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598 Cards in this Set
- Front
- Back
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moxatag
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Pulsatile release amoxicillin w/ 3 pellet formulation IR, DR1, and DR2
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Effexor
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SR using coated beads or granules
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Biaxin
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SR using both eroding matrix and hydrocolloid
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Inderal LA
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SR using coated beads/pellets
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Ocusert
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Opthalmic system for glaucoma; inserts into conjunctival sac; decreases fluid pressure
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Pilopine gel
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Opthalmic system for glaucoma; contains Carbopol; put strip of gel into eye at night
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Lupon
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SR injectable microspheres; matrix system, not a coating; prostate and breast cancer; made by organic phase separation; polyester, hydrolyzes in body to lactic acid and glycolic acid; not sterilized at end, start sterile; reconstituted
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Alza
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Osmotic pump
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Erythromycin stearate
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No coating needed; insoluble in acid; hydrolyzed and dissolved in duodenum.
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Methocel K4M, K15M
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Most used for Matrix tablets; retardant
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Methocel K100M
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Hydrates very slowly; used with others.
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Xanthan gum
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Thickening agent
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Guar gum
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Thickening agent
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Allegra D
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Matrix(?); layer of pseudoephedrine HCL and Fexafendadine (no ER needed)
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Aquacote
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Ethyl cellulose pseudo latex made from preformed polymers; true latex such as Eudragit are made from a monomer into a polymer.
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Lactose spray dried
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Filler in matrix tablets
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Magnesium stearate
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Lubricant in matrix tablets
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Theophylline beads
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Coated w/ DBS plasticizer; increase DBS -> increase
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Oros
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Oral osmotic pump system; zero-order release = rate independent of concentration; also called GITS = GI Tract Systems
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Oros push-pull
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Two layers of drug
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E-mycin
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Erythromycin delayed release tablet w/ enteric coating
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Compazine
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ER coated pellets; antinausea
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Procanbid
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ER tablets w/ wax matrix; antiarrhythmic
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Glucotrol XL
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ER osmotic
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Covera-HS
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ER osmotic; antianginal
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Catapress/Clonidine
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Transdermal
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Testoderm/testosterone
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Transdermal; placed on scrotum
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Duragesic/Fentanyl
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Transdermal
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Climara/Mylan
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Transdermal
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Emsam/Selegiline
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Transdermal
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Scopalamine
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Transdermal; astronauts used for motion sickness. Best site = postauricular > back > chest > stomach > forearem > thigh
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Nitroglycerin
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Transdermal; best on chest near heart.
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Habitrol/Nicotine
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Transdermal; best anywhere
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Estraderm/Estradiol
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Transdermal
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Androderm/testosterone
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Transdermal; placed on back or other areas, not scrotum.
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Micro K
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Microencapsulated potassium chloride
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Efidac
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Osmotic pump; chlorpheniramine maleate or pseudoephedrine HCl
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Myocet
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Liposome; doxyrubicin citrate for cancer treatment; combine w/ cyclophosphamide for breast cancer.
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Liposyn
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IV fat emulsion
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Diazemul
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IV fat emulsion used for drug delivery
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Diprivan/Propofol
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IV fat emulsion used for drug delivery; killed MJ; crosses BBB in 40s.
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Tussionex
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Pennkinetic ER suspension of CPM (?) and hydromorphone bitartrate
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Lidocaine HCl
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Jelly; anesthetic for urethritis
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Phenylephrine HCl
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Jelly; nasal.
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Pramoxine HCl
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Jelly; rectal anesthetic.
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VersaFoam
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Foam for delivery of corticosteroids
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DMSO
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Sulfoxide permeation enhancer; cosolvent
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Propylene glycol
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Polyol permeation enhancer; humectant
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PEG
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Muco-adhesive hydrogel
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HPMC
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Muco-adhesive hydrogel
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Polyethylene glycol ointment
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Water soluble ointment base
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Steryl alcohol
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Allows emulsification of aqueous phase into absorption phase
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Sodium borate
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Emulsifying agent when combined with free fatty acids in waxes; forms Na soaps that are emulsifiers
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Hydrophilic ointment
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Listed as a cream; actually an o/w ointment
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Potassium stearate
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Monovalent soap formed from KOH and stearic acid; promotes o/w emulsion.
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Silicone oil
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Added to cream to make cream disappear more quickly on skin
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Zinc oxide paste
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Astringent
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Zinc oxide & salicylic acid paste
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Used for acne
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Triamcinolone Acetonide dental paste
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For inflammation, canker sores
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Aluminum stearate
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Gelling agent
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Fumed silica
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Thickening agent
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TEA (Triethanolamine)
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Gelling agent when preparation is mostly water.
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DIPA (Diisopropanolamine)
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Gelling agent when base is alcohol
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Petrolatum
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Hydrocarbon ointment base
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White petrolatum
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Hydrocarbon ointment base
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Yellow ointment
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Hydrocarbon ointment base
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Yellow wax (bees wax)
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Hydrocarbon ointment base
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Plastibase
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Not a base; stiffening agent.
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White ointment
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Hydrocarbon ointment base
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Anhydrous lanolin
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Absorption ointment base; can absorb water to form w/o emulsion
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Hydrophilic petrolatum
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Absorption ointment base; allows emulsification of water in absorption phase
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Aquaphor
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Not absorption base for ointments; helps incorporate aqueous phase to form emulsion.
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Mineral oil
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Levigating agent; not a base
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Paraffin
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Stiffening agent; not a base
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Lanolin
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w/o emulsion ointment base
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Rose water ointment
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w/o emulsion ointment base
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Cold cream
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w/o emulsion ointment base
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Velvachol
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o/w emulsion ointment base
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Unibase
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o/w emulsion ointment base
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What drug factors affect inhaled therapy?
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(1) solubility; (2) pH(?); (3) taste; (4) hygroscopicity; (5) size
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What affects aerosol generation and delivery?
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(1) particle morphology; (2) distribution;
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What is the primary factor of inhalation?
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humidity
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What factors affect transport into blood?
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(1) molecule size; (2) site of deposition; (3) solubility
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What does the physiology of the nose provide for?
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Exchange of heat and moisture
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What are the two purposes of the nose?
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(1) olfactory; (2) conditioning of inspired air
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T/F Mouth breathing is more effective than nasal breathing to heat and humidify inspired air
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FALSE
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What happens during nasal filtration?
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Particle (1) clearance (2) deposition
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What size particles are deposited in the nose?
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> 10 µm
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Which particle sizes bypass nasal passages and go directly to lungs?
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< 2 µm
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T/F The nose can protect against soluble gases
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True (ex. Was formaldehyde)
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Drug absorption in the upper airway depends on (4 items)
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(1) electrical charge of particle; (2) lipophilicity; (3) size/mol wt; (4) drug distribution over ciliated epithelium
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How does mol weight affect absorption?
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++mw = --absorption
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What size particles are not well absorbed?
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> 1000 daltons (<1% bioavailability)
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T/F electrical charge is pH independent
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False (ionized vs unionized)
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T/F hydrophilic drugs have better absorption
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False (lipophilic > hydrophilic)
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What are the three types of nasal delivery systems?
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(1) drop bottle; (2) aqueous pump spray; (3) metered-dose inhaler
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Drop bottles provide
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large liquid volume (vasocontrictors)
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Aqueous pump sprays require
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preservatives (phenylethanol; benzalkonium Cl) which can be irritating
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Purpose of phenylethanol?
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preservative (pseudomonas)
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Purpose of benzalkonium Cl?
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preservative and cationic surfactant
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Characteristics of metered-dose inhaler
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(1) precision low vol dosing (2) pt preferred (3) 50% drug will reach epithelium (4) expensive
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What is the pharyngeal barrier?
