Miderterm #3

Question 1

Definition of Stability

Answer 1

• extent to which a drug product (drug in dosage form) retains within specified limits
• the same properties and characteristics that it possessed at the time of its manufacture
• Stability Criteria:
  
  • physically, chemically, microbiologically, toxicologically, therapeutically
  • 90% of labeled content of active ingredient is generally recognized as the minimum acceptable potency level

Question 2

Stability Testing in Drug Development: Early Development

Answer 2

• **Early Development: **type of marketed formulation is selected (dosage form)
  
  • based of route of administration, dose, therapeutic indication, marketing etc

Question 3

Stability Testing in Drug Development: Preformulation Studies

Answer 3

performed on the active pharmaceutical ingredient (API) in order to understand its physical and chemical properties

• Chemical stability of drug?
• Which salt form?
• Which crystal form?
• What are the invitro chemical degradation pathways?
• Compatible and useful excipients?
• Compatible with container?
• Storage conditions for the formulation? (formulation will have impact on stability)

Question 4

Forced Degradation Studies

Answer 4

• Studies for drug stability
• *Very *extreme conditions
  
  • high temperature, high humidity, different pH, and exposure to light for up to a week.
• During development, each formulation for clinical trials must be tested for stability

Question 5

Stability, FDA approval and NDA

Answer 5

• The to-be-marketed formulation for the drug product (in final dosage form and in final container) must be tested for stability as part of the FDA approval of the New Drug Application [NDA].

Question 6

Accelerated Stability Testing

Answer 6

• Final product in it’s final container
• short term studies
• elevated temperature (not as high as forced degradation studies)
• 40 degrees C and 60% humidity

Question 7

Long Term Stability Testing

Answer 7

• Final product in final container
• continually testing under expected “normal” conditions
• throughout marketing life
• “real time stability testing”
• extensive and expensive
• If not agree with hypothesis, then have to adjust expiration date

Question 8

Expiration Date

Answer 8

• required by FDA Good Manufacturing Practice (GMP)
• expiration date is the last day of the specified month

Question 9

Beyond-Use-Date on multi-dose prescription container, single-unit or unit-dosed repackaged medications (nonsterile)

Answer 9

• expiration date or one year from dispensing
  
  • whichever is sooner
• product label for storage info
• Pharmacists advise patients with special circumstances
  
  • infrequent use, traveling to harsh climate
• Exception for reconstituted products

Question 10

Beyond-Use-Date on extemporaneously-compounded prescription medications

Answer 10

• Consult and apply drug-specific and general stability information from authoritative sources, compendium, or literature
• If a manufactured drug product is used as the source of the active drug substance, the expiration date on the drug product does not necessarily apply as the beyond-use date
• Beyond-use dates should be assigned conservatively
• Beyond-use date should be shorter than the expiration date of the least-stable component

Question 11

Compounding pharmacists should consider the following when assigning BUD

Answer 11

• nature of drug substance and its possible chemical degradation mechanism
• nature and degradation of excipients
• container used for packaging
• type of formulation (for example, liquid or solid)
• expected storage conditions
• intended duration of therapy

be observant for stability issues during all steps in the compounding, dispensing, and storing

Question 12

In the absence of specific information applicable to a specific drug and compounded preparation use the guidelines below for BUD

Answer 12

• tight, light-resistant containers
• store at (controlled) room temperature
• Non-aqueous liquids and solid compounded formulations:
  
  • ingredients from manufacture product: BUD no later than ingredient expiration date or 6 months, whichever is sooner
• Water-Containing Oral Compounds (from solid ingredients):
  
  • 14 days when stored at cold temperatures
• All other compounded formulations (topical suspensions):
  
  • not later than intended therapy or 30 days, whichever is sooner

Question 13

Degradation of active drug compound can lead to:

Answer 13

• loss of potency
• infrequently produce a toxic product (small amounts of decomposition product could be highly toxic)
  
  • ​Ex: Penicillin and cephlasporins

Question 14

Degradation of other ingredients (excipients) in the dosage form

Answer 14

• Preservatives, solubilizers, emulsifying, suspending agents, etc. may degrade
• alter the “stability environment” and bioavailability performance of the dosage form

Question 15

Example of Chemical Degradation: Hydrolysis

Answer 15

• ​(solvolysis if the solvent is something other than water)
• Aspirin
• Benzylpenicillin or penicillin G (

Question 16

Factors that affect rate of hydrolysis:

Answer 16

• Prescence of Water; control moisture
  
  • ​dry powder form
  • formulate w/o water (PEG, glycerin)
  • film coat
  • add a descicant
• Temperature
  
  • store in refridgerator
• Light
  
  • Protect with cardboard, aluminum foil, amber vial
• Acid/Base Buffers
  
  • choose an optimum pH for stability and acceptability
  • sometimes a compromise

Question 17

Rate of hydrolysis of aspirin as a function of pH

Answer 17

Notice that it is in log units. Going over enormous range. Minimize hydrolysis by keeping at pH of 2 or so. Trade-off, solution tastes horrible.

Question 18

Example of Chemical Degradation: Oxidation

Answer 18

• Some functional groups subject to auto-oxidation
• Epinephrine
  
  • colored product, adrenochrome, can be toxic
• Morphine to pseudomorphine and morphine N-oxide

Question 19

Factors that affect the rate of oxidation

Answer 19

• Prescence of oxygen
  
  • air-tight containers
  • nitrogen or argon gas in headspace of injectables
• Exposure to light
  
  • amber/opaque, protect with aluminum foil
• Prescence of heavy metal ions
  
  • Chelating agents (EDTA)
• Variation in storage temperature (high temp)
  
  • Store in the refridgerator
• pH
  
  • add buffer

Question 20

Example of Chemical Degrations: Photolysis

Answer 20

• complex, difficult to characterize and understand
• chlorpromazine
  
  • semiquinone free radical

Question 21

Example of Chemical Degradation: Racemization

Answer 21

• one enantiomeric form of a chiral drug into its other enantiomers
  
  • one isomer might be of lower activity
• tetracycline, epinephrine, pilocarpine
  
  • toxic below 3%, need to worry about breaking down

Question 22

Example of Chemical Degradation: Polymerization

Answer 22

• two or more identical drug molecules combine to form a complex molecule
• Ampicilin

