Hormonal Drug Delivery

Question 1

… forms are essentially pharmaceutical products in the form in which they are marketed for …

Answer 1

Dosage forms are essentially pharmaceutical products in the form in which they are marketed for use

Question 2

Pharmaceutics is the science of turning a … into a … form

Answer 2

Pharmaceutics is the science of turning a drug into a dosage form

Question 3

Examples of dosage forms

Answer 3

Question 4

Why do we have dosage forms?

• Drug often comes in … form
• … doses of drug
  
  • e.g. mg or μg quantities
• Bulk up with …
  
  • such as w.., l.. etc..

Answer 4

• Drug often comes in powder form
• Tiny doses of drug
  
  • mg or μg quantities
• Bulk up with excipients
  
  • such as water, lactose etc..

Question 5

Why do we have different dosage forms?

• 1. Different … conditions
• 2. Different … of …
• 3. Different … of …
• 4. Different … properties of drug

Answer 5

• 1. Different clinical conditions
• 2. Different types of patient
• 3. Different routes of administration
• 4. Different physicochemical properties of drug

Question 6

Why do we have different dosage forms? - 1) Different Clinical Conditions

• e.g. a rash can be treated by a … but an emergency or a seizure needs a dosage form that works … such as an … or a s… (if cannot swallow).

Answer 6

• e.g. a rash can be treated by a cream but an emergency or a seizure needs a dosage form that works rapidly such as an injection or a suppository (if cannot swallow).​

Question 7

Why do we have different dosage forms? - 2) Different Types of Patient

Answer 7

• Elderly vs Child

Question 8

Why do we have different dosage forms? - 3) Different Routes of …

Answer 8

• administration

Question 9

Why do we have different dosage forms? - 4) Different Physiocochemical Properties

• e.g. if a drug is not active … because it cannot pass through … … it needs to be formulated as an … e.g. insulin (which is also broken down by stomach enzymes)

Answer 9

• e.g. if a drug is not active orally because it cannot pass through cell membranes it needs to be formulated as an injection e.g. insulin (which is also broken down by stomach enzymes)

Question 10

Factors to Consider when Designing Dosage Forms

• 1. … factors
     * Solubility, partition coefficient, pKa, stability, molecular weight
• 2. … factors
     * Absorption, bioavailability, route of administration
• 3. … factors
     * Disease, patient, route, local vs. systemic delivery

Answer 10

• 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 11

What 3 Factors do we need to consider when designing Dosage Forms?

Answer 11

• 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 12

Main routes of administration

Answer 12

1. Oral or Peroral (swallowed by mouth)
2. Oral cavity (absorbed from mouth, but not swallowed)
   • Oral mucosa
   • Buccal (between gum and cheek)
   • Sublingual (from under the tongue)
3. Rectal
4. Parenteral (injected)
5. Epicutaneous (skin) – including topical or transdermal
6. Ocular (eye), aural (ear), nasal (nose)
7. Pulmonary (lungs)
8. Vaginal

Question 13

Main route of administration is …

Answer 13

oral or peroral (Swallowed by mouth)

Question 14

Oral cavity administration includes: (3)

Answer 14

• oral mucosa
• buccal (between gum and cheek)
• sublingual (from under the tongue)

Question 15

Parenteral route of administration means…

Answer 15

injected

Question 16

Epicutaneous route of administration means …

Answer 16

skin - including topical or transdermal

Question 17

ocular administration …

Answer 17

eye

Question 18

aural administration …

Answer 18

ear

Question 19

nasal administration …

Answer 19

nose

Question 20

pulmonary administration …

Answer 20

lungs

Question 21

Local Delivery

• Site of administration = site of …
• … onset of action
• … drug required
• Absorption into the … … is not required (but some absorption could occur)
  
  • Absorption into the … … can lead to … … …

Answer 21

• Site of administration = site of action
• Rapid onset of action
• Less drug required
• Absorption into the blood stream is not required (but some absorption could occur)
  
  • Absorption into the blood stream can lead to unwanted side effects

Question 22

Systemic delivery

• Effect results from entry of drug into … system
• Drug transported to site of action in the …
• Drug can be placed … in …
  
  • E.g. by … injection
• Or … into bloodstream
  
  • Following … or other route of administration

Answer 22

• Effect results from entry of drug into circulatory system
• Drug transported to site of action in the blood
• Drug can be placed directly in bloodstream
  
  • E.g. by intravenous injection
• Or absorbed into bloodstream
  
  • Following oral or other route of administration

Question 23

Systemic delivery: bioavailability

• Bioavailability relates to the … and … of drug absorption into the blood.

