Hormonal Drug Delivery 2023.pptx

Hormonal Drug Delivery Dr Alison Lansley [email protected] BSMS Module 203 Hormonal Drug Delivery • Factors affecting oral delivery of hormones and modification of formulations such as sustained release. • Alternative routes of administration such as nasal, inhaled, injected, transdermal....

Hormonal Drug Delivery Dr Alison Lansley [email protected] BSMS Module 203 Hormonal Drug Delivery • Factors affecting oral delivery of hormones and modification of formulations such as sustained release. • Alternative routes of administration such as nasal, inhaled, injected, transdermal. • Formulation of hormones for sustained release. • Recent advances in hormone delivery, e.g. noninjected insulins. Learning outcome: • using specific examples, to appreciate the different formulations and routes of administration available for hormone delivery and the risks, benefits and indications for each. Examples of dosage forms, also called medicinal forms (BNF)? Why do we have dosage/medicinal forms at all? Why do we have dosage/medicinal forms? • Drug often in powder form • Tiny doses of drug • mg or mcg quantities • Bulk up with excipients • such as water, lactose Why do we have different dosage/medicinal forms? Different clinical conditions Different types of patient Different routes of administration Alamy https://health.clevelandclinic.org/nasal-sprays-work-best-when-you-use-themcorrectly-heres-how/ Different physicochemical properties of drug Lipophilicity of drug molecule Particle size of solid 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 Examples of routes of administration? Types of hormone • Modified amino acid derivatives • (derived from tyrosine or tryptophan) • e.g. dopamine, levothyroxine • Peptide and proteins • (derived from amino acids) • e.g. neuropeptides (vasopressin), pituitary hormones (gonadotropins), 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 Absorption phase RATE and EXTENT of absorption Elimination phase Entry into blood is required How does drug get into the blood? Average serum concentration (mcg/ml) 6 Maximum safe concentration 5 4 Cmax Therapeutic range 3 2 Minimum effective concentration 1 AUC Tmax 0 0 1 2 3 4 5 6 7 8 9 Time after drug administration (h) 10 11 12 Consider the duration of action Multiple oral dosing Zero-order Controlled release Modified amino acid derivatives e.g. levothyroxine and corticosteroids e.g. hydrocortisone •Drug factors •Low dose required •Biopharmaceutical factors – which route? •Orally bioavailable •Therapeutic factors •Local vs. systemic delivery Dose of drug small e.g. 25mg levothyroxine • Excipients for tablets, capsules, solutions • Diluents/fillers e.g. lactose, water • Surfactants e.g. polysorbates • Lubricants e.g. magnesium stearate • Disintegrants e.g. starch • Coating • 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 blood stream is not required • Absorption into the blood stream can lead to unwanted side effects Local delivery of corticosteroids • To avoid systemic side effects need many different dosage forms • Intra-articular injections – e.g. hydrocortisone for tennis elbow • Creams and ointments – e.g. betamethasone for eczema • Inhalers - e.g. beclometasone for asthma • Eye drops – e.g. dexamethasone for inflammation • Suppositories – e.g. hydrocortisone for haemorrhoids Beclometasone Peptide hormone e.g. insulin • Drug factors • Peptide hormone, large molecule MW ~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 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, Continuous subcutaneous insulin infusion (CSII) of rapid analog Pulmonary route – mainly for local delivery but … Systemic delivery • Large surface area • (80 – 140 m2) • Thin epithelial barrier • (0.1 – 0.2 mm) • 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 ~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 • Either cyclical or continuous administration required Need alternatives to oral route Systemic delivery • To increase bioavailability • To offer sustained release • Parenteral route - IM injection, implant • Transdermal route – patch, gel or spray • 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) Testosterone 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 molecule from oily depots of long-chain esters in muscle tissue Muscle tissue STEROID-ESTER Muscle STEROID-ESTER STEROID Oil phase STEROID STEROID-ESTER Subdermal implant of etonogestrel (Nexplanon) Is this systemic or local? Transdermal Delivery of estradiol - systemic Intranasal administration - systemic Advantages • Large surface area (~150 cm2) • Highly vascularised • Avoids first pass hepatic metabolism • Good bioavailability for low MW compounds Disadvantages • Mucociliary clearance • Metabolic activity • Poor bioavailability for high MW compounds • Product on the market • Desmopressin Buccal administration - systemic • Mucoadhesive testosterone buccal delivery system • Applied twice daily • Adheres to gum or inner cheek • Sustained release of testosterone through buccal mucosa Vaginal administration - systemic • Self-insertion and removal • Continuous release • Good patient compliance • Bioadhesive vaginal gel (Crinone) • Progesterone released over 25 – 50 h Vaginal administration (local) device • Vaginal ring (Estring) • Estradiol released over 90 days Vaginal administration (local) pessary • Estradiol 10 mcg vaginal tablets (inserts) (Vagifem) Intra-uterine progestogen-only device • Intrauterine system (IUS) (Mirena, Jaydess, Levosert) • levonorgestrel (52 mg) released into uterine cavity over 3 or 5 years – local action Release of levonorgestrel (LNG) from different dosage forms Eicosanoid hormones • Prostaglandin E2 (Prostin E2, dinoprostone) • Vaginal gel • Vaginal pessary/tablet (Propess) • PGE2 released over 12 hours, local action to ripen cervix Types of hormone • Modified amino acid derivatives • e.g. dopamine, thyroxine • Peptide and proteins • e.g. neuropeptides (vasopressin), pituitary hormones (gonadotropins), GI hormones (insulin) • Steroids • e.g. sex hormones (testosterone), corticosteroids (hydrocortisone) • Eicosanoids • e.g. prostaglandins, leukotrienes Learning outcomes • To be able to give an example of a delivery device/dosage form suitable for use with each drug/group of drugs. • To know why chosen dosage form is suitable? • To consider: • • • drug factors biopharmaceutical factors therapeutic factors when selecting a dosage form Medicinal forms (dosage forms) • Medicinal forms (dosage forms) of estradiol • Medicinal forms (dosage forms) of progesterone • Testosterone gel