Question 23

5 Chemcial Degradation Reactions to keep in mind

Answer 23

• Hydrolysis
• Oxidation
• Photolysis
• Polymerization
• Racemation​

Question 24

Microbial Growth

Answer 24

• Unexpected contamination
• storage conditions not met
• insufficient preservative
• preservative degradation

Question 25

Physical Degradation

Answer 25

• Polymorphic Reversion (change in crystal structure)
• Tablet becomes friable or discolored; hardening of capsule
• Precipitation from solutions
• Suspension instabilities
  
  • particle growth (dissolution and recrystalize)
  • deflocculation (caking)
• separation of emulsions (creaming, sedimentation, cracking, inversion)

Question 26

Zero-order kinetic model for drug degradation

Answer 26

• degradation of a drug is constant with respect to time
• Rate of degradation is independent of drug concentration

Question 27

Mathematical Decription of Zero-Order rate

Answer 27

Question 28

Equation that we use to determine concentration remaining at a certain time

Answer 28

• C=C₀-k_ot
• k₀=(C₁-C₂)/(t₂-t₁)

Question 29

time required for the drug concentration to decrease to 90% of its starting value (i.e., accepted minimum potency) for a zero-order process ( t90% ):

Answer 29

• t_90%=(1/10)(C₀/k₀)
• **predicted shelf life depends on amount of drug concentration in the formulation **

Question 30

First-order kinetic model for drug degradation

Answer 30

• degradation of a drug is directly proportional to the concentration of drug remaining

Question 31

Mathematical Description of First-Order Kinetics

Answer 31

Question 32

Equation to determine drug concentration for first-order kinetics

Answer 32

*

Question 33

Half-Life

Answer 33

• time required for the concentration to decrease by 50%
• t_0.5=(ln2)/k
• t_0.5=0.693/k

Question 34

Equation for time required for the drug concentration to decrease to 90% of its starting value for a first-order process

Answer 34

• t_90%=ln(100/90)/k

Question 35

Arrhenius Equation (“Arrhenius Law”) for Accelerated Stability Testing

Answer 35

• relates temperature and reaction rates

Question 36

How is the Arrhenius equation used in accelerated stability studies?

Answer 36

• Step 1: Perform several short-term (brief) accelerated stability studies at different temperature
  
  • Estimate a rate constant k for each stability study
    
    • degradation rate increases as temperature increases
• ​Step 2: Plot the ln or log of the degradation rate constant k as a function of 1/T
• Step 3: Use the graph to estimate the rate constant for degradation at lower temperatures by extrapolation
  
  • Then calculate t_0.5 and t_90% for room temperature storage from the extrapolated rate constant
• Summary: In a few days, have calculated degradation rate constant
  
  • can estimate shelf life at room temp.
  • can estimate rate constant for storage in fridge

Question 37

Q₁₀

Answer 37

• ratio of degradation rate constant for a 10°C elevation above room temperature (25°C)
  
  • (fold increase in k for a 10 degree C raise)
• Relative change in rate constant stays about the same as you increase the temperature
• Most degradation reaction increase by ~3 fold every 10 degrees
• For a 20 degree raise: 3^2=9 fold
  
  • Q₁₀^t/10

Question 38

Role of Dissolution in Oral Drug Absorption

Answer 38

• **Only dissolved drug can effectively penetrate the GI mucosa **
  
  • Mostly by passive diffusion
    *

Question 39

Passive oral drug absorption is generally favored by:

Answer 39

• Sufficient water solubility for drug to dissolve readily within fluids of the GI tract (required for all absorptive mechanisms)
• Good drug stability in the fluids of the GI tract
• Sufficient lipid solubility for drug to partition from solution in the GI fluids (aqueous) into the GI mucosa (lipoidal)
  
  • ionization of weakly acidic and basic drugs (as determined by pKa and pH at locations along the GI tract) also play a role
  • Optimum LogP in range of 1 to 3
• Smaller molecular size
  
  • more readily diffuse through the GI mucosa

Question 40

Rate-Limiting Step for Drug Absorption

Answer 40

• disintegration –>dissolution–>permeation, one of these processes could become rate-limiting
  
  • disintegration rarely rate-limiting
• Case A: low lipid solubility (low logP)
  
  • dissolution>>>permeation
  • permeation limits drug absorption rate
  • permeation rate limited
• Case B: high lipid solubility (high logP)
  
  • dissolution<<<< li=””> <>
  • dissolution into fluids limits drug absorption rate
  • absorbtion highly dependent on formulation
  • dissolution rate limited

Question 41

Drug Dissolution Model and Factors Affecting Drug Dissolution Rate

Answer 41

Dissolved drug molecules diffuse from the saturated film adjacent to the solid particle surface into the bulk solution (i.e., across the stagnant diffusion layer), thereby establishing a concentration gradient between C_s at the saturating film and C_t in the bulk (well-mixed) medium at time t.

Question 42

Equation for Drug Dissolution

Answer 42

Question 43

Equation for Drug Dissolution during sink conditions

Answer 43

Question 44

physicochemical factors that govern the drug dissolution rate:

Answer 44

• aqueous solubility (Cs); what affects Cs?
  
  • pH
  • salt form of the drug
  • buffering agent (maintains favorable pH in diffusion layer)
  • polymorphic or pseudo-polymorphic form
    *

Question 45

Variation of pH along the GI tract

Answer 45

• Stomach pH of 1-3, Small intestine pH of 5-7, Large intestine pH of 7-8
• significant ionization may or may not occur, depending upon where the drug is located in the GI tract

Question 46

Ionization and Drug Dissolution

Answer 46

• **Ionization of drug increases its solubility in water remarkably **
• weakly acidic drug: solubility greater at higher pH
  
  • total solubility (C_s) for a weak acid equals the intrinsic solubility of the non-ionized acid HA (C₀) plus the equilibrium concentration of the anion [A

Question 47

Ionization and drug permeability across GI mucosa

Answer 47

• nonionized into GI mucosa easier
• pH effects on dissolution rate is opposite to their effects on permeation rate

Question 48

Ionization and drug permeability across GI mucosa: **In theory **

Answer 48

• weakly basic drugs dissolve readily in the low pH of the stomach, but absorption is more optimal in the small intestine because of improved permeability at higher pH
• even though low pH in the stomach affords good permeability of weakly acidic drugs, it is poor condition for dissolution. Once the formulation reaches the small intestine, dissolution can proceed more efficiently; however, permeability is less optimal.

