1
Q
What are the main things to consider in Oral Drug Delivery?
A
- Advantages & Disadvantages of oral delivery route.
- Types of dosage forms used.
- Formulation factors affecting oral bioavailability
- Structure & Physiology of GI tract.
- Physiological factors affecting oral bioavailability
- Patient counseling
2
Q
What are some advantages for oral delivery route?
A
- Patient acceptability & compliance.
- Large surface area for absorption.
- Rich Blood supply.
- Prolonged Retention.
- Possible for zero-order controlled release.
- Inexpensive.
- For local or systemic delivery.
3
Q
What are some disadvantages of oral drug delivery?
A
- Variability in patient population.
- Adverse reactions.
- Proteins & Peptides cannot be delivered.
- Metabolism & efflux issues.
4
Q
What factors effect systemic absorption & Bio-availability?
A
- Physiochemical properties of the drug.
- Formulation Factors.
- Anatomy and physiology of the drug absorption sites.
5
Q
What are some physiochemical properties of drugs?
A
- pKa leading to Ionization
- log P between 1-3, Lipophilicity
- Solubility of drug in solution and absorption
6
Q
What are some common types of dosage forms used for oral delivery?
A
- Solutions
- Emulsions
- Suspensions
- Powders
- Tablets
- Capsules
- Modified release granules, tablets & capsules
7
Q
Which formulation factors affect oral bio-availbility?
A
- Particle size
- Excipients
8
Q
What are the five most common types of Excipients?
A
- Wetting Agents/Surfactants
- Diluents
- Binders (adhesives)
- Disintegrants
- Lubricants
9
Q
What are some advantages of Wetting Agents/Surfactants?
A
Help with dissolution by lowering interfacial tension (e.g. polysorbate 80)
Help with absorption of drug (e.g. sodium dodecyl sulfate)
10
Q
What are some advantages of Diluents?
A
- Bulk up formulations.
- Lactose, Dextrose, Sucrose, Microcrystalling cellulose.
- hydrophylic diluents promote rapid tablet disintegration (create channels in erosion matrix ER products).
- hydrophobic diluents decrease dissolution rate of drug.
11
Q
What are some advantages of Binders (adhesives)?
A
- Bind powders during the granulation processes & help with compression.
- Starch mucilage, gelatin and polyvinylpyrrolidone (PVP)
- Coat drug particles so binders dissolution can determine drug release rate.
- soluble binders (gelatin, pvp) -> fast drug dissolution
- slow dissolving binders (starch) -> slow tablet disintegration & delayed drug release.
12
Q
What are some advantages of disintegrants?
A
- Swell in presence of water to burst open tablet. (slightly swell and press together)
- Starch and cation exchange resins.
- High swelling disintegrants -> rapid dissolution & higher bio-availibility.
13
Q
What are some advantages of lubricants?
A
- To help tablet ejection from machines & improve flow.
- Stearic acid & its Mg & Ca salts widely used.
- Tend to be hydrophobic & retard dissolution.
14
Q
Transport Routes and Mechanisms
A
Transcellular passive diffusion
Paracellular passive diffusion
Carrier-mediated transport
Transport through transcytosis
Efflux Transporters
15
Q
Gastrointestinal Motility
A
Phases I-IV (fasted state) 3-6hrs
Goes into the (Fed State) Liquids do not trigger fed state.
16
Q
Migrating Myoelectric complex (MMC)
A
Housekeeper wave of phase 3, cleans out stomach and small intesting between meals, flushes undigested particles & un-disintegrated dosage forms
17
Q
How is dosing affected by the MMC, how does stomach act prior to fed state?
