Pharmaceutics Flashcards
What is the blood supply to the brain?
100 billion capillaries
Over 400 miles long
Surface area of around 20 m2
Why can’t all drugs enter the brain?
The brain requires significant amounts of small, hydrophilic molecules such as glucose and amino acids
CNS and peripheral pools of neurotransmitters & neuroactive agents need to be kept separate
The passage of these species is very tightly controlled by specific barriers to ensure the brain has exactly the right biochemical make up, excluding potential neurotoxic compounds
What is the BBB?
BBB is barrier from capillaries to brain, protection
Brain blood vessels have extra protection, a physical and biochemical barrier. Tight junctions mean the BBB can physically restrict passage of molecules
Many disease states disrupt the barrier function, e.g., stroke, Alzheimer’s disease, HIV, brain tumours, MS, Parkinson’s disease
Bradykinin can open tight junctions
What are the 4 transport pathways across the BBB?
Water soluble through junctions
Lipid-soluble through oathway
Glucose enters through transport proteins
Insulin through transcytosis
What is passive diffusion across the BBB?
The mechanism by which the majority of small drug molecules enter the brain
Non-saturable diffusion down a concentration gradient
Can only occur if
- LogP around 1.5 to 2.5
- MW ~400
As lipophilic as possible eg Nicotine (mannitol very hydrophilic so bad)
(D-glucose is active transport)
What are the 8 methods of non-invasive delivery to the BBB?
- Improving peripheral PK
- Transporter-Mediated Transport
- Nanoparticles
- Receptor-Mediated Transport
- Conjugation with Cell-Penetrating Peptides (CPPs)
- Inhibiting efflux systems
- Viral vectors for gene delivery
- Bypassing the BBB
Improving peripheral PK to cross the BBB
Peptide and nucleic acid analogues, protein PEGylation (add poly ethylene glycol reduced clearance in kidneys, in blood longer). Enhancing Lipophilicity to make them more fat-soluble to diffuse across the BBB. Can lead to issues with lack of specificity.
Transporter-Mediated Transport to cross the BBB
Exploiting natural transporters (e.g., glucose, amino acid transporters) to carry drugs across the BBB.
Nanoparticles to cross the BBB
Using nanoparticles (liposomes, micelles, dendrimers) to encapsulate drugs and facilitate their crossing of the BBB.
Receptor-Mediated Transport to cross the BBB
Targeting specific receptors (e.g., transferrin receptor) on the endothelial cells of the BBB to facilitate drug uptake.
Conjugation with Cell-Penetrating Peptides (CPPs) to cross the BBB
Attaching drugs to peptides like Tat peptides that can cross the BBB.
Inhibiting efflux systems
P-gp can be inhibited by verapamil, a voltage-gated Ca2+ channel blocker, verapamil has shown promising results in drug-resistant epileptics. However, many endogenous and exogenous ligands are P-gp substrates - potential neurotoxicity
Viral vectors for gene delivery
Gene therapy to treat certain diseases, ideally administer systemically and virus crosses BBB
Bypassing the BBB
Olfactory epithelium, BBB not present. Drugs can enter by paracellukar diffusion.
What are the 3 methods of invasive delivery to the BBB?
- Convection-Enhanced Delivery (CED)
- Disruption of the BBB: Hyperosmotic infusion
- Disruption of the BBB: Physical disruption
Disruption of the BBB via physical disruption
Focused ultrasound (FUS): mAbs are generally ~150 kDa and do not normally penetrate. BBB can be perturbed temporarily by FUS
MRI-guided focused ultrasound (FUS):
1. Injection of Herceptin
2. Sonication
3. Injection of MRI contrast reagent
Microbubbles are essential for the BBB disruption
Disruption of the BBB via hyperosmotic infusion
Hypertonic solution of arabinose or mannitol infused into the carotid artery for 30 s. Non-specific 10-fold increase in BBB permeability lasting ~10 min following hyper-osmotic exposure
Results in malignant brain tumour treatment are encouraging, but procedure not widely accepted
Convection-Enhanced Delivery (CED)
Continuous positive-pressure infusion of a solution containing a therapeutic agent. It is targeted to diseased region and can be monitored in real-time. Better penetration than diffusion-based delivery
What are CDDSs?
