T2 - Week 1 Flashcards
What is mass transfer?
Net movement of “mass” from one location to another in response to applied driving forces of a concentration gradient
What aspects is mass transfer important for?
- Dosage form
- ADME (absorption, distribution, metabolism, and excretion) studies
Describe mass transfer in the human body
Occurs across different cell membranes under different physiological conditions
What is dissolution?
The release of a drug from its dosage form slowly leaking into the solution in the body
What happens to a drug after dissolution?
Drug enters GI fluids creating a solution to where it is ready to permeate biological membrane (absorption)
What are the steps required for a drug to diffuse through a biological membrane?
- Drug’s diffusion through the aqueous medium that bathes the membrane (diffusion step)
- Passage of drug molecules from aqueous medium of the GI fluid into lipid bilayer (partitioning step)
- Diffusion of the drug through the membrane (permeation step)
What is drug permeation?
Molecular diffusion of the drug through relatively nonporous media
What factors affects drug permeation?
- Drug partitioning
- Structural nature of biological membrane (composition and thickness)
- Nature of diffusion layer (GI content)
What is drug partitioning?
The ability of the drug to distribute in a mixture of an aqueous (polar) and lipid (nonpolar) system
What is Kd?
Ratio of octanol concentration to water phases, constant to a drug
What does log P measure?
Lipohilicity (lipid solubility) of the drug
What are the factors that affect lipophilicity of a drug?
- Aqueous solubility (polarity) decreases as Log P increases
- Permeability increases as Log P increases
What affects the solubility of a weak acid or basic drug?
- pKa
- pH of a solution
Explain is the differences between ionized and unionized drugs and their relationship to solubility
Ionized drugs have greater aqueous solubility due to its polarity than un-ionized since they are nonpolar
How is a drug affected by the pH of its surrounding fluid?
- Solubility
- Dissolution
- Permeation
What is the predominate form of weak acid drugs?
They are predominately unionized (nonpolar) at lower pHs of gastric fluids
Why does the weak acidic drug need to be unionized?
It favors the stomach and duodenum for permeation
Describe how weak bases are absorbed?
Weak bases are poorly absorbed in the stomach because of its ionized (polar) form
When would permeation of a weak basic drug be permeable in the intestine?
pKa value less than 4 remaining unionized
What are the components of a biological membrane?
- Polar heads of lipids
- Lipophillic core
What kind of drugs can be absorbed by passive diffusion?
High lipophiliciy and molecular weight 100-400
What drives the passive diffusion?
Concentration gradient across a membrane
What drug is absorbed by pore transport?
Water soluble drugs with a molecular weight less than 100
What drug is absorbed by carrier-mediated transport?
Structure specific drugs with affinity for carriers transported from specific sites
What drug is absorbed by ion pair transport?
Drugs that are ionized at all pH conditions complexing with oppositely charged ions
What drug is absorbed by endocytosis?
Macromolecular nutrients and drugs as solid particles or oily droplets
What is a diffusion coefficient?
A measure of the diffusion resistance offered by the membrane to any molecule and is related to the molecular size
What is Pm?
Permeability of drug through membrane (cm/h)
What is dA/dt?
Amount of drug diffusing per unit of time (mg/h)
What is Cu GIT?
Unbound drug concnetration in GI tract
What is Cu Plasma?
Unbound concentration in plasma
What is h in Fick’s law?
Thickness of the membrane (cm)
What are the components of Fick’s law?
dA/dt = [(Cu GIT - Cu plasma) DKdSA]/h
dA/dt = [(Cu GIT - Cu plasma) *Pm
What transcellular transport?
Drug that diffuses through the matrix of a membrane
What factors affect transcellular transport?
- Lipophilicity
- Polarity
- MW of drug molecule
What is paracellular transport?
Drug that diffuses between the water-filled gaps of adjacent cells
What factors affect paracellular transport?
- Size of junction
- Size of drug
What is active transport considered more important than facilitated diffusion for drug absorbtion?
Drugs are considered foreign and facilitated are used for things found in the body
What are transporters?
Proteins on biological membranes and facilitate the passage of chemicals into or out of cell
Where are transporters located?
Intestinal membrane influence drug absorption → hepatocytes metabolism → renal tubular membrane for excretion
What is the difference between influx and efflux transporters?
Influx: (uptake) transports drugs into the tissue/cell
Efflux: transports drug out of the tissue/cell
List examples of both influx and efflux transporters?
I: OATPs
E: p-gp/MDR1, BCRP
What is the significance of pore transport?
Aqueous channels that allow very small hydrophilic molecules (urea, water, small sugars) that are transported into the cell
What is the difference between pinocytosis and phagocytosis?
Pino: (cell-drinking), dissolved solutes enter the cell by binding of non specific or specific membrane receptors
Phago: Particulate matter is taken inside a cell
What are the 3 layers of the skin?
