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118 Cards in this Set
- Front
- Back
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Advantages of transdermal drug delivery |
- avoid GI tract problems (stomach pH, interaction with food) - substitute for oral route (N/V) - avoid risks of parenteral delivery - identifiable in case of emergencies/overdoses - avoid first pass metabolism - improve patient compliance - can give drugs with short half lives |
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Disadvantages of TDD |
- poor route for certain drugs - limited number of drugs can be administered - must be potent drug - must be lipophilic but not too much, and can't have large molecular size - drug effects continue after patch is removed - difficult/expensive to develop |
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Skin layers: bottom to top |
- subcutaneous fat layer - Dermis - Epidermis -> Basal cell layer -> squamous cell layer -> stratum corneum |
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Thickness of skin |
- Dermis is 2mm - epidermis is 100 microns - stratum corneum is 10 to 15 microns |
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Subcutaneous fatty tissue |
- can act as drug depot - if drug is too lipophilic, it can accumulate here and not get carried by bloodstream |
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Dermis |
- gives shape and feel - consists matrix woven from collagen and elastin - has a lot of blood flow: reaches within 0.2mm of skin surface, absorbing any chemicals that penetrate the skin |
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Epidermis function and structure |
- protection from the external environment - wavy shape called Rete's ridges that keep epidermis and dermis connected - basal cells at bottom, then squamous cells, then stratum corneum at the top (nuclei break down as the cells move up) |
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Epidermal cell types |
- Keratinocytes - Melanocytes - Merkel cells - Langerhans cells |
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Keratinocytes |
- approximately 90% of epidermal cells - protective sheath that repels pathogens and guards against fluid loss - mitosis renews the epidermis and replaces cells shed |
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Melanocytes |
- pigment producing cells - distributed among the basal cells of the epidermis |
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Merkel cells |
mechanoreceptor associated with the sensation of touch |
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Langerhans cells |
involved in immune response: present antigens and create rashes |
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Stratum corneum |
- 10 to 15 layers of flattened, keratinized cells stacked in a highly organized fashion - brick and mortar wall configuration |
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Skin surface |
- has emulsified sweat, sebum, loose dead skin cells: needs to be washed off before applying patch |
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Skin appendages |
- blood vessels and nerves: from sibcitaneous tissue to dermis (not in epidermis) - sweat glands (ducts rise through dermis and epidermis) - sebaceous glands and hair follicles (extend up to surface of skin) |
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List the three primary routes of drug penetration through the skin |
- intracellular: most well known, uses concentration gradient, lipophilic drug - transcellular route: hydrophilic drugs, slow - transappendegeal route: through sweat glands and follicles, not very important |
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List factors to consider in transdermal permeation |
- location - blood flow (more blood flow, increased absorption) - disease (broken skin= higher permeability) - age (skin cracks, intracellular spaces widen) - passive diffusion/concentration gradient |
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Locations on skin with best and worst penetratability |
- scalp, forehead, jaw, scrotum are most permeable - palms and feet are hardest to permeate - forearms and back are in the middle |
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Factors affecting percutaneous absorption (through the skin) |
- drug concentration on outside of the skin - size of application area - absorption time - physiochemical properties of the drug (solubility, oil/water partition coefficient) - thickness/hydration of the stratum corneum (more hydrated=more permeability) |
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Objectives of a TDD system |
- physicochemical properties to release the drug - occlude skin so drug only travels in one direction (make sure no evaporation off skin happens) - adhere well to skin - adhesive/vehicle/drug should not irritate skin - size/placement/appearance of patch - no bacterial growth beneath occluded skin - must have therapeutic advantage over other routes |
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Why is it important to place patch in a different location each time? |
- avoid bacterial growth under occluded skin |
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Structure of Liquid-filled laminate patch |
- backing-> drug in solution-> rate controlling membrane-> adhesive-> liner - Liquid fill: drug is in a hydro-alcoholic solution - rate controlling membrane: needed especially in narrow therapeutic window drugs |
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Structure of solid-state laminate patch |
- backing-> drug reservoir-> membrane-> adhesive-> liner - drug dissolved in semi-solid gel usually and diffusion out of gel controls the rate - membrane is not rate-controlling |
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Structure of drug in adhesive patch |
- backing-> drug in adhesive-> liner - drug reservoir and adhesive are one layer - drug diffuses out of adhesive into the skin |
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Structure of Foam adhesive and Polymer Matrix patch |