Preparations designed in such a way that the rate or location of API release is controlled
Often referred to as modified release or extended release preparations
What are the 4 reasons CDDSs are used?
- Reduce fluctuations in drug plasma concentrations
Reduce concentration-related side-effects e.g., rapidly absorbed drugs
Often used for drug with a narrow therapeutic index - Reduce dosing frequency
Improve patient compliance
Especially useful for drugs with short half-lives - Control delivery site
Releases drug at site of optimum absorption or site of action (e.g., colon for bowel disease, tumour targeting) - Timed release
Drug release is delayed or pulsed, so it occurs when there is a clinical need e.g., angina, asthma, etc; hormones; vaccines
What are the 4 mechanisms for CCD?
Water Penetration-Controlled DDS
- Swelling
- Osmosis
Diffusion-Controlled DDS
- Reservoir devices
- Monolithic devices
Chemically-Controlled DDS
- Monolithic devices – surface or bulk erosion
- Pendant systems
Responsive DDS
- Physical
- Chemical
What are the 3 types of water penetration CDDSs?
Hydrogels
Osmotic Systems
Polymeric Matrices
What are hydrogel water penetration CDDSs?
These are materials that absorb a lot of water and swell up when they come into contact with it. The drug is trapped inside, and as the material swells, the drug slowly escapes. Polyethylene glycol (PEG)-based hydrogels. The rate of swelling is a key factor in controlling the release rate.
What are osmotic system water penetration CDDSs?
These systems use the pressure from water entering the system to push the drug out in a controlled way. Think of it like a small pump inside the body where water moves in, creating pressure that releases the drug.
Example: Some extended-release tablets that release the medicine over time by letting water push the drug out.
What are polymeric matrix water penetration CDDSs?
These are materials made of long polymer chains that swell or dissolve when they absorb water. The drug can be spread throughout the polymer, and as the polymer swells, the drug gradually comes out.
Example: A controlled-release pill that slowly lets go of the drug as it breaks down with water.
What are the 4 types of diffusion-controlled DDS?
Reservoir
solution diffusion
pore diffusion
matrix
How does a Matrix Diffusion CDDS work?
The drug is dispersed throughout a polymer matrix. As the matrix comes in contact with body fluids, the drug gradually diffuses through the polymer.
Example: A tablet or capsule that has the drug spread throughout the polymer, and as the material absorbs fluid, the drug is slowly released.
How do reservoir diffusion CDDS work?
In this system, the drug is contained in a core (reservoir) surrounded by a semipermeable membrane. The membrane allows the drug to diffuse out at a controlled rate.
Example: A drug-filled capsule or implant with a membrane around it that releases the drug slowly over time.
How do solution diffusion CDDS work?
Solution Diffusion-Controlled Drug Delivery Systems release drugs gradually by allowing a drug dissolved in a solution to diffuse out through a membrane or matrix. The system controls the rate at which the drug moves from inside the system to the outside environment, allowing for steady, sustained release over time. These systems are used for extended-release medications and can improve bioavailability and patient convenience by reducing the need for frequent dosing.
How do pore diffusion CDDS work?
Pore Diffusion-Controlled Drug Delivery Systems use tiny pores in a membrane or matrix to allow a drug to gradually diffuse out of the system. The rate of diffusion controls how quickly the drug is released into the body. These systems are often used to provide steady, sustained drug release over time, improving patient compliance and therapeutic outcomes. The design of the system—especially the size and number of pores—determines how fast or slow the drug will be released.
Polymer matrix Chemically-Controlled DDS
Diffusion-Controlled Release:
The drug is released as it diffuses from the polymer matrix through its pores or channels. The polymer matrix does not degrade; instead, it simply allows the drug to diffuse out gradually.
Degradation-Controlled Release:
Some polymers are designed to degrade over time, releasing the drug as the polymer hydrolyzes or undergoes other types of chemical degradation.
This mechanism is often used in biodegradable polymers like PLGA, where the polymer’s degradation rate is controlled to release the drug gradually over a period of time.
PLGA breaks down into lactic acid and glycolic acid, which are naturally metabolized by the body.
