L20 - Hormonal drug delivery Flashcards
Example of dosage forms
IV drip
Tablets
Injections
Patch
Inhalers
Topical treatments
Oral syrups
Why do we have dosage forms?
Drug often in powder form
Tiny doses of drug
-mg or msg quantities
Bulk up with exipients
-such as water, lactose
Why do we have different dosage forms?
Different clinical conditions
Different types of patient
Different routes of administration
Different physicochemical properties of drug
Factors to consider when designing dosage forms
Drug factors
-solubility, partition coefficient, pKa, stability, MWt
Biopharmaceutical factors
-absorption, bioavailability, route of administration
Therapeutic factors
-disease, patient, route, local vs. systemic delivery
Types of hormones
Modified amino acid derivatives
-derived from tyrosine and tryptophan e.g. dopamine, thyroxine
Peptide and proteins
-derived from amino acids e.g. neuropeptides (vasopressin), pituitary hormones (gonadotrophins), GI hormones (insulin)
Steroids
-derived from cholesterol e.g. sex hormones (testosterone), corticosteroids (hydrocortisone)
Eicosanoids
-derived from lipids e.g. prostaglandins, leukotrienes
Systemic delivery: bioavailability of drugs
entry into blood is required
When might you not want systemic delivery?
Side effects e.g. corticosteroids
Bioavailability is low e.g. peptide hormones, sex hormones
Modified amino acid derivatives e.g. thyroxine and corticosteroids (hydrocortisone)
Drug factors
-low dose required
Biopharmaceutical factors
-orally bioavailable
Therapeutic factors
-local vs systemic delivery
Excipients when the dose of the drug is low
- Diluents/fillers e.g. lactose, water
- Surfactants e.g. polysorbates
- Lubricants e.g. Mg stearate
- Disintegrants e.g. starch
- Viscosity enhancing agents e.g. cellulose derivatives
- Flavours, colours, perfumes
- Sweetening agents
- Preservatives
Local delivery
Site of administration = site of action
Rapid onset of action
Less drug required
Absorption into the bloodstream is not required
Absorption into the bloodstream can lead to unwanted side effects
Local delivery of corticosteroids
To avoid systemic side effects need many different dosage forms
- intra-articular injections - tennis elbow
- creams and ointments - eczema
- inhalers - asthma
- eye drops - inflammation
- suppositories - haemorrhoids
Peptide hormone e.g. insulin
Drug factors
-peptide hormone, large molecule MW approx 5800 Da
Biopharmaceutical factors
-not absorbed after oral administration
Therapeutic factors
-need systemic action
-aim to mimic insulin secretion by normal pancreas
=>basal and bolus
Not absorbed after oral administration because enzymatic degradation in lumen of GIT, any that survives can’t readily cross GI epithelium into blood because too large
Insulins characterised by differences in:
Onset
-how quickly they act
Peak
-how quickly they achieve maximum impact
Duration
-how long they last
Route of delivery
-subcutaneous, inhaled
Continuous subcutaneous insulin infusion (CSII) of rapid analog
Dosage instructions are entered into the pump’s small computer and the appropriate amount of insulin is then injected into the body in a calculated controlled manner
Provides the basal insulin replacement, as well as the mealtime and high blood sugar correction insulin replacement
Pulmonary route
Mainly for local delivery but
Systemic delivery:
Large SA
-80-140m^2
Thin epithelial barrier
-0.1-0.2um
Good blood supply
-100% cardiac output
Avoids harsh environment of GI tract
Avoids first-pass hepatic metabolism
Inhaled insulin - Afrezza (June 2014 FDA)
Rapid-acting inhaled insulin
Taken at the beginning of each meal
Used in combination with a long-acting injected insulin
Sex hormones
Drug factors
-steroid, lipophilic, MW approx 270 Da
Biopharmaceutical factors
- variable absorption after oral administration
- extensive first pass hepatic metabolism, short t1/2
Therapeutic factors
- systemic delivery required but try to avoid oral route
- ethical cyclical or continuous administration required
Why do you need alternatives to oral route?
To increase bioavailability
To offer sustained release
Types of routes in systemic delivery
Parental route - IM injection, implant
Transdermal route - patch or gel
Intranasal route - spray
Buccal route - mucoadhesive system
Vaginal - gel
IM injection
Oily injections - sustained release
- testosterone enantate (caster oil)
- testosterone decanoate, isocaprate, phenylproprionate and proprionate, proprionate, undecanoate
Implants - sustained release
-nexplanon (progestogen-only contraception)
Ester at position 17
Decreases water solubility
Increases oil solubility
Deactivates molecule
-can’t bind to androgen receptor
Ester cleaved/hydrolysed in blood
-restores -OH so can attach to receptor
Release of steroid molecules
from oily deposits of long-chain esters in muscle tissue
Oil has some affinity for water and thus allows penetration of water; the ester is hydrolysed at the surface of the droplet.
The total surface area of the droplet can influence release rate and hence pharmokinetics of the drug.
Droplet dimenions and total surface area influenced by:
force of injection
viscosity and surface tension of oil phase
size of needle
environment into which it’s injected – exercise can increase plasma levels by increasing surface area of droplet
Subnormal implant of etonogestrel (Nexplanon)
Nexplanon - progestogen only contraception
Contains etonogestreln 68mg in each flexible rod
Delivered by sub dermal implantation
Provides effective contraception for up to 3 years unless BMI greater than 35 in which case may not provide effective contraception in 3rd year
Transdermal delivery of estradiol - systemic
Patch design and technology
- there are 2 major types of transdermal delivery system (TDS) products:
1) Reservoir
2) Matrix