- Epidermis
- Dermis
- Subcutaneous
What is components of the epidermis?
Keratinocytes that form keratinized, horny layer of the skin (stratum corneum)
What are the components of the stratum corneum?
- Keratins (70%)
- Lipids (20%)
How is the stratum corneum arranged?
- 15-25 layers that overlap and are linked by intercellular bridges
- Intercellular space is comprised of lipophilic matrices alternated with hydrophilic layers
What are key properties of the stratum corneum?
- Acidic film made of emulsified lipids covers its surface
- Hygroscopic
- Thickness varies and is slightly permeable to water
What are the 4 effects when drugs are applied to the skin?
- Effect on the skin surface
- Effect within the stratum corneum
- Effect requiring penetration into the epidermis and dermis
- Effect on the dermis to the vasculature to produce therapeutic systemic concentrations
List some skin surface effects
- Forming film on the skin surface as protective agents
- An action against surface microorganisms (anti-infectives)
- A cleansing effect (soaps)
What is the importance of a film?
Provide a moisturizing effect by diminishing loss of moisture from the skin surface
What occurs during skin hydration?
- Hydration of dry outer cells by forming surface films
- Integration of water in the lipid rich intercellular laminae
- Occlusive agents increase moisturization
What is psoriasis and how is it treated?
Abnormal stratum corneum with thickened scaly plaque is treated by keratolytic agents (salicylic acid) that break up or sloughing of corneum cell aggregates
Why is the stratum corneum important for topical drugs?
Serves as a reservoir where topically drugs accumulate to partition or bind to skin
What is the purpose of the stratum corneum to be a reservoir?
Limit the migration of the drug away from the the corneum unless capacity of layer is exceeded
What is an example drug that is has a significant skin interaction?
Corticosteroids
What are the prime routes of drug permeation through the skin from least to most important?
- Through appendages (hair, sweat glands)
- Transcellular and intercellular
What are the physiochemical properties affecting drug permeation?
- Low molecular weight
- Increased but balanced logP value and solubility
What is the purpose of a formulation when it comes to skin interaction?
Alters skin properties by enhancing or retarding the permeation of a drug by increasing or decreasing its diffusivity and/or solubility within the corneum
What are examples of semisolid dosage forms?
- Ointments
- Creams
- Gels
- Paste
- Sticks
- Suppositories
- Lip balm
What is the difference between topical dermatological and transdermal products?
- TDP: treats local dermal disorders
- TP: Deliver drugs through skin for systemic effects
What is the use of a unmedicated semisolid?
- Protectant
- Lubricant
What is a cream?
Emulsions of oil and water (aqueous cream)
What is an ointments?
Greasy preparations that can be both insoluble in water and soluble
What is an ointment bases?
Are vehicles/diluents for drugs designed to facilitate drug transfer into the skin
What are the USP classifications of ointment bases?
- Oleaginous bases
- Absorption bases
- Water-removable bases
- Water-soluble bases
What are effects of oleaginous/hydrocarbon bases when applied to the skin?
- Have emollient/soothing effect that skin softening and moisturization effect
- Humectants protect against the escape of moisture
- Effective occlusive dressing has an moisturizing effect
- Remain on the skin for long periods without drying
- Difficult to wash due to being immiscible in water
How are hydrocarbon bases incorporated into powdered substances?
Levigating agents such as mineral oil
What are examples of hydrocarbon ointment bases?
- Petrolatum
- White petrolatum
- White ointment
- Yellow ointment
What is petrolatum according to USP?
Purified mixture of semisolid hydrocarbons obtained from petrolatum
What is commercial product of petrolatum?
Vaseline
What is the purpose of petrolatum?
Used as an ointment base either alone or combination
What is the melting point of petrolatum?
38C - 60C
What is white petrolatum according to USP?
White petroleum jelly that is decolorized petroleum used as an ointment base either alone or combination
What is the commercial product of white petrolatum?
White Vaseline
What is yellow and white ointment according to USP?
Simple ointment that is purified yellow or bleached and purified yellow (white) wax of the honeycomb of bee
What are the ingredients of yellow or white ointments?
- Wax: 5 parts
- Petrolatum: 95 parts
How do you prepare yellow or white ointments?
- Melt the wax in a water bath
- Add the petrolatum until the mixture is uniform
- Cooled while stirred until congealed
Describe the viscosity than plain petrolatum and yellow/white ointments
Ointment has a slightly greater viscosity than petrolatum
What are the types of absorption bases?
- Oleaginous bases that contain a w/o emulsifying agent permitting aqueous solution incorporations
- w/o emulsions that permit incorporation of additional quantities of aqueous solutions (lanolin)
What is the purpose of absorption bases?