- backing and foam adhesive are one piece - polymer adhesive contains the the drug - no membrane - properties of polymer matrix determine the rate of delivery |
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Proper use of Transdermal delivery systems |
- apply to clean, dry skin - patch in contact with skin - skin should be hairless or low hair - replacing patch: remove old one and discard - new patch: place in different location than old one - wash hands after handling - never cut patches |
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Precautions of transdermal delivery systems |
- if patch pulls off: replace with new one in new place and don't try to tape back on - never use for immediate relief - patches may contain drug dissolved in alcohol (problem if on antabuse) - absorption varies depending on site of application - condition of skin is important: moisturizers, broken skin can accelerate permeation |
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Passive methods of maximizing transdermal drug delivery |
- goal is to increase the passive diffusion process by increasing the concentration of drug in the patch or skin - vesicles and topical preparations: liposomes, gels/sprays -stratum corneum modified: hydration, chemical enhancers, thermal |
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Poration methods of maximizing transdermal drug delivery |
- mechanical: microstructure array, stratum corneum removal, high velocity particles - electrically driven methods: sonophoresis, iontophoresis, thermal poration |
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Mechanism of liposomes |
- spherical vesicle with a membrane composed of phospholipid and cholesterol bilayer - encapsulates an aqueous solution inside - hydrophobic drugs dissolved into the membrane - lipid bilayer fuses with skin and delivers liposome contents |
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Advantages of liposomes |
- improved drug incorporation into stratum corneum - permeation enhancement: better than without liposome |
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Disadvantages of liposomes |
- aqueous - poor stability - hard to combine with patch technology: usually in gels, creams, semisolids |
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Mechanism of transdermal sprays |
- sprays in circle where device is touching - reservoir formation in upper epidermal layers |
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Advantages of transdermal sprays |
- improved handling compared to semisolids - improved dosing compared to semisolids: very accurate - less irritation compared to occlusive systems |
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Disadvantages of transdermal sprays |
- limited application area compared to semisolids - impact of showering, bathing, swimming - person to person contamination |
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Mechanism of transdermal gels |
- reservoir formation in upper epidermal layers - evaporation of solvent typically results in drug supersaturation -> rub in gel, gel dries, have supersaturated layer, drives the concentration gradient |
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Advantages of transdermal gels |
- enlarged application area - less irritation compared to occlusion - virtually disappears after application |
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Disadvantages of transdermal gels |
- limited control of application area - can't always know how much drug is going on - risk of contact contamination - increased environmental risk when excessive drug is washed off |
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Function of chemical penetration enhancers |
- chemical agents that reversibly alter the permeability of the stratum corneum - leads to increased percutaneous absorption of drugs - selected by efficacy, lack of toxicity, and compatibility with other components |
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Three different mechanisms of chemical penetration enhancers |
1. solvent action: directly solubilize tissue-skin components 2. interaction with intracellular lipids: disrupt the highly ordered lamella structure 3. interaction with intracellular protein: promote permeation through corneocytes |
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Mechanisms of thermal transdermal delivery systems |
- increased permeability of the stratum corneum - warm the system: things become looser - increased dermal perfusion: bringing more blood to the surface increases absorption - CHADD (controlled heath aided drug delivery) patch is applied on top of drug patch |
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Advantages of thermal drug delivery |
- shortening of lag time - increase of permeation rates by a factor of 2 to 3 |
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Disadvantages of thermal delivery |
- electrical heating requires large batteries - chemical delivery only for one-day patches |
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Preferable applications of thermal delivery |
- local anesthetics - pain management (decrease lag time) |
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Mechanism of sonophoresis |
- disordering of lipid bilayers - uses sound waves to vibrate the stratum corneum - creates more space between layers |
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Advantages of sonophoresis |
- shortening of lag time - transdermal application of peptides, proteins, and other macromolecules |
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Disadvantages of sonophoresis |
- limited or no mobility due to system size and energy requirement - skin irritation above certain energy levels and duration |
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Application uses of sonophoresis |
- local anesthetics, pain management - monitoring of body liquids by transdermal analyte extraction |
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Mechanism of iontophoresis |
