Vagina And Rectal Drug Delivery

Question 0

What are the limitations with vaginal and rectal drug delivery?

Answer 0

Poor patient acceptability and compliance
Problem of leakage
Insertion problems
Upward movement of suppository from local site can increase FPM
Rectally administration may rigger defecation reaction-formulation may be expelled out
Rate of drug absorption is slow from suppository base
High cost of manufacturing, special formulation and packaging required.

Question 1

What is vaginal and rectal drug delivery needed?

Answer 1

Painless, safe and simple route
Bypasses FPM
Effective for children, elderly, non-cooperative, terminally ill and unconscious patients
Efficient route for drugs liable to degrade in GIT
Large doses of drugs can be given

Question 2

What are the different rectal and vaginal formulations ?

Answer 2

Suppositories
Pessaries
Tablets and capsules
Ointments, creams and aerosol foams
Gels and jellies
Contraceptive sponges
Intrauterine devices
Powers 
Solutions

Question 3

What are NZ products of rectal preparations?

Answer 3

Annusol suppositories and ointment (zinc oxide Peru balsam)
Protcosedyl suppositories (cunchocaine HCl, hydrocortisone)
Hydrocortisone acetate rectal foam
Panadol suppositories
Diclofenac suppositories
Arthrexin; indomethacin suppositories

Question 4

What are NZ examples of vaginal preparations?

Answer 4

Acetic acid
Aci-Jel
Clotrimazole cream, pessaries, combination packs
Miconazole nitrate cream
Oestradiol cream
Progesterone gel (prolonged release) 
Mirena, IUD

Question 5

What are the main physiological characteristics of the vagina?

Answer 5

Thin walled, fibromuscular tube about 7.5cm long

Vaginal fluid originates in cervix and is rich in mucous (mix of polysaccharides and proteins)

There is lower enzymatic activity

PH is 3.5-4.2

Blood supplied via vaginal artery, which bypasses the hepatic portal system.

PH is affected by hormone levels, age and individual lifestyle

Question 6

What is mirena?

Answer 6

Intrauterine device
Contains 52mg of levonorgestrel and indicate for contraception, Menorrhagia, and HRT.

Needs to be fitted by a medical doctor, funded by PHARMAC by special authority with conditions around menorrhagia (not contraception alone).

Question 7

How does Mirena work?

Answer 7

The hormone elastomer core is mounted in the vertical stem of a T body.
It is covered with plaque tubing which regulates the release of levonorgestrel.

The release rate is initially ~20ug/24 hours and declines to 10ug/24 hours after 5 years

It is removable - this is important in case the woman changes her mind and wants to have a baby

Question 8

What are the physiological characteristics of the rectum?

Answer 8

The rectum is the terminal part of the large intestine (15-20cm long)
Rectal epithelium is one cell thick and contains cylindrical and goblet cells which secrete mucous

Total mucous volume is 3.0mL which is spread over a total surface area of 300cm^2

The pH of the mucous is 7.5 (neutral)

Question 9

What are suppositories?

Answer 9

Solid, single dose preparations

The shape, volume and consistency of suppositories are suitable for rectal administration

Question 10

What are pessaries?

Answer 10

Solid, single dose preparations,

They have various shapes, usually ovoid, with a volume and consistency suitable for insertion into the vagina

Question 11

What do suppositories and pessaries have in common?

Answer 11

Both contain one or more active substances dispersed or dissolved in a suitable base.
The base may be soluble or dispersible in water or may melt at body temperature.

Common excipients like diluents, adsorbents, surface active agents, lubricants, antimicrobial preservatives and colouring matter are authorised by the competent authority and may be added if necessary

Question 12

What are the characteristics of the ideal suppository base?

Answer 12

Non toxic and non irritating
Compatible with a variety of drugs
Melting or dissolving in rectal/vaginal fluids
Physically stable during manufacturing and on storage
Chemically stable and inert
High viscosity after melting or dispersion to avoid leakage

Question 13

What are the main classifications of suppository bases?

Answer 13

Fatty/oleaginous
Water miscible
Miscellaneous

Question 14

What are examples of fatty/oleaginous base?

Answer 14

Theobroma oil (cocoa butter)
Hydrogenated fatty acids of vegetable oils
Witepsol

Question 15

What are exmample of miscellaneous suppository bases?

Answer 15

Polyoxyl 40 stearate

Hydrogels

Question 16

What are examples of water miscible suppository bases?

Answer 16

Glycerinated gelatin
Polyethylene glycols (MW>1000)

Question 17

What is cocoa butter?