Question 49

Ionization and drug permeability across GI mucosa: **In reality **

Answer 49

• small intestine is the major site of absorption (permeation) for most weakly acidic drugs
  
  • Small intestine has a much greater absorptive surface area
  • ionization doesn’t completely restrict absorption; ionic equilibrium is reversible
    
    • Non-ionized drug is absorbed, ionized drug reacossiate with H+ to form non-ionized drug
    • ionization affects dissolution more than permeability

Question 50

GI motility and drug absorption

Answer 50

• GI motility can affect both the rate and extent of oral drug absorption
• Gastric emptying rate: important for how quickly drug to small intestine
  
  • Food slows gastric emptying and in turn slows the onset and rate of drug absorption.
  • slowed by drugs with anticholinergic effect and accelerated by prokinetic agents
• Anticholinergic also slows intestinal motility, allows more complete dissolution (opposite for prokinetic agents)
• GI content can affect dissolution and gastric emptying rate

Question 51

Formulation Factors Affecting Drug Dissolution and Oral Drug Absorption: Salt form of the drug

Answer 51

• generally, greater solubility of the salt form
• drug is initially presented entirely in ionized form into the saturating film, thereby ‘buffering’ the film pH.
• sodium or potassium salts of weak acids dissolve much more rapidly than free acids
• examples of organic salts that have a lower aqueous solubility than the free acid or base

Question 52

Example: Sodium salicylate vs. salicylic acid

Salt and pH

Answer 52

Salt is more water soluable and less affected by pH

As pH incrase, solubilty of weak acid increases, increases in dissolution rate.

Question 53

Example: Tolbutamide

Salt Effects

Answer 53

• generic hypoglycemic drug used in the treatment of Type II diabetes
• Different salt forms of tolbutamide have different solubility and accordingly different dissolution rate. Therefore, their absorption rates will differ leading to significantly different glucose-lowering effects.

Question 54

Formulation Factors Affecting Drug Dissolution and Oral Drug Absorption: Buffering Agents

Answer 54

• Some salts are deliquescent and would pose a storage problem.
  
  • Deliquesce: to dissolve and become liquid by absorbing moisture from the air.
• Fix by forming the salt in situ by co-administering a mixture of buffering agent and drug.
  
  • increasea solubility (Cs) of drug in the dissolution layer, thereby increasing drug dissolution rate.

Question 55

Formulation Factors Affecting Drug Dissolution and Oral Drug Absorption: Drug Polymorphs

Answer 55

• More than one crystal form
• same chemical structure, but show different physical properties
• Metastable polymorphs may have higher aqueous solubility than the stable form
  
  • **Metastable polymorphs are useful if they have sufficient stability (conversion to stable polymorph over many months) **
• Polymorphic forms may arise during pharmaceutical manufacturing through:
  
  • recrystallization during synthesis of the drug substance
  • milling and compression

Question 56

Ex: Chloremphenicol

Polymorphs and Dissolution

Answer 56

• ​ less soluble palmitate ester of chlorampenicol used because less bitter tasting
• hydrolyzed in GI tract and absorbed
• absorption rate-limited by dissolution of the palmitate ester
  
  • can depend on the chloramphenicol palmitate polymorph selected
  • **Chloramphenicol palmitate polymorph B is metastable **

Question 57

Formulation Factors Affecting Drug Dissolution and Oral Drug Absorption: Solvate Forms of the Drug

Answer 57

• solvent molecules incorporated in the crystal lattice
  
  • pseudo-polymorphism
• Hydrates
• Organic solvates: improve dissolution rates, tend to be unstable

Question 58

Solvate Forms of Drugs: Hydrates

Answer 58

• ​adducted with water
• ampicillin, caffeine, theophylline
• less water soluble and, therefore, have slower dissolution rates
  
  • other sources state that no general rule can be made about comparing the dissolution of solvates vs. non-solvated forms of a drug substance;

Question 59

Ampicillin Hydrate Dissolution Example

Answer 59

• Dry crystals in 65 degree air
  
  • tihydrate that is slightly soluable (1/5 solubility)
• Dry crystals in vacuum
  
  • monohydrate that is sparingly soluable (half the solubility)

Question 60

Formulation Factors Affecting Drug Dissolution and Oral Drug Absorption: Particle Size

Answer 60

• soluble and moderately soluble drugs: 10 to >100 μm.
• Microionization to 5-10 μm or less can improve solubility of drug
  
  • timely and expensive, try and avoid
    *

Question 61

potential problem for very fine drug particle

Answer 61

• powdered form of some hydrophobic drugs tends to agglomerate
  
  • float on surface
• wetting problem
  
  • reduce contact surface area between particles and dissolution medium
• fix by adding surfactant or wetting agent
  
  • lowers interfacial tension
    ​

Question 62

“Wetting”-related dissolution rate problems are less of a problem with a well- formulated compressed tablet or with capsule formulations, because

Answer 62

• drug powder is mixed with usually hydrophilic diluents and granulating agents (starches and gelatin), which render the surface of hydrophobic drug particles more hydrophilic
• gastric fluids have relatively low surface tension due to the presence of conjugated bile acids and lysolecithin

Question 63

“Controlled-Release”

Answer 63

• particle size of an active drug is optimized ​
  *

Question 64

Dissolution Testing (In Vitro): Applicability and Uses

Answer 64

• applicable for drugs whose GI absorption is rate- limited by dissolution
• Uses:
  
  • rapid in vitro screening procedure during the **development of suspension or solid dosage forms **
  • quality control
  • assure bioequivalency between commercial products of a drug (prove consistency)

Question 65

General types of injectable formulations:

Answer 65

• Injection: Liquid preparation that is a solution of a drug in a liquid vehicle
• For injection: Dry solids that upon addition of a vehicle become an injection solution
• Injectable emulsion: Liquid preparation of a drug dissolved or dispersed in an emulsion medium (e.g., propofol iv)
• Injectable suspension: Liquid preparation of a solid drug suspended in a liquid vehicle (betamethasone sodium phosphate and betamethasone acetate, Celestone Solupan im)
• For injectable suspension: Dry solid that upon addition of vehicle yields a an injectable suspension (e.g., octreotide acetate, Sandostatin LAR Depot)

Question 66

Intravenous

Answer 66

• injection rate/volume:
  
  • bolus in less than a minute or two; small injection volume (1 to 10 mL)
  • short-term infusion from minutes to few hours; decrease peakconcentration; larger injection volume, up to several hundred mL
  • long-term infusion to achieve steady-state plasma drug levels; may need IV bolus loading dose to achieve therapeutic levels sooner
• achieve rapid action and allow control of duration
• 100% systemic availability of the dose
• invasive (risk of infection)
• potential for adverse effects; cardiac arrhythmia with rapid injection (e.g., phenytoin)
• drugs that are caustic or prone to cause phlebitis require central venous access (internal jugular, subclavian or femoral) via catheter
• not suitable for insoluble materials, unless drug particle size is sufficiently small to avoid formation of emboli (e.g., Abraxane ─ nanoparticles of albumin-bound paclitaxel in a injectable suspension)
• poorly water soluble drugs may precipitate if injected too rapidly or into a vein with low blood flow; classic examples: diazepam, phenytoin
• it can be slowly administered by using short-term infusions of the drug dissolved in a sufficient volume of vehicle and administered immediately to avoid precipitation issue
• microemulsions of fat-like or fat-soluble materials (e.g., propofol)

Question 67

Intraosseous

Answer 67

into the bone marrow (as an alternative to intravenous access)

Question 68

Intra-articular

Answer 68

within the cavity of a joint

Question 69

Notes about parenteral administration of drugs

Answer 69

• Note: all parenteral routes are vulnerable to risk of infection
• Any of the above may contain buffers, preservatives, and other excipients.

Question 70

Intrathecal or Epidural Administration

Answer 70

• primarily used to administer analgesics and anesthetics for regional effects
• morphine (or other opioids) by this route
  
  • intraoperative or postoperative use
  • also for the control of chronic pain
  • activity is through spinal opioid receptors
  • increased duration of effect, and a lower incidence of respiratory depression and other CNS effects
  • if respiratory depression is observed by this route, it often is observed hours after the administration of the drug as it spreads rostrally via the CSF or via systemic redistribution to supra- spinal sites

Question 71

Subcutaneous (SC)

Answer 71

• needle penetrates the epidermal and dermal layer to deposit drug into the loose subcutaneous fatty tissue
• usual injection volume of about 0.5 mL; range 0.5 to 1.5 mL, 2 mL injections may cause a feeling of painful pressure
• injected formulation volume produces the “drug delivery site” within the interstitial fluid
• larger volumes may be administered (over longer time) by SC infusion
• large number of potential injection areas on the body to choose from (see accompanying figure)
• readily self-administered by patient (and patient acceptance may be increased with prefilled syringe)
• good route for multiple dosing or continuous infusion
• muscle mass is not an issue in cachectic or elderly patients
• risk of infection is present because the needle breaks the protective barrier of the skin
• systemic bioavailability for a given drug may be 100% or < 100%, mainly related to formulation factors and drug stability at the SC injection site
  
  • bioavailability information is difficult to find for the SC route

Question 72

Small molecule drugs and SC

Answer 72

• small molecule drugs are generally rapidly absorbed following SC injection; rate of absorption depends on
  
  • drug dissolution if formulation is a suspension or if drug precipitates out of solution at the injection site
  • absorption involves diffusion through interstitial fluid and tissues, and passage across vascular membranes into surrounding blood capillaries
• absorption rate may be influenced by massage, exercise (such as running) and heat (as in a sauna or hot tub), because of the increase in blood flow
• vasoconstrictors are used to slow dissipation of local anesthetics; e.g., lidocaine hydrochloride and epinephrine injection for infiltration and nerve block ​

Question 73

Protein drugs and SC

Answer 73

• protein drugs have the following issues
  
  • instability at the sc site; proteolysis
  • slow absorption depending on size:
    
    • small proteins (insulin ~6 kd) are taken up into the interstitial capillaries
    • larger protein >16 kd (Mabs ~150 kd) are absorbed indirectly via the lymphatic system (see accompanying figure), which is a slow process occurring over some hours (tmax >24 hours)

Question 74

Intramuscular (IM)

Answer 74

• range of injection volumes:
  
  • 0.5 to 2.0 mL for deltoid
  • 1 to 5 mL for gluteus maximus
  • 1 to 5 mL for vastus lateralis
• as with SC injection, formulation volume that is injected IM produces the “drug delivery site” within the interstitial fluid
• drugs irritating to SC tissue may be given IM
• risk of infection is present as the protective barrier of the skin is broken
• considerations of rate and extent of absorption are generally the same as for SC administration
• absorption rate for lipophilic small drug molecules is generally in the order of deltoid > vastus lateralis >> gluteus maximus, because of blood perfusion and amount of fatty tissue at the injection site
• poorly soluble small molecule drugs can precipitate on administration and actually form crystals at the site of injection
  
  • can cause of pain at the injection site and at times muscle injury
  • crystals may dissolve very slowly and apparently incompletely, possibly resulting in less than 100% bioavailability; e.g., phenytoin and diazepam
• absorption rate for small drug molecules can be decreased or at least compromised when the injection does not actually reach the muscle, but is instead deposited in the subcutaneous fat
  
  • lower blood flow in fat
  • more sequestration and slower release of lipid soluble drug from fat
  • muscle site, length of needle and angle of injection are important determinants of the likelihood of deposition in fat
  • deltoid and thigh are less likely to result in this problem, more likely with injection into the buttocks
• absorption in infants and young children may be unpredictable due in part to insufficient muscle tone and vascularity of muscle tissue
• decreased muscle mass of many older adults may result in faster small drug molecule absorption; approximate 25% decline in muscle strength occurs between the ages of 20 and 60 years, and a decline in muscle strength corresponds with a decrease in muscle mass
• protein drugs are usually slowly absorbed (depending on size), again as with SC absorption, because of lymphatic involvement

Question 75

Percutaneous: Definition and other equivalent terms

Answer 75

• process by which drug passes into and/or through the skin after application to the surface of the skin
• Other terms
  
  • topical drug administration
  • dermal drug administration
  • transdermal drug administration

Question 76

Topical administration is intended either for:

Answer 76

• local effect “dermal drug delivery”
  
  • unintentional systemic drug exposure may occur, depending on physicochemical drug properties, dosage formulation design, concentration of drug in formulation, and frequency of application
• systemic effect “transdermal drug delivery”

Question 77

Skin Barrier

Answer 77

all skin tissues between the surface and the capillaries in the dermis.