- physical method to enhance transdermal delivery - electrical current used - deliver ionized species and high molecular weight drugs (proteins and peptides) - apparatus with positive and negative terminals: drug in negative terminal and saline in the return reservoir - can also be used for biofluid sampling: glucowatch |
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Two types of iontophoresis |
- external iontophoretic delivery - iontoc patch: has its own internal battery |
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Mechanism of microfabricated microneedles |
- long enough to penetrate the stratum corneum - short enough not to stimulate nerves - microneedles are coated with drug: push down and drug goes into skin - increase permeability: makes tiny holes - can deliver high molecular weight drugs |
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How microscrub systems enhance drug permeation |
- stratum corneum removed by rubbing directly over the skin -allows drug to go through - stratum corneum is renewable so comes back in about a wekk - allows for finite limit of cell removal and prevents excess dermal abrasion |
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How dry powders and liquids are administered through the skin without needles |
- Dry powder: need high velocity to penetrate: use helium as propellant - Liquid injection: spring-loaded - used for vaccine delivery: no sharps - still hurts like a needle |
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Ointments |
-semisolid preparations intended for external application to the skin or mucus membrane - medicated or unmedicated - used for physical effects: protectants, emollients, lubricants |
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Creams |
- semisolid preparations containing one or more medicinal agent dissolved or dispersed in a O/W or W/O emulsion - vanishing creams: contain large amounts of water - creams often preferred: spreadability and ease of removal |
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Gels |
-semisolid system consisting of dispersions of small or large molecules in an aqueous liquid vehicle - made jellylike by gelling agent |
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Gelling agents |
- synthetic macromolecules - cellulose derivatives - natural gums |
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Single phase gel |
- macromolecules are uniformly distributed throughout a liquid with no boundaries |
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Two phase gel |
-floccules of small distinct particles - also called magma |
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Thixotrope |
- gels may thicken and stand - products must be shaken before use to allow pouring |
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Properties of oleaginous ointment bases |
- hydrocarbon bases - less hydrophilicity -emollient effects on skin (occlusive) - reside on skin for prolonged periods - difficult to wash off - small amount of aqueous preparations can be incorporated with difficulty - solids can be incorporated by levigation |
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Examples of oleaginous bases |
Petrolatum Yellow ointment Neosporin |
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Properties of Absorption ointment bases |
- permit the incorporation of aqueous solution resulting in W/O emulsions - W/O emulsions permit additional water - not as occlusive as oleaginous - semi occlusive - not easily removed with water |
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examples of absorption ointment bases |
- hydrophilic petrolatum - lanolin |
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Properties of water removable ointment bases |
- O/W emulsions that resemble creams - easily washed from the skin - able to be diluted with water or aqueous solutions - can absorb serous discharge |
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example of water removable ointment base |
Hydrophilic ointment |
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Properties of water soluble ointment bases |
- more hydrophilicity - no oleaginous components - completely water washable (greaseless) - does not incorporate water or aqueous solutions well (softens) - mostly used for incorporation of solids |
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Example of water soluble bases |
Polyethylene glycol ointment |
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Parts of selection of appropriate base |
- desired release rate - topical or percutaneous absorption - degree of occlusion of moisture from the skin - stability of drug in base - effect of drug on consistency of base - water washability - surface to be applied (dry or weeping/oozing) |
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Fusion method of preparing ointments |
- all or some of the components of an ointment are combined by melting together and cooled with constant stirring until congealed - highest melting point substances melted first - non-melting componentes are added with constant stirring during cooling |
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Incoporation method of preparing ointments |
- components are mixed until a uniform preparation is attained - may use mortar and pestle or ointment slab and spatula |
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Incorporation of solids |
- use geometric dilution to combine base and fine powders together and blend |
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Levigation |
-mixing solid material in a vehicle in which it is insoluble to make a smooth dispersion - in mineral oil or glycerin |
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Incorporation of liquids |
- need to consider the base capacity to absorb liquid - often use small amount of hydrophilic base to add to hydrophobic base - alcoholic solutions of small volume may also be easily added to oleaginous bases |