Answer 17

Fatty/oleaginous base obtained from roasted seeds of theobroma caco
It is a yellowish white solid with a chocolate like odor

Contains a mixture of glyceryl esters of different unsaturated fatty acids such as oleic/palmitic

Question 18

What are the advantages of cocoa butter?

Answer 18

Melting range of 30-36 degrees which means it is solid at room temperature and melts in the body

Ease of processing

Non irritating

Miscible with many ingredients

Question 19

What are the disadvantages of coca butter?

Answer 19

Exhibits marked polymorphism
Could adhere to mould

Melting point is reduced by soluble ingredients like phenol, chloral hydrate
Rancid in storage
Poor water absorptive power
Expensive

Question 20

What are examples of synthetic fatty bases?

Answer 20

Fattibase: contains triglycerides from Palm or coconut oil with self emulsifying glyceryl monosterate and polyoxyl stearate.

Witepsol base contains triglycerides of saturated fatty acids C12-C-8

Question 21

What are the advantages of synthetic fat bases ?

Answer 21

Solidifying points unaffected by overheating
Good resistance to oxidation because of lower content of unsaturated fatty acids
Difference between melting and settling points is small so they set quickly and the risk of sedimentation of suspended ingredients is low.
They are marketed in a series of grades with different melting point ranges

Question 22

What are glycero-gelatin bases?

Answer 22

Mixture of glycerine and gelatin; hydrophilic nature
Commonly used in the preparation of pessaries but not very useful as rectal preparation as they tend to absorb water causing discomfort

Question 23

What are the components of glycerol suppositories base (USP)?

Answer 23

Gelatin 14% w/w
Glycerol 70% w/w
Water Q.S to 100%

Question 24

What are the components of glycerol-gelatin base USP?

Answer 24

Gelatin 20% w/w
Glycerol 70% w/w
Water Q.S to 100%

Question 25

What are polyethylene glycol bases?

Answer 25

Polymers of ethylene oxide and water
The physical state is dependent on chain length and molecular weight.
-lower MW 200 appear solid in nature

They do not melt at body temperature but dissolve slowly in body fluids

Question 26

What does selection of suppository base depend on?

Answer 26

Formulation parameters like composition, melting behaviour, rheological properties

Drug related factors like solubility in vehicle, particle size, amount of drug

Question 27

What drugs lower the melting point of suppository bases?

Answer 27

Volatile oils, creosote, phenol, chloral hydrate
White wax or cetyl ester can be used to raise melting point

Caution: addition of excess quantity of wax can increase MP beyond 37 degrees C

Question 28

What happens if drugs are highly soluble in the vehicle?

Answer 28

They won’t tend to leave the vehicle so the release rate into the rectal fluid will be low

Question 29

What is the relationship between melting point and drug release?

Answer 29

Low melting point results in a higher more rapid drug release

Question 30

How much does a suppository weigh?

Answer 30

Typical weight is 1-4 grams but the 2g suppository is most commonly used

Question 31

How much drug is commonly loaded into the suppository ?

Answer 31

Drug loading ranges from 0.1-40% w/w

Question 32

What are the two classes of factors affecting absorption of drug from suppository ?

Answer 32

Physiological

Physicochemical

Question 33

What are physiological factors which affect drug absorption from suppository?

Answer 33

Quantity of fluid available
Properties of mucous
Contents of rectum
Motility of rectal wall

Question 34

What are physicochemical factors which affect absorption of the drug from the suppository?

Answer 34

Drug solubility
Particle size
Concentration
Surface area

Question 35

What are the weight and length of suppositories containing different doses of diclofenac ?

Answer 35

12.5mg weighs 900mg and is 2.5cm long
25mg weighs 1000mg and is 2.5cm long
50mg weighs 2000mg and is 3cm long
100mg weighs 2140mg and is 3cm long

Question 36

How much fluid is available in the rectum?

Answer 36

Approximately 3mL

Dissolution of slightly soluble substances is the slowest step in the absorption process

Question 37

What factors affect the colonic content and therefore affects the absorption of drug from the suppository ?

Answer 37

Faecal matter
Diarrhoea
Colonic obstruction due to tumorous growths
Tissue dehydration

Question 38

What are the properties of the rectal mucous that should be considered when determining the absorption of drug from the suppository?

Answer 38

Essentially neutral in pH (7-8)

Lacks buffering capacity

Question 39

What are the three main methods of preparing suppositories?

Answer 39

1. Moulding from a melt
2. Compression moulding
3. Hand rolling

Question 40

What is the moulding from a melt method of suppository preparation?