Question 78

• debate whether drugs penetrate
  
  • SC
  • sweat gland, hair follicles and sebaceous glands (transappendageal route).

Answer 78

• likely both routes are involved
• transappendageal route difficult to study and thought to be minor
  
  • corticosteroids cross the stratum corneum relatively slowly (polar) so the thought is that the rapid clinical response is due to their passage by diffusion through the pores
  • evidence of transappendageal route

Question 79

Skin Permeation Model

Answer 79

• Fick’s first law of diffusion
• assuming sink conditions

Question 80

Permeability coefficient in the stratum corneum is governed by several factors

Answer 80

Question 81

Partition Coefficient

Answer 81

Question 82

Diffusion Coefficient

Answer 82

Question 83

• As K_SC increases, P_SC of the drug…
• P_SC will be …. related to the molecular weight
• P_SC will vary depending on…, which describes skin variations and temperatures

Answer 83

• As K_SC increases, P_SC of the drug** increases**
• P_SC will be **inversely **related to the molecular weight
• P_SCwill vary depending on** ß**, which describes skin variations and temperatures

Question 84

Permeability coefficient in the viable tissue

Answer 84

Question 85

Factors controlling percutaneous absorption of drugs

Answer 85

• Sytemic exposure of drug will depend upons
  
  • drug concentration
  • formulation design (influence of the formulation vehicle and the excipients on the partitioning of drug from formulation into the skin)
    
    • change feel and look of skin
  • area of skin covered
  • length of exposure
  • physiochemical properties
  • skin integrity and hydration
  • variation in skin permeability
    
    • patient’s age
    • site of application
    • skin temperature
  • Solvent effects

Question 86

Physiochemical properties of drug affecting absorption

Answer 86

• molecular size
• logP
• pKa
• peak absorption positvely correlated with logP
  
  • more lipid soluable, more systemically absorbed
• Protracted absorbtion of estradiol (highest logP) because of aqueous insolubility, slow dissolution

Question 87

Example of biphasic relationship between skin penetration and lipophilicity

Answer 87

• Higher LogP not necessarily the best
• Trend goes backwards at too high of LogP because gets trapped in the SC
• Sequestration of the lipophilic fentanil opioids in the epidermis explains the reversal in relationship between flux rate and K_o/w

Question 88

Drug Absorption: Skin integrity and hydration

Answer 88

• drug permeability is high in broken skin, and polar solutes are several log orders more permeable when administered over abrasions and cuts
• permeability to drugs increases after serious thermal burns and is again altered with debridement/healing

Question 89

Variability in skin permeability between patients is thought by some to be as much as 10-fold

Answer 89

Due to age and site of application/thickness and skin temperature

Question 90

Patient’s Age and drug skin permeation

Answer 90

• premature neonates have inordinately permeables kins
  *

Question 91

Site of application/thickness and skin-drug permeation

Answer 91

• varying degrees of drug absorption, which may not be accounted simply by the thickness of stratum corneum
  
  • Example: hydrocortisone absorption may vary as much as 42-fold between forearm and scrotum; up to 6-fold higher at forehead than forearm
• differences are likely due to a combination of skin thickness, hair follicles, density of capillaries in the skin, lipid content, degree of **skin hydration **

Question 92

Skin temperature and drug permeation

Answer 92

• increased temp can increase rate of diffusion through stratum corneum
• physiologically by affecting blood capillary flow;

Question 93

Solvent effects/absorption enhancers (penetration enhancers)- skin permeation

Answer 93

• some chemicals (skin penetration enhancers or absorption promoters) are deliberately added to dermal formulations or transdermal devices to increase the permeability of skin and improve drug delivery
• unfortunately, many skin penetration enhancer are irritants or toxic to the skin and have objectionable odor
• Absorption promoters are found in **veterinary pharmaceuticals **

Question 94

Transdermal drug delivery (TDD), and advantages

Answer 94

• transdermal “patch” is an alternate strategy to controlled or extended release dosage form
• Advantages:
  
  • bypassing gastrointestinal incompatibility
  • bypassing hepatic ‘first pass’ effect
  • minimization of some inter- and intra-patient variability in gastrointestinal absorption
  • predictable and extended duration (over days) of activity
  • reduction of side effects due to a less fluctuating blood drug concentration-time profile
  • reversibility of drug delivery upon removal of drug source, although absorption does not always cease immediately
  • enhancing patient compliance
    
    • eliminate frequent or daily dosing schedules
    • better accepted by patients having difficulty swallowing tablets and capsules
    • avoid irritation of the gastrointestinal mucosa by orally administered drugs

Question 95

Challenges in the development and use of TDD:

Answer 95

• Limited dose loading per patch (μg to 10-30 mg)
  
  • Need drugs that are potent
• Drug must have adequate skin permeability and reasonable solubility
  
  • recalls because of recrystalization
• Manufacturing difficulties (fentanyl patch recall due to membrane breach)
• Skin irritation

Question 96

Three types of TDD

Answer 96

• drug-in-adhesive
• reservoir system
• matrix system

Question 97

Drug-in-adhesive TDD

Answer 97

• single of multi-layer
• multi- layer system: the layer closer to the skin is for immediate release and the outer layer is for controlled release of the drug
• Disadvantage: little control over release rate; limited amount of drug can be loaded into the adhesive.

