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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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 1. Definition of Mass transport : Movement of molecules from one region to another by specific driving force. SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 Pharmaceutical transport systems Solute transport 1. 2. 3. 4. Passive transport Facilitated transport Active transport Cellular transport Solvent transport 1. Osmosis SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 Fig. Movement of solutes across a permeable membrane. D.L.Nelson and M.M.Cox, Lehninger Principles of Biochemistry 3rd Edit., (2000) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 1. Types of solute transport Active Transport - Movement of molecules against the concentration gradient Energy needed - Saturable process ATP ADP Energy SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 1. Types of solute transport • Examples of Active Transport : - Na+/K+ pump - Proton (H+) pump in the stomach - P-glycoprotein (Pgp) - Renal secretion SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 III. Diffusion 2. Equations related to diffusion Sink Conditions : concentration of Cr is zero When? Rate of exit of drug > rate of entry (no accumulation) dM/dt = (DSK/h)Cd M = PSCdt P = permeability coefficient (cm/s) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 Fig. Butyl paraben diffusing through guinea pig skin from aqueous solution. / H. Komatsu and M. Suzuki, J. Pharm. Sci., 68 596 (1979) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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. SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 III. Diffusion 3. Significance of diffusion Diffusional release system: - Reservoir system 1. Characteristics of reservoir system: - Structure (oral) Rate- controlling membrane (ethylcellulose) Drug reservoir SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 III. Diffusion 3. Significance of diffusion • Diffusional release system: Reservoir system 1. Characteristics of reservoir system: - Released by zero order (Fick’s Law) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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. SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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]} SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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% SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 III. Diffusion 3. Significance of diffusion - Factors of distribution 2. Protein binding *Unbound drugs affects the receptors SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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. SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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) SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 IV. Transport Systems - 2 2. Significance of osmosis OROS system (Alza Corporation of Palo Alto, CA) 1. Structure SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실 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 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 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 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 1. Applied Physical Pharmacy; Mansoor M. Amiji, Beverly J. Sandmann; McGraw-Hill 2003 2. Applied Biopharmaceutics and Pharmacokintics, 4th edition; Leon Shargel, Andrew Yu; A Simon &Schuster Company 1993 3. Lehninger Principles of Biochemistry, 3rd edition; David. L. Nelson, Michael M. Cox; Worth Publishers 2000 4. Understanding Human Anatomy & Physiology, 3rd edition; Sylvia S. Mader; WCB McGraw-Hill 5. Lecture notes from Pharmaceutics SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실