- Used as emollients/soothing agents that don’t have a degree of occulsion therefore not easily removed from skin (oily)
- Absorb water up to 2-3 times their weight, useful to help incorporate a water-soluble drug
How is absorption bases a useful pharmaceutical adjuncts?
To incorporate small volumes of aqueous solutions into hydrocarbon bases
What is lanolin?
- Wool of sheep that is purified wax-like substance cleaned, deodorized, and decolorized
- 0.25% water or less
What is modified lanolin?
Processed to reduce free lanolin alcohol and any detergent and pesticide residues
What are the ingredients of hydrophilic petrolatum?
- Cholesterol
- Stearyl alcohol
- White wax
- White petroleum
What are water-removable bases?
- W/o emulsions that are easily washed
- Can be an hydrophilic ointment
What are the ingredients of hydrophilic ointment?
- Stearyl alcohol and white petrolatum oleaginous phase
- Purified water (aqueous)
- Sodium lauryl sulfate (emulsifying agent)
- Propylene glycol (antimicrobial preservatives)
What are water-soluble bases?
- Don’t contain oleaginous components
- Completely water washable
- Used for incorporation of solid substances
What is PEG ointment?
Polymer of ethylene oxide and water
Describe the sizes of PEG
- MW <600: clear, colorless liquids
- MW >1000: wax-like white materials
- MW >600<1000: semisolids
What are the general formulas for PEG prep?
- PEG 3350: 400g
- PEG 400: 600g
What are the factors of choosing an ointment base?
- Site of applications (whether dry or moist site)
- Required rate of drug release
- Chemical stability of the drug
- Effect of the drug on viscosity of the product
Why is it important for occlusive ointment bases retain moisture?
- Important in treatment of dry skin clinical conditions
- Not applied to sites with fluid exudate due to maceration effect
Why must a drug be chemically stable?
To avoid degradation where drugs are prone to hydrolysis that should not be incorporated into a water-based ointment
What is lotions?
Water-based liquid formulations often antiseptic and astringent
What is gels?
Thickened lotions that is hydrophilic and hydrophobic bases
What is pastes?
Semi-solid preparations consisting of finely powdered solids suspended in an ointment
Describe the incorporation method
Preparation of small quantities of ointments by mixing small quantities of ingredients using a mortar and pestle, or spatula and ointment slab
What are the 2 method of incorporation?
- Method 1: Reduced particle size of the solid and incorporation into ointment based done by levigation
- Method 2: Solids soluble in common solvent may first be dissolved in that solvent, then resulting solution is added to incorporate this solution to the ointment base
What are the types of levigating agents?
- Mineral oil for bases in which oils are the external phase
- Glycerin for bases in which water is the external phases
How do you incorporate an aqueous solution in an hydrophobic base ointment?
- The aqueous solution is incorporated into minimum amount of hydrophilic base
- Mixture is then added to the hydrophobic base
Describe the fusion method
- Mixing ingredients by melting in a steam bath to about 70C-75C
- Components that can’t be melted are added to the molten mixture while cooling and congealing
- Heat-labile and volatile components are mixed at the end of the ointment preparation when the temperature of the melt is below their degradation temperature
What are the advantages of ointments?
- Easily spread and retained on application site
- Form occlusive layer by preventing moisture loss from the skin and provide a greater extent of drug release
- Possess lubricating/emollient properties by reducing trauma of an affected site upon spreading
What are the disadvantages of ointments?
- Greasy and difficult to remove (cosmetically unacceptable)
- Stains clothes
- May not be applied to exuding sites
What are the limitations of ocular drug penetrations?
- Short residence time of drugs on the surface of the eye
- Small surface area of the cornea for drug absorption
- Corneal natural resistance to drug penetration
What is an ophthalmic ointment?
Provide extended residence time on the surface of the eye
How is an ophthalmic ointment base selected?
- Not irritating to the eye
- Permit diffusion of the drug substance
- Have a softening point close to body temperature
- Meet the USP sterility and metal particles tests
What are sterilization techniques that are ineffective for ophthalmic ointments?
- Thermal
- Steam
- Chemical (ethylene oxide)
What is a rectal semisolid?
Ointments, creams, and gels that are used for topical application to the perianal area
What are the ointment bases for rectal semisolids?
Combinations of PEG 300 and 3350 emulsion
What are cream bases of rectal semisolids?
Cetyl alcohol and cetyl esters wax, and white petrolatum and mineral oil
What are anitmicrobial preservatives for rectal semisolid?
- Methylparabe
- Propylparaben
- Benzyl alcohol
- Butylated hydroxyanisole
What is the minimum fill test?
Determination of the net weight or volume of the contents of filled containers to ensure proper contents compared with the labeled amount
How should ointments be packaged?
- Large mouth ointment jars or in metal or plastic tubes
- Stored in well-closed containers in cool place
- Light sensitive preparations and packaged in opaque or light-resistant containers