Question 98

reservoir system TDD

Answer 98

• holds a solution or suspension of the drug in a liquid or gel behind a rate-controlling membrane
• release kinetics is usually zero-order
• contact adhesive may contain drug for immediate release.

Question 99

matrix system TDD

Answer 99

• Newer
• semi-solid matrix containing dispersed drug or suspended drug particles
• Release rate is governed either by diffusion through the matrix or a rate-controlling membrane separates the matrix from the contact adhesive
• contact adhesive may contain drug for immediate release.

Question 100

Notable Features of TDD

Answer 100

• Release of drug from the transdermal system is preferably the rate-limiting step, which minimizes intersubject variations in skin permeability.
• Skin enhancer is at times incorporated into the system and delivered along side with the drug to improve skin permeability.
• For very lipophilic drugs (e.g., fentanyl), following the initial application of a transdermal patch, the skin underneath the patch absorbs and concentrates the drug to form a depot. The drug then becomes available to the systemic circulation. Hence, blood concentration of the drug continues to rise over the first few applications until a steady-state is reached.
• After removal of the patch, continued absorption of the drug from the depot means that it may take some time to clear the drug from the body system.

Question 101

Drugs are applied topically to the eye for various local effects:

Answer 101

• Pupil dilation (tropicamide, phenylephrine)
• Anesthesia (proparacaine; tetracaine)
• Treatment of:
  
  • bacterial conjunctivitis (antibiotics)
  • allergic conjunctivitis (ketorolac, prednisolone)
  • glaucoma (prostaglandins, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, miotics or cholinergics)
  • eye inflammation and pain (scopolamine

Question 102

Injections into the eye

Answer 102

• intravitreal injection of ranibizumab (Lucentis®) has become common for the treatment of “wet” type age-related macular degeneration.

Question 103

Drugs can be delivered directly to the anterior portions of the eye

Answer 103

• Only about 3% (range 1 to 5%) of the drug dose applied topically to the eye by conventional topical dosage forms is taken into the anterior part of the eye
• Sterile aqueous solution, aqueous suspension, ointment, or conjunctival inserts are used
• Challenging barriers exist for delivery of drugs to the posterior segments of the eye

Question 104

Obstacles to topical drug delivery to the eye:

Answer 104

• Spillage during instillation, lacrimal drainage, and tear dilution
• Systemic (non-productive) absorption through the conjunctiva (leaky, large
• area, highly vascularized)
• Corneal barriers to drug diffusion (corneal epithelium), especially for protein drugs
• Enzymatic breakdown of drugs (pilocarpine, levobunolol, epinephrine, peptides)
• Binding of drug by uveal pigment (timolol)

Question 105

Eye drop is a relatively inefficient means of delivery

Answer 105

• Typical drop is 20 to 50 μL (average about 25-30 μL) in volume
• Compared to precorneal fluid space of only ~7 to 10 μL
  
  • excess tear and eye drop volume rolls down the cheek
  • or exits through the nasolacrimal duct to the nasopharynx, allowing for systemic drug absorption
• Turnover of tears (precorneal) and aqueous humor (anterior chamber); the ocular residence time for topically applied ophthalmic drugs is relatively short
• Surface area of the cornea (main portal to aqueous humor) is limited
• Therefore, adequate therapy with eye drops usually requires either:
  
  • being able achieve a high initial effect (i.e., maximize drug dose) to extend drug effect for a sufficient period of time
  • or, more frequent applications of a lower dose ─ compliance issue!

Question 106

Optimum formulation development of topical ocular agents is very important for achieving:

Answer 106

• adequate ocular bioavailability
• comfort and safety

Question 107

Formulation requirements include the following for ocular drugs:

Answer 107

• adequate drug solubility (required dose in small drop volume)
• optimization of pH (avoid lacrimation response, optimize absorption)
• osmolarity (minimize irritation)
• preservative effectiveness (multidose formulations)
• drug stability in solution

Question 108

Corneal epithelium is the major barrier to drug absorption into anterior chamber of aqueous humor

Answer 108

• The usual physicochemical considerations apply to ocular drug absorption: corneal permeability is related to drug lipophilicity and ionization
• Eye inflammation could alter corneal permeability depending on the drug molecule
• pH probably governs the diffusion of weak acids and bases across the cornea into aqueous humor. Studies in the rabbit eye showed
• absorption of pilocarpine into aqueous humor increased (>2-fold) as pH is raised from pH 5 to pH 8
  
  • pilocarpine is a cholinergic agonist used to control intraocular pressure in glaucoma; a weak base with pKa = 6.78 (some sources pKa = 7.1), log P = 0.12, water solubility 31.2 mg/mL; higher nonionized fraction is achieved as pH rise above pKa
• parallel increase in absorption of a nonionized marker, glycerin
• later study showed that lacrimation response decreases over this pH range, which may have resulted in a slower turnover of precorneal fluid volume and contribute to the pH effect

Question 109

Eye drop volume and interval affects absorption

Answer 109

• Animal studies have suggested that instillation of smaller eye drop volumes of somewhat higher drug concentration might be more effective (leading to more drug absorption)
• Instillation of 10 μL of a 2% epinephrine solution (20 mg/mL x 0.01 mL = 0.2 mg) to rabbits gave the same pupillary response as did 50 μL of a 1% solution (10 mg/mL x 0.05 mL = 0.5 mg), and 10 μL produced less pain and lacrimation
• Unfortunately, conventional eye drop bottles cannot dispense volumes <20 μL accurately; also patients cannot feel the tiny drop!
• In addition, drug absorption is altered by adding a saline drop either 30 seconds later or 2 minutes later
• An interval of at least 2 to 5 min between ophthalmic dosing appears to be required for effective absorption due to volume effects
  
  • This argues for a combination ophthalmic product, where possible, rather than separate solutions

Question 110

Nasal lacrimal duct obstruction (NLO) slows the drainage of tears and increases drug exposure

Answer 110

• NLO can be achieved by pressing a fingertip on the inside corner of the eye (punctual occlusion) after application of the drop; simple eyelid closure achieves the same effect

• NLO decreases lacrimal drainage and increases drug residence time in the precorneal fluid, thereby increasing drug absorption into anterior chamber

Question 111

Local and systemic effects of drugs can occur for drugs administered by the ophthalmic route

Answer 111

• Therefore, unintended and “unwanted” systemic absorption of ophthalmic non-selective beta-blockers could affect pulmonary or cardiac function. FDA has required timolol ophthalmic products to carry warning of the potential of aggravating broncospasm in asthmatic patients or provoking cardiac failure in patients with preexisting cardiac dysfunction.

