1. Modulation of drug release from dosage form
Techniques -
Modulation of drug release from dosage form

2. List of contents Introduction Mechanisms of controlled release
Intelligent controlled release DDS
Examples
Recent advances
References
A commercially available responsive drug delivery system – insulin pumps

3. Introduction: Fluctuating plasma level in conventional DF.
Development of CR ,SR, TR Etc.
A commercially available responsive drug delivery system – insulin pumps

4. Targeted delivery
It has goal of delivering the drug to specific cell types, tissues or organs.

5. Controlled release
Assigned to release the DRUG at a PREDETERMINED Rate.

6. Release of drug at a variable rate controlled by
Modulated release
Release of drug at a variable rate controlled by
Environmental conditions,
Biofeedback,
Sensor input
External control device.

7. Sustained release (SR)
In SR –Drug release is affected by External environment.
- Release is slow than conventional DF.
In CR – Release is dependant on the
design of dosage form.

8. ADVANTAGES OF DRUG RELEASE MODULATION
Prolonged duration of action.
Increase Controlled delivery at predetermined rate
In patient compliance
Reduction in frequency of dosing
Reduced fluctuations
More uniform effect

9. Increased first pass clearance.
DISADVANTAGES
High cost
Poor IVIVC.
Dose dumping.
Increased first pass clearance.

10. DRUG RELEASE MODULATION
ADVANTAGES
DISADVANTAGES
DRUGS UNSUITABLE FOR CR

11. Threshold of effectiveness
Blue- uncontrolled unsafe dose
Dotted-uncontrolled safe dose
Red-controlled release
Toxic level
Drug
Threshold of effectiveness
Time

12. Different controlled release systems
Burst like release
Pulsatile release
Zero order (linear) release
Cumulative
release
Diffusion controlled release
Lag followed by
Burst release
Time of release

13. FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS
Drug related
Biological
Physiological
Pharmacokinetic
Pharmacological

14. FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS
partition coefficient
aqueous solubility
molecular size
Drug related
protein binding
drug stability

15. FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS
absorption
distribution
disease state
Biological
elimination
side effects
duration of action
margin of safety

16. FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS
variability on GI
emptying & motility
prolonged drug absorption
Physiological
GI blood flow

17. FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS
dose dumping
first pass metabolism
Pharmacokinetic
variability of urinary pH
effect on drug elimination

18. FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS
changes in drug effect
upon multiple dosing
Pharmacological
Sensitivity / tolerance

19. DRUGS UNSUITABLE FOR CR
posses following features
Short/long elimination half-life
Narrow therapeutic index
Poor absorption
Large doses
Low aqueous solubility
Extensive first pass metabolism

20. BASIC PRINCIPLES OF CR
DIFFUSION
SWELLING
BIODEGRADABLE or BIOERODIBLE

21. CONTROLLED RELEASE – MECHANISM
Diffusion controlled
Dissolution controlled
diffusion & dissolution controlled
Water penetration controlled
Chemically controlled
Hydrogels
Ion exchange resins

22. Schematic depiction of various classes of controlled release system
Reservoir and monolithic
Encapsulation
Matrix
Matrix
Diffusion
Dissolution
Reservoir
Diffusion and Dissolution
Ion exchange resin
Controlled
release system
Water penetration controlled
cation
anion
Swelling
osmotically
Hydrogel
Chemically controlled
Chemically
Drug linked polymer
Diffusion
Erodible
Environmental
Swelling

23. Diffusion controlled release system (monolithic matrix device)
  In monolithic devices, the drug is uniformly dispersed or dissolved in the polymer, and it is released by diffusion from the polymer as shown in Figure . 

24. DIFFUSION CONTROLLED SYSTEMS MONOLITHIC-MATRIX SYSTEMS
Drug +
polymer

25. MATRIX CHARACTERISTICS
MONOLITHIC-MATRIX SYSTEMS Materials used as retardants in matrix tablet formulations :-
MATRIX CHARACTERISTICS
MATERIAL
Insoluble, inert matrix
Polyethylene
Polyvinyl chloride
Ethylcellulose
Insoluble, erodable
Carnauba wax
Polyethylene glycol
Castor wax
hydrophilic
Methyl cellulose
Carboxypolymethylene
Sodium alginate
HPMC

26. Diffusion controlled reservoir system
In membrane-controlled reservoir devices, the drug is contained in a core, which is surrounded by a polymer membrane,
The drug release limiting structure is the polymer layer surrounding the reservoir