Polysaccharide-based systems (like chitosan or alginate) can also degrade over time, releasing drugs in a controlled manner as they break down.
What types of natural polymers are used in chemically controlled DDSs?
Natural polymers
Polysaccharides: alginate, chitosan, dextran, hyaluronic acid, and starch.
Proteins: Albumin, collagen, and gelatin are examples of proteins that can be used to create drug delivery systems.
What types of synthetic polymers are used in chemically controlled DDSs?
Poly(lactic acid) (PLA) and Poly(lactic-co-glycolic acid) (PLGA): These are biodegradable and biocompatible, hydrolysedn into non-toxic products
Polyethylene glycol (PEG): PEG is used to increase solubility or modify the release rate. PEG can form micelles or nanoparticles for drug encapsulation.
Polycaprolactone (PCL): Used in creating slow-release systems due to its slow degradation rate
Polylactic acid (PLA): PLA is used in controlled-release systems where slow degradation is needed
9 factors affecting polymer degradation rate of Chemically-Controlled DDS
- Chemical structure of polymer
- Polymer molecular weight
- Presence of low MW compounds, e.g., drugs and excipients, residual solvent
- Crystalline vs amorphous polymers
- Size and shape
- Processing method
- Porosity
- Site of implantation
- Degradation mechanism - enzyme vs water
What are enteric coated drugs?
Tablets coated with a polymer that is insoluble in the highly acidic environment of the stomach, but dissolves in the small intestine (>pH 5.5)
Can protect the drug from the stomach (e.g. erythromycin) or the stomach from the drug (e.g. NSAIDs)
Numerous polymers available, including cellulose derivatives and methacrylic acid co-polymers (Eudragit®)
Release area can be tailored depending on pH/solubility profile
How are enteric coated drugs made?
3D printed
Fused deposition modelling (FDM) is the most accessible type of 3D printing
Uses a polymer filament, which is melted and extruded layer by layer to form a 3D print
Huge interest in all types of 3D printing, including FDM, for production of personalized dosage forms - tailoring dose and release profile
Polymer and drug melted together and extruded to generate a filament
Drug matrix printed within enteric coating of different thicknesses
chemical-controlled release - bulk erosion
Common polymers used for bulk erosion include polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly(caprolactone).
Bulk erosion occurs when water penetrates the polymer matrix, causing it to degrade from the inside out.
As the polymer matrix absorbs water, it begins to break down chemically through processes such as hydrolysis, enzymatic degradation, or chemical cleavage of the polymer chains.
The polymer loses its integrity as the degradation progresses, and this allows the active drug to diffuse out of the matrix at a controlled rate.
Bulk Erosion: rate of release controlled by
The chemical composition of the polymer,
The degree of cross-linking within the polymer,
The molecular weight of the polymer chains,
The hydration properties of the polymer
chemical-controlled release - surface erosion
In surface erosion systems, the drug is usually encapsulated in a polymer that degrades from the surface inward. The degradation occurs at the outer surface first, forming a degradation front that moves inward as the polymer erodes.
The polymers used in surface erosion are often hydrophobic (water-repelling) and are designed to degrade via chemical breakdown when exposed to water or body fluids.
Common polymers for surface erosion include polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polyethylene glycol (PEG).
What are the 5 advantages of chemical-controlled release - surface erosion?
More Predictable Drug Release
Linear Drug Release
Less Risk of Residual Material
Control Over Release Duration
Targeted Delivery
chemical-controlled release - pendant systems
the drug is covalently attached to a polymer backbone through pendant groups or side chains.
The drug is released through, linker degradation, diffusion, or cleavage, offering a controlled and sustained release profile.
Electrospun Matrices for Controlled Drug Delivery
Numerous applications for drug release throughout the body (e.g., dressings, implants), plus tissue engineering and regenerative medicine.
They are highly customizable, allowing for precise control over drug release rates, matrix structure, and fiber morphology.
Drug is mixed with polymer and electrospun to give matrix or chemically-controlled DDS
PEVA does not degrade - diffusion-controlled matrix release
Effectively created a reservoir system, with the PCL layers acting as a rate-controlling membrane
Electrospinning is a process where a polymer solution or melt is subjected to a high voltage, causing the polymer to stretch into fine fibers.
