage form design. Since most drugs are either weak acids or weak bases, the release from sustained release formulations is pH dependent. However, buffers such as salts of amino acids, citric acid, phthalic acid phosphoric acid or tartaric acid can be added to the formulation, to help to maintain a constant pH thereby rendering pH independent drug release..

57. pH– Independent formulations A buffered sustained release formulation is prepared by mixing a basic or acidic drug with one or more buffering agent, granulating with appropriate pharmaceutical excipients and coating with gastrointestinal fluid permeable film forming polymer. When gastrointestinal fluid permeates through the membrane, the buffering agents adjust the fluid inside to suitable constant pH thereby rendering a constant rate of drug release e.g. propoxyphene in a buffered sustained release formulation, which significantly increase reproducibility

58. 61 CHEMICALLY CONTROLLED RELEASE SYSTEMS Chemically controlled release systems are the systems that change their chemical structure, when exposed to biological fluid. Mostly, biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically safe and progressively smaller moieties. It is of two types and they are Erodible systems Pendent chain system

59. 62 Erodible systems I n erodible systems, the mechanism of drug release occurs by erosion. Erosion may be two types and they are a) Bulk erosion process b) Surface erosion process Bulk erosion:- polymer degradation may occur through bulk hydrolysis. Surface erosion:- Polymers like polyorthoesters and polyanhydrides etc occurs degradation only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the delivery system .

60. 63 “a” indicates bulk erosion “b” indicates surface erosion

61. 64 PENDANT CHAIN SYSTEM Pendant chain systems consists of linear homo or copolymers with the drug attached to the backbone chains. The drug is released from the polymer by hydrolysis or enzymatic degradation of the linkages. Zero order can be obtained and the cleavage of the drug is the rate controlling mechanism. Example for polymer used in pendant chain systems like n-(2-hydroxy propyl) methacrylamide .

62. PENDANT CHAIN SYSTEM Pendant-chain systems have degradable linkages that release drug molecules upon exposure to water.

63. Ion exchange resins controlled release systems This systems are designed to provide the controlled release of an ionic (or ionizable ) drug . It is prepared by first absorbing an ionized drug onto the ion exchange resin granules such as codeine base with Amberlite , and then after filtration from the alcoholic medium, coating the drug resin complex granules with a water permeable polymer, e.g. a modified copolymer of polyacrylic and methacrylic ester, and then spray drying the coated granules to produce the polymer coated drug resin preparation.

64. 67 Cationic Drugs A cationic drug forms a complex with an anionic ion-exchange resin e.g. a resin with a SO 3 - group . In the G.I tract Hydronium ion (H + ) in the gastrointestinal fluid penetrates the system and activity the release of cationic drug from the drug resin complex . H + + Resin – SO 3 - Drug + R esin – SO 3 - H + +d rug + .

65. 68 Anionic Drugs An anionic drug forms a complex with a cationic ion exchange resin, e.g. a resin with a [N (CH 3 ) 3 + ] group. In the GI tract , the Chloride ion (Cl - ) in the gastrointestinal fluid penetrates the system and activates the release of anionic drug from the drug resin complex. Cl - + Resin –[N (CH 3 ) 3 + ] Drug- Resin –[NCH 3 ) 3 + ]Cl - + Drug-

66. Polymers Polymers: a. Introduction b. Classification c. Properties d. Advantages and application of polymers in formulation of controlled release drug delivery systems

67. What are Polymers ? Long Chain Molecules Extraordinary Range of Physical properties

68. What is a Polymer ?

69. What is a polymer?

70. Classification of polymers: Based on source

71. Classification of polymers: Based on Backbone Chain

72. Classification of polymers: Based on their degradability

73. Classification of polymers: Based on their thermal resistance

74. Based on Types of Atoms in Polymer Backbone

75. Based on monomers:

76. Based on Order of repeating units in backbone

77. Polymers

78. Conventional Polymer Structure

79. Conventional Polymer Structure

80. Based on chain arrangement: Polymers are Natural or synthetic substances of high molecular weight made up of repeating monomer units. Polymer molecules may be linear or branched, and separate linear or branched chains may be joined by cross links. Extensive cross-linking leads to a three-dimensional and often insoluble polymer network.

81. Polymers There are usually between about 100 and 10,000 monomer units in a chain. There may also be homopolymers with much smaller chains including dimmers (2 monomer units), trimers (3 units) and tetramers (4 units). These small chains are called oligomers .

82. Polymers Side chains or substituents (R) may be attached to the repeating monomer unitsThese may have: All the R groups on the same side of the polymer backbone ( isotactic ) a regular alternation of the R groups above and below the backbone ( syndiotactic ) a random arrangement of R groups above and below the backbone ( atactic ) The different monomers can be arranged in a linear chain in either a random manner or in an alternating pattern along the chain .

83. Polymers

84. Polymer properties

85. https://www.youtube.com/watch?v=_cCqNyB3lPk