27. RESERVOIR SYSTEMS
Oral system

28. RESERVOIR SYSTEMS First layer Of the drug crystals Polymer phase
Diffusion
layer

29. DIFFUSION CONTROLLED SYSTEMS
Matrix system
Achievement of zero order is difficult
Suitable for both degradable & non-degradable systems
No danger of dose dumping
Not all drugs can be blended with a given polymeric matrix
Reservoir system
Achievement of zero order is easy
Degradable reservoir systems may be difficult to design
Rupture can result in dangerous dose dumping
Drug inactivation by contact with the polymeric matrix can be avoided

30. Combined reservoir – monolithic system
Initially the active agent must diffuse across the membrane , as the time passes the outer layers of the monolithic reservoir are depleted , the agent travels through the monolithic material and the membrane sequentially.
This type of system is designated in two phase ( 1, 2)

31. COMBINED RESERVOIR-MONOLITHIC SYSTEMS
Phase I – outer membrane layers
Phase II – reservoir matrix material
Outer membrane layer (phase I)
Dispersed agent in polymer matrix
(phase II)

32. COMBINED RESERVOIR-MONOLITHIC SYSTEMS
Matrix (phase II)
Outer membrane
(phase I)
Initially the release rate of diffusion through the phase 1 ,as the time progress ,a layer depleted from the active agent is generated in phase 11 reservoir material immediately adjacent to the membrane layer.
Agent loaded
Matrix layer
Agent depleted
Matrix layer

33. DISSOLUTION CONTROLLED RELEASE SYSTEMS
Two classes:
Encapsulation dissolution control
Matrix dissolution control

34. DISSOLUTION CONTROLLED SYSTEMS Encapsulation dissolution control
systems involve coating of individual particles of drug with a slow dissolving material & the coated particles can be compressed directly into tablets or placed in capsules.

35. Matrix dissolution control
In this approach drug is dispersed in slow dissolving matrix consisted of polymer.
The rate of penetration of dissolution fluid in to the matrix determines the drug dissolution and subsequent release.

36. Matrix dissolution control
Membrane controlled
Polymer erosion controlled
drug
membrane

37. DIFFUSION & DISSOLUTION CONTROLLED SYSTEMS
Release rate is dependent on
surface area
diffusion coefficient of drug though pore in coating
conc. of drug in dissolution media.
membrane
drug

38. WATER PENETRATION CONTROLLED SYSTEMS
rate control is obtained by penetration of water into the system.
classified into 2 parts.
swelling controlled systems
osmotically controlled systems

39. SWELLING CONTROLLED SYSTEM
The system is initially dry & when placed into any body fluid, it absorbs the fluid & swells.
This swelling increases the aqueous solvent content within the formulation & also polymer mesh size & so make the drug to diffuse through the swollen network into the external environment.

40. SWELLING CONTROLLED SYSTEM
“Non-fickian case II” type diffusion,
solvent
Swollen
matrix
Swelling zone
Unswollen
polymer matrix

41. SWELLING CONTROLLED SYSTEM
“Non-fickian case II” type diffusion
Swollen
matrix
Swelling zone
Unswollen
polymer matrix
solvent

42. CHEMICALLY CONTROLLED SYSTEMS
delivery systems that change their chemical structure , when exposed to biological milieu
This system include biodegradable polymer that degrade within body as a result of natural biological process ,eliminating the need to remove the delivery system after exhausting of active agent from system

43. Biodegradable drug delivery system
The polymers used in the formulation and fabrication of biodegradable drug delivery devices erode (with or without changes to the chemical structure) or degrade (breakdown of the main chain bonds) as a result of the exposure to chemicals (water) or biologicals (enzymes)

44. CHEMICALLY CONTROLLED SYSTEMS
The polymer degradation by 2 ways:
Bulk erosion surface erosion

45. MECHANISM OF POLYMER EROSION
Type IA – cleavage of cross links
Type IB – disintegration of water soluble polymer backbone

46. MECHANISM OF POLYMER EROSION
Type II – Water insoluble macromolecules are converted into water soluble compounds by hydrolysis, ionization or protonation of a pendent group.
hydrolysis
Ionization
protonation
Water insoluble molecules
Water soluble molecules

47. MECHANISM OF POLYMER EROSION
Type III – erosion mechanisim
Hydrolytic
cleavage
Water insoluble molecules
Water soluble molecules

48. MECHANISM OF DRUG RELEASE
bioactive covalently linked to polymer backbone , scission of the bonds connecting the drug to polymer backbone.

49. List of biodegradable polymer
Polylactides (PLA).
Polyglycolides (PGA).
Poly(lactide-co-glycolides) (PLGA).
Polyanhydrides.
Polyorthoesters.