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90° bend traps drugs in an area not in the lungs
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What are the consequences of drugs in the pharyngeal barrier?
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(1) Can still cause (systemic) side effects; (2) may be swallowed
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What is the role of a spacer?
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(1) dead vol (~100 ml); (2) deacceleration of particles; (3) allows pt to breathe normally
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++ inhalation =
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--deposition to back of throat
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What are the three zones of the lung?
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(1) conducting (no alveoli, no oxygen ex); (2) transitional (some alveoli); (3) respiratory (air exchange)
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What are the limits of aerosol use?
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(1) Patient compliance (lack of training); (2) Breathing maneuvers; (3) Irritant activity; (4) epithelial permeability; (5) bronchoconstriction
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Describe breathing maneuvers
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Slow deep breath (fast breath != deep lung penetration)
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Why is epithelial permeability important?
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Topical vs. systemic absorption requirements
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What controls drug deposition in the lower airway?
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(1) Flow rate; (2) patient factors; (3) particle size distribution of emitted dose; (4) particle density and shape; (5) hygroscopic growth
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T/F Pressurized meter dose inhalers can only be used for drug delivery to the lungs
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False (formulation of particle size determines location of deposition)
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T/F The same drug can be used in lung and nasal deliver
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True (BUT must use different formulations)
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How does hygroscopic growth affect drug deposition?
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100% humidity of respiratory tract may lead to solubilization of drug and particle size growth
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What are the three types of inhalation drug delivery systems?
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(1) Nebulizers; (2) MDI (pressurized, non-pressurized; (3) DPI
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What are the two types of nebulizers?
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(1) Ultrasonic; (2) Air jet
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What influences performance of nebulizers?
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(1) Type used and its operation; (2) Cost; (3) Brand vs. Brand w/in brand; (4) Evaporative loss
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Describe an ultrasonic transducer
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pizoelectric cell generates ultrasonic waves. Droplets for at the crests. High energy source.
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What is the primary problemwith ultrasonic nebulizers?
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Increased heat may increase evaporation and cause; (1) increased drug concentration; (2) precipitation
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What size nebulized particles stay in the oropharnyx?
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> 8 µm
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What size nebulized particles arrive at the alveoli?
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< 5 µm
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Problem with the Pari LC plus nebulizer?
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too many pieces. Need higher education
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Advantage of Pari LC plus nebulizer?
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one way valve limits droplet formation on expiration
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Are droplets in the collodial size range?
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No! (visible)
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What are the formulation of components
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(1) Drug; (2) Solvent; (3) Osmotic agent; (4) Chemical stabilizer; (5) Buffer; (6) Preservative
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Role of solvent
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solutions or micronized particles, may need co-colvent (glycerine)
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Problem with EtOH as cosolvent
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rapid absorption may lead to intoxication
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Role of osmotic agent
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adjust for tonicity
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Role of chemical stabilizer
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antioxidant
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What is the preferred buffer range?
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pH 5-7 (pH >5)
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T/F all nebulized drugs require preservatives
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False (unit dose usually sterilized, no preservatives needed)
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Describe vibrating mesh technology
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(1) Fine particles in a low velocity aerosol; (2) less heat and shear -> less destructive; (3) small primary particle size; (4) low fill vol (0.5 ml); (5) short nebulization time (little temp change)
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What are the two types of vibrating mesh?
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(1) passive; (2) active
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What is the key in adaptive aerosol delivery?
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Trains patient to extend inhalation time (mouthpiece vibrates as trigger)
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Desribe the difference between passive and active vibrating meshes
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Drug is extruded through passive mesh while an active mesh deflects, causing pumping action
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What are soft mist aerosols?
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Extrudes a single unit does through a disposable nozzle (composed of laser machined holes 1 µm in diameter)
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What factors affect nebulizer formulations?
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(1) Excipients should be minimized
(2) Primarily consists of aqueous solutions or fine dispersions (3) Solution must be above pH 5 AND be isotonic (4) Generally filled as unit dose (5) performance may vary based on physical properties of forumlation |
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Why is unit dose preferred?
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sterilized, thus free of preservatives which may cause bronchospasm
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What physical factors of formulation affect nebulizer performance
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(1) viscosity; (2) surface tension too much != vaporization
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T/F Increased viscosity increases output
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FALSE
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T/F Viscous formulations are more quickly nebulized by micropumps
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True (vs. vibrating mesh)
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T/F Flumist is a nasal spray intended for lung absorption
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False (nasal spray)
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What counseling should be given with pulmicort respules (budesonide)
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Corticosteroid--gargle w/ water or listerine to reduce irritation
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Define pressurized meter does inhalers
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Pharmaceutical aerosols are presurized dosage forms containing one or more active ingredients whichupon actuation emit a fine dispersion of liquid and/or solid materials in a gaseous medium
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What factors uniquely affect pressurized metered dose inhalers?
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Container, valve assumbly, propellant
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Desribe pMDIs
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(1) one or more gaseous or liquefied propellants; (2) on activation of vavle assumbly, pressure of propellants force contents of the package out through valve opening
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What happens to the propellant on exit from package?
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evaporates to leave particles
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Where to 5 µm particles deposit?
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Respiratory bronchioles, alveoli
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Where to 7-8 µm particels deposit?
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Large conducting airways
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Where to >8-10 µm particles deposit?
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Oropharnyx
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What are the advantages of aerosol dosaging?
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(1) Aliquot from reservoir; (2) Hermetic seal; (3) No touch topical; (4) Precise dosing
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Purpose of hermetic packaging
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Protection from oxygen, moisture, light but moisture may ingress on long shelf life
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What is the primary burden of pMDIs?
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Huge FDA requirements
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What is components undergo product testing?
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(1) API; (2) raw materials; (3) device components
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What type of testing is unique to pMDIs?
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pressure testing of container over time
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What's the purpose of an epoxy coating?
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protective coating but api may stick to coating--> has lead to recalls for low potency
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What are amphiphiles?
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surfactants: affect valve lubrication and reproducibility
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What is the primary formulation type for pMDI?
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Solution (then suspension)
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What happened once we switched from CFC's to HFA's?
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significant increase in efficiency -> changes in dosing
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Where are the critical controls of pMDI?
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Delivery properties that control spray (1) velocity; (2) uniformity; (3) geometry
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What is tail-off?
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Drop in drug availability for final doses within container
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What causes tail-off?
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(1) valve design (high friction ); (2) formulation (no lubricant); (3) CCS (leak)
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What is required with high velocity pMDI systems?
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Spacer!
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What happens when a spacer is used?
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2x lung deposition with less in throat
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Define suppository
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Solid dosage form intended for insertion into the body orifices where it melts, softens, or dissolves--and exerts localized or systemic effects
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List the 5 primary types of suppositories
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rectal, vaginal, urethral, aural, nasal
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Describe importance of disintegration
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suppository must absorb moisture from surrounding area to dissolve drug from the base
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Internal body temperature
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37 degrees C
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What is the standard size for a rectal suppository?
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32 mm, cylindrival, tapered ends. ~2 g (USP cocoa butter)
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What is the standard size for an infant or child suppository?
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1 gm (half adult)
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What is another name for vaginal suppositories?
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Pessaries
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How are vaginal suppositories shaped?
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Globular, oviform, or conical
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How much do vaginal suppositories weight?
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2-5 gm
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What are urethral suppositories called?
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Bougies
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How do male and female urethral suppositories differ?
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Males 3-6 mm x 140 mm, 4 g Females 1.5-3 mm x 70, 2 g
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How common are nasal or aural suppositories?