A
Stomach remains in MMC until it senses food
18
Q
What Factors influence gastric emptying
A
Volume Type of meal (high fat or high carbs decrease rate of emptying)
Physical state of gastric contents (liquids vs solids)
Hydrogen ion concentration (acidity)
Viscosity (faster for less viscous)
19
Q
Metabolism in the GI tract occurs in _______, ________ or ______ and experiences ________
A
Gut fluids, within microvilli of enterocytes in cytoplasm or lysosomes, or SI mucosa
The first pass Effect
20
Q
Cytochrome P450-3A4
A
Is highly expressed in SI
Metabolizes many drugs (120+)
Inhibitis pre-systemic clearance of grapefruit juice, which can increase BA of some drugs
21
Q
Effect of grapefruit juice on BA
A
Inhibits Cyp3A4
may need to stop drug use or lower dose due to increased time
generally raises BA
22
Q
P-glycoprotein (P-gp) drug Efflux is often expressed in…
A
Energy Dependent Drug efflux pump,
There is high expression in epithelial cells of SI Hydrophobic vacuum cleaner (lipophilic, Cationic)
Can effect Oral BA significantly
23
Q
Counseling with Grapefruit Juice
A
If you consume GF juice, let the physican and pharmacist know you are starting a new medication
Avoid GF with some drugs
Many mixed juices contain GF
Alternative medicines if not willing to give up GF juice.
24
Q
Name a method to decrease drug BA
A
increased activity of P-gp will result in a decreased BA of the drug
25
How does presence of Food effect drug absorption?
In general, drug absorption is less efficient when food is present in the GI tract.
26
In which dosage forms does GI transit not change significantly?
Solutions Suspensions/Dispersions IR dosage forms
27
In which dosage forms does GI transit change significantly?
EC tablets
ER tablets (matrix or reservoir systems)
28
Drug Delivery Systems consist of what two major components?
Drug/Active compound with intrinsic pharmacological activity (drug/Excipient)
Delivery System that insures the active compound is transported from the site of administration to site of action. (Administration device and route of administration)
29
Ideal characteristics of a drug delivery system?
Release the drug at the appropriate location
Its Convenient and easy for patient to take
Its aesthetically pleasing to the patient (taste, smell, appearance)
30
What is the purpose of drug excipients?
Drug Release
Stability
Elegance
31
What are the components of drug solutions, what excipients are used and what are the routes of administration?
Active drug completely dissolved in a medium (aq or non-aq)
Excipients - Buffers, preservatives, Stabilizing agents (antimicrobial or antioxidants), Flavors, colors
Routes of administration - Oral, Parenteral, topical, nasal, pulmonary, otic and opthalmic
32
What are the components of drug dispersions, what excipients are used and what are the routes of admnistration?
drug in two immiscible phases
(suspension (s/aq) or emulsion (aq/aq))
Excipients - suspending or emulsifying agent, buffers, preservatives, stabilizing agents, flavors, colors
Routes - Oral, Parenteral, topical, otic, opthalmic, nasal and pulmonary
33
What are the components of Semisolids, what excipients are used and what routes of administration?
Drug in Creams, gels, ointments or pastes
Excipients - Emulsifiers, Viscosity-increasing agents, antimicrobial agents, antioxidants, stabilizing agents
Routes - Topical, transdermal, opthalmic, vaginal and rectal
34
What are the dosage forms of solids, what routes of administration?
Tablets, Powders, Capsules Majority Oral, topical, vaginal and pulmonary.
35
What are the benefits of Local Action drugs?
They work as intended at their sites of action, and proximity to application site
Side effects are caused primarily by absorption into blood.
36
What are the uses of systemic effect drugs?
Their intended site of action can be in close proximity or distal to the application site.
