Dúvidas denucci @ dglnet.com. br Arquivo Novos Slides Solicite aula para : guilherme@lexxa.com.br

1. Dúvidas denucci@dglnet.com.br Arquivo Novos Slides Solicite aula para: guilherme@lexxa.com.br

2. Evolution of drug dissolution profiles from oral drug delivery systems: (a) immediate release; (b) sustained release; (c) pulsatile or sustained release following a lag period Chronopharmaceutical drug delivery Pulsatile Sustained % Lag time (c) t Sustained % Technical complexity (b) t % Immediate (a) t 1950 1960 1970 1980 1990 2000 Chronology Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.1

3. Osmotic delivery system for providing modulated drug delivery of salbutamol Coated tablet Tablet core Laser-drilledhole Salbutamol sulfate + Sodiumchloride Semipermeablemembrane Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.2

4. Modulated release of salbutamol as a function of diminishing sodium chloride content in Oros tablet Chronopharmaceuticaldrugdelivery 2.0 1.0 0 Salbutamol release rate (mg/h) 1 6 12 Time (h) Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.3

5. Oros tablet with barrier layer to provide delayed release of drug Coated tablet Laser-drilledhole Semipermeablemembrane (allowsfluid IN, butnotdrug Out) Tablet core Drug-freelayer (hydrophilicpolymerprovidesbarrier to waterreachingthe interior) Drugformulation + hydrogelcarrier (absorbsfluidandcarriesdrug out throughorifice) Osmagent (absorbsfluid, swell, createsosmoticpressure, pushes out drugformulation) Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.4

6. Time-delayed drug release from tablets coated with a swellable barrier layer Drug release by diffusion through gel-barrier layer Hydrophilicpolymerlayeraround core tablet Hydration of barrier layer Uncoated core tablet Coated % Release Time Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.5

7. Biphasic release from a partially coated tablet Immediate-release drug layer Barrier layer exposed to fluids Barrier layer removed; release of second drug dose Impermeable coat (partial) Lag 2nd dose % Release 1st dose Time Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.6

8. Time-delayed drug release from a tablet coated with an erodible barrier layer Chronopharmaceutical drug delivery Erodible layer around core tablet Drug release as core tablet disintegrates Erosion of barrier layer % Release Time Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.7

9. Time-delayed drug release from a bursting tablet Permeablecoatingaround core tablet Fluidenters, causingdisintegrant to swell Internalpressurerupturescoat, releasingdrug Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.8

10. Coated pellet delivery system affording a sigmoidal dissolution profile Chronopharmaceuticaldrugdelivery Coating Eudragit RS+ ethylcellulose Sigmoidal release % Release Core Diltiazem Microcrystallinecellulose Sodiumcarboxymethylcellulose Time Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.9

11. Pulsatile dissolution profiles from the TES pellet delivery system showing influence of coating thickness on burst time Coating Ethycellulose Coatthickness Core Sugar bead Drug Low-substituted hydroxypropylcellulose % Release Lag-time Time Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.10

12. Pulsatile pellet system Coating Insolublepermeablefilmwith permeability-reducingcomponent Soluble, permeability-enhancing component Core Drug + swellingagent Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.11

13. Pulsatile hydrogel capsule system developed by Rashid Capsule shell Contents Plug, crosslinkedhydrogel Thick-walled, permeable, crosslinkedhydrogel Drugformulation Swellingagent (crosslinkedhydrogel) Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.12

14. PORT capsule system developed by Crison et al Capsule shell Contents Waxplug Waterpermeable, coatedgelatincapsule Drugformulation + swellingagent Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.13

15. Pulsincap capsule system developed by Scherer DDS Ltd Cap Solublegelatin Capsuleshell Water-impermeable, ethylcellulose-coatedgelatincapsule Contents Swellablehydrogelplug Drugformulation Expulsionagent Gelatincap dissolves; plugswells in contactwithfluidandestarts to slide out ofcapsule Swollenplugejects, fluidenterscapsule, expulsionagentswellsanddrug is released Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.14