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Rarely used: ~5 g, 32 mm long
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What is the base for a nasal suppository?
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Glycinerated gelatin
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How should suppositories be stored?
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Refrigerated in tightly closed glass or individually wrapped.
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How does humidity affect suppositories?
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High: absorbes water from atmosphere Low: loosewater to atmosphere (becomes brittle)
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Reactions of lipophilic drugs in suppositories
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(1) slow release in an oil base (2) moderate release in water soluble/miscle base (3) drug dissolves slowing in aqueous compartment
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Reactions of water soluble drugs in suppositories
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(1) rapid relese in oily base (2) rapid to slow relesae in water soluble/miscle base
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What affects water soluble drug release?
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(1) rate of dissolution of base (2) diffusion of drug out
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T/F A more viscous base will increase dissolution rate
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False (++ viscosity -> slower drug release)
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Define local action
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Drug is intended to remain in area where it will have effect
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What are some examples of local action?
|
relieve constipation or hemorrhoidal pain
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What is a hemorrhoid?
|
Vascularized, finger-like protrusions from anus caused by stress, tension, travel, constipation, standing
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Common ingredients in hemorrhoidal formulations
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(1) local anesthetic (2) Vasoconstrictors (3) Astringents (4) Soothing & protecting agent
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Purpose of astringents in hemorrhoidal formulation
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itching, tightening mucosa
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What happens to lanolin?
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Acts as a physical barrier and is not absorbed
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When is glycerin used as a suppository?
|
Irritant causes natural laxative action--hygroscopic properties draws water from membrane
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What characterizes PEG action?
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Does not melt at body temp--dissolves in body fluid
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What are the problems with suppositories?
|
Physical stability problems--brittle, muschy (in high humidity), hard to handle
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What is the mechanism of action of suppositories?
|
Mucous memebranse of rectum and vagina permit RAPID absorption of soluble drugs due to high vascularization
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What are the advantages of suppositories?
|
(1) rapid absorption (2) no first pass effect (3) pH of medication will affect rectum contents (no buffering action) (4) good for patients who cannot swallow or are vomiting
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T/F Suppositories rely on local pH
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False (local pH can be manipulated by medication-> typically increased absorption)
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What are the common drugs for systemic absorption in suppositories?
|
(1) Aminophylline (2) Indomethacin (3) Prochlorperazine (4) Ondansetron (5) Chloral Hydrate (6) Oxymorphone HCl (7) Aspirin (8) Acetaminophen
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Suppository base properties
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(1) non-irritating (2) chemically/physiologically inert (3) firm enough for insertion (4) can control drug release
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Why do suppository bases need to be non-irritating
|
risk of ejection
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T/F Water soluble bases are the most common in suppositories
|
False (Oil soluble [cocoa butter])
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What are the critical temperatures of the primary polymorph of cocoa butter?
|
Soften = 30, Melts = 35, Melted = 37
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T/F Cocoa butter is a pure substance
|
False (mixture of triglycerides)
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T/F Cocoa butter -gamma is the most desirable with the highest melting point
|
False (least, lowest at 18)
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T/F All cocoa butter will revert to the most stable form given time
|
TRUE
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Which is the desired form of cocoa butter and what are its characteristics?
|
Beta: Most stable form to which others convert. Mp 35-37
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What causes metastable cocoa butter?
|
Rapid, careless melting
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What are other oil soluble bases?
|
palm kernel oil, cotton seed oil
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What is a eutectic mixture?
|
Mix of two ore more substances whos mp is LOWER than that of any single contributor
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What is a primary problem with using Theobroma oil?
|
Eutectic mixes causes mp lowering.
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What are common solidifying agents?
|
Cetyl Esters Wax, White Wax
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T/F Any percentage of solidify agent may be used to stabilize mp
|
False (under 3%, soldifiying agents may cause mix to become eutectic)
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How is wax type and composition determined?
|
Drug (1) amount (2) type
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Describe witepsols
|
Mix of synthetic triglycerides, do not exhibit polymorphism, contain emulsifiers, release well from molds
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Why is ability to absorb water important for suppositories?
|
Drug may be added in dissolved form which can then be incorporated into the oily base
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Describe glycerinated gelatin base
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(1) mold requires lubrication (2) vaginal only (3) may hold 1/2 vol in aqueous solution (4) translucent, resilient, hygroscopic
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Why are glycerinated gelatin bases not for rectal use?
|
Gel will swell in rectal fluid, is dehydrating, and dissolves in mucus secretions but takes a long time
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What action should be taking with water soluble suppositories prior to use?
|
Dip in water prior to insertion
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T/F PEG 200-400 is high molecular weight and liquid at RT
|
False (low molecular weight)
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T/F PEG high molecular weight PEG is more viscous than low molecular weight
|
TRUE
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T/F PEG mix bases do not melt at body temperature
|
TRUE
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T/F PEG bases must dissolve to release drug
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TRUE
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T/F PEG bases contain no water so as to prevent irritation
|
False (need 20%+ water to prevent irritation)
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T/F Polybase is miscible and dissolves
|
TRUE
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T/F Polybase contains cocoa butter and polysorbate 80
|
False (PEG + Polysorbate 80)
|
|
|
T/F Polysorbate 80 is an ionic surfactant
|
False (non-ionic surfactant)
|
|
|
Which drugs are soluble in Theobroma Oil?
|
(1) Zinc Oxide (2) Bismuth Subgalate (3) Iodoform (4) ASA
|
|
|
T/F Insoluble liquid substances can form W/O emulsions w/ cocoa butter
|
True, (10-20% of liquids)
|
|
|
T/F Volatile liquids cannot be solubilized in a suppository base
|
False (but will form a eutectic mix)
|
|
|
Name the three common solid drug substances soluble in suppository base
|
(1) Phenol (2) Rescorcinol (3) Chloral Hydrate
|
|
|
How should soluble drug substances be incorporated into the base?
|
Dissolve in either water of glycerin as appropriate prior to dispersal in base
|
|
|
T/F Water is a common excipient in suppositories
|
False (avoid! Enhances oxidation, promotes microbial growth, accelerates drug/base interactions)
|
|
|
T/F Preservatives and antioxidents are commonly used
|
False (only if water or in an oxidizing base and the drug is shelf-stable)
|
|
|
How is silica gel used in suppositories?
|
1-10% as a suspending agent if base has low viscosity
|
|
|
List toughening agents for suppositories
|
Tween 80, glycerin, propylene glycol, castor oil, sweet almond oil
|
|
|
Describe releasing agent
|
Used to free suppository from mold: mineral oil (water soluble), glycerin/propylene glycol (batty base)
|
|
|
T/F Methyl cellulose and alginic acid delay drug release
|
TRUE
|
|
|
T/F Emulsifying agents decrease drug release rate
|
FALSE
|
|
|
What does release rate depend upon?
|
(1) Melting time (2) Dissolution time (3) Diffusion rate of drug from base (4) Dissolution rate of drug in body fluids
|
|
|
T/F Sweet almond oil and liquid paraffin lower MP
|
TRUE
|
|
|
T/F White wax, cetyl esters was, beeswax all lower MP
|
False (raise)
|
|
|
What are the two methods of forming suppositories?
|
(1) molding (2) compression
|
|
|
T/F Drugs dissolved in the base will increase melting point
|
FALSE
|
|
|
T/F Dense drugs should use a rapidly crystallizing base
|
TRUE
|
|
|
T/F Expiration date for suppositories is a max of 12 months after manufacture
|
False (shortest of 6 months or 25% date of shortest expiration date of ingredient)
|
|
|
What are signs of suppository instability?
