Transcript 11.물질의 이동(확산 포함) - Physical Pharmacy Laboratory

SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
I.
Introduction
1. Definition of mass transport
2. Principles in mass transport
II. Transport system - 1
1. Types of solute transport
III. Diffusion
1. Types of membrane
2. Equations related to diffusion
3. Significance of diffusion
IV. Transport system – 2
1. Principles of osmosis
2. Significance of osmosis
V. References
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1. Definition of Mass transport :
Movement of molecules from one region to another
by specific driving force.
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2. Principles in Mass transport
Mass transport
Thermodynamics
- Where does the energy (reaction)
move to?
Kinetics
- How much time the reaction takes?
- Ex. Drug absorption in GI tract
 toward a decrease in free energy
- End point is the time when two free
energies are equal, which is called
equilibrium.
- Ex. Drug absorption in GI tract
GI tract
Bloodstream
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SKKU Physical Pharmacy Laboratory
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Pharmaceutical transport systems
Solute transport
1.
2.
3.
4.
Passive transport
Facilitated transport
Active transport
Cellular transport
Solvent transport
1. Osmosis
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1. Types of solute transport

Passive transport  NO ENERGY needed
Diffusion
• Driving force : conc. Gradient
• Effect of temp. :
↑temp. → ↑kinetic E.
∴ Molecules move faster.
• At equilibrium : no conc. differential
• Charged molecules
• Example :
- absorption of drug
- permeation through biological tissue
- reabsorption in the nephron
Convection
• Convection depends on the flow
properties of the carrier fluid
• Example :
- transport of O2, nutrients, drugs and
other molecules by the blood
- paracellular mechanism of small
water-soluble molecules
- transport of molecules through a
porous matrix
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Movement of solutes across a permeable membrane.
D.L.Nelson and M.M.Cox, Lehninger Principles of Biochemistry 3rd Edit., (2000)
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1. Types of solute transport

Facilitated Transport
- Movement of molecules by a carrier
- Greater permeability of the drug-carrier complex
* Absorption of Vitamin B12
- A neutral complex of charged drug molecules with a carrier
molecule
* Absorption of ion-paired propranolol with oleic acid
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1. Types of solute transport

Active Transport
- Movement of molecules against the concentration
gradient  Energy needed
- Saturatable process
ATP
ADP
Energy
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1. Types of solute transport
• Examples of Active Transport :
- Na+/K+ pump
- Proton (H+) pump in the stomach
- P-glycoprotein (Pgp)
- Renal secretion
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1. Types of solute transport

Cellular Transport
Into  Pinocytosis : liquid
Endocytosis : colloidal matter
Phagocytosis : large matter
Out to  Exocytosis
* Insulin excretion from the β islet cells
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III. Diffusion
1. Types of Membrane
Membrane : physical barrier

Biological Membrane
 Skin
 Blood-brain barrier
 Mucosal membrane

Synthetic Membrane
 Silicone rubber
• Principle of synthetic membrane
• Nonporous membrane - diffusion only
• Porous membrane - diffusion + convection
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III. Diffusion
2. Equations related to diffusion

Fick’s law
J= dM/Sdt
J = flux
S= unit area (cm2)
T= time (sec)
M= amout of material (gram or mol.)
“Steady state” (정상상태)
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III. Diffusion
2. Equations related to diffusion
• Fick’s law

J ∝ dC/dx
 dC/dx : change in concentration
over infinitely small distance

J = -D dC/dx
 D: diffusion coefficient (cm2/s)
• 정상상태 흐름
• 시간과 약물의 농도변화
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III. Diffusion
2. Equations related to diffusion
• Fick’s law

dM/dt = -DS(dC/dx)
where,
dC/dx = [(C1 – C2) / h]
* C1 : Conc. in the memb. at the donor side
C2 : Conc. in the memb. at the receptor side
 dM/dt = (DS/h) (C1-C2)
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III. Diffusion
2. Equations related to diffusion
• Fick’s law
Rate of transport : dM/dt = (DS/h) (C1-C2)
where, using partition coefficient (K)
K = C1 / Cd or C2 / Cr
therefore,
C1 = KCd and C2 = KCr
 dM/dt= (DSK/h)(Cd-Cr)
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III. Diffusion
2. Equations related to diffusion

Sink Conditions : concentration of Cr is (almost) zero
 When? Rate of exit of drug > rate of entry
(no accumulation)
dM/dt = (DSK/h)Cd
= PSCd
P = permeability coefficient (cm/s)
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III. Diffusion
2. Equations related to diffusion