Answer 23

• Bioavailability relates to the RATE and EXTENT of drug absorption into the blood.

Question 24

Consider the duration of action

• E.g. painkiller for headache - dose, increase in drug concentration and decrease again
• To give drug all the time - … oral … regimen - give second dose before concentration has decreased again to maintain drug in … window

Answer 24

• E.g. painkiller for headache - dose, increase in drug concentration and decrease again
• To give drug all the time - multiple oral dosing regimen - give second dose before concentration has decreased again to maintain drug in therapeutic window

Question 25

_Types of hormones_ * Modified amino acid derivatives (derived from tyrosine or tryptophan) e.g. d.., t... * Peptide and proteins (derived from amino acids) e.g. neuropeptides (v..), pituitary hormones (g...), GI hormones (insulin) * Steroids (derived from c...) e.g. sex hormones (t...), corticosteroids (hydro...) * Eicosanoids (derived from l...) e.g. prostaglandins, leukotrienes

Answer 25

* Modified amino acid derivatives (derived from tyrosine or tryptophan) e.g. **dopamine, thyroxine** * 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

Question 26

_Modified amino acid derivatives e.g. thyroxine and corticosteroids e.g. hydrocortisone_ * Drug factors * ... dose required * Biopharmaceutical factors – which route? * ... bioavailable * Therapeutic factors * ... vs. ... delivery

Answer 26

* Drug factors * **Low** dose required * Biopharmaceutical factors – which route? * **Orally** bioavailable * Therapeutic factors * **Local** vs. **systemic** delivery

Question 27

_Dose of drug - small e.g. 25microgram thyroxine_ * E... such as: * Diluents/fillers e.g. lactose, water * Lubricants e.g. Mg stearate * Disintegrants e.g. starch * Surfactants e.g. polysorbates * Viscosity enhancing agents e.g. cellulose derivatives * Flavours, colours, perfumes * Sweetening agents * Preservatives

Answer 27

* **Excipients** such as: * Diluents/fillers e.g. lactose, water * Lubricants e.g. Mg stearate * Disintegrants e.g. starch * Surfactants e.g. polysorbates * Viscosity enhancing agents e.g. cellulose derivatives * Flavours, colours, perfumes * Sweetening agents * Preservatives

Question 28

_Local Delivery of Corticosteroids_ * To avoid ... side effects need many different dosage forms: * Intra-... injections – tennis elbow * C.. and O... - eczema * I... - asthma * ... drops - inflammation * S... - haemorrhoids

Answer 28

* 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

Question 29

_Peptide hormone e.g. Insulin_ * 1. Drug factors * Peptide hormone, ... molecule MW ~5800 Da * 2. Biopharmaceutical factors * Not ... after ... administration * 3. Therapeutic factors * Need ... action * Aim to mimic insulin secretion by normal pancreas * b.. and b..

Answer 29

* 1. Drug factors * Peptide hormone, **large** molecule MW ~5800 Da * 2. Biopharmaceutical factors * Not **absorbed** after **oral** administration * 3. Therapeutic factors * Need **systemic** action * Aim to mimic insulin secretion by normal pancreas * **basal** and **bolus**

Question 30

_Insulin Administration_ * Insulin is injected ...

Answer 30

* Insulin is injected **subcutaneously**

Question 31

_Insulins characterised by differences in:_ * O... * How ... they act * Peak * How quickly they achieve ... ... * D.. * How long they ... * Route of delivery * s..., i..