|
(1) excessive softening (2) drying or shriveling (3) staining of packaging (4) hardening (5) discoloration
|
|
|
What factors affect bioavailability?
|
particle size, ionization, pH, emulsivication, migration to lower GI (first pass effect!), rheological properties of the base
|
|
|
How to enhance bioabilability in cocoa butter?
|
Add poloyoxyethlene sorbitan monostearate, SLS (nonionic surfactant), cetyltrimethlamonium bromide [increase spreading and degree of contact of base with mucosa]
|
|
|
Why is testosterone better in Witepsol H than cocoa butter?
|
Will dissolve in the hot witepol but crystalizing out during cooling (high bioavailability). Forms a solid solution in cocoa butter
|
|
|
T/F W/O emulsions of water-soluble drugs yield high bioavailability
|
False (drug is forced to partition from W into O then back into W in the compartment)
|
|
|
What factors should be considered in quality assurance?
|
(1) rate of melting or disintegration (2) Rate of dissolution (3) Content uniformity (4) Texture uniformity (5) weight uniformity (6) Packaging integrity
|
|
|
What is the criteria for content uniformity?
|
esp important when < 2 mg/suppository or < 2% w/w of API
|
|
|
What is the criteria for weight uniformity?
|
weigh 20 suppositories: NMT 2 deviate by > 5% from ave; all not more than 10%
|
|
|
How to check for packaging integrity?
|
Measure weight gain or loss of suppositories after storage
|
|
|
Why motivated the development of dry powder inhalers? DPIs
|
Phasing out of CFC's and the idea of no propellants
|
|
|
What are some broad advantages of DPIs
|
No coordination required with actuation, increased stability, dosing advantages
|
|
|
What particle sizes will get stuck in the oropharyngeal region?
|
5-30 µm
|
|
|
Why do particles get stuck in the oropharyngeal region?
|
inertial impaction--airflow stream separates out very large particles
|
|
|
What is the term of particles stopping in the trachea?
|
sedementation
|
|
|
Sedimentation occurs to what size particles?
|
1-5 µm
|
|
|
What size particles go make it to the alveolar region?
|
< 1 µm
|
|
|
What happens to particles that enter the alveolae?
|
Diffusion
|
|
|
What happens to particles that are smaller than 0.5 µm?
|
Brownian motion prevents deposition of particles unless the breathis held a LONG time
|
|
|
What is considered the good particle range size for inhalation?
|
between 0.5 and 5 µm (0.5 < good < 5 µ)
|
|
|
What four characteristics of particles affect deposition?
|
(1) Density 2) Charge (3) Shape (4) Solubility/Hygroscopicity
|
|
|
Density affects
|
inertia (controllable)
|
|
|
Charge causes
|
(1) aggregation (2) deposition by image charges in airways
|
|
|
Shapes that are
|
seriously deviant from sphericity effects deposition
|
|
|
Solubility/hygroscopicity influence
|
deposition in the lungs which are at high humidity due to increased particle size from water absorption
|
|
|
What is the characteristic of asbestos?
|
Long,thin needles are aerodynamically small but sticky
|
|
|
What is the mechanism behind fluidization of powders?
|
Who knows?
|
|
|
What two factors affect fluidization?
|
(1) particle size (2) varying attractive forces between particles
|
|
|
Why does chalk stick on the blackboard?
|
van der Waals forces overpower gravitation allowing for adhesion
|
|
|
What are carrier particles used for?
|
Lactose is used because it is large enough to be fluidized and very small particles will adhere to it
|
|
|
What is the magnitude of vdw?
|
10^9 - 10^7
|
|
|
What is the magnitude of electrostatic?
|
10^18 - 10^10
|
|
|
What is the magnitude of capillary?
|
10^7 - 10^6
|
|
|
T/F Adhesions forces are material dependent
|
True (mechanical interlocking/solid bridging from irregular shapes)
|
|
|
How does capillary force affect adhesion?
|
moisture builds a liquid bridge
|
|
|
What are the 4 steps in drug delivery?
|
(1) Metering (2) Entrainment (3) Deaggregation/Aerosolization (4) Inhalation
|
|
|
What are the two types of metering?
|
(1) pre-metered (capsule, blister) (2) metered during application
|
|
|
Which methods require active drug delivery?
|
(1) pressurized air (2) Piezo vibration (3) Impeller
|
|
|
When are all CFC inhalers gone?
|
2013
|
|
|
What's the difference between passive and active DPI's?
|
Passive rely on patient to provide energy. Active uses an outside energy source
|
|
|
What size lactose is used as a carrier?
|
50-100 microns
|
|
|
What is entrainment?
|
drag forces
|
|
|
What is the most common carrier in DPI formulation?
|
lactose
|
|
|
Why is lactose used in inhalants?
|
increased size aids in entrainment, descreases deaggregation, improves powder flow
|
|
|
What is a disadvantage of lactose in inhalants?
|
Inefficient detachment of drug from lactose carrier
|
|
|
Benefits of DPI's
|
(1) Higher dose delivery (2) breath-actuation (3) no propellants (4) ++ compliance (5) ++ lung deposition (6) wide range of therapeutics (proteins and peptides)
|
|
|
Disadvantages of DPI's
|
(1) low formulation flexibility (2) inspiratory effotr still necessary (3) dose dependency on flow rate (4) --compliance (5) safety (6) hygroscopicity (7) cost (8) excipients few and few FDA approved
|
|
|
What are the comliance issues converning DPI?
|
(1) advantages: portable, reusable, dose counters (2) disadvantages: reloading, multiple operation steps (complexity)
|
|
|
What are the two tested DPI excipients
|
(1) lactose (2) mannitol
|
|
|
What is the preferred patient delivery method for DPI?
|
Multiple dose, factory metered (blister repack, ease of use!)
|
|
|
What aspects affect DPI formulation?
|
(1) physical powders properties (2) approaches to realize required aerodynamic diameter (3) drug factors (4) mositure protection
|
|
|
List some physical powder properties
|
(1) aerodynamic diameter (size + density)(2) ashesion/cohesion (surface charges, etc) (3) flow properties (metering accuracy) (4) hydroscopicity (stability, metering)
|
|
|
How do protect against moisture?
|
(1) blister packing (2) device design (3) dessicant
|
|
|
Describe characteristics of the Diskus
|
30 doses but only 10-15% lung deposition, looks cool
|
|
|
What is the fine particle fraction of twist inhalers?
|
35-40%
|
|
|
What made the skyehaler unpopular?
|
Had to be verticle when loading
|
|
|
Describe the cost, complexity, performance of passive dispersion
|
Cost=low Complexity=low, mod Performance = flow rate dependent
|
|
|
Describe the cost, complexity, performance of active dispersion
|
Cost=high Complexity=mod, high Performance = Independent of flow rate
|
|
|
Advantages of factory metering
|
(1) increased accuracy (2) dose protection (3) in process controls (4) metering is patient independent
|
|
|
Disadvantages of factory metering
|
(1) production efficiency (many discarded doses) (2) reloading unit dose systems difficulty
|
|
|
Advantages of device metering
|
(1) Production efficiency (2) multiple doses!!!! (3) Compact
|
|
|
Disadvantages of device metering
|
(1) Metering is patient dependent (2) high dose variability (3) component tolerance (4) dispension variation (5) inprocess control (6) poor moisture protection
|
|
|
T/F Patients prefer single dose inhalers
|
False (multidose preferred)
|
|
|
Zeta potential
|
A particle dispersed in a liquid solvent will normally have a charge. The zeta potential is the potential on that particle, and governs how it will interact with other particles dispersed in the medium.