Zero-order process
M= PSCdt
- Amount of drug transported is constant over time
- Only if Cd does not change
* diffusion of drug from transdermal patch
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III. Diffusion
2. Equations related to diffusion
Example 2
To study the oral absorption of paclitaxel(PCT) from an
oil-water emulsion formulation, an inverted closedloop intestinal model was used.
- drug instilled in the intestine (maintained at 37°C
(98.6°F) in an oxygen-rich buffer medium)
- surface area for diffusion = 28.4 cm2
- concentration of PCT in intestine = 1.50 mg/ml.
- the permeability coefficient was 4.25 x 10-6 cm/s
Calculate the amount of PCT that will permeate the
intestine in 6 h of study
(zero-order transport under sink conditions)
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III. Diffusion
2. Equations related to diffusion
Solution
Using the equation
M= PSCdt ,
M = (4.25 x 10-6)(28.4)(1.50)(21,600)
= 3.91 mg
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III. Diffusion
2. Equations related to diffusion

First-order transport
If the donor conc. changes with time,
ln (Cd)t = ln (Cd)0 – (PS/Vd)t
(Cd)t : donor conc. at any time
(Cd)0 : initial donor conc.
Vd : volume of the donor compartment (mL)
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III. Diffusion
2. Equations related to diffusion

Lag time, Burst effects
 Lag time : time of molecules saturating the membrane
tL = h2 / 6D
h : membrane thickness (cm)
D : diffusion coefficient (cm2/s)
 M = PSCd(t - tL)
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III. Diffusion
2. Equations related to diffusion

Lag time, Burst effect
 Burst effect : time of initial rapid release of drug
tL = h2 / 3D
h : membrane thickness (cm)
D : diffusion coefficient (cm2/s)
 M = PSCd(t + tB)
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Fig. Butyl paraben diffusing through guinea pig skin from aqueous
solution. / H. Komatsu and M. Suzuki, J. Pharm. Sci., 68 596 (1979)
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III. Diffusion
2. Equations related to diffusion
Example 2
The lag time of methadone, a drug used in the treatment of heroin
addiction, at 25°C (77°F) through a silicone membrane transdermal
patch was calculated to be 4.65 min. The surface area and
thickness of the membrane were 12.53 cm2 and 100 um, respectively.
a. Caculate the permeability coefficient of the drug at
25°C (77°F) (K = 10.5).
b. Calculate the total amount in milligrams of methadone released
from the patch in 12 h if the concentration inside the patch was 6.25
mg/mL.
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III. Diffusion
2. Equations related to diffusion
Solution
a. To use the equation P = DK/h ,
the diffusion coefficient D should be determined.
Therefore, using the lag-time equation tL = h2 / 6D
D= h2 / 6 tL
= (1.00 x 10-2)2 / (6)(279)
= 5.97 x 10-8 cm2/s
Therefore,
P = DK / h
= [(5.97 x 10-8)(10.5) / (1.00 x 10-2)
= 6.27 x 10-5 cm/s
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2. Equations related to diffusion
Solution
b. Using the equation M = PSCd(t - tL),
M = [(6.27 x 10-5)(12.53)(6.25)][(43,200) – (279)]
= 210.8 mg
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III. Diffusion
3. Significance of diffusion

Diffusional release system:
- Reservoir system 1. Characteristics of reservoir system:
- Structure (oral)
Rate- controlling membrane (ethylcellulose)
Drug reservoir
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III. Diffusion
3. Significance of diffusion
• Diffusional release system:
- Reservoir system 1. Characteristics of reservoir system:
- Structure (transdermal)
Backing
Drug reservoir
Rate controlling membrane
Adhesive
Release liner
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III. Diffusion
3. Significance of diffusion
• Diffusional release system: Reservoir system
1. Characteristics of reservoir system:
- Released by zero order (Fick’s Law)
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III. Diffusion
3. Significance of diffusion
• Diffusional release system: Reservoir system
2. Advantages :
1) predictable release of drug amount
2) predict the release property of drug by changing
membrane
3. Disadvantages:
1) “Dose dumping”
Do not chew, brake or cut the drug made in reservoir type
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III. Diffusion
3. Significance of diffusion
• Diffusional release system:
Reservoir system
4. Examples of reservoir system
Ocusert (Alza)
Progestasert
Norplant
Pilocarpine
Progesterone
Levonorgesterol
(20ug or 40ug/h for 7days)
(for 1year)
(for 5years)
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TABLE 9-3 Some Examples of Diffusional Reservoir Delivery Systems
Route of
Administration
Product
Active Ingredient
Oral
Nico-400
Nitro-BID
Cerespan
Measurin
Niacin
Nitroglycerin
Papaverin hydrochloride
Acetylsalicylic acid
Transdermal
Catapress-TTS
Duragesic
Estraderm
Clonidine
Fentanyl
Estradiol
Nicoderm CQ
Transderm-Scop
Transderm-Nitro
Ocusert
Progestasert
Norplant
Nicotine
Scopolamine
Nitroglycerin
Pilocarpine
Progesterone
Levonorgesterol
Ophthalmic
Uterine cavity
Implant
Therapeutic
Indication(s)
Hyperlipidemia
Angina
Smooth muscle relaxant
Analgesic, antipyretic,
anti-inflammatory,
platelet aggregation
inhibitor
Hypertension
Chronic pain
Postmenopausal
symptoms and
osteoporosis
Smoking cessation
Motion sickness
Angina
Glaucoma
Contraception
Contraception
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III. Diffusion
3. Significance of diffusion
• Diffusional release system: Matrix System
1. Structure of matrix system
- Drug is evenly dispersed throughout the matrix
*The release of drug is slower than
reservoir system.
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III. Diffusion
3. Significance of diffusion
• Diffusional release system: Matrix System
2. Characteristics of matrix system

Higuchi Equation
M = kt ½
M = amount released
t = time
k = CsDm(2Co-Cs)
DsCa(δ/ε)(2Co- δ Ca)
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III. Diffusion
3. Significance of diffusion
• Diffusional release system: Matrix System
3. Advantages of matrix system
1) Inexpensive compare to reservoir type
2) no problem with dose dumping
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III. Diffusion
3. Significance of diffusion
• Diffusional release system: Matrix System
TABLE 9-4 Some Examples of Diffusional Matrix Delivery System
Route of
Administration
Oral
Transdermal
Product
Active Ingredient
Desoxyn-Gradumate
Methamphetamine
hydrochloride
Fero-Gradumate
Proscan SR
Choledyl SA
Ferrous sulfate
Procainamide hydrochloride
Oxytriphylline
Nitrodur
Nitroglycerin
Therapeutic Indication(s)
Attention-deficit
hyperactivity disorder
and narcolepsy
Iron supplement
Arrhythmia
Bronchodialator for
asthma, bronchitis,
emphysemia, and
chronic obstructive
pulmonary disease
Angina
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III. Diffusion
3. Significance of diffusion - Factors of absorption
Drug Absorption  by Diffusion
1. Concentration of drug
Water Solubility = Absorbed concentration
•Rate limiting steps:
- low solubility drugs = dissolution step
- Controlled or Sustained release drugs = release rates
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III. Diffusion
3. Significance of diffusion - Factors of absorption
2. Size of molecule
Molecular weight = Absorption
3. Partition Coefficient
* What is Partition Coefficient?
 Showing the hydrophobicity of a molecule
* Optimal Partition Coefficient for absorption:
 10~100
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III. Diffusion
3. Significance of diffusion - Factors of absorption
4. Surface area
Surface Area = Absorption
5. Blood flow
 An important factor of drug transport in the body
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III. Diffusion
3. Significance of diffusion - Factors of absorption
6. Ionization state - pH partition hypothesis
Drugs penetrates into the membrane in unionized form
• Henderson - Hasselbalch equation
1) Weak acid (acetylsalicylic acid, penicillin)
pH = pKa + log{[ionized]/[unionized]}
2) Weak base (codeine, pilocarpine)
pH = pKa + log{[unionized]/[ionized]}
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III. Diffusion
3. Significance of diffusion - Factors of absorption
6. Ionization state - pH partition hypothesis
1) Weak acid (acetylsalicylic acid, penicillin)
 % ionized = 100 / [1+antilog (pka-pH)]
 % unionized = 100 – (%ionized)
2) Weak base (codeine, pilocarpine)
 % ionized = 100 / [1+antilog (pH-pka)]
 % unionized = 100 – (% ionized)
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III. Diffusion
3. Significance of diffusion - Factors of absorption
Example 4
Calculate the percent ionized and unionized of morphine, a weak base (Kb = 7.4
×10 7),
in the plasma where the pH is 7. 4 at 37 °C
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III. Diffusion
3. Significance of diffusion - Factors of absorption
Solution
First, pKb = -log (Kb) is calculated to be
pKb = -log(7.4×107)
= 6.13
Second, pKa = 14 – pKb
pKa = 14 – 6.13
=7.87
Using the equation % ionized = 100/[1+antilog (pH- pKa)]
% ionized = 100/[1+antilog (7.4 – 7.87)]
% ionized = 74.7%
∴ %unionized = 100- 74.7  25.3%
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III. Diffusion
3. Significance of diffusion - In other areas
1. Lung
Optimal state for the lung absorption =
to the aveolar
Advantage of lung absorption:
1) Large surface area
2) Blood flow
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III. Diffusion
3. Significance of diffusion - In other areas
2. Mucosal membrane  There is no first pass effect
Ex. Pilocarpine (pka 6.8)
Pilocarpine + Tears (pH 7.3) = ionized pilocarpine
 Absorbance , Quickly wash away by tears
Hydrophobic prodrug or controlled release drug
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III. Diffusion
3. Significance of diffusion - In other areas
3. Transdermal absorption  No first pass effect
- Problems in transdermal absorption:
1 ) stratum corneum (rate – limiting step)
By… 1. Chemical permeation enhancer (dimethylsulfoxide)
2. low voltage
3. ultrasound
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III. Diffusion
3. Significance of diffusion - In other areas
3. Transdermal absorption :
Problems in transdermal
absorption
2) Absorption of drug depends of the thickness of the skin
Attach to the upper arm or the abdominal area
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III. Diffusion
3. Significance of diffusion - Factors of distribution
1. Blood flow to the tissue
Blood vessel = Drug concentration
(lung, liver, kidney)
Blood vessel =
Drug concentration
(skin, nail)
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III. Diffusion
3. Significance of diffusion - Factors of distribution
2. Protein binding
*Unbound drugs affects the receptors
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III. Diffusion
3. Significance of diffusion - Factors of distribution
3. Ionization state of molecule
1) Dopamine (pka 10.6, weak base)
Dopamine in the plasma  ionized,
cannot penetrate BBB
Sinemet (levodopa + carbidopa)
: carbidopa (decarboxylase inhibitor)
inhibits levodopa to change into
dopamine in systemic circulation
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III. Diffusion
3. Significance of diffusion - Factors of distribution
3. Ionization state of molecule
2) Ion trapping : treating toxic effects of drug
- Phenobarbital poison
sodium bicarbonate  pH of plasma increases
less permeable through BBB
becomes water soluble  to urine
- Cocaine
Lower the pH plasma  increase ionization
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IV. Transport Systems - 2
1. Principles of osmosis