Answer 31

* **Onset** * **How quickly they act** * **Peak** * **How quickly they achieve maximum impact** * **Duration** * **How long they last** * **Route of delivery** * **Subcutaneous, inhaled**

Question 32

_Long acting insulin:_ * Provides ... insulin * Insulin detemir (Levemir®) or insulin glargine (Lantus®) * Injected ... or ... daily * Formulated so that the insulin is ... water soluble, making it self ... and precipitate into microcrystals which act as a depot releasing the insulin ... over time.

Answer 32

* Provides **baseline** insulin * Insulin detemir (Levemir®) or insulin glargine (Lantus®) * Injected **once** or **twice** daily * Formulated so that the insulin is **less** water soluble, making it self **aggregate** and precipitate into microcrystals which act as a depot releasing the insulin **slowly** over time.

Question 33

What is Continuous subcutaneous insulin infusion (CSII) of rapid analog?

Answer 33

Question 34

_Pulmonary Route: Mainly for local delivery but..._ * Can also be used for ... delivery * ... surface area (80 – 140 m2) * ... epithelial barrier (0.1 – 0.2 μm) * Good ... supply (100% ... output) * Avoids harsh environment of ... ... * Avoids ...-... hepatic metabolism *

Answer 34

* Can also be used for **systemic** delivery * **Large** surface area (80 – 140 m2) * **Thin** epithelial barrier (0.1 – 0.2 μm) * Good **blood** supply (**100**% cardiac output) * Avoids harsh environment of **GI tract** * Avoids **first-pass** hepatic metabolism

Question 35

_Inhaled Insulin - Afrezza (June 2014 FDA)_ * ...-acting inhaled insulin * Taken at the beginning of each ... * Used in combination with a ...-acting ... insulin

Answer 35

* **Rapid**-acting inhaled insulin * Taken at the beginning of each **meal** * Used in combination with a **long**-acting **injected** insulin

Question 36

_Sex Hormones_ * 1. Drug factors * S.., Lipo..., MW ~270 Da * 2. Biopharmaceutical factors * ... absorption after oral administration * Extensive first pass ... metabolism, ... half life. * 3. Therapeutic factors * ... delivery required but oral route not always ideal * Either cyclical or continuous administration required

Answer 36

* 1. Drug factors * **Steroid, lipophilic**, MW ~270 Da * 2. Biopharmaceutical factors * **Variable** absorption after oral administration * Extensive first pass **hepatic** metabolism, **short** half life. * 3. Therapeutic factors * **Systemic** delivery required but oral route not always ideal * Either cyclical or continuous administration required

Question 37

_Need alternatives to oral route_ * To increase ... and to offer ... release need alternatives to oral route. * Systemic delivery * ... route – intramuscular (IM) injection, implants • Transdermal route - patch or gel * ... route - spray * ... route – mucoadhesive system * ... – gel

Answer 37

* To increase **bioavailability** and to offer **sustained** release need alternatives to oral route. * Systemic delivery * **Parenteral** route – intramuscular (IM) injection, implants • Transdermal route - patch or gel * **Intranasal** route - spray * **Buccal** route – mucoadhesive system * **Vaginal** – gel

Question 38

_IM injections of testosterone/progesterone_ * * Testosterone - use ... injections – sustained release * Testosterone enanthate (in ... ...) * Testosterone decanoate, isocaproate, phenylproprionate, propionate and undecanoate * Progesterone - use ... – sustained release * Nexplanon (progestogen- only ...)

Answer 38

* Testosterone - use **Oily** injections – sustained release * Testosterone enanthate (in **caster oil**) * Testosterone decanoate, isocaproate, phenylproprionate, propionate and undecanoate * Progesterone - use **Implants** – sustained release * Nexplanon (progestogen- only **contraception**)

Question 39

**Sustanon 250 is used in adult men for ... replacement to treat various health problems caused by a lack of ... (male ...)**

Answer 39

**Sustanon 250 is used in adult men for testosterone replacement to treat various health problems caused by a lack of testosterone (male hypogonadism).**

Question 40

_Testosterone Esters (Sustanon 250)_ * Esters have ... water solubility/... oil solubility * But the ester deactivates molecule (can’t ... to androgen receptor) * Ester is C.../ H... in blood – this restores the OH group, restoring activity.