Question 112

Formulation can influence the magnitude and duration of ocular response

Answer 112

• Comparison of solution and suspension formulation of flurometholone, an ophthalmic anti-inflammatory agent
• Concentrated solution has a longer effect

Question 113

Nasal drug administration and absorption

Answer 113

• Drugs are administered intra-nasally for the alleviation of local symptoms as well as for systemic effects; examples for
  
  • local delivery includes decongestants, antihistamines, and corticosteroids
  • systemic delivery includes nicotine, desmopressin, oxytocin, salmon calcitonin, LHRH agonists (buserelin, nafarelin)

Question 114

Nasal anatomy and drug absorption

Answer 114

• Human nasal cavity has a 5-10 mL total volume and a total surface area of 150 cm²; however, the effective delivery volume for conventional nasal spray is limited to 100-150 μL because of the labyrinth of the nasal passage
• Drug absorption occurs mainly across the mucosa in the respiratory region, which is constituted by the epithelium, basement membrane, and lamina propia (vascularized by fenestrated capillaries, lymphatic drainage)
• Drug diffusion barrier includes the respiratory nasal epithelium and its 5- μm thick mucus covering
• Nasally absorbed small molecule drug directly enters the systemic circulation, thereby avoiding hepatic first-pass metabolism

Question 115

Intranasal administration may offer an alternate delivery strategy for drugs with significant oral first-pass metabolism

Answer 115

• Propranolol is a high hepatic clearance drug subject to significant first-pass hepatic metabolism. Comparison of plasma propanolol AUC after PO, IV and intranasal routes of administration; n = 6 male subjects
  
  • Nasal about as good as IV
• Examples of other high first-pass drugs delivered by nasal spray: butorphanol (Stadol NS), fentanyl (Lazanda)

Question 116

Intranasal administration of nicotine provides faster rate of absorption than chewing gum dosing

Answer 116

These data explain the relative lack of success of nicotine gum for smoking cessation

Question 117

Influence of physicochemical parameters on bioavailability of small molecular weight drugs administered by intranasal route

Answer 117

• The usual physicochemical variables, i.e., molecular size, lipid solubility, and ionization of weak acids and weak bases, apply to nasal absorption
• Drugs with MW larger than 1000, e.g., polypeptides, exhibit poor nasal bioavailability, a MW threshold higher than that of GI mucosa (~500)
• However, the relationship of MW or molecular size and nasal bioavailability is curvilinear and varies across species

Question 118

Absorption enhancers for nasal drugs

Answer 118

• Drugs with poor nasal bioavailability could be formulated with permeation enhancers (absorption promoters) to improve absorption
• Surface active agents (bile acids) are effective enhancers; however, there is concern of tolerability and safety over their long-term application to the nasal mucosa
• Nasal cilia functions to propel overlying mucus containing trapped dust, allergens and bacteria to the back of the throat; some drugs and enhancers are known to suppress nasal cilia movement

Question 119

Absorption characteristics of the lung

Answer 119

• The alveolar epithelium allows remarkably efficient exchange of gases and volatile compounds, as well as absorption of drugs due to its
  
  • high permeability
    
    • rich vascular supply
  • large absorptive surface
  • (~75 to 100 m2, compared to ~200 m2 for small intestine)
• However, delivery of aerosolized drug to the distal portion of the bronchial structure poses a challenge. Drug deposition along the pulmonary tract is governed by:
  
  • physical properties of the droplets (liquid) and/or particles (solid) being delivered
  • mechanical aspects of aerosol dispersion from the delivery device aerosol = a gaseous dispersion of fine solid or liquid particles
  • individual’s **respiratory function **

Question 120

Advantages of pulmonary delivery of drugs: In the treatment of respiratory diseases (local effect)

Answer 120

• delivers high drug concentrations directly to the disease site
• minimizes risk of systemic side-effects
• produces rapid clinical response
• bypasses the barriers to oral delivery, such as poor gastrointestinal absorption and first-pass metabolism in the liver
• achieves a similar or superior therapeutic effect at a fraction of the oral dose
  
  • for example, oral salbutamol 2 to 4 mg is therapeutically equivalent to 100 to 200 μg by MDI for treatment of asthma and COPD

Question 121

Advantages of pulmonary delivery of drugs: treatment of systemic disease (in principal)

Answer 121

• a noninvasive ‘needle-free’ delivery system
• no gut and hepatic first-pass metabolism that occurs with oral administration
• suitable for a wide range of substances from small molecules to very large proteins
• There are few examples of drugs delivered by inhalation for systemic use (withdrawal of Exubera – inhaled insulin). Reasons being:
  
  • use of inhalation device is a challenge for a significant segment of patients
  • many protein pharmaceuticals are difficult to deliver in inhaled form
  • lung toxicity from long-term, high drug exposure is a concern (lung cancer with Exubera)

Question 122

Biophysics of inhalation delivery

Answer 122

• Physical properties of delivered aerosol droplets and particles influence their fate during transit through (into or out of) the airways of the lungs
  
  • Aerosol droplet or particle “diameter” is important in determining their deposition site
  • Density and shape may also be important (most pharmaceutical aerosol particles are symmetrical and behave as if they are spheres)

Question 123

Optimal aerosol/particle size for delivery to the alveoli

Answer 123

• thought to be ~1 to 5 μm, depending on particle shape and delivery mechanism
  
  • Large particles (>5 μm) are quickly cleared by impaction in the mouth, throat, and upper airway
  • Some intermediate size particles (3-5 μm) are filtered out by gravitational sedimentation in the upper and mid portions of the bronchial tree, where absorption is minimal because of limited epithelial surface area
  • Most small particles (<3 μm) reaches the alveoli. However, retention is limited to particles >1 μm; particles <1 μm are exhaled.
• Delivering the appropriate aerosol droplet or particle size is challenging, but it is critical in determining the efficacy of the inhaled drug