Osmosis
- Transport of solvent molecules across semipermeable
membrane as a result of the osmotic pressure gradient
- Direction : lower conc.  higher conc.
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IV. Transport Systems - 2
1. Principles of osmosis

Equation on osmotic pressure (π)
π = CRT
π = osmotic pressure (atm)
C = concentration of solute (mol/L)
R = gas constant (0.0821 L atm/mole K)
T = absolute temperature (273.15+°C)
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IV. Transport Systems - 2
1. Principles of osmosis

Equation on osmotic pressure (π)
π (in
dyne/cm2)
= hρg
h = height of rise in sol’n volume (cm)
ρ = density of sol’n (g/cm3)
g = gravity acceleration (980 cm/s2)
hρg = (1.013 X 106)CRT
h=(1.034×103)CRT
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IV. Transport Systems - 2
1. Principles of osmosis

Terms in osmosis
- Isotonic :
drug solution = biological fluid(~310 mOsmol/L)
- Hypertonic :
drug solution > biological fluid
- Hypotonic:
drug solution < biological fluid
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IV. Transport Systems - 2
2. Significance of osmosis

OROS system (Alza Corporation of Palo Alto, CA)
1. Structure
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IV. Transport Systems - 2
2. Significance of osmosis
2. Characteristics of OROS system
M = [(S/h)(k’π Cs)t]
*Released in zero-order
M = amount of drug released
S = surface area of semi-permeable membrane (cm2)
h = thickness of the membrane (cm)
k’ = permeability of water through the membrane (cm2/atm.h)
π = osmotic pressure (atm)
Cs = saturated solubility in water
t = time
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IV. Transport Systems - 2
2. Significance of osmosis
TABLE 9-6 Some Example of Oral Osmotic Delivery System
Product
Concerta
Ditropan XL
Glucotrol XL
Procardia XL
Volmax
Active Ingredient
Methylphenidate
Oxybutynin chloride
Glipizide
Nifedipine
Albuterol
Therapeutic Indication(s)
Attention deficit-hyperactivity disorder
Overactive bladder
Insulin-independent diabetes mellitus
Angina and hypertension
Bronchospasm
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
IV. Transport Systems - 2
2. Significance of osmosis

Osmotic pressure of drugs = blood
 However, the drugs tend to be hypertonic than the system
circulation
Sol. The drug’s isotonicity should be adjusted
with NaCl or other compounds
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
IV. Transport Systems - 2
2. Significance of osmosis
3. Advantages
1. can be used for any size of molecules
2. release rate is independent of pH or ionic
strength
3. can be tailored for complete release to occur
4. Disadvantages
1. laser-drilled hole can get plugged
2. dose dumping
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
IV. Transport Systems - 2
2. Significance of osmosis

Exception to the adjustment of isotonicity
 Mannitol solution ( 5~25% w/v)
Why?
- Osmotic diuretic for glaucoma and cerebral edema
- By its hypertonic character, excess fluids is execreted
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실