|
|
|
When stabilizing colloids and course suspensions, electrically
|
Want not completely repelled or attracted. We want controlled flocculation or reduction of repulsion. We want to manipulate the charge by adding a counter ion (oppositely charged). Usually in water, things take on a negative charge.
|
|
|
Critical zeta potential
|
Found in hydrophobic colloids. These are difficult to get suspended, don’t have a great attraction to suspending medium. So, will have a defined critical zeta potential.
|
|
|
Above zeta potential
|
Repulsive forces greater than attractive forces.
|
|
|
Foccules
|
Loose agglomerates of particles, desirable because they are loose and will rapidly come apart and be resuspended when sheared.
|
|
|
We want controlled flocculation
|
Stabilized, coarse suspension. No cake cuz fused particles! No aggregation.
|
|
|
Delta eff equals gamma sub ess ell times delta a
|
Free surface energy equals interfacial tension between the solid and liquid phase times the surface area
|
|
|
Less interfacial tension
|
The more they like each other, and the more stable. We'll see this again in emulsions
|
|
|
To reduce interfacial tension
|
Use surfactant, this reduces the gamma term. Or you could reduce particle size, but they have more energy and can aggregate uncontrolled
|
|
|
Smaller particles are more energetic
|
and tend to aggregate in an uncontrolled manor - not our floccules
|
|
|
Floccule settling sys
|
Will settle quickly and may take the entire container as one large floccule
|
|
|
Floccules Will not cake
|
because you have manipulated the charge so the particles cannot get close enough
|
|
|
Floccules are easy
|
To resuspend
|
|
|
Defloc particles
|
Settle slowly as individual particles
|
|
|
Defloc particles
|
No charge control (zeta potential not adjusted) and particles can get very close - fuse and form hard cakes
|
|
|
Defloc particles
|
Difficlut to resuspend to original particle size
|
|
|
Problem with particles in suspension
|
Growth of particle size is problem, affects absorbtion, dissolution rate, settling, temp fluctuations cause this (as small as 5 to 10 degrees)
|
|
|
Ostwald ripening
|
Lose surface molecules from small. Phenom where smaller (energetically favored) particles have molecules on their surface go into solution and be absorbed by the larger particles.
|
|
|
Small 5 to 10 degree temp changes
|
result in ostwald ripening. Small particles will be taken up by large particles because it's not as thermodynamically favored
|
|
|
Particle growth
|
Tend to lose small particle fraction and gain large particles. Overtime overall particle size increases. Our drugs generally have problems with bioavailability any way. These grow outside the range. Causes recalls.
|
|
|
Triamcinolone - solvation problem
|
If products sterilized with dry heat and then solvated in aqueous medium, particles will grow into needles.
|
|
|
Novobiocin solvation problem
|
is amorphous but will crystalize. Only bioavail as amorphous.
|
|
|
In properly flocculated suspension,
|
the floccules take up the full volume
|
|
|
Flocculating agents
|
Purpose is to allow particles to bind of link together lightly into loose agglomerates. Loose 3-D structures of agglomerated particles. Can easily be broken apart due to properly manipulated Zeta potentials.
|
|
|
The nonionic flocculating agents
|
tend to show the fewest incompatibilities. (no charge)They work as a protective colloid coating the surface of the particle.
|
|
|
Classes of flocculating agents:
|
Surfactants, hydrophilic polymers, clays, electrolyte. Some are viscosity enhancers too, which slow settling.
|
|
|
Clays
|
Small anionic particles that swell and can be flocculating agent
|
|
|
From the flocculating agent list
|
be able to recognize these are used to stabilize the colloidal dispersion by manipulating Zeta potential as a flocculating agent
|
|
|
Some of the flocculating agents
|
also increase viscosity according to Stoke's law. Dual function
|
|
|
Coagulation
|
When 2 particles come together and fuse, a step toward sedimentation and caking.
|
|
|
The issue with flavorings and colorants is they could affect
|
suspension stability. They may have a charge
|
|
|
Patient wants strawberry flavor added to coarse suspension (which has alcohol). The API has some solubility in alcohol. Drug is insoluble in water, but some solubility in alcohol.
|
Adding this will speed up Ostwald ripening and particle growth
|
|
|
When you make suspensions/colloidal dispersion, you don't want any
|
solubility in the vehicle.
|
|
|
Calcium solubilty?
|
not soluble in water (divalent)
|
|
|
Simethicone is effective at
|
reducing foaming, it's a viscous liquid
|
|
|
Na-CMC can be
|
flocculating agent, likely what it is doing here. It's also a suspending agent
|
|
|
Suspending agent properties
|
Rheologic behavior, ionic charge, amount used (want to use the least inactives), internal/external use, stable pH range, incompatibilities
|
|
|
Why use emulsion?
|
_______; if drug tastes bad and is oil soluble, it is hidden in aqueous phase whend in oil ---- patient doesn't detect the taste
|
|
|
|
1.) mask taste by hiding drug in internal; 2. ______; 3. For irritating active drug to make it less irritating
|
|
|
Why do some topicals have oily external phase?
|
Barrier to sooth, protect (diaper ointment
|
|
|
Challenge in emulsions
|
Keep from separating, so we reduce interfacial tension
|
|
|
Emulsifying agent must be
|
Aphiphilic
|
|
|
Surfactants generally are what kind of molecut
|
Charged fatty acids
|
|
|
Imagine an amphiphilic surfactant oriented in line
|
Like the interphase, self orients and forms cohesive film. On top is oil phase. LCFA orients toward oil phase.
|
|
|
Surfactant molecule does what
|
Orient & form cohesive film around droplet of dispersed phase. So, each dispersed phase droplet is surrounded, and the droplets don't combine.
|
|
|
Ideal surfactant
|
Amphiphilic, non-toxic (GRAS listed), have no therapeutic activity, High HLB (8 to 18)
|
|
|
HLB Scale
|
1 to 20, higher number is more hydrophilic and will have more propensity to from o/w type emulsions, generally greater than 11
|
|
|
Scale was originally used
|
To describe hydrophilicity of nonionic surfactants, but now used also for anionic and cationic
|
|
|
External emulsions can be
|
o/w or w/o; it depends on how deep do you want the drug to penetrate?
|
|
|
Topical vs Transdermal
|
Topical will stay external, the goal will determine the emulsifier
|
|
|
For o/w, want more hydrophilic surfactant
|
So choose water soluble sufactant like monovalent soaps
|
|
|
Soap is
|
a salt of LCFA C12-C18
|
|
|
Divalent soaps as sufactants in emulsions
|
have two fatty acid chains - tend to be more lipid soluble Better when oil is the external phase.
|
|
|
Stability of emulsions means
|
absences of coalescence, absence of creaming, nice color (Yellow not favored), pleasant odor(use rosewater) esthetic appearance
|
|
|
Esthetic -
|
what is pours like, looks like
|
|
|
Flocculation in emulsion
|
also occurs with droplets, depends on charge
|
|
|
Creaming
|
describes movement of the dispersed phase still droplets though, and can be re-dispersed, reversible
|
|
|
Upward creaming seen in
|
o/w emulsion
|
|
|
Downward creaming seen in
|
w/o emulsion
|
|
|
Coalescence and breaking
|
Irreversible phase separation of an emulsion, from poor formulation, can't re-emulsify with shaking
|
|
|
If have sodium stearate as emulsifier
|
Be careful of calcium ions, because they will form insoluble calcium stearate, and you won't have an emulsifying agent left
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Floccules in droplets in emulsions
|
are okay, they are redispersible.
|
|
|
Creaming in emulsions isn't desired
|
can usually be re-dispersed usually
|
|
|
Emulsion preserving
|
More complicate to preserve.