16. Pharmacokinetics of salbutamol when given at 22.00 as tablet and 4 h detayed Pulsincap 6 5 4 3 2 1 0 4 h Pulsincap Plasma Salbutamol (ng/ml) Tablet 22°° 00°° 02°° 04°° 06°° 08°° 10°° Time of day Pulsincap and immediate-release tablet administered at 22.00 Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.15

17. Chronset capsule system developed by the Alza Corporation Semi-permeablecap Swellablecontents Contents Rigidbarrier Drugformulation Expulsionagent Capsuleshell Water-impermeable, ethylcellulose-coatedgelatimcapsule Capcontentsswellandcap starts to slide off capsule Capejects, barrierdetaches, fluidenterscapsule, expulsionagentswellsanddrug is released Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.16

18. Erodible plug, time-delayed capsule system developed at Strathclyde Cap Soluble gelatin Contents Erodible plug Drug formulation Expulsion agent Capsule shell Water-impermeable, ethylcellulose-coated gelatim capsule Plug fully eroded, fluid enters capsule, expulsion agent swells and drug is released Gelatin cap dissolves; plug starts to erode in contact with fluid Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.17

19. Time-delayed dissolution profiles of propranolol (50 mg) for fast (A) → slow (C) eroding tablets Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.18

20. Influence of tablet weight (thickness) and composition (HPMC content) on time-delayed release of propranolol (50 mg) 160 120 80 40 0 50 40 30 20 10 0 Tablet weight (mg) Quantity of HPMC in erodible (mg) 0 4 8 12 0 4 8 12 t50% drug release (h) t50% drug release (h) Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.19

21. Time-delayed delivery from na insoluble capsule with pores and swellable contents Capsule shell Thin-walled, water-impermeable, ethylcellulose capsule Contents Drug formulation Swellable excipient Pores to permit entry of fluid Detachment of cap Fluid enters and causes swelling and generation of internal pressure or Rupture of shell Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.20

22. The hydrolic sandwich capsule and the influence of HPMC viscosity on t50% drug release Outergelatincapsulecontaining HPMC 350 300 250 200 150 100 50 0 E50 E15/E50 E15 E3/E50 t50% drug release (min) E6 E5 E3 0 20 40 60 Innergelatincapsulecontainingdrug Viscosity of 2% HPMC solution (MPa s) Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.21

23. Absorption of paracetamol from the hydrophilic sandwich capsule 7 6 5 4 3 2 1 0 PK Parameter tmax Cmax AUC Time of first detection in saliva Value (SD) 7.9 h (±0.96) 5.36 μg/mL (±2.56) 565 μg/min/mL (±353) 5.7 h (±0.69) (Profile from one subject) Paracetamol in saliva (μg/ml) (n = 13) 0 100 200 300 400 500 600 700 800 900 Time (min) Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.22

24. Both normal subjects and asthmatic patients have circadian alterations in lung function, with nadirs occurring at approximately 04.00. Circadian variation in lung function is increased in asthmatics compared to normal subjects. PEFR, peak expiratory flow rate; FEV1, Forced expiratory volume in one second. Normal 16.00 04.00 PEFR or FEV1 Asthmatic 16.00 04.00 Time of day Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.1

25. This figure illustrates the marked frequency of nocturnal asthma symptoms independent of medication in 3129 mainly asthmatic patients. 400 350 250 150 Frequency of symptoms 110 70 30 10 10°° 13°° 16°° 19°° 22°° 01°° 04°° 07°° Time of day Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.2

26. Circadian variation in bronchial reactivity to methacholine between 16.00 and 04.00 in asthmatics with minimal alteration in overnight FEV1 (left) compared to those with marked decline in overnight FEV1 >20% (right). Horizontal lines represent mean values 10 1.0 0.1 0.01 Methacholine (Logscalle) Asthma Nocturnal asthma 16°° 04°° 16°° 04°° Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.4