What are the 6 types of responsive DDS?
Drug release controlled by:
- pH
- Chemicals (metabolites)
- Enzymes
- Ultrasound
- Magnetism
- Light
Predominantly used in implantable devices or parenterally delivered DDS
pH-Sensitive Polymers
Changes in ionization or cleavage of functional groups due to altered pH can affect sol-gel behaviour
e.g. Poly(propylene imine) dendrimers:
They are particularly useful in areas where the pH varies, such as in the gastrointestinal tract (GI tract), tumor microenvironment, or inflammatory sites.
Polymeric hydrogels that swell and release the drug at low pH
Acid-Sensitive Linkers
The tumour microenvironment can be 0.5 to 1.0 pH units lower than normal tissues
Acid-sensitive linkers are designed to release drug in the acidic conditions in tumours, endosomes and lysosomes
Binds to circulating albumin following administration
Does not accumulate at non-specific sites (heart, marrow GI tract)
Reduced side effects, improved efficacy and quicker to reach the tumour than doxorubicin alone
Enzyme-Responsive DDS
Ulcerative colitis, Crohn’s, etc
These systems use the presence of specific enzymes (either endogenous or exogenous) to trigger drug release.
Enzymes like proteases, lipases, or hydrolases can break down the polymeric matrix or cleave a drug-linker to release the therapeutic agent.
Polymers with peptide linkers that are cleaved by specific enzymes, such as matrix metalloproteinases (MMPs), which are often overexpressed in tumor tissues.
Polysaccharides like chitosan, which can degrade in the presence of specific enzymes (e.g., chitosanase).
Magnetism and Delivery/Release
Magnetism can be used for both targeting and release of drugs
Drug can be attached by a chemical bond or embedded in the polymer matrix
Release by diffusion, pH change, magnetic field or interaction with cellular component
Can directly kill or remove cancer cells
These systems respond to magnetic fields and can be used for targeted drug delivery. Magnetic nanoparticles or carriers loaded with drugs can be directed to specific sites in the body using an external magnetic field, and drug release can be triggered by the field.
Magnetic nanoparticles that can be loaded with drugs and directed to a tumor site using a magnetic field. The magnetic field can also induce local heating (hyperthermia), which facilitates drug release.
Responsive DDS: Mesoporous Silica Nanoparticles
Mesoporous silica nanoparticles (MSNs) are inorganic nanoparticles. They are made from silica (SiO₂) and characterized by uniform pores typically 2–50 nm. These give MSNs a high surface area, allowing them to hold a large amount of drug. Thermally stable, easy to functionalize, controlled particle size, great potential for controlled delivery of traditional drugs, proteins and nucleic acids.
Following drug loading, pores can be capped with nanoparticles that can be selectively be removed by pH, light, magnetism, antigen, S-S reduction or saccharide
What are the 3 pros of controlled DDS: Implantable Devices?
Convenience
Compliance
Control
What are the 4 cons of controlled DDS: Implantable Devices?
Surgery
Failure
Potency
Reactions/compatibility
What are the 5 long term uses of controlled DDS: Implantable Devices?
Contraception
Pain management
Diabetes
Incontinence
Systemic infection
What are the 5 localised uses of controlled DDS: Implantable Devices?
Ocular
Dental
Contraception
Pain
Vasculature
Rods – Diffusion-Controlled DDS
Jadelle®:
Used from late 1990s
75 mg drug per rod
100 µg/day → 40 µg/day → 30 µg/day
Coils - Diffusion-Controlled DDS
52 mg levonorgestrel
PDMS
20 µg/day → 14 µg/day
Local delivery
Easily reversible
Vaginal rings– Diffusion-Controlled DDS
Flexible, drug-containing polymer rings (usually silicone-based) which are seated around the cervix
Numerous products on the market, in trials or development for the delivery of:
Contraceptive therapy
HRT
IVF therapy
microbicides (HIV, herpes, etc)
Different types of ring with release of drug from 3 weeks to 3 months
NuvaRing®
2” diameter ethylene-vinyl acetate copolymer ring
Controlled release of contraceptive for 3 weeks
99% effective
RETISERT™ Intravitreal Implant (pSivida) – Diffusion-Controlled DDS
Chronic noninfectious uveitis
Approx. 3 mm x 2 mm x 5 mm
0.59 mg tablet of fluocinolone acetonide
Silicone elastomer cup
PVA membrane and suture tab
0.6 µg/day → 0.3 to 0.4 µg/day
30 months total
Age-related Macular Degeneration (AMD)
Diabetic Macular Edema (DME)
Glaucoma
BravoTM polymer matrix
Drug release up to 2 years
15 minute procedure
Sub-conjunctiva
What are Drug-Eluting Stents (DES)
Drug-eluting stents (DES) help to prevent narrowing of the artery by delivering drugs that inhibit cell proliferation and reduce inflammation.
While they offer improved long-term outcomes compared to bare-metal stents, DES come with increased risks (e.g., stent thrombosis, longer need for antiplatelet therapy) and higher costs.
The choice of drug and biocompatibility of the coating play a crucial role in their effectiveness and safety.
Polylactic acid backbone, stent is bioabsorbed in 2 years by bulk erosion
Implantable Osmotic Delivery Devices
~150 µl drug formulation
Zero-order release up to 12 months
Drug protected
Subcutaneous implant
Controlled Delivery to the Brain
For treatment of high-grade malignant gliomas
After surgery, residual glioma cells can double in number every 10 days, treatment usually starts 14 days after surgery
Typical life-span post-surgery < 1 year
GLIADEL wafers contain 7.7 mg of the chemotherapeutic carmustine
Systemic delivery can cause low blood count and lung toxicity
14.5 x 1 mm wafers erode over 2 to 3 weeks
Combined with radiotherapy
Implantable Pumps
Used for:
Chronic intrathecal or epidural infusion of morphine sulphate for chronic, intractable pain
Chronic intrathecal infusion of ziconotide sterile solution for the management of severe chronic pain
Chronic infusion of baclofen for severe spasticity of spinal or cerebral origin
Chronic intravascular infusion of floxuridine or methotrexate for the treatment of cancer
What are the requirements for Future Directions of CDDSs
Requirements:
1. A shape and size that can be ingested by a subject
2. The ability to adopt a conformation in the stomach the prevents passage to small intestine
3. Ability to carry large drug load
4. Controlled drug release for weeks or months with little or no potential for burst release
5. Maintain long-term drug stability in low-pH
6. Degrade/dissolve or dissociate into forms in a predictable manner that can exit the stomach and pass through the GI lumen with no potential for obstruction or perforation
7. Safety mechanisms enabling dissociation of the device if it accidentally passes into small intestine
What are the 5 cons of implantable pumps?
Always “wearing” a device
Change the set every three days
Skin irritation/infection
Some poor skin insert sites
Peripheral insulin delivery
Dissolution and Release processes as rate-limiting steps
Drugs with poor solubility:
The rate constant for dissolution is smaller than the rate constant for absorption
A very slow dissolution process can limit the rate of the following steps
When this occurs, dissolution becomes the “rate-limiting step”.
Modified-release formulations:
Sustained and extended forms which release the drug slowly over an extended period of time
The rate constant for release is smaller than the rate constant for absorption
The slow release process limits the rate of the following steps and becomes the “rate-limiting step”.
When an increase/decrease in the dissolution rate leads to faster/slower absorption. E.g., drug in solid dosage form compared to drug in solution
When an increase/decrease in the release rate leads to faster/slower absorption. E.g., immediate versus slow-release formulations.
Either dissolution or release is slow.
Any drug dissolved/released is readily absorbed.
But absorption cannot proceed faster than dissolution/release.
Thus:
The systemic input of the drug (absorption) is rate-controlled by either the dissolution or the release process.
Changes in dissolution rate or in the release rate will modify profoundly the rate of absorption of the drug
Absorption rate-limited by permeability
Dissolution and release are fast, but absorption is limited by poor permeability.
Most of the drug is dissolved before a significant fraction of the drug is absorbed.
Thus:
The systemic input of the drug is absorption (permeability) rate-limited.
Modifying the dissolution and release rates will have little effect on the rate of absorption of the drug.
Elimination as the rate-limiting process
The most frequent case.
When the absorption rate constant is greater than the elimination rate constant. Or in other words, when the absorption half-life is shorter than the elimination half-life:
The absorption process is faster than the elimination process
and the elimination step controls the decline of the drug concentration during the terminal phase.
Most of the drug has been absorbed and little has been eliminated when the peak is reached.
The decline of the drug in the terminal phase is primarily determined by the elimination (disposition) of the drug.
The rate constant (half-life) obtained from the terminal phase corresponds to the elimination rate constant (elimination half-life).
Absorption rate-controlled kinetics (k > kabs)(“flip-flop” kinetics)
Less frequently, the absorption process is slower than the elimination process.
The absorption rate constant is smaller than the elimination rate constant. Or in other words, the absorption half-life is longer than the elimination half-life.
A very slow absorption will rate-limit all subsequent processes including the drug elimination and therefore, the terminal phase of the PK-profile.
At any time, most of the dose of a drug is:
either at the absorption site or has been eliminated.
A considerable amount of drug has not yet been absorbed when the peak (tmax,Cmax) is reached.
The decline (elimination) of the drug during the terminal phase is rate-controlled by the absorption process: The drug is eliminated as fast as it is absorbed.
The rate constant (half-life) obtained from the terminal phase corresponds to the absorption rate constant (absorption half-life).
How to decide the rate-limiting factor
Look at the properties of the drug: good or poor solubility/permeability?
Type of formulation: immediate or sustained or controlled release
Which step is controlling the kinetics:
- dissolution/release
- absorption
- elimination (most frequent case)
Absolute certainty requires an IV Bolus/infusion to estimate either the elimination rate constant (k) or elimination half-life (t1/2) in the absence of absorption.
Benefits of transdermal drug delivery
Usually patch based
Good patient compliance
- painless
- easy to apply
- multiple dose ease
Can be used for all ages
Avoids first-pass metabolism
Continuous supply of drugs locally and into systemic circulation
Able to maintain drug level within therapeutic window for longer
Relatively easy to stop treatment (peel off patch)
Routes of entry into the skin
Intercellular: In between cells (predominant pathway)
Intracellular: Through cells
Follicular: Through hair follicles
What makes a drug suitable for TDD
- molecule size
- hydrophilic + hydrophobic
- potency important
- sensitization & irritation
- patch size
What is the bricks and mortar model?
Bricks: Corneocytes (terminally differentiated flat keratinocytes filled with keratin)
Corneodesmosomes link the ‘bricks’
Mortar: Lipid matrix (a mixture of ceramides, cholesterol and free fatty acids)
Hydrophobic drugs can travel through the ‘mortar’ while hydrophilic drugs travel mainly via the ‘bricks’ (though they still have lipid-rich mortar to navigate through)
Hair follicles only cover approx. 0.1% of skin surface therefore not ideal
Comparison oral vs topical
Oral absorption rapid (faster rate of absorption than rate of elimination), topical absorption is slow(slower rate of absorption than rate of elimination- ‘flip-flop’ kinetics)
Oral: quick rise of Cp to maximum with t1/2 corresponding to kinetics of elimination, topical: slow rise of Cp to maximum with t1/2 (decay) longer than ODD
Oral: high Cp but repeated doses needed to maintain, topical: Cp not as high but sustained (reduced dosing frequency and increased control)
Avoiding fluctuating Cp
Cp can be somewhat controlled (or rather fluctuating Cp levels avoided) by:
- patch size
- skin site
- adjuvant/ skin penetration enhancers
- easily controlling the lag time between patches
Nitroglycerin
Glyceryl trinitrate (GTN)
Vasodilatory drug: relief from anginal chest pains
Sublingual tablet or spray, IV, ointment and transdermal patch
Decreasing angina attacks where sustained drug delivery is useful
Many side effects: dizziness, palpitations, vertigo, severe headaches, nausea and vomiting
log P ~2, MW ~300 and liquid at room temperature
Avoiding tolerance: drug-free intervals of 10-12 hours needed
An ideal TD
Low MW (<500 Da)
Lipophilic log P/ partition coefficient (octanol-water): 1-5 for optimal permeability
Solubility in water (pH 6-7.4)
Half-life in hr (<10)
Dose <10mg/day
Non irritating and nonsensitizing
Patch size <50 cm2………
What are the 4 parts of TDD systems
Backing: Impermeable side facing clothes (flexible polymers)
Adhesive: Binds patch parts together and adheres patch to skin
Liner: Peelable part to protect patch during storage
Membrane: Added control of drug release profile (polymers/ elastomers)
Scopolamine
Transderm-Scop: motion sickness and post-operative recovery
Patch behind the ear (postauricular), releases drug over 3 days (approx. 5 µg/hr)
Based on the reservoir system
Clonidine
Catapres-TTS: ‘Transdermal Therapeutic System’ vasodilator for hypertension
Usually applied every 7 days (upper, outer arm or upper chest). Issue with adhesion
Drug held in reservoir, membrane to control rate of delivery (steady state obtained in ~3 days).
Sensitization issues, multiple wear difficult (patch size small)
Estradiol
Estradot/ Vivelle/ Evorel…: Post-menopause hormone replacement therapy
Highly potent, delivered via reservoir system (was ethanol which diffused into skin) or matrix system (either twice weekly or once weekly)
Log P < 3 and MW ~230, high clearance, short t1/2
Oral: high first-pass effect in liver (high dose of conjugated equine estrogens with elevated estrone/ estradiol ratio- and therefore side-effects)
Transdermal patch
- restores ratio in post-menopausal women (see plot)
- sustains plasma levels (better outcome)
Fentanyl
Opioid drug for managing severe and persistent post-operative/chronic cancer pain
Requires monitoring (side-effects include breathing difficulties)
(0.3-2.4 mg/ day) - reservoir initially to adhesive matrix
Replacement of patch every 72hrs (12-24 hrs for Cp to stabilise; habit forming (therefore controlled decrease needed + careful disposal)
Good hydrophilic and hydrophobic properties (+ low MW and high potency)
Adhesive can peel (extra adhesive dressings sometimes)
Buprenorphine
Butrans/Transtec: another opioid analgesic (semisynthetic with both agonistic and antagonistic receptor-binding)
Better safety profile (lower opioid dependency than fentanyl) but some studies report better pain management with fentanyl
7-day patch via matrix adhesive
Nicotine
Well-known for smoking cessation (and remains most popular TD patch)
~20 mg/ day (16hr/24hr)
Adhesive/layered/reservoir systems (gum, tablets, inhaler, spray also available)
‘Invisibility’ and size important to users (smaller than credit card + clear or ‘skin’ colour)
Testosterone
Hypogonadism
Review of other drugs used (not with licorice: reduces Cp blocks conversion of androstenedione to testosterone)
24 hr (reservoir and matrix adhesive). Testoderm was originally applied to scrotum (compliance low, moved to upper arm, thigh, abdomen, site rotation/irritation).
Neither popular (gel more conventional)
Norelgestromin-ethinyl estradiol
Ortho Evra/ Evra…: contraceptive impacting ovulation (combination drug: progestin and estrogen)
28 days cycle. New patch applied each week for 3 weeks, and week four is patch-free (recommended 7-day adjustment period- steady-state)
Abdomen, upper body, upper outside of arm, buttocks (adhesive matrix)
150 μg/day of norelgestromin and 20 μg/day of ethinyl estradiol
Oxybutynin
For incontinence
Anticholinergic: blocks acetylcholine preventing ‘urgency’ of urination (inc. uncontrolled release)
Adhesive matrix system- very thin! (rapid absorption, steady-state ~1 hr). 3.9 mg delivered/ day
Extensive 1st-pass effect (metabolised by CYP3A4)
Twice weekly (abdomen, hip or buttock). Changed every 3–4 days to different site
Transdermal methylphenidate
ADHD in children 6-12 years
Adhesive matrix system (multipolymer: acrylic and silicone).
Delivery rate affected by time worn (9 hrs on alternating hip) and size of patch
Avoids 1st pass metabolism: better Cp than oral formulation (and higher Cmax) therefore lower dose required
Selegiline
EMSAM…: Depression in adults and Parkinson’s disease
Matrix adhesive system (potent: 6-12 mg/ day)
Higher Cmax than oral: extensive 1st-pass metabolism avoided, sustained Cp
Decreased metabolite production (therefore decreased side-effects)
Transdermal rotigotine
Parkinson’s disease and moderate-severe restless leg syndrome
Dopamine receptor agonist
24 hr patch with Cp similar to IV infusion (steady-state within 1-2 days of daily application)
Polymer matrix with a permeation enhancer
Rivastigmine
Parkinson’s disease-associated dementia
24 hr patch (drug-loaded matrix) to upper torso
Starting with low dose and increased to 9.5 mg/ day over 4 weeks to build tolerance
Granisetron
Prevention of nausea/ vomiting due to chemotherapy (blocks serotonin)
Up to 7-day patch (large patch size on abdomen or upper arm) delivering 3.1 mg/ 24 hrs
Side-effects complicated by chemotherapy: decreased appetite, dry mouth etc.
Donepezil
Alzheimer’s dementia. Donepezil is reversible inhibitor of the enzyme acetylcholinesterase
7-day patch (drug in matrix with a rate controlling membrane). 5 mg/ day. Increased to 10 mg/ day if required after 4-6 weeks)
Applied to back (avoid using same site for 2 weeks after removal of patch)
Mild skin irritation reported
Metabolite kinetics
Metabolites can be:
Inactive waste products that could be used to:
- measure bioavailability of the parent compound and assess bioequivalence
- detect exposure to illicit drugs.
The active compound:
- a prodrug is administered that depends on metabolism to be activated.
Pharmacologically active and modify the response to the parent compound
- sum to the effect of the parent drug
- have a different effect than the parent compound
- cause toxic effects.
Modify the disposition of the parent compound.
What do we need to know about metabolites
Potential properties of the metabolite:
Activity
Toxicity
Alter binding of the parent compound or other drugs
Alter response to parent drug
Concentration and PK profile of the metabolite
Drug elimination rate-limits the metabolite kinetics
Metabolism of a drug results in a metabolite that is eliminated faster than the parent compound.
Typical examples:
Metabolites such as glucuronide, sulphate and glycine conjugates are more polar and water soluble than the parent compound and are eliminated faster than the parent compound.
The elimination of the metabolite is rate-limited by its formation (or parent drug elimination). Thus, the slope of the terminal phase reflects k
Metabolite kinetics rate-controlled by metabolite elimination
Metabolism of a drug results in a metabolite that is eliminated more slowly than the parent compound.
Typical examples:
Acetylated or other metabolites which are less polar / less water soluble than the parent compound
and
are eliminated more slowly than the parent compound.
The elimination of the metabolite is rate-controlled by its own elimination (kME)
Metabolite accumulation occurs.
Preferable scenario for pro-drugs
Active metabolite from several 7-chloro-benzodiazepine drugs with long t1/2
Nordazepam Css ~ twice diazepam Css following oral multiple doses (see also the different slopes for drug and metabolite terminal phase)
Nordazepam kinetics independent of parent drug administered as they are controlled by its own elimination (see parallel terminal phase decline)
ADME of phenytoin
ABSORPTION
Slowly but completely orally absorbed
Low solubility (14 mg/L) and weak acid (pKa = 8.3)
DISTRIBUTION
Distribution equilibrium in 30-60 min. Vss = 0.6-0.7 L/kg
Rapid distribution to brain; Cbrain Cp
Crosses placental barrier and distributes into breast milk
fu~0.1 in plasma for usual 0.65 mM albumin. fu constant as far as Cphen < 0.1 mM
ELIMINATION
Mostly metabolized, 1-5% renal clearance.
Inactive hydroxylated metabolites, some further metabolized (glucuronides)
60-90% of a dose recovered in urine as p-HPPH and glucuronide p-HPPH
CYP2C9 predominant. PGx variation up to 10-fold in vivo. CYP2C19 also involved
Clinical relevance of capacity-limited metabolism
C and AUC are not directly proportional to the dose
Small changes in dosage cause a large, disproportionate difference in Cp
Narrow therapeutic window: 10-20 mg/L and poor correlation between dose and Cp
Difficult dose adjustments
“Do not switch brands” advice
Need for therapeutic drug monitoring (TDM)