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List the compendial requirements for semi-solid dosage forms |
- microbial content: not sterile, but meet standards - minimum fill: net weight or volume - packaging: well-closed large mouth jars or plastic tubes; opaque - storage: cool place - labeling: include type of base used |
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Opthalmic compendial requirements |
- sterility tests: strict methods of aseptic processing-> each component is made sterile and then made into final product - metal particle test: less than 50 particles per micron - packaging: collapsible tube with narrow tip |
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Pastes |
- 25% proportion of solid materials - stiffer than ointments - levigating agent is part of the base - remain in place after application - can absorb serous secretions - not suited for hairy parts |
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Plasters |
- solid or semisolid masses spread on a backing - also have an adhesive - applied to the skin to provide prolonged contact - different sizes - used in pain relief patches: Tiger Balm - band-aids |
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Glycerogelatins |
- plastic masses containing 15% gelatin, 40% glycerin, 35% water, and 10% medicinal agent - applied to skin for long term effect - hardens, covered with bandage and remains in place |
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Liquid bandage |
- topical skin treatment that creates polymeric layer on the skin - protect the wound from dirt and germs and keeps moisture in - similar to glycerogelatins but uses polymers |
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Semisolids for nasal use: |
- topical treatment of nasal mucosa - drugs primarily used for local effects: decongestants - can have systemic effects as well: nose has rich blood supply |
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Semisolids for rectal use |
- topical application to perianal area and insertion into rectal canal - mucosal linings - drugs may be systemically absorbed, by are limited by insolubility of drugs - local: inflammation and hemorrhoids - drug categories: astringents, lubricants, anesthetics, antipruritic, anti-inflammatory |
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Semisolids for vaginal use |
- used to treat infections - vaginitis - endometrial atrophy - contraception |
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Rectal suppositories size and shape |
- cylindrical and has one or both ends tapered - about 2 grams in weight |
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Vaginal suppositories |
- usually globular, oviform, and cone shaped - about 5 grams |
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Urethral suppositories |
- slender, pencil shaped - 5 grams - half the size for females |
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Local action of rectal suppositories |
- constipation: glycerin promotes laxation by dehydration effects - Pain, itching, and inflammation: anesthetics, vasoconstrictors, astringents, soothing emollients, protective agents |
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Local action of vaginal suppositories |
- contraceptives, antiseptics, antibacterials, or antifungal |
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Local action of urethral suppositories |
- antibacterial or local antiseptic in preparation for a urethral exam |
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Systemic action of suppositories: advantages |
- mucous membranes of rectum and vagina permit absorption of soluble drug - advantages: - avoid low pH of stomach - avoid stomach irritation - avoid 1st pass effect - allows drug administration to patients who can't swallow - effective in treatment of vomiting patients |
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Drug Absorption of suppositories |
- Colonic content: greater absorption in a void rectum- may need enema before - Circulation route: abundant vascularization of submucosal region or rectum wall with blood and lymphatic vessels - pH and lack of buffering capacity: rectal fluids are neutral and have no buffering capacity (no change in drug ionization) |
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Physiological and Physicochemical properties affecting drug absorption from suppositories |
- lipid-water solubility: lipophilic drug in fatty base has lower tendency to escape to surrounding aqueous fluid - particle size: smaller particles absorb more readily - Nature of base: must be capable of melting, must not interact to inhibit drug release, must not irritate membranes |
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Cocoa butter suppository base |
- melting point of 30 degress C
- exhibits polymorphism - when heated too rapidly, forms alpha crystal that have much lower melting point - must melt slowly and evenly to avoid crystal formation |
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Water-soluble suppository bases |
- glycerinated gelatin - polyethylene glycol - mixed by infusion to achieve desired consistency and characteristics - does not melt at body temp, but slowly dissolves in body fluids |
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Counseling points on rectal suppositories |
- come to room temp before use - rub cocoa butter suppositories to melt surface - glycerinated gelatin or PEG suppositories should be moistened with water - remove all wrappings |
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Shear stress |
velocity of a material spread over a small distance that it travels (rate of shear) is proportional to shear stress - application of horizontal force over area |
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Non-newtonian Rheology |
- relationship between shear stress and rate of shear is non-linear - viscosity is independent of shear stress: absolute viscosity - slope is constant - often have low molecular weights - viscosity decreases sharply with increasing temp |