27. Potential mechanisms that contribute to the worsening os asthma at night. Epi, epinephrine (adrenaline); Temp, Temperature; SaO2, Blood oxygen saturation Circadian Variation Vagal tone Inflammation Mediators Temp Cortisol Epi β2 Receptor SaO2 Upperairway Sinus apnoea Bronchialreactivity Nocturnalasthma Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.4

28. The number per volume (Nv) of eosinophils in nocturnal asthma (NA) and non-nocturnal asthma (NNA) groups in endobronchial (airway tissue, EBBX) and transbronchial (alveolar tissue, TBBX) biopsies at 04.00 and 16.00. 16.00 04.00 (26.4, 57.1) 40 30 20 10 0 40 30 20 10 0 NNA NA Nv (103/mm3) Nv (103/mm3) (2.1, 35,2) (2.7, 16.8) (5.4, 14.5) (0.7, 5.9) (0.0, 13.3) (0.0, 0.0) (0.0, 1.4) EBBX TBBX EBBX TBBX Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.6

29. Gastric emptying of liquid and solid foods 100 80 60 40 20 0 Solid Percentretention Liquid 20 40 60 80 Time (min) Chronotherapeutics – Peter Redfern – capitulo 6 – fig. 6.1

30. Cumulative mean gastric emptying of indigestible solids (2 mm and 10 mm insert markers) in 6 healthy subjects 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 No meal 1 meal Markers emptied (cumulative) 3 meals (n = 6) 0 1 2 4 6 Chronotherapeutics – Peter Redfern – capitulo 6 – fig. 6.2

31. Space lattice of sodium chloride crystal. Each sodium ion is octahedrally surrounded by six chloride ions and each chloride ion is octahedrally surrounded by six sodium ions Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.1

32. The seven possible primitive unit cells with atoms or molecules only at each corner of the unit cell. Drug moleculeswill typically form triclinic, monoclinic and orthorhombic unit cells Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.2

33. Variations on primitive cells Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.3

34. Cubic crystal showing planes with Miller indices of (a) (101) and (b) (010) Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.4

35. Planes in a two-dimensional array b Y (110) X a Y X (230) Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.5

36. The solid state in pharmaceutical science: pontential causes ans effects of structural change Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.6

37. Crystal habits of a hexagonal crystal Tabular Primatic Acicular Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.7

38. (a) Effect of anionic and cationic surfactants on the habiti of adipic acid crystal. (b) A diagrammatic (not to scale) representation of the arrangement of molecules at the crystal surface Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.8

39. Spironolactone Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – structure I

40. Unit cells of spironolactone Form 1 Form 2 Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.9

41. Crystal fromes of spironolactone Form 1 Form 2 Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.10

42. Scanning electron micrographs showing the crystal habit of (a) Form 1 and (b) Form 2 of paracetamol grown from supersaturated IMS a b Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.11

43. Paracetamol Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – structure II

44. Melting points of some polymorphic forms of steroids, sulfonamides and riboflaven Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – tab. 1.1

45. Photomicrographs showing the solution phase polymorphic conversion of orthorhombic paracetamol (needles) to monoclinic paracetamol (prisms and plates) a b Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.12

46. Three representations of cholesterol are show: a space-filling molecule (top right), a structural diagram (bottom) and a simplified black diagram (top lefet) (a) Cell membranes are composed primarily of phospholipid amphiphiles. (b) Cholesterol molecules act as rigidifiers which make the membrane stiffer. Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.1

47. Ideal lipophilic character of drug (log Po) in different regions of the body Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.1

48. Hydrogen ion concentrations (CH+) at intervals after a test meal (mean results are show ± 2SEM); the zero samples were taken just before the meal was begun, and the 1 hour sample just before 45 cm³ of water Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.13

49. Effects of antacids on gastric volume and pH in the rata,b Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.4

50. Commercially available drug-delivery systems for systemic delivery by the oral mucosal routea Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.5