Answer 40

* Esters have **lower** water solubility/**higher** oil solubility * But the ester deactivates molecule (can’t **bind** to androgen receptor) * Ester is **cleaved**/ **hydrolysed** in blood – this restores the OH group, restoring activity.

Question 41

_Release of steroid molecule from oily depots of long chain esters in muscle tissue_ * Sustained action due to lower partition from ... phase to ... environment of tissue * Testosterone ester is hydrolysed at the surface of the droplet, slowly releasing active testosterone. * Released over ...-... weeks

Answer 41

* Sustained action due to lower partition from **oily** phase to **aqueous** environment of tissue * Testosterone ester is hydrolysed at the surface of the droplet, slowly releasing active testosterone. * Released over **2-3** weeks

Question 42

_Subdermal Implant of Etonorgestrel (Nexplanon)_ * ... contraceptive – effective for up to ... years! * Delivered by sub-dermal implantation

Answer 42

* **Progesterone only** contraceptive – effective for up to **3** years! * Delivered by sub-dermal implantation

Question 43

_Transdermal Delivery of Estradiol - Systemic Delivery_

Answer 43

Question 44

_Intranasal Administration - Systemic Delivery_ * Advantages * ... surface area (~180 cm2) * Highly ... * Avoids ... ... ... metabolism * Good ... for low MW compounds * Disadvantages * M... clearance * M... activity * Poor ... for high MW compounds * Product on the market: **Desmopressin**

Answer 44

* Advantages * **Large** surface area (~180 cm2) * Highly **vascularized** * 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**

Question 45

_Buccal Administration - Systemic Delivery_ * Mucoadhesive t... buccal delivery system * Applied ... daily * Adheres to ... or inner ... * ... release of ... through buccal mucosa

Answer 45

* Mucoadhesive **testosterone** buccal delivery system * Applied **twice** daily * Adheres to **gum** or inner **cheek** * **Sustained** release of **testosterone** through buccal mucosa

Question 46

_Vaginal Administration - Systemic Delivery_ * ...-insertion and removal * ... release * ... patient compliance * Used to assist ... * B... vaginal gel (Crinone) * Progesterone released over ..-..h

Answer 46

* **Self**-insertion and removal * **Continuous** release * **Good** patient compliance * Used to assist **reproduction** * **Bioadhesive** vaginal gel (Crinone) * Progesterone released over **25-50**h

Question 47

_Vaginal Administration (device) - Local Delivery_ * Vaginal ... (Estring) * Estradiol released over ... days * Used in ... atrophy of the vagina

Answer 47

* Vaginal **ring** (Estring) * Estradiol released over 90 days * Used in **postmenopausal** atrophy of the vagina

Question 48

_Vaginal Administration (Pessary) - Local Delivery_ * E.. 10 μg vaginal tablets (inserts) (Vagifem)

Answer 48

* **Estradiol** 10 μg vaginal tablets (inserts) (Vagifem)​

Question 49

_Intra-uterine Progestogen-only device - Local delivery_ * ... Intrauterine system (IUS) (Mirena, Jaydess, Levosert) levonorgestrel (52 mg) released into uterine cavity over ... or ... years

Answer 49

* **Contraceptive** Intrauterine system (IUS) (Mirena, Jaydess, Levosert) levonorgestrel (52 mg) released into uterine cavity over **3 or 5** years

Question 50

_Release of LNG from different dosage forms_

Answer 50

* The levonorgestrel (LNg) intrauterine device (IUD) releases small amounts of levonorgestrel, a form of progesterone, into the uterus each day.

Question 51

_Eicosanoid hormones - Local delivery_ * Prostaglandin E2 (Prostin E2, dinoprostone) * ... gel (Primigyn) * Vaginal .../... (Propess) * PGE2 released over ... hours, local action to ripen the cervix

Answer 51

* Prostaglandin E2 (Prostin E2, dinoprostone) * **Vaginal** gel (Primigyn) * Vaginal **pessary**/**tablet** (Propess) * PGE2 released over **12** hours, local action to ripen the cervix