Lack of efficacy caused by inappropriate blood levels
37
Oral drug Delivery adminstration and absorption location
drug administered through the mouth and intended for absorption via the GI tract
38
Oral Trans-mucosal
drug administered into the oral cavity (local or systemic (buccal tabs)
39
Transdermal drug delivery
Drug administerd on the skin for systemic absorption
40
Topical drug delivery
Drug for the treatment of the local conditions of the skin (do not want absorption through the skin)
41
Opthalmic drug delivery
administerd ocularly for the treatment of local conditions of eyes
42
Nasal Drug delivery
administered into nasal cavity for topical or systemic use
43
Vaginal Drug delivery
Topical application for local or systemic treatment
44
Anal/Rectal drug delivery
for the local treatment or systemic absorption
45
Parenteral drug delivery
administration by injection, includes intramuscular, intravenous or subcutaneous
46
Types of Capsules
Hard gelatin Capsules (HGC) Soft Gelatin Capsules (SGC)
47
Advantages Of Capsules
Versatile Can conceal odor and mask taste Easy to fill/administer For placebos can be used to administer liquids or solids Have higher oral BA than tablets Drugs may have higher stability Convenient
48
Disadvantages of Capsules
Tend to be larger than tablets, (swallowing issues)
Tampering issues
Requires specialized manufacturing equipment
Liquid filled capsules can have stability problems
49
Alternatives to Gelatin Capsules
Pullulan
Hydroxy Propyl Methyl Cellulose
50
Physiochemical drug properties needed for Capsules
Liquids (non aq) or Solids
All types of drugs and excipients (except highly hygroscopic)
Most used for drugs with poor compression properties that require a high dose
51
Presence of what chemical components distinguishes soft shell capsules form hard shell capsules
Glycerin or Sorbitol which act as a plasticizer
52
Possible Capsules contents include:
Liquids (volatile oils, aromatic or aliphatic hydrocarbons, ethers, esters, alcohols)
Combination of miscible liquids
Solutions of solid in liquid (Suspensions)
Solids
53
Capsule routes of administration
Oral and Vaginal
54
Tablets in Capsules
Capletception is a thing in both commercial and clinical trials (used to disguise in placebo/ blinded studies)
55
In a compound setting, what type of capsules can be used, what methods are used?
Hard Gelatin Capsule
Punching
Filling Machines
56
Between Capsule and Tablet, which dosage forms allows for higher bioavailability, and what is the rate limiting step?
Capsule allow for more BA
Rate limiting step is rupture, dissolution of gelatin in G
57
What Stability issues arise with capsules?
Physical (moisture content changes in shell)
Chemical (Depends on drug exposure, or use of opacifiers, antioxidants to protect drug)
Microbiological (contain preservatives to prevent microbial growth)
58
What is the moisture content of HGCs vs SGCs
HGC - 13-16%
SGC - 20+%
59
Routes of administration for SGC
Oral, Vaginal, Rectal or Opthalmic
60
Advantages of SGC
liquids can be encapsulated Specialized dosage forms can be prepared (chewable, ER, etc)
61
Disadvantages of SGC
Water containing materials cannot be used
Highly moisture sensitive
Stick to each other
More costly than HGC
Increased possibility of interactions between drug and shell
62
What percentage of patients report difficulty swallowing tablets? Report they hesistate taking medication due to tablet size?
40%, 84%
63
SGC stability issues
Physical (capsules stick, moisture content (cracking/dissolution) \
Chemical (depends on drug)
Biological (microbial growth bigger issue than HGC)
64
How are Tablets define and classified?
Tablets are solid dosage forms containing drug substances and excipients prepared by molding or compression (IR, Rapidly Dissolving, modified Release)
65
What is Fick's Laws of diffusion?
Process by which molecules spread from high areas of [C] to low.
J = -D (dc/dx)
J - flux of component across plane
D - diffusion coeffecient,
dc/dx - concentration gradient
66
What is the Stokes-Einstein Equation
D = (kT) / (6 π η r)
Helps define diffusion of solvents
67
What is Dissolution and what is a dissolution rate?
The act of a solute going into a solution
Dissolution Rate is the time required for a drug substance to dissolve in the fluids at the absorption site. ( often the rate limiting step in the absorption process)
68
What is the Noyes-Whitney equation?
Another equation which helps determine the dissolution and diffusion of a drug
dC/dT = DS/Vh (Cs-C)
69
What are some ways to increase dissolution rates?
Decrease particle size Increase solubility in diffusion layer
Alter pH of dissolution medium
Increase agitation of dissolution medium
70
What is Disintegration?
The process of by which a tablet breaks down into coarse and finer particles.
71
What is Deaggregation
The process by which coarse particles break up into finer particles
Can be increased by using deaggregants and increasing agitation
72
What excipients are the most common
Diluents
Binders/adhesives
Disintegrants
Lubricants
Glidants
Preservatives
Coating polymers
Antioxidants/Stabilizers
Colorants & Flavorants
73
Why are excipients needed?
Spatial control of drug release protect the drug in certain regions of body
Aid in drug absorption
Ensure product stability for shelf life of product
Aid in drug identification
Improve drug's organoleptic properties for patient compliance
Aid in the manufacturing process
74
Effect of excipients on drug absorption
Effecting tablet disintegration
Effecting drug dissolution
Effecting drug absorption-permeation enhancer and p-glycoprotein inhibitor
75
What are the 11 types of tablets?
Compressed tablets
Multiple compressed tablets
Sugar coated tablets film coated tablets gelatin coated tablets
Enteric coated tablets
Buccal and sublingual tablets
Chewable tablets
Effervescent tablets
Instantly disintegrating/dissolving tablet
Vaginal tablets
76
What are the most popular tablets?
Compressed tablets, made from one compression cycle
77
What is the structure of multiple compressed tablets and what are the reasons for its use?
multi-layered tablet or tablet within tablet (at least 2 layers)
To separate incompatible drugs into different layers
To deliver drugs at different rates or different sites
78
What are the benefits of sugar coated tablets?
Designed to dissolve quickly after swallowing, used to mask taste, smell and prevent oxidation
79
What are film coated tablets and what are its advantages?
Compressed tablets w/ thin layer of polymer useful for IR or MR More durable and less time consuming than sugar tabs
80
Non-aqueous film-coating components and purpose
Surfactants to enhance spreadbility of film during application.
Opaquants and colorants to make the appearance of the coated tablets handsome and distinctive
Sweeteners, flavors and aromas
Glossant to provide luster without polishing
Volatile solvent to allow spread of other components over tablet
81
Chewable tablet properties
Compressed tablet that is chewed to dissolved smoothly and rapidly. It is useful for large tablet administration in children and for adults with trouble swallowing.
82
Effervescent Tablet properties
Tablets that dissolve rapidly in water. (contains sodium bicarbonate or citric acid which breaks down into carbon dioxide in water)
83
Instantly disintegrating and dissolving tablets properties
Rapidly dissolve in the mouth (10sec-1min) Liquiefy on tongue & patients swallow liquid
packing and storage is important to avoid moisture absorption
84
Vaginal Tablets design
Ovoid shaped for insertion, requires an administration device Requires SLOW dissolution of tablet with no disintegration to release drug
85
Tablet advantages
Convenient Can modulate drug release
Except for proteins, all drug classes can be administered by tablets
Inexpensive easy to manufacture highest stability of all dosage forms
86
Tablet Disadvantages
Absorption greatly dependent on physiological conditions
Certain drugs have poor compressability, hard to make into tablets
Difficult to administer in some populations
87
Modified Release Dosage forms include:
Delayed release (DR)
Repeat Action (RA)
Targeted Release
Extended Release (ER, XR)
88
What are the pharmacokinetics of the different release tablets?
89
What are some examples and advantages of Delayed Release dosage forms?
IR w/ delayed onset
Enteric Coated dosage forms
To protect the drug from stomach pH
To protect the stomach from iritation from drug
To prevent regurgitation
90
What are the properties and coating materials used in EC tablets
Insoluble @ pH 1-3
Soluble @ pH 5-8
Coating Materials include: Cellulose Acetate phthalate, Polyvinylacetate phthalate, HPMC phthalate, Pharmaceutical Shellac, HPMC succinate
91
What is the purpose of Repeat action dosing of an IR with an additional DR or ER?
