Oral Drug Delivery

Front 1

keys to optimal drug delivery

Back 1

right drug
right amount
right time
right location
right patient

Front 2

oral formulations account for _____% of drug dosages

Back 2

84%

Front 3

Stomach:
Volume
pH fasted
pH fed

Back 3

1.6 L
1.7
5

Front 4

Back 4

Front 5

Back 5

Front 6

segregation of particles

Back 6

small particles will sink to the bottom (like mixed nuts)

Front 7

hard gelatin capsules are filled with:

Back 7

- solids
- powders
- granular or pelletized materials
- oils

Front 8

soft gelatin capsules are filled with:

Back 8

- semisolids
- liquids
- granular or pelletized materials

Front 9

alternatives to gelatin capsules

Back 9

1. Pullulan- a water soluble polysaccharide

2. HPMC- a water soluble polymer

Front 10

most common oral dosage form

Back 10

tablet

Front 11

best way to make a drug more soluble

Back 11

make the particles as small as possible

Front 12

types of tablet coating

Back 12

1. sugar coating
2. film coating
3. enteric coating

Front 13

disadvantages of tablets

Back 13

- inflexible dosage form
- not prepared extemporaneously
- large no. of ingredients
- dissolution of drug
- drugs sensitive to moisture, oxygen, light
- what is pharmacist's responsibility in regard to tablets?

Front 14

MCT

Back 14

multiple compressed tablet

-layered tablets, press-coated tablets, inlays

Front 15

DT

Back 15

dispensing tablet

Front 16

advantages of buccal and sublingual tablets

Back 16

- rapid onset
- avoid 1st pass metabolism
- avoid gastric fluids

Front 17

binder

Back 17

granules which help the formulation flow

Front 18

implants

Back 18

act as a resevoir for the drug

Front 19

disintegraters

Back 19

cause tablet to break up

Front 20

main problem with lubricants

Back 20

all lubricants are insluble in water and and ruin absorption or look unappealing

Front 21

common flow problems

Back 21

- non-uniform flow disrupting uniformity
- uneven flow cause segregation of active ingredients
- need for force feeders, vibrators, custom hoppers, etc.
- non reproducible manufacturing operations
- low process yields due to inefficient material handling & high reject levels

Front 22

Basic tablet manufacturing processes

Back 22

1. direct compression
2. wet granulation
3. dry granulation

Front 23

direct compression suitable for drugs which:

Back 23

- drugs that have large doses
- drugs that are free flowing and crystalline
- drugs that have cohesive properties

Front 24

advantages of direct compression

Back 24

- simplicity and time
- no prior granulation
- avoid moisture and heat

Front 25

disadvantages of wet granulation

Back 25

- usually needs a solvent that needs to be removed
- more complicated process

Front 26

Back 26

capping

Front 27

Back 27

lamination

Front 28

Back 28

a- picking

b- stress cracking

Front 29

Back 29

chipping

Front 30

Purposes of tablet Coating

Back 30

1. Enhance palatability
2. Increase stability of active drug
3. Increase mechanical integrity of tablet
4. Enhance elegance
5. Protect hands and clothes from staining
6. Modify drug release profile
7. Avoid side effects (i.e. gastric irritation)
8. Avoid incompatibility
9. Identification of product

Front 31

rate of dissolution

Back 31

the amount of drug substance that goes in solution per unit time under standard conditions of liquid/solid interface, temperature, and solvent composition

Front 32

difference between solubility and dissolution

Back 32

solubility- how much can dissolve

dissolution- the process of dissolving

Front 33

dC/dt

Back 33

dissolution rate (change in solute concentration per unit time)

Front 34

A

Back 34

the effective surface area of the solid being dissolved

Front 35

Cs

Back 35

concentration of solid in the boundary layer

Front 36

Ct

Back 36

concentration of solid in the medium
- usually ignored (sink conditions)

Front 37

k1

Back 37

new dissolution rate constant

Front 38

D

Back 38

diffusion coeffficient of the solid

Front 39

V

Back 39

volume of the dissolution medium

Front 40

h

Back 40

thickness of the diffusion layer

Front 41

w

Back 41

mass of drug remaining to dissolve at time t

Front 42

polymorphism

Back 42

when a substance exists in more than one crystalline form

Front 43

stable polymorph has _________ energy state, ___________ MP, and _________ aqueous solubility than metastable polymorph

Back 43

lower energy state
higher MP
lower aqueous solubility

Front 44

what happens to a metastable polymorph when it precipitates out of solution?

Back 44

It will change into the stable polymorph

Front 45

Dissolution testing apparatus (2)

Back 45

Apparatus I:
- rotating basket for tablets

Apparatus II:
- paddle for tablet, capsules, modified drug products

Front 46

Components of Fasted State Simulated Intestinal Fluid (FaSSIF)

Back 46

- Sodium taurocholate
- Lecithin
- Na OH pellets
- NaH2PO4H2O
- NaCl
- purified water

Front 47

Components of FeeSSIF)

Back 47

- Sodium taurocholate
- Lecithin
- NaOH pellets
- Glacial Acetic Acid
- NaCl
- Purified water

Front 48

f2

Back 48

similarity factor used in dissolution profile comparison

- when two profiles are identical, f2 = 100
- an average difference of 10%, f2 = 50

Front 49

API standard for Bioequivalence

Back 49

If dissolution in vivo and permeability are the same, then we can assume that metabolism in GI-wall, metabolism, and excretion will also be the same.

Front 50

Back 50

Front 51

Biopharmaceutics Class I:

- RLS
- IVIVC
- when is dissolution not likely to be rate limiting?
- Examples (3)

Back 51

HS/HP

RLS: Gastric Emptying

IVIVC: Correlation if dissolution rate < gastric emptying; otherwise no correlation

When dissolution rate > gastric emptying,
dissolution is not likely to be rate limiting

Ex: Metoprolol, Verapamil, Propanolol

Front 52

Biopharmaceutics Class II:

- RLS
- IVIVC
- Examples (3)

Back 52

LS/HP

RLS: Dissolution

IVIVC: Yes, if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high

Ex: Naproxen, Carbamazepine, Ketoprofen

Front 53

Biopharmaceutics Class III:

- RLS
- IVIVC
- Examples (3)

Back 53

HS/LP

RLS: Permeability

IVIVC: No

Ex: Atenolol, Cimetidine, Ranitidine

Front 54

Biopharmaceutics Class IV:

- RLS
- IVIVC
- Examples (2)

Back 54

LS/LP

RLS: varies (In vitro dissolution may not be reliable)

IVIVC: Limited or none

Ex: Furosemide, Hydrochlorothiazide

Front 55

FDA requirements for BE study waiver

Back 55

- BCS Class I
- absorption > 90%
- highest dose soluble in <250 ml pH 1-7.5
- dissolution in vitro >85% in 30 min
- f2 dissolution profile similarity test
- only well established excipients
- not drug with narrow therapeutic window

Front 56

IVIVC

Back 56

In-vitro in-vivo correlation

- mathematical model describing the relationship between in vitro and in vivo properties of drug

Front 57

Methods to achieve IVIVC

Back 57

- pharmacological correlation
- Semi quantitative correlation
- Quantitative correlation

Front 58

Levels of IVIVC Correlation

Back 58

- A
- B
- C
- multiple level C

Front 59

Level A Correlation

Back 59

Front 60

Level B Correlation

Back 60

Front 61

Multiple Level C Correlation

Back 61

Front 62

Steps to develop an IVIVC Model

Back 62

1. Use 2 formulations with ≥ 2 release rates (≥3 recommended)
2. Attain in vitro dissolution profiles
3. Determine in vivo plasma conc. as a function of time
4. Estimate in vivo drug release rate via deconvolution
5. Correlate % absorbed (in vivo data) as a function of % dissolved (in vitro data)

Front 63

in vivo data

Back 63

% absorbed

Front 64

in vitro data

Back 64

% dissolved

Front 65

Advantages of Buccal Delivery

Back 65

- mucosa is well supplied with both vascular and lymphatic
drainage; first-pass metabolism avoided
- patient acceptance
- control and manipulation of drug permeation
- delivery of orally inefficient drugs and peptides

Front 66

Disadvantages of Buccal Delivery

Back 66

- inconvenience
- swallowed drug is subject to first pass metabolism
- limited to small doses

Front 67

Buccal-
Sublingual-
Gingival-
Palatal-

Back 67

Buccal- cheek
Sublingual- ventral tongue; floor of mouth
Gingival- gums surrounding teeth
Palatal- roof of mouth

Front 68

Potential losses of Buccal drug delivery

Back 68

- swallowing
- dilution by saliva
- protein binding
- metabolism
- absorption in other oral regions

Front 69

Methods to enhance cell permeability of drugs

Back 69

- organic solvents (toluene, DMSO, phenethyl alcohol)
- chelating agents (EDTA)
- surfactants, detergents
- lysolecithin
-antibiotics
- proteins

Front 70

Striant

Back 70

Buccal system for testosterone replacement

Front 71

Advantages of Conventional Oral Delivery

Back 71

- convenient
- cheap
- variety of dosage forms

Front 72

Disadvantages of Conventional Oral Delivery

Back 72

- inefficience due to partial absorption
- first pass effect
- effect of food & GI motility on absorption
- local effect (i.e. antibiotics kill GI flora)
- patient must be able to swallow dosage

Front 73

Methods of crossing membranes

Back 73

1. diffusion through channels
2. dissolving in lipid phase + soluble in aqueous phase
3. carrier-mediated transport

Front 74

At same pH, acids with _______ pKa values are absorbed less, whereas bases with ______ pKa values are absorbed more

Back 74

lower; lower

Front 75

At same pKa, acids are absorbed more in ______ pH environment, whereas bases are absorbed more in _______ pH environment.

Back 75

lower pH; higher pH

Front 76

Classic Paradigm of Cyclosporine

____% loss to feces
____% metabolized by liver
____% to systemic circulation

Back 76

65% feces
8% liver
27% systemic

Front 77

New Paradigm of Cyclosporine

____% loss to feces
____% metabolized by gut wall
____% metabolized by liver
____% to systemic circulation

Back 77

14% feces
51% gut wall
8% liver
27% systemic

Front 78

Efflux Pump

Examples (2)

Back 78

protein pumps which transport molecules out of the cell

- PGP, cytochrome P450 3A

Front 79

Effect of polymorphs on solubility and bioavailability

Back 79

in most cases, no major changes

***we do need to know when it is important***

Front 80

Chloramphenicol Form B

Back 80

form B is more bioavailable, but less stable

- can effect shelf life as B morphs into more stable, less soluble A

Front 81

Dissolution rate of an anhydrous phase
usually is ______ than that of the hydrate

Exception:

Back 81

higher

Exception= erythromycin

Front 82

Methods to increase dissolution

Back 82

- reduce particle size
- oral solution
- wetting agents
- salt form
- lipid solubilization
- prodrug

Front 83

Use of relationship between Half-life and Serum creatinine level of drug

Back 83

can use to adjust dosage for a patient

Front 84

Effect of__________ on gastric emptying

- large glass of water
- large meal
- small snack

Back 84

water: fast emptying

large meal: slow emptying

small snack: slow emptying

Front 85

Estimated transit times:

50% of stomach
Total emptying of stomach
50% of small intestine
transit through colon

Back 85

50% of stomach 2.5-3 hr
Total emptying of stomach 4-5 hr
50% of small intestine 2.5-3 hr
transit through colon 30-40 hr

Front 86

The _______ the stomach emptying the higher the plasma concentration.

Back 86

quicker -> higher plasma conc.

Front 87

Griseofulvin

Back 87

a drug that's absorption is improved by presence of fatty food (exception)

- apparently the poorly soluble drug is griseofulvin is dissolved in the fat and then more readily absorbed

Front 88

Physiochemical Barriers to Oral Drug Delivery

Back 88

- chemical degradation
- thermodynamics
- partitioning, extent and rate
- absorption effects
- molecular size
- solubility/dispersability

Front 89

Biological Barriers to Oral Drug Delivery

Back 89

- bacterial degradation
- enzymatic degradation
- first pass
- immunological (GI associated immunities)

Front 90

Physiological variables affecting Oral Drug Delivery

Back 90

- pH of GI tract
- membrane permeability
- site specific absorption
- gut wall metabolism
- blood flow
- GI motility
- luminal contents
- gastric/intestinal secretions

Front 91

Benefits of Oral Sustained Release

Back 91

- increased patient compliance (reduced frequency of dosing)
- sustained pharmacodynamic response
- reduced side effects (fewer peaks/valleys)
- enhanced bioavailability

Front 92

LA

Back 92

Long Acting

Front 93

SA

Back 93

Sustained Action

Front 94

SR

Back 94

Sustained Release

Front 95

TR

Back 95

Time Release

Front 96

ER

Back 96

Extended Release

Front 97

"Magic Bullet"

Back 97

Drug selectively directed to site of action -> no side effects

Front 98

Stealth Concept

- method

Back 98

a PEG coated liposome is not seen by defense mechanisms in the blood, hence it successfully carries drug molecules to the target cells

-by controlling size, you can direct where molecule will leave blood vessels

Front 99

Monolithic system

Back 99

tablets

Front 100

Multiparticulate System

Back 100

granules or pellets in capsules

- can use two or more types of beads to get multiple delivery rates

Front 101

Mechanisms of Controlled Release
in Oral Delivery Systems

Back 101

- Diffusion
- Solvent-activated release
- polymeric degradation

Front 102

Diffusion Controlled Release System

Back 102

- drug is either encapsulated in a polymer membrane or suspended within a polymer matrix

- water diffuses into the membrane or matrix, drug dissolves, then drug diffuses out of the polymer

Front 103

Solvent Activated System

Back 103

-An osmotic agent draws water into the membrane through a small hole
- the drug is then forced out through the hole due to increased pressure

Front 104

OROS

Back 104

an osmotic control system

Front 105

Polymeric Degradation

Back 105

-drug is contained within a polymer membrane or matrix
- polymer degrades and releases drug at specific location

Front 106

Degradation Mechanism A

Back 106

water-soluble polymers are made insoluble by cross-linking them together.
When the cross-links are broken at some point in the body, the polymer will dissolve.

Front 107

Degradation Mechanism B

Back 107

water-insoluble polymers are made soluble by hydrolysis or ionization of side groups.

Front 108

Degradation Mechanism C

Back 108

involves the use of insoluble polymers that are cleaved into soluble monomers

Front 109

Responsive Drug Delivery System

Back 109

stays inactive in the body until a person is exposed to danger

- i.e. insulin pumps

Front 110

Why are drugs good or bad candidates for
oral delivery?
- HIGH DOSE
• Good: Better for manufacturer
• Bad: Inconvenient for patient
-LONG HALF-LIVES
• Good: less frequent administration
• Bad: Increased duration of side effects
- VERY POTENT DRUGS
• Good: good bioavailability
• Bad: Hard to ensure content uniformity
- POORLY WATER SOLUBLE COMPOUNDS
• Good: Useful for controlled (extended release formulation)
• Bad: Poor dissolution can lead to poor bioavailability
- NOT GOOD AT ALL
• Irregularly or poorly absorbed drugs
• Drugs that do not exhibit a relationship between plasma levels and biological activity
- Of course exceptions will occur

Back 110

-

Front 111

Back 111

Front 112

Back 112

Front 113

Back 113

Front 114

Back 114