Answer 40

The base is melted and the medicament is incorporated.
The melt is poured into the moulds and cooled to congeal into suppositories
The suppositories are removed from the mould

Question 41

What sort of suppository bases is the moulding from a melt method suitable for?

Answer 41

Cocoa butter
Glycerinated gelatin
PEG bases

Question 42

What is the compression moulding method of preparing suppositories?

Answer 42

The cold mass of the base containing the medicament is compressed into suppositories

Question 43

What are the advantages of the compression moulding method for preparing suppositories?

Answer 43

Simple
Suppositories more elegant than hand rolling
Prevents Sedimentation of solids in the base
Suitable for heat labile medicaments as no melting required

Question 44

What are the disadvantages of the compression moulding method of preparing suppositories ?

Answer 44

Air entrapment can take place resulting in weight variation

Drug or base may be oxidised

Question 45

What is the hand rolling method of preparing suppositories ?

Answer 45

Drug is made into a fine powder and incorporated into the suppository base by kneading.
Or it could be triturated in a mortar.
This kneaded mass is rolled between fingers into rod shaped units which are then cut into pieces.
One end is then pointed for easy insertion

Question 46

What is the main advantage and disadvantage of the hand rolling method?

Answer 46

+ useful for preparing a small number of suppositories as does not require specific equipment
- there is no uniformity in shape and size

Question 47

What are the quality control tests regarding suppositories?

Answer 47

Appearance
Weight
Disintegration
Melting range test
Liquefaction/softening time
Mechanical strength 
Content of active ingredient 
Dissolution (drug release)

Question 48

What is Assessed in the appearance test for QC of suppositories?

Answer 48

Odour
Colour
Surface condition
Shape

Question 49

What is assessed in the weight uniformity test for QC of suppositories?

Answer 49

Taken from BP and EP 2013:
20 individual units are taken at random and average mass is determined

Acceptance criteria is where no more than 2 individual masses deviate from the average by more than 5%
And none deviates by more than 10%

Question 50

How is disintegration assessed in QC of suppositories?

Answer 50

From BP/EP 2013:
-moulded suppositories: disintegration must occur within 30 minutes for fat based suppositories, and within 60 minutes for water soluble suppositories

• moulded pessaries: within 60 minutes
• rectal capsules and vaginal tablets and capsules: within 30 minutes

Question 51

What is the melting range test for QC of suppositories?

Answer 51

There are three main methods to determine melting range

1. Open capillary tube method
2. U-tube method
3. Drop point method

The tests consists of placing suppository on surface of water thermostatically controlled at 37°C and verifying the complete melting point of the suppository

MP should be equal or less than 37°C and should completely melt in a few minutes

Question 52

What is the liquefaction/softening time test for the QC of suppositories ?

Answer 52

This provides info on behaviour of suppository under pressures similar to those found in rectum (~30g) in the presence of water at 37°C

Krowczynskis method is commonly used. This measures the time required for the suppository to liquefy under pressure conditions matching the body,

Liquefaction should take no longer than 30mins

Question 53

What is the mechanical strength test for QC of suppositories?

Answer 53

• tests the mass in kg that the suppository can bear without breaking
• suppository is positioned in upright position and increasing weights are placed on it until it loses its structure and collapses
• ideal pressure is at least 1.8-2kg

Question 54

What is the purpose of the mechanical strength test for suppositories?

Answer 54

So that we can ensure Suppositories can be transported under normal conditions and administered to the patient

Question 55

What is the content uniformity of active ingredient test for QC of suppositories?

Answer 55

This ensures dose to dose uniformity of each suppository
An assay of the drug substance is carried out as per the pharmacopoeia monograph to determine whether the individual content is within the limits set

Question 56

What is the dissolution test for QC of suppositories ?

Answer 56

This is required to demonstrate the release of the active substance from the dosage unit.
USP dissolution apparatus used
Compared to pharmacopoeia monograph

Question 57

How should the suppositories be packed?

Answer 57

Generally packed individually in foil or plastic material

Coca butter suppositories have to be individually wrapped or separated in compartmentalised boxes

Glycerinated gelatin suppositories have to be tightly closed, screw capped glass containers

Question 58

How should suppositories be stored?

Answer 58

Cocoa butter suppositories should be stored below 30°C and prferably in the refrigerator between 2-8°C

Glycerinated gelatin suppositories should be stored below 35°C and routinely stored at controlled temperatures of 20-25°C

Polyethylene glycol suppositories can be stored at the usual room temperature without the requirement of refrigeration