Vagina And Rectal Drug Delivery Flashcards
What are the limitations with vaginal and rectal drug delivery?
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.
What is vaginal and rectal drug delivery needed?
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
What are the different rectal and vaginal formulations ?
Suppositories Pessaries Tablets and capsules Ointments, creams and aerosol foams Gels and jellies Contraceptive sponges Intrauterine devices Powers Solutions
What are NZ products of rectal preparations?
Annusol suppositories and ointment (zinc oxide Peru balsam)
Protcosedyl suppositories (cunchocaine HCl, hydrocortisone)
Hydrocortisone acetate rectal foam
Panadol suppositories
Diclofenac suppositories
Arthrexin; indomethacin suppositories
What are NZ examples of vaginal preparations?
Acetic acid Aci-Jel Clotrimazole cream, pessaries, combination packs Miconazole nitrate cream Oestradiol cream Progesterone gel (prolonged release) Mirena, IUD
What are the main physiological characteristics of the vagina?
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
What is mirena?
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).
How does Mirena work?
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
What are the physiological characteristics of the rectