Pharm tech - parenteral & transdermal

Parenteral delivery - Drug delivery via injection

Parenteral delivery - Parenteral to brain access

Parenteral delivery - Barriers and disadvantages

Parenteral delivery - Advantages

Bypasses hepatic first pass metabolism

Can control dosage - cause you know the blood conc

Relatively low drug concentration (and low toxicity)

Direct access to brain (intrathecal)

Sustained release (intramuscular depots, intrathecal reservoirs)

Ideal for non-compliant, unconscious or dysphagic patients - guarantee med was given

Parenteral delivery - Blood to brain transport

Drug solution flows through circulatory system

Reticuloendothelial system (RES)

Unless there is active targeting, drug will distribute everywhere

Drugs must bypass the blood brain barrier (BBB) to access the brain. Coats every blood vessel

Parenteral delivery - blood brain barrier

Parenteral delivery - Ideal drug candidates for parenteral (non-intrathecal)

Parenteral delivery - Delivery systems (formulations)

Parenteral delivery - Common excipients of solutions for injection

Parenteral delivery - Packaging & storage

Parenteral delivery - Haloperidol/Hadol

IM Haloperidol/Hadol - composition

Sesame oil - solvent

Benzyl alcohol - preservative

Haloperidol

No pH, osmolality (lipophilic)

IM Haloperidol/Hadol - PKPD

Sustained release from depot - long term, as chronic condition

Steady state plasma levels reached within 2 – 4 mths

Half-life = 3 weeks

Metabolised in liver

Plasma protein binding ~ 88 – 92%

Parenteral delivery - Baclofen/Lioresal

IV/PO Baclofen/Lioresal - Active ingredient

Molecular weight = 213.67 g/mol

LogP = 1.3

Hydrogen bond donors = 3

Hydrogen bond acceptors = 4

Ionisable = yes

pKa, 1 = 3.87 (carboxyl group)

pKa, 2 = 9.62 (amino group)

IV/PO Baclofen/Lioresal - composition

Water - solvent

Sodium chloride - tonicity

Baclofen - AI

pH: 5 – 7

Osmolality: 270 - 300 mOsm/kg (0.05 mg/mL) - NaCl + baclofen

IV/PO Baclofen/Lioresal - PKPD

Baclofen concentration in CSF is ~100x higher than after oral administration

Infusion - for minor effects, chronic

Antispastic action seen ~6 – 8 hrs after administration (infusion)

Maximum efficacy observed ~24 – 48 hrs

Bolus - emergency, may have other SE

Onset ~ 0.5 – 1 hr after administration

Peak antispastic effect ~ 4 hrs after dosing and last 4 – 8 hrs

Parenteral delivery - Ziconotide/Prialt

N-type voltage-gated calcium channel blocker

Management of severe chronic pain

PRIALT: one vial per carton

25 μg/mL in glass vial (20 mL)

100 μg/mL in glass vial (1 or 5 mL)

Medtronic SynchroMed® II infusion system or CADD-Micro ambulatory infusion pump

IV Ziconotide/Prialt - active ingredient

Molecular weight = 2639.2 g/mol

LogP = -2 or -23 (from DrugBank) - very hydrophilic

Hydrogen bond donors = 42

Hydrogen bond acceptors = 46

Ionisable = yes

Many a.a. - polypeptide

IV/IT Ziconotide/Prialt - composition

Water - solvent

Sodium chloride - tonicity

L-methionine - antioxidant (peptide stability)

Ziconotide acetate

pH: 4 – 5

Isotonic

IV Ziconotide/Prialt - PK

Half-life: 4.6 ± 1.8 hrs

Metabolised by peptidases/proteases

VD ~ 140 mL (volume of CSF)

50% bound to human plasma proteins

Transdermal delivery - Skin anatomy and physiology

Transdermal delivery - Transdermal vs topical delivery

Transdermal delivery - Advantages

Controlled release (reservoirs, duration of contact). Decreased dosing frequency

No GI degradation/irritation

Bypasses hepatic first pass effect

Easy termination of input

Non-invasive

Transdermal delivery - Disadvantages and barriers

Variability between people and location of administration on body - genetic variations

Stratum corneum - Slow absorption

Skin irritation (interactions and removal)

Could be removed by the patient

Metabolic enzymes

Blood brain barrier (via systemic delivery)

Systemic side effects

Transdermal delivery - Factors that affect delivery

Skin condition: age, disease, injury, site

Skin thickness (thickness of diffusion layer)

Hydration of skin (stratum corneum) - Natural or “manufactured” (occlusive: physical/chemical)

Stimulation of the skin (phonophoresis/ultrasound, iontophoresis, heat)

Physicochemical properties of drug (lipophilicity, diffusion coefficient)

Permeation enhancers - Reversible reduction in the barrier resistance of the stratum corneum without damaging viable cells

Concentration gradient

Area of contact between formulation and skin

Transdermal delivery - Transdermal to brain access

Transdermal delivery - Ideal drug candidates

Transdermal delivery - Delivery systems (formulations)

Some types include:

Topical

Gel, creams (water-based/oil-based) and ointments

Transdermal

Patches (solutions/suspensions in reservoirs)

Patches (polymer matrix) - provide occlusion, increase retention time

Transdermal delivery - Products on the market

Transdermal patches

Rotigotine/Neupro

Management of Parkinson’s

Treatment of restless leg syndrome

Fentanyl/Duragesic

Pain relief

Estrogen/Estraderm

Hormone replacement therapy

Nicotine/Nicotinell

Nicotine replacement therapy

Transdermal delivery - Common excipients of solutions for patches

Preservatives

Solvents/co-solvents

Viscosity modifier

Permeation enhancers

Adhesives

Transdermal delivery - Polymer matrices

Drug release dependent on

Diffusion coefficient of drug

Surface area

Concentration

Porosity/tortuosity of polymer matrix - Determined by intramolecular interactions (crosslinking, hydrogen bonds)

Transdermal delivery - Packaging & storage

Patches sealed in individual pouches

Plastic/polymer lining

Aluminium lining

Sealed packaging

Maintain integrity of adhesive

Maintain integrity of product

Maintain hydration

Transdermal delivery - Design of patches

Transdermal delivery - special considerations for patches

Release rate of drug from patch

Potential for leaching and extraction of drug into backing/other layer

Temperature - 25c

Crystallinity of drug over time

Strength of adhesion (between layers, influence of sweat, hair etc.)

Disposal

High concentrations

Transdermal delivery - Rotigotine/Neupro

Dopamine receptor agonist

Treatment of Parkinson’s

Cartons of 30 patches

Rotigotine/Neupro patches - application

Rotigotine/Neupro patches - active ingredient

Molecular weight = 315.48 g/mol

LogP = 4.7

Hydrogen bond donors = 1

Hydrogen bond acceptors = 3

Ionisable? Yes OH

Rotigotine/Neupro patches - composition

Ascorbyl palmitate - fatty acid. Antioxidant

Povidone - viscosity

Silicone- adhesive

Sodium metabisulfite - preservative/antioxidant

DL-alpha-tocopherol - antioxidant

Rotigotine - AI

What is the design of the patch? - drug in adhesive

Rotigotine/Neupro patches - PK

~45% released in 24 hrs (0.2 mg/cm2)

Cmax dependent on patch dose

Removal of patch: plasma levels decreased with a terminal half-life of 5 – 7 hrs

Transdermal delivery - Fentanyl/Duragesic

Fentanyl/Duragesic patches - Active ingredient

Molecular weight = 336.5 g/mol

LogP = 4.05

Hydrogen bond donors = 0

Hydrogen bond acceptors = 2-3

Ionisable? y, tert amine

Fentanyl/Duragesic patches - composition

Alcohol* - permeation enhancer

Ethylene-vinyl acetate copolymer - membrane

Hydroxyethyl cellulose - suspending agent

Polyester - backing layer

Silicone

*minute amounts

Fentanyl/Duragesic patches - PK

Steady state plasma concentrations after ~3 days

Plasma concentration dependent on patch dosage

Half-life ~ 7 hrs after removal of patch