Convenience of 2 doses in 1 unit, increases patient compliance, is accomplished using a time-dependent polymer coat
92
How is targeted release achieved?
Drug release is targeted to a specific region by coating drug in a polymer that only dissolves in a certain pH setting. Especially helps with Colonic Drug delivery.
93
Drug Candidates for ER products require....
A Moderate rate of the drug absorption and excretion (slow --\> long acting)
Uniformly absorbed for the GI tract
Administered in relatively low dose
Wide Therapeutic window
Used for the treatment of chronic rather than acute conditions
94
What are the goals of an ER tablet?
Constant Plasma Concentration (mimic IV infusion at SS)
Input rate into Plasma = elimination Rate from plasma
Tablet must not disintegrate (Dissolve slowly and consistently)
95
ER Dosage Form system strategies include:
Coated Particle Systems
Microencapsulated Systems
Matrix Systems
Reservoir Systems
Osmotic Systems
Ion exchange Resins
96
Coated particle System characteristics
Granules, Beads or pellets (coated w/ water soluble polymer)
Coat thickness varies (variable dissolution w/ 3-4 sets of granules in a dose, may have different colors to differentiate)
Mixture of coated granules ( filled into capsules, or compressed into tablets)
Advantages (Large surface area for consistent dissolution, spreads the dose out over entire GI tract)
97
Microencapsulated System characteristics
Tiny Microcapsules or microspheres prepared by coating solids, liquids or gases
Coating w/ Insoluble, semipermeable membrane that allows the drug to diffuse out of the microcapsule or the microsphere
Different rates of drug release by changing ratio of core to wall
98
Soluble Matrix System Characteristics
Drug + slowly dissolving Polymer = granule
Granules with (ER) and without polymer (IR)
Polymer - HPMC
No disintegrants used
Water penetrates the tablet, and a gel forms on surface and soluble drug diffuses through it.
Pevents disintegration and slow dissolution.
Drug Release controllled by Erosion Rate, Particle size, solubility and diffusion
99
Insoluble Matrix system characteristics
Drug dispered in an insoluble matrix
Matrix shell remains intact and is excreted in feces
Contains excess drug to maintain constant in its dissolution rate
Its channel formation contrals release rate, and often uses a channeling agent such as NaCl for water soluble excipients
100
Reservoir systems characteristics
Core of drug + excipients surrounded by a polymer coat/membrane
Membrane is insoluble at any pH, Permeable to water and dissolved drug
Rate of release is controlled by Nature and thickness of membrane
Empty shell is excreted in feces
Tablet cannot be split
101
Osmosis based system characteristics
Core tablets surrounded by semi-permeable membrane coating with a tiny hole.
Water permeates the membrane, and using osmosis pushes drug out the shell into the body.
Rate of release is constant as long as osmotic gradient remains constant
Release rate depends on SA, thickness of membrane, and diameter of hole
102
Ion Exchange Resin characteristics
Drug forms complex w/ resin through ionic interactions
THis complex is put into a tablet/capsule or suspended in liquid
Drug release is dependent upon pH of the environment or electrolyte concentrations in the environment
103
What are the physiochemical drug properties needed for ER?
Dose size \< 500 mg
MW \< 500 Da
Solubility - Intermediate (highly soluble -\> Rapid dissolution -\> difficult to formulate) (Poor Solubility -\> dissolution-limited -\> difficult to formulate)
Log P between 1-3
Stable in GI tract: pH stable & stable to enzymes & microbes
Ionization - only uncharged molecules will permeate
104
What are the Biological parameters for drugs in ER dosage forms?
1. Rate of drug absorption \>\>\>\> rate of drug release from dosage form
2. 2 \< t1/2 \< 8hr
3. Not potent
4. Wide therapeutic index (MTC \>\> ER strength)
5. Used for chronic therapy
6. Should not have high accumulate in tissues (large Vd)
7. Should not exhibit saturable kinetics
8. Should not induce/inhibit enzymes
9. Not for antibiotics (resistance development)
Winter P1
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