Hormonal Drug Delivery

Question 1

What is a dosage form and why do we have different dosage forms?

Answer 1

• the form in which a pharmaceutical product is marketed as

1. different clinical conditions
2. different types of patients (age, activity level)
3. different routes of administration
4. different physicochemical properties
   
   • may not be orally active etc (insulin)

Question 2

What three key factors need to be considered when designing dosage forms?

Answer 2

1. Drug factors
   
   • solubility, partition coefficient, pKa, stability, molecular weight
2. Biopharmaceutical factors
   
   • absorption, bioavailability, route of administration
3. Therapeutic factors
   
   • disease, patient, route, local vs systemic delivery

Question 3

What is Bioavailability?

Answer 3

• this relates to the rate and extent of drug absorption into the blood

Question 4

What types of hormones are there? (4)

• give examples

Answer 4

• Modified amino acid derivatives
  
  • dopamine, thyroxine
• Peptide and proteins
  
  • neuropeptides - vasopressin, pituitary hormones- gonadotropins, GI hormones- insulin
• Steroids
  
  • sex hormones -testosterone, corticosteroids-hydrocortisone
• Eicosanoids
  
  • prostaglandins, leukotrienes

Question 5

What factors need to be considered when formulating modified amino acid derivatives drugs and corticosteroids?

Answer 5

• low dose required (thyroxine)
  
  • use excipients to make up the rest of the product
• orally bioavailable
• local vs systemic delivery (corticosteroids)
  
  • different dosage forms used to avoid systemic side effects

Question 6

Give common examples of different dosage forms of corticosteroids

Answer 6

• Intra-articular injections - tennis elbow
• Creams and ointments- eczema
• Inhalers - asthma
• Eye drops - inflammation
• Suppositories - haemorrhoids

Question 7

What factors need to be considered when developing peptide hormone delivery?

(insulin)

Answer 7

• peptide hormone, with a large molecule MW ~ 5800 Da
• not orally viable (digested in the GI)
• needs systemic action - mimic normal secretion by the pancreas
  
  • basal and
    
    • Long-acting insulin: Insulin detemir (Levemir), insulin glargine (Lantus)
    • once or twice daily
    • less water-soluble so self aggregates and gradually releases insulin overtime
  • bolus action
    *

Question 8

What is a CSII?

Answer 8

• Continuous subcutaneous insulin infusion
• can be used to give rapid analogue of long-acting insulin
• dosage instructions are entered into the pump’s small computer
• the appropriate amount of insulin is injected into the body in a calculated controlled manner

Question 9

Give an overview of inhaled insulin

Answer 9

• Afrezza
  
  • rapid-acting, taken at the beginning of each meal
  • used in combination with a long-acting injected insulin
• avoids harsh environment of the GI tract
• avoids first-pass hepatic metabolism

Question 10

What factors need to be considered when developing sex hormone drug delivery?

Answer 10

• they are lipophilic steroids with a MW ~270Da
• variable absorption after oral administration
• first-pass hepatic metabolism is high
• they also have a short half-life
• it needs to be systemically delivered but the oral route is not always ideal
  
  • parenteral - IM
  • transdermal - patch or gel
  • intranasal - spray
  • buccal route - mucoadhesive system
  • vaginal- gel
• either cyclical or continuous administration required to produce a therapeutic effect

Question 11

What IM injections are there for testosterone/progesterone?

Answer 11

• Oily injections - sustained release
  
  • Testosterone Enanthate (in caster oil)
  • Testosterone decanoate, isocaproatem phenyproprionate, propionate undecanoate
• Implants - sustained release
  
  • Nexplanon (progestogen-only contraception - subdermal 3 years effective)

Sustained-release due to lower partition from oily phase to the aqueous environment of tissue. Testerone esters is hydrolysed at the surface of the droplet –> slowly releases active testosterone over 2-3 weeks

Question 12

Give an overview of the delivery of testosterone esters

Answer 12

Sustanon 250

• esters have lower water solubility/ higher oil solubility
• the ester form deactivates the molecule
  
  • it can’t bind t the androgen receptor
• the ester is cleaved/ hydrolysed in blood
  
  • this restores the OH group, restoring activity

Question 13

What are the advantages of Intranasal administration of hormones?

Answer 13

• Large, highly vascularized SA for the drug to be absorbed through
• Avoids first pass-hepatic metabolism
• Good bioavailability for low MW compounds

Question 14

What are the disadvantages of Intranasal administration of hormones?

Answer 14

• Mucociliary clearance
• Metabolic activity
• Poor bioavailability for high MW compounds

Question 15

Overview of buccal administration of testosterone

Answer 15

Mucoadhesive testosterone buccal tablets

• applied twice daily
• adheres to gum or inner cheek
• sustained release of testosterone through buccal mucosal

Question 16

Overview of vaginal administration of systemic delivery

• progesterone

Answer 16

Crinone (bioadhesive vaginal gel) - progesterone 8%

• self-insertion and removal
• continuous release over 25-50h
• good patient compliance
• used to assist reproduction

Question 17

Overview of vaginal administration of local delivery

Answer 17

Estring - estradiol 2mg

• vaginal ring,
• estradiol released over 90 days
• used in postmenopausal atrophy of the vagina

Pessary Vagifem - estradiol 10mg

Intra-uterine progestogen-only device - levonorgestrel 52mg

• contraceptive intrauterine system (IUS)
• released into the uterine cavity over 3-5 years

Question 18

How are Eicosanoid hormones delivered locally?

Answer 18

• Prostaglandin E₂ (Postin E2, dinoprostone)
• delivered as a vaginal gel (Primigyn)
• as a vaginal pessary/ tablet (Propess)
  
  • PGE₂ released over 12 hours, gives local action to ripen the cervix (improve fertility)