50. Factors Affecting Biodegradation of Polymers
Chemical structure.
Chemical composition.
Presence of unexpected units or chain defects.
Configuration structure.
Molecular weight.
Molecular-weigh

51. HYDROGELS
Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers.

52. Classification:- 1) Diffusion controlled release
HYDROGELS
Classification:-
1) Diffusion controlled release
- reservoir
- matrix
2) Chemically controlled release
- biodegradable polymers
- covalently linked drug & polymer
3) Swelling controlled release
4) Environmentally responsive hydrogel systems

53. Advantages Highly biocompatible
Applied for both hydrophilic & hydrophobic drug
Release of therapeutics agent regulated controlling water swelling & cross linking agent
Low interfacial tension

54. Limitation
Poor mechanical strength
Toughness after swelling

55. Swelling controlled release
HYDROGELS
Swelling controlled release
consists of drug dispersion within glassy polymer matrix. When the system comes in contact with biofluids, it starts swelling.
Drug release
Glassy
polymer
Swollen gel
water

56. Environmentally responsive hydrogel systems
some polymers show drastic change in their swelling behavior with changes in
external temp.,
pH,
ionic strength,
enzymatic & chemical reaction,
magnetic & chemical stimulus.

57. Environmentally responsive hydrogel systems
The changes in network structure in response to external environment are reversible in nature. - T T pH - pH

58. Type of hydrogel Super porous hydrogel pH sensitive hydrogel
Temperature sensitive hydrogel
Glucose sensitive system
Neutral hydrogel
Oral insulin hydrogel

59. Electronic microscopic fig of super porous hydrogel
Mainly for speedy swelling
Carried out by making very fine particle of dried hydrogel having short diffusion path length
Electronic microscopic fig of super porous hydrogel

60. Recent application of super porous gel in drug delivery
DEVELOPMENT OF GASTRIC
RETENTION DEVICES
Development of fast dissolving tablet
Development per oral peptide delivery system

61. Per oral octreotide delivery system

62. ION-EXCHANGE RESIN Zero order release obtained
kinetics Drug release depends only on the ionic environment of the resins containing drug
2 types.- cation exchange resin & anion exchange resin.

63. CATION EXCHANGE RESIN :-
Synthesized by copolymerization of divinyl benzene & styrene.
divinyl benzene
styrene

64. Anion exchange resin
is prepared by chloromethylation of benzene rings of three dimensional styrene-divinyl benzene copolymer network leading to insertion of –CH2Cl groups & forms strong anion exchange resin.

65. ION-EXCHANGE RESIN - - - - - + + Electrolytes + In gastric +
Environment - + + - - + +
Cationic drug +
Anionic resin -
Positively charged
Electrolyte. +

66. INTELLIGENT CONTROLLED RELEASE DRUG DELIVERY SYSTEMS:-
Provide the bioactive in response to the physiological need & should ‘sense’ the changes & manipulate the drug release in response to external stimuli like heat, ultrasound, magnetic field, pH and/or conc. of specific molecules.

67. electically regulated
:- CLASSIFICATION:
pH sensitive
electically regulated
thermosensitive
pulsatile systems
responsive systems
ultrasonically modulated
inflammation responsive
magnetically modulated
INTELLIGENT
CONTROLLED
RELEASE SYSTEMS
Glucose sensitive
photoresponsive
urea responsive
systems utilizing
enzymes
systems utilizing
chelation
systems utilizing
antibodies
glucose responsive

68. Pulsatile drug delivery system
Pulsatile systems are basically time-controlled drug delivery systems in which the system controls the lag time independent of environmental factors like pH, enzymes, gastro-intestinal motility, etc.

69. PULSATILE SYSTEMS :- Electrically regulated systems :-
Drug release is due to action of an applied electric field on a rate limiting membrane or directly on the solute & so control the transport across the membrane.

70. PULSATILE SYSTEMS :- Ultrasonically modulated systems :-
Because of ultrasound, the polymer erosion is enhanced & therefore, drug release is enhanced .
The extent of this enhancement is regulated by the frequency, intensity or duty cycle of the applied ultrasound.

71. PULSATILE SYSTEMS :- Magnetically modulated systems :- No applied
field
Field turn on
Drug release

72. :- PULSATILE SYSTEMS :-
Photoresponsive systems :-
Photoresponsive polymer consists of a photoreceptor usually a photochromic chromophore & an functional part. Photoresponsive gels change their physical or chemical characteristics upon exposure to photoradiation.
On catching the optical signal, isomerization of the chromophores in the photoreceptor converts it to a chemical signal.