|
|
|
Oils more susceptible to hydrolysis
|
oils go rancid and degrade
|
|
|
Emulsion Preservative
|
must be soluble in both oil and water phase
|
|
|
Unpreserved and compromised emulsion
|
Will get phase separation (from organism waste/feeding), discoloration, gas formation (from organism feeding), change in rheology - much less viscous
|
|
|
Example emulsion preservative
|
Methyl/propyl parabens have pretty good solubility in both phases
|
|
|
Ways to make emulsions
|
Industrial homogenizer or mortar & pestle
|
|
|
Methods of emulsion making
|
Dry gum/wet gum, varies on the order in which materials are added
|
|
|
Dry gum method
|
Emulsifying agent plus oil, then add water; 4:2:1 oil:gum:water
|
|
|
Wet gum method
|
Emulsifying agent plus water (make triturate) then add oil slowly. Thicker preparation than dry gum
|
|
|
High shear hand held homogenizer.
|
Caution: since using surfactant, if you incorporate air you will get a stable foam. 30mL air = million bubbles
|
|
|
Hand homogenizer
|
pushes through a nozzle to create the emulsion - can make multiple passes
|
|
|
Emulsifying agent classifications
|
Anionic, cationic, nonionic
|
|
|
Alkali Soaps
|
Some anionic emulsifiers are soaps, salts of fatty acids, promote o/w emulsions
|
|
|
Metallic soaps
|
Like calcium oleate, promote w/o emulsions
|
|
|
Organic soap
|
Triethanolamine oleate Anionic - have negative charge in water Promote o/w (more hydrophobic than lipohilic)
|
|
|
Sulfated compounds- alkyl sulfates
|
Ex: Sodium Laurel Sulfate; Good surfactant, used in shampoos and toothpaste; Has history with safety issues, but seems okay now Promote o/w
|
|
|
Sulfonates
|
Promote o/w; Example Aerosol OT
|
|
|
Quaternary ammonium compounds
|
Cationic emulsifying agent, tend to be more hydrophilic, promote o/w; Soluble over wide pH range; Should not use with anionic s surfactants because charge incompatibility would affect the ability to make the stable emulsion; Primarily, secondary, and tertiary amines
|
|
|
Cationic surfactant examples
|
benzalkonium chloride (typically ophthalmic, nasal solutions (might be absorption enhancer)
|
|
|
Nasal calcitonin
|
1% to 2% absorbability with benzalkonium chloride. So what?
|
|
|
|
|
|
|
|
|
|
|
PEG 400 is at room temp, and it's use
|
Liquid; used as a cosolvent (like PG, glycerin) with water insoluble drugs
|
|
|
PEG 400 monostearate at room temperature, mp, HLB
|
is a solid (esterified); feels waxy, mp 50-70 depending on FA used. HLB = 11.7. 11 is the cutoff, above 11 it tends to be hydrophilic, promote o/w emulsions
|
|
|
HLB cutoff
|
11. Above that it tends to be hydrophilic
|
|
|
At HLB 11 an emulsifier in water
|
is dispersible in water, but not really water soluble.
|
|
|
Span'sHLB
|
have lower HLB
|
|
|
Span 40 -
|
Sorbitan monopalmitate; HLB is 6.7, promote w/o, dispersible in water, but not real soluble in water, soluble in oil phase
|
|
|
Span 80
|
Sorbitan monooleate, HLB 4.3, promotes w/o, dispersible in water, more soluble in oil
|
|
|
Polyoxyethylene sorb itan derivatives
|
Called Tweens; differ from spans with ethylene, 2 carbons, then an oxygen, much more hydrophilic than Spans
|
|
|
Polyoxyethylene sorbitan monooleate
|
Tween 80 - HLB = 15; Promote o/w emulsion;More water soluble
|
|
|
Polyoxyethylene sorbitan monolaurate
|
Tween 20 - HLB = 16.7; Soluble more in wate; Promotes o/w
|
|
|
Gumsas emulsifiers
|
Form hydrophilic colloids in water; provide high viscosities and slow down movement of dispersed phase - promote o/w
|
|
|
Lipids (lecithin) as emulsifier
|
not water soluble, swells in water (unique) and promotes formation of emulsion by forming lipid bilayer
|
|
|
How to prevent oxidation in emulsions
|
Antioxidants: 3 types: chelating, compounds that are preferentially oxidized; and chain terminators
|
|
|
Chelating agents in emulsions
|
Bind divalent, trivalent ions before they can oxidize; Citric acid;EDTA; Phosphoric acid; Tartaric acid
|
|
|
Compounds that are preferentially oxidized
|
Ascorbic acid (vit. C); Sodium bisulfite; Sodium sulfite
|
|
|
Chain terminators
|
Two types depends on solubility; Water soluble (thiols, like cysteine HCl) and oil soluble
|
|
|
Oil soluble chain terminator examples
|
(Antioxidants)BHA - butylated hydroxy anisol; BHT - butylated hydroxy toluene; Alpha tocopherol (vitamin E)
|
|
|
Surface tension
|
Inward force or stress or tension that ends to pull molecules into the liquid, force per unit area, surface or interface
|
|
|
Surface tension units
|
Dyne/cm or erg
|
|
|
Forces sum up to zero
|
|
|
|
|
Cohesive forces that are pulling ?
|
|
|
SAA
|
Amphipilic, polar and nonpolar portion, will orient at surface, will always reduce the surface tension, not completely hydro/lipo-phobic (solubility in both);
|
|
|
When will surfactants increase the surface tension?
|
Never
|
|
|
SLS
|
An SAA; Same as sodium dodecyl sulfate (12 C's); depicted as ____
|
|
|
Measurement of surface tension
|
Du Nuoy Tensiometer, ??
|
|
|
Force per unit length at interface between two immiscible liquids
|
Interfacial tension
|
|
|
Water/liquid paraffin surface tension
|
57 dynes/cm
|
|
|
Water/ether surface tension
|
10.7 dynes//cm (not a good solution for stability ____:13)??
|
|
|
To improve miscibility of systems
|
Use surfactant to lower surface tension
|
|
|
Orientation of SAA in water
|
Lipophilic tails up in the air
|
|
|
HLB Value target for SAA
|
Want balance, if too hydrophilic it will dissolve in aqueous phase, vice versa, if too extreme it won't be at the interface.
|
|
|
Surfactant uses; other names for
|
ALL are surfactants: Detergents to remove dirt, wetting agents to remove air (for wetting drug particle in stomach), solubilizers to render drug in molecular form, emulgents: to emulsify
|
|
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HLB System
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Was developed for nonionics, but used for all now. Quantitates hydrophilicy/lipophilicity
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HLB range
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0 to 20
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HLB values
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Below 9 - lipohilic / above 11 hydrophilic
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HLB 1-3
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Antifoaming, simethicone, ___ oil
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HLB 4-6
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W/O emulgent
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HLB 7-9
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Wetting
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HLB 8-18
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o/w emulgent
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HLB 13-15
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detergent
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HLB 10-18
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Solubilizer
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If you know the HLB value
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You can deduce its use
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Micelle
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Spherical; colloidal (indicates size); aggregate.(indicates multiple molecules of surfactnat) In the care, lipophilic drugs can be dissolved to increase bioavailable.
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Negatives of micelles
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May only get 3 or 4 molecules of drug into a micelle, so a large number of micelles required for the dose
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Critical Micelle Concentration
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Concentration of the surfactant at which the micelles begin to form - basically no more room on the surface
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Graph of Surface tension & CMC
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Adding surfactant initially has steep decline in surface tension, then slope decreases at the CMC?