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Plastic rheology |
- no flow occurs in response to shear stress until a transition point is reached - yield value: min shear stress required to flow - once yield is reached, relationship btwn shear stress and rate of shear becomes linear - Bingham bodies - seen in gels, ointments, and creams |
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Pseudoplastic rheology |
- systems that deform and flow instantaneously with applied stress - relationship is not linear - shear-thinning system: viscosity at point A is higher than at point B - increased shear stress leads to lower viscosity |
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Dilatant Rheology |
- systems that deform and flow instantaneously with applied stress - relationship is not linear - shear-thickening system: viscosity at point A is lower than at point B |
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Thixotropy |
- the comparatively slow recovery of the material structure on standing that was lost by shear thinning - time required for the recovery of polymer configuration once stress has been removed - degree of hysteresis: time to reacquire structure and become viscous upon standing |
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Oil in water emulsion |
- O/W - oleaginous internal phase and aqueous external phase - may be diluted with water |
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Water in oil emulsion |
- W/O - aqueous internal phase and oleaginous external phase - may be diluted with oil-miscible liquid |
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Role of emulsions |
- enable pharmacist to prepare a stable a homogeneous mixture of two immiscible liqiuds - can disperse liquid drugs as globules rather than in bulk - increases palatability - increases absorption of active - active ingredient less irritating when in internal phase - external phase influences usage |
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How the external phase influences usage: |
- W/O emulsion can spread easily - O/W can be easily washed off |
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Surface tension theory of emulsification |
- surface active agents are used to reduce the interfacial tensions between two immiscible liquids - interfacial tension resists large globules of liquids from breaking into smaller - smaller globules have more tendency to coalesce |
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Oriented wedge theory of emulsification |
- monomolecular layers of the emulsifying agent surround the internal phase - emulsifying agents have both hydrophilic and lipophilic regions - size, shape, solubility, and orientation of the emulsifying agent create a wedge that surounds the internal phase - the phase in which the emulsifying agent is more soluble will become the external phase |
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Plastic or interfacial film theory of emulsification |
- the emulsifying agent at the interface between oil and water prevents coalescing of the internal phase - type of emulsions depends on the solubility of emulsifying agent in the two phases - water soluble agents promote O/W and oil-soluble agents promote W/O |
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Types of emulsifying agents |
- carbohydrates O/W - proteins O/W - high molecular weight alcohols O/W - wetting agents O/W or W/O - finely divided solids O/W or W/O |
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The HLB system |
- categorizes emulsifying agents based on their chemical make-up - number assigned based on polarity - polar or hydrophilic substances have high numbers - less polar and lipophilic substances have lower numbers |
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Applications and their HLB range |
- Antifoaming: 1-3 - W/O emulsifying agent: 3-6 - Wetting agent: 7-9 - O/W emulsifying agent: 8-18 - Detergents: 13-15 - Solubilizers: 15-16 |
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Continental emulsion preparation |
- also called Dry gum - 4:2:1 oil:water:emulsifier - gum titrated with oil in rough mortar - add water all at once and triturate immediately: creamy, white emulsion with cracking sound - other liquids miscible with external phase are then added - emulsion transferred to graduate and made up volume with water |
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English emulsion preparation |
- also called wet gum - same proportions - gum is titrated with water then oil is slowly added in portions - after oil added and mixed, other materials are added - brought up to volume with water |
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Bottle or forbes bottle emulsion preparation |
- used for emulsions made from volatile oils or low viscosity oils - 1 part gum and 2 parts oil added to bottle and shaken - volume of water equal to that of oil is added in portions and shaken - then diluted to proper volume with water |
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Creaming |
- aggregates of globules at top or bottom of emulsions - reversible: by shaking - can increase risk of coalesce of globules - Factors that affect: particle size of internal, large differences between viscosities of phases, decreased viscosity of external |
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Cracking or breaking |
- coalescence of globules of the internal phase and separation into a layer - irreversible: layer of emulsifying agent surrounding the internal phase is destroyed |
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Advantages of emulsions |
- unpalatable oil-soluble drugs can be administered in palatable form - aqueous phase easily flavored - oily sensation removed - increased absorption rate - can include two incompatible ingredients |
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Disadvantages of emulsions |
- preparation needs to be shaken before use - measuring device needed - storage conditions affect stability - prone to microbial contamination |