73. :- RESPONSIVE SYSTEMS:-
Combination of Biosensors & controlled release system
Sense continuously to manage unpredictable condition
Immediate respond with appropriate countermeasure
Give the patients more flexibility and less disruption of the daily life

74. RESPONSIVE SYSTEMS:- Commercially available Responsive
Noninvasive reverse iontophoresis devices
Implantable fusion pumps
Duros implant technology controlled release
Responsive
Closed loop
Smart polymers

75. RESPONSIVE SYSTEMS:- pH sensitive systems:-
Alteration in pH of the environment cause swelling or deswelling of the polymer
An enzyme substrate interaction produces a pH change that is utilized to modulate the erosion of pH sensitive polymer containing a dispersed bioactive.

76. RESPONSIVE SYSTEMS:- Thermo sensitive systems :-
Mainly classified in to two classes
based on polymer water interaction & based on polymer-polymer interactions along with polymer water interactions.

77. RESPONSIVE SYSTEMS:- Inflammation responsive systems :-
Based on biodegradable hydrogels of cross-linked hyaluronic acid.

78. RESPONSIVE SYSTEMS Glucose sensitive polymers :-
Glucose in
Glycosylated insulin out
Polymer membrane
Concavalin A
Sepharose 4B beads
glucose
Glycosylated insulin

79. RESPONSIVE SYSTEMS Glucose sensitive polymers :- Polymer A Polymer B
insulin
glucose
microcapsule
release

80. SYSTEMS UTILIZING ENZYMES
a) Urea responsive delivery systems Urea is converted into NH4HCO3 & NH4OH by the action of urease that increases the pH.
Hydrogel prepared by immobilizing urease
In cross-linked bovine serum albumin
N-hyxyl half ester with dispersed drug

81. SYSTEMS UTILIZING ENZYMES
b) Glucose responsive insulin delivery :-
This system utilizes enzyme-glucose oxidase which converts glucose into gluconic acid.
Glucose + O2  gluconic acid + H2O G
NR2
GluOx G G
NR2 G
HNR2
GluOx
NR2
GluOx G
NR2
NR2
NR2 G
GluOx
NR2

82. SYSTEMS UTILIZING ENZYMES
b) Glucose responsive insulin delivery :-
GOD
HOOC
COOH
insulin
GOD
-OOC
COO-
insulin
glucose
insulin

83. SYSTEMS UTILIZING ANTIBODY INTERACTIONS
e.g. controlled release of ethinyl estradiol (EE).
EE stimulates biosynthesis of sex hormone binding globulin (SHBG).
High serum levels of EE stimulates the production of SHBG, which increases the conc. of SHBG attached to the polymer surface & reduces the EE release rate.

84. SYSTEMS UTILIZING CHELATION
Concept is based on the property of metals to accelerate the hydrolysis of carboxylate or phosphate esters & amides.
Tagging of the chelator to a polymer chain by a covalent ester or amide link prevents its premature loss by excretion & reduces its toxic effects.

85. Insulin pump,Gluco watch
Examples:
Insulin pump,Gluco watch
An insulin reservoir (like a regular syringe)
A small battery operated pump
A computer chip for control
Combination with Glucose sensors
Reservoir and pump are incorporated in a plastic case about the size of a beeper.

86. Recent information Polymer therapeutics
covers natural or synthetic polymers,
which have either inherent therapeutic potential or carry covalently bonded drugs.
The covalently bonded drugs have to be released at the desired tissue or cell type. Polymeric therapeutics are
e.g.
polymeric drugs,
polymer-protein conjugates,
polymer-DNA complexes,
polymer-drug conjugates or
polymeric micelles.

87. Chemo mechanical polymer drug delivery system
Chemomechanical polymers, developed by Professor Hans-Jorg Schneider and his team at the University of Saarland, Germany, have greatly improved functionality compared to existing expanding / contracting materials used to perform biomedical functions, and could be used in applications such as actuators, implants, drug release systems and drug screening.

88. New polymer enables near zero order drug release
Cavilink TMd
Highly porous polymer micro bead

89. Advance technologies in modified release from dosage form
TIMERx MASRx & COSRx systems
Procise (comprised of a compression coated core) Drug Delivery Systems Based on Geometric Configuration
Ringcap Technology – tablets

90. Advance technologies in modified release from dosage form
Smartrix system – multiple layered tab. Novel Erosion-Controlled Oral Delivery System
Theriform Technology – novel method of fabrication based on three dimensional printing, a solid freeform fabrication technology- implants
Accudep technology – layered capsules

91. Advance technologies in modified release from dosage form
Threeform technology ,- Meltrex technology – melt extrusion process
Dissocubes –,IDD technology – insoluble drug delivery technology
Zydis oral fast dissolving dosage form.
Orasolv & Durasolv – efficient technologies for production of orally disintegrating tablets.

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