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CMC, graphically
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Point at which the surface is saturated, and the lipophilic tails (that are below the surface since the surface is saturated) and the drug starts becoming soluble
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Adsorption problem of SAA peptides
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Proteins can adsorb to the container, so you can use ___
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Micelle solubilization
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Process of dissolving lipophilic drug in paraffin like core
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Why solubilize with micelles?
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To improve stability, improve absorption, improve solubility, reduce irritation (Iodophores)
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To estimate HLB if not known
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If you add ___ to water and shake it, if it stays ___ 1-4 range; If it makes a poor (temporary) dispersion, 3-6; if it makes "milky" 6-8; If it stays milky a little longer then 8-10; if it starts to become translucent then 10-13; if can't see anything remaining then >13
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Reasons for
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Stability (reduce oxidation in vitamin A); improve drug absorption; improve solubility, reduce irritation (iodores)
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SEDDS
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Self emulsifying DDS, 100 to 300 nm
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SMEDDS
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Self micro emulsifying DDS <50 mn
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SEDDS/SMEDDS
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No water, forms the emulsion when added to water or in gastric juice
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General classes of SEDDs/SMEDDS (sample excipients)
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Fatty acid salts and esters, fatty alcohols, oils and oil esters, phospholipids/waxes
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Type I
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Normal type of emulsion size > 1 micron
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As move from Type I to Type IV??
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Decreasing amount of lipid material, decreasing hydrophobic surfactants (HLB<12), increasing use of hydrophilic surfactants with HLB>12, increasing use of organic cosolvent
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Trend from SEDDS to SMEDDS
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This is a solution, it forms emulsion when you add to water
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Mix these around
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Comparison of Coenzyme Q10 as powder vs. SEDDS
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AUC was over double for SEDDS; Cmax was over double
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Cyclosporin A study
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For immune suppression in tissue transplant. Sandimmune was solution (no emulsion) with low and variable bioavailability caused rejection. Neoral is a SEDDS type oral solution that forms emulsion was 2.39x more bioavail?
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Wetting agent definition
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Lower advancing contact angle and aids in displacing air from surface with liquid phase
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Lung surfactant drug
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DPPC (natural lung surfactant, a phospholipid)- Exosurf - reconstituted powder, Tyloxopol (nonionic surfactant approved for lung promotes o/w emulsion); cetyl alcohol (weak emulsifying agent)
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Cetyl alcohol
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When used alone promotes w/o emulsion, when used with ___ helps stabilize O/w emulsion
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Mucin
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Natural surfactant in eye in corneal tear interface
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Zeta potential
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Is a point further out from a charged particle. (That's where the surface potential is). Oppositely charge ions will interact - they are attracted to the particles.
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Indispersion, what moves
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Particle plus the outer charges that are within the zeta potential range. That's what gives it stability to not cream or settle, stay suspended in media.
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What kind of colloids are difficult to stabilize and why?
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Hydrophobic, they don't have much interaction with the dispersion medium.
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Machine to disperse hydrophobic colloid
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Colloid mill
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Coated hydrophobic colloid
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To stabilize, it's coated with hydrophillic colloid like gelatin, acacia, albumin, tragacanth, MC, Na oleate
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Course suspension
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Particle is greater than one micron. Often the ones we talk about may be 25 microns.
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Suspension
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Heterogeneous system with continuous phase that is liquid or semisolid and dispersed phase is solid
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Properties of acceptable suspension
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Not settle rapidly (to get consistent dose); when they settle, no cake; viscous for uniform dose but pourable
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Heterodisperse
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In reality, particle size varies
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Particle size in reality for suspension
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Want greater than 1 micron, but usually greater than 10 and sometimes 100.
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Continuous phase is complex
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Viscosity inducing agents, flavors, etc all of which can affect pH and charge
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Course dispersion particle shape
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Usually non-spherical, often needles
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Solids content in course dispersions
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Greater than 50% solids
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Solubility of NCE's
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40% of drugs in discovery are insoluble or practically insoluble
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Taste of suspension
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Masked when in non-dissolved, can make water insoluble form like Chloramphenicol (which tastes like garlic) so use palmitate salt which is not soluble
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Organoleptic
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Like taste smell, effects compliance
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Penicillin G suspension
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Rapid hydrolysis in solution - not time even for shelf stability, but Procain Penicillin G is insoluble in water so no hydrolysis
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Suspensions control release rate
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Luperolide - release over months, insulin, not in solution so release slower
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Beagle dog suspension study
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Crystal drug of 3 different particle sizes, Amorphous drug will supersaturate, in HPC SLS and water, fed & fasted ratio; larger particle had lower AUC; For nonoCrystals there is no food effect; there is food effect for other.
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HPC
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Hydrophilic polymer, viscosity enhancing
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SLS
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Anionic surfactant
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Particle size in Beagle study
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13 micron (hammer mill); 2.4 (jet milled); 220 nanometers wet milled.
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Nano systems?
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Mill 100 micron sized particles with small spheres
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Generally, the smaller the particles
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The less food effect
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Increase in Bioavail and absorption rate
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With colloid particles
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Colloid vs Micronized suspension
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DissoCubes
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High pressure homogenization method milling method to reduce particle size
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TPGS
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Surfactant - protectectiv colloid in fenofibrate. Inhibits p-glycoprotein which can metabolize fenofibrate.
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Fenofibrate
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Abbott, 300 nm (colloidal) suspension, hydrophobic so use surfactant for wetting agent and protective colloid, HEC 0.4% is acting as protective colloid.
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Fenofibrate study
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Simple Syrup vs. HEC vs. Dissocube. Dissocube had higher absorption and bioavailability
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Stoke's law describes
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Settling, applicable to coarse particles because they have no Brownian. This is despite failing some of the assumptions (dilute solution, spherical)
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Peptizing agent
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Added to a suspending medium to promote uniform particles that don't interact with each other, or have controlled flocculation.
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Rate of settling
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Inverse to viscosity
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Suspending agents
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Acacia
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Tracacanth
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Carboxymethycellulose
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Veegum
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Carbopol
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Preparing suspension with diffusible powders
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No suspendg agent needed
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With indiffusable powders
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Susp agent required to keep suspended log enough: ASA sulfa, sulfur in topical
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Deagglomerate in prep
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Micromill
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Has stainless or zirconium spheres
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Can form suspension in situ by chemical reaction
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Potassium sulfide plus Zinc sulfate precipitates ZnS
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Alteration of solvent
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To precipitate out the active by changing pH, different solvent
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Classes of suspending agents
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Gums & derivs, clays, cellulose derivatives
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Gum dervie
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Carbohydrate, water soluble, non-toxic, and able to form hydrophilic colloids when added to water - very useful
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Rheology may vary
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Based on concentration
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Emulsion
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2 immis, one of which is dispersed in globular form throughout the other. Usually an oil phas e and a water phase. The key is immisicible
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Dispersed phase
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Also internal phase, generally the one in the smallest amount, the "droplets", a/k/a the discontinuous phase
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Continuous phase
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The carrier, it suspends the dispersed phase, enables them to be dosed in a homogenous way
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o/w emulsion
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Oil is dispersed, water is the continuous.