Question 124

Inhalation delivery devices

Answer 124

• Nebulizer which uses compressed air or ultrasonication to create aerosol droplets from a drug solution or suspension, administered through a mouth piece; unsuitable for widespread use in ambulatory setting, hard to carry around
• Propellant-driven or pressurized aerosol inhaler (metered dose inhaler); aerosol solutions and powders
• Dry powder inhalers (e.g., Diskus

Question 125

Nebulizer: Advantages and Disadvantages

Answer 125

• Advantages:
  
  • delivers large doses
  • suitable for infants/sick people physically unable to use other devices
• Disadvantages:
  
  • Bulky
  • Nonportable
  • Contents easily contaminated

Question 126

MDI: Advantages and Disadvantages

Answer 126

• ​Advantages:
  
  • Compact
  • Portable
  • Multidose
  • sealed environment (no drug degradation)
• Disadvantages:
  
  • inhalation technique and coordination required
  • High oral deposition

Question 127

Dry Powder Inhalers: Advantages and Disadvantages

Answer 127

• Advantages:
  
  • Breath actuated
  • No hand-mouth coordination required
• Disadvantages
  
  • Respirable dose dependent on inspiratory flow rate
  • Humidity may cause drug aggregation

Question 128

MDI: Parts and Pieces

Answer 128

• Canister
• Actuator (mouth piece)
• metered valve
• surfactants to stop clumping
• lubricants to get drug through valves
• shake well to mix ingredients
• shearing forces break droplets into aresol
• Formulation for a propellant-driven MDI consists of propellant(s), drug in cosolvents, and surfactants. Used to be CFC, had to change to HFA. Costly change.
• accurate metering of small doses of drug is achieved by a small but complex metering valve (dependable and reproducible)

Question 129

Typical distribution of drug when delivered by a metered dose inhaler (MDI)

Answer 129

• Drug particles deposited on the surface of the trachea and bronchi and left unabsorbed are swept retrograde by ciliary movements into the oropharynx and swallowed

Question 130

Limitations with a metered dose inhaler (MDI)

Answer 130

• Synchronization of the release of metered dose (actuation) with the beginning of a deep inspiration (hand-lung coordination) is needed
  
  • 1/2 to 2/3 of patients use improper techniques of inhalation
  • **~15% or more of patients unable to coordinate even after instruction **

Question 131

Spacer devices

Answer 131

• designed to help individuals with coordination problems for MDI
  
  • slow the aerosol jet stream and thereby reduce impact in the oropharynx
  • introduce a time delay between actuation and inspiration (improve hand-lung coordination)
  • studies have shown that spacers are best indicated for patients with coordination problems (e.g., children) or who develop oral candidiasis (thrush fungus) with inhaled corticosteroids and topical side effects

Question 132

Breath-actuated pressurized metered dose inhaler

Answer 132

circumventing hand-lung coordination challenge (3M Autohaler

Question 133

Dry Powder Inhalers

Answer 133

• All are breath-actuated; circumvents the hand-lung coordination problem
• Some patients find that the fine powder irritates their upper airway
• Patients suffering from a severe asthmatic attack or patients with severe chronic obstructive pulmonary diseases might have **trouble taking a deep enough inspiration to deliver the dose fully **

Question 134

Gargling and rinsing of the mouth with water

Answer 134

• recommended following each use of inhaled corticosteroids delivered either by MDIs or dry powder inhalers to avoid oral oral candidiasis from local immunosuppression.

Question 135

Rectal route considered when

Answer 135

• Oral drug dosing is not feasible (e.g., patient nauseous or vomiting) and/or for local effect
• Suppositories are used more frequently in children than in adults
• Rectal route is far more popular outside of the United States

Question 136

Examples of rectal drugs:

Answer 136

• Antipyretics and analgesics ─ aspirin, acetaminophen
• Anticonvulsants ─ diazepam, paraldehyde
  
  • diazepam can be a prefilled rectal syringe that needs to be set by the pharmacist
• Antiemetics ─ prochlorperazine, cyclizine
• Antipsychotics ─ chlorpromazine
• Corticosteroids ─ hydrocortisone

Question 137

Dosage forms of rectal drugs

Answer 137

• Retention enema (solution)
• Suppositories
  
  • oleaginous base (theobroma oil or cocoa butter)
  • water soluble polymer base (mixed polyethylene glycols)

Question 138

Anorectal anatomy and physiology

Answer 138

• Length of human rectum 10 to 15 cm; circumference 15 to 35 cm (distended); diameter 2.5 to 5 cm; total surface area of 200 to 400 cm²
• Mucosa is devoid of villi; therefore limited absorbing surface area, compared to small intestine
• Richly vascularized ─ lower, middle, and upper hemorrhoidal veins; **only the upper vein drains into portal blood supply **

Question 139

Drug absorption via the rectal route

Answer 139

• Rectal drug absorption is more variable than oral drug absorption
• Volume of fluid in the rectum is about 1-3 ml and fluid is rather viscous, so drug dissolution is a problem
• Presence of fecal matter can further decrease drug dissolution rate, or retard diffusion to the absorbing surface; predose cleansing enema can improve drug absorption
• Retention of drug suppository in rectum is a critical factor for drug bioavailability, therefore evacuation or urge to evacuate bowel is a problem
  
  • High MW PEG is irritating and can cause evacuation
• Vehicles or formulation components that are irritating to the rectum are generally avoided
• There are notorious examples of poor absorption from badly formulated rectal suppositories (especially extemporaneous preparations)

Question 140

A potential advantage of rectal drug administration is the **avoidance of hepatic first-pass drug metabolism **

Answer 140

• middle and inferior rectal veins drain the lower part of the rectum and enter into the inferior vena cava; hence, by-passing the liver, avoid first-pass metabolism, and increased systemic availability
• blood from the superior rectal vein flows through the portal circulation into the liver, and some hepatic first pass drug metabolism can occur
• Plasma concentrations of lidocaine following 200 mg IV infusion, 300 mg rectal and 300 mg oral administration.
• Lidocaine subjected to extensive first-pass in the liver, such that its oral bioavailability = 35%. In comparison, rectal bioavailability ~100%!