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oil means lipid phase and anything dissolved in it, water is aqueous phase
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Floccule droplets when improperly formulated
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Can come together and coalesce
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Natural surfactant
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Bile salts, etc… can help dissolve lipohilic drugs
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Lung surfactants
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Facilitate gas exchange
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Advantage of supp
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When patient can't swallow, or hold down med
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Supp def
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Solid dosage for insertion where it melt or dissolves
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Suppository characteristics
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Size & shape promote use and facilitate retention, ___
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Suppository local site of action
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Remain in rectum
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Categories Ingredients in hemorrhoidal supp
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(drugs meant for local) Local anesthetic (topical - not meant to be absorbed), vasoconstrictor, astringent, soothing agent
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Since HCl salts - not
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Oil soluble
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Hemorrhoidal astringent
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Calamine, zinco oxide (itching, tightening mucosal membrane)
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Hemmorrhoidal soothing agent
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Lanolin - physical barrier to separate from other rectal contents
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Laxativ supp
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Glycerin supp, hygroscopic, acts as irritant, causing defacation
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PEG Bases in suppositories
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Deliver bisacodyl, senna
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Laxative PEG's
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Increase MW, Increase Mp, wont melt: dissolve, bisacodyl, senna
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Stability of suppositories
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Generally have physical issues, become brittle, mushy
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Sytemic action suppository - when oral not tolerated
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Rectum is well vascularized (rapid), no first pass (bypass liver), little buffer capacity in rectum,
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Buffer in rectum
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Very little, so pH of drug determines the pH of rectum, usually best to use ionic form of drug
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Absorption of suppository API
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About 40%, in general
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Suppository
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Best to use ionic form of drug for absorption
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Common systemic drugs in suppository
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Dose may be large, see example list, includes asthma - aminophylline, indomethacin (NSAID), prochoperazine, Ondasetron
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Chloral hydrate
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Deliquescent, hypnotic, commonly admistered in suppository
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Deliquescent
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Absorbs moisture and becomes liquid
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Suppository bases
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Non irritating or will act as irritant and come back out - not time for drug to be released (glycerin does this)
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Suppository bases
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Chem, phys, inert; not interact with API; firm enough to be inserted; can control release with base (acts as matrix)
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Cocoa butter
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Theobroma oil
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Oleagenous supp bases
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Oil soluble - cocoa butter, palm kernel, cottonseed
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mp cocoa butter
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Molten 30 /melts 35/melted 37
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Cocoa mixture of ________ and exhibits _________
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Triglycerides; polymorphism (4)
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Polymorphs of cocoa butter
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Gamma mp 18C; alpha 22-28C; beta' 28C; beta 35-37C (the one you want)
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How polymorphs of cocoa butter form
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Heat too fast, less stable polymorph change over time - days to weeks to the beta
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Oil soluble supp bases not cocoa butter
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Palm kernel oil; cottonseed oil
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Problems w/cocoa butter supp
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Drug with lower mp may form eutectics so must use solidifying agents (example of drugs: volatile oils, phenolic drugs, chloral hydrate)
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Solidifying agents in supp
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Cetyl esters wax 20% - mp 45C; white wax 4-6% mp 62C (must use more than 3% or they will contribute to forming eutectic)
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Eutectic
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Mixture or two or more substances that have a lower melting point than either of the individual constituents
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Witepsol
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oleaginous supp base, Synthetic triglycerides, no polymorphism; has emulsifier glycol distearate ester (so can add aqueous solution to witepsol)
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Stability of witepsol
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Won't go rancid
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Removing witepsol suppositories from molds
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Releases from molds
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Witepsol drug release
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Witepsol will release water soluble drugs even faster than PEG bases
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Fattibase
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Supp base, mp 32 to 36.5; opaque white; made of palm - palm kernal - and coconut oils; good stability; faster release than cocoa butter because water soluble, faster
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Glycerinated gelatin
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Sticks to mold (lubricate the mold), glycerin can be irritant to rectum, gelatin swells in water and can cause defecation, primarily for vaginal/not for rectal
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Making gly gel supp
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Dissolve/susp drug in water, mix with glycerin cosolvent, add gelatin, low heat, stir w/o air
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PEG base for supp
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Water sol,
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As heat PEG bases..
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Want more viscous supp
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Use higher mw PEG - they're more solid at RT too
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PEG melting
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Not at body temp, so dissolve in aqueous fluid and release drug, no refrigeration needed
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PEG consulting for faster release
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Dip in water first before inserting, hydrates and drug will release faster
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Polybase
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Commercial supp base; contains PEGs and polysorbate 80; water miscible, dissolves not melt
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Supp: if drug soluble in theobroma oil
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Use low heat to molten, spatulate in. examples: Zinc oxide, bismuth subgalate, lodoform, ASA
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Insoluble in cocoa butter
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Strategy: Can from w/o emulsion; can absorb 10 - 20% of liquids
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Volatile liquids in cocoa butter
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Will lower mp eutectic, need solidifying agent - use another was to increase mp
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If drug soluble in base
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Need to make sure it will come out of the base - or dissolve in water or glycerin if soluble in that
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Antioxidants, preservatives in supp
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If water, need to preserve. No water,probably don't need
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Suspending agent in supp
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Settling during preparation; 1-10% silica gel (viscosity enhancing);
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Toughening agents in supp
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Less brittle; all liquids at RT, Tween 80 - glycerin - PG - castor oi - sweet almond oil
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Agents to release from mold
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Mineral oil (water sol bases); glycerin or PG for fatty base
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Modify drug release in supp
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Delay - MC, alginic acid; speed up - emulsifying agent
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Alter mp in supp
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Lower: sweet almond oil, liquid paraffin. Raise: white wax, cetyl exters, bees
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Preparation of supp
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Melt base + drug, pour in mold. Or compression for tablets
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Supp base and bioavailability
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Make sure base doesn't interfere with bioavailability - whether topical or systemic
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If drug dissolves in supp base
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likely eutectic
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If drug is dense in supp
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use base that crystallizes rapidly such that drug doesn't separate out. Density 1.3 for most organic drugs, so base would need to be denser
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Minimize surfactant in supp
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they are irritating
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Expiration date of supp (actually applies to all compounded)
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Never more than 6 mos; don't exceed 25% of remaining time on shortest expiration date of ingredients
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Indications of instability
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Softening, drying, staining package, hardening, discolor
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Supp bioavail & particle size
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If not soluble, use smallest particle size (doesn't matter if soluble
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Supp bioavail & Ionization
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Use ionized to enhance water solubility
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Supp bioavail & pH
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H-H equation
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Supp bioavail & Emulsification
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increase contact area but possible consequence of irritation
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Suppository migration & bioavailability
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Only rectum avoids first pass effect, could lose 90% of drug on first pass
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Rheology of supp base & bioavail
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Agents that swell in rectal fluid and are viscous could slow down release of drug
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Absorption rates increase for cocoa
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Polyoxyethylene sorbitan
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Nonionic, a tween
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Solubility in base
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Testosterone dissolves in hot witepsol but crystallizes out during cooling, for high bioavail. Testost froms solid solution with theobromoa oil (poor bio)
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Testosterone
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Doesn't like witepsol base, so comes out rapidly; likes cocoa butter base and doesn't come out
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w/o emulsion of water sol drug
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Poor bioavail. Drug must partition from w into o and then into w again
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Suppositories - local action
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Remain in rectum
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Rectal supp weight
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2 gm adult/ 1 gm child
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Vaginal supp weight
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2-5 gram
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Dissolution of supp
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Lipophilic drug will like lipophilic base, so it will tend to not release. Opt to use more water soluble form like salt form of drug
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Water soluble drug in oily based supp
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Will readily release, usually. Sometimes needs a surfactant but will cover that later
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Viscosity of supp base
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Drug may settle if not viscous enough while preparing it, but tradeoff is this decreases rate of dissolution
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Drug particle size in supp
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Smaller particle size has faster dissolution
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Physical form of cocoa butter
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Waxy solid at room temperature, can melt from hand heat, easier to process when grated
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Supp molds types
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Plastic, aluminum
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If no formula to compound supp
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Look for a similar compound
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Waste in supp compound
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5% max (williams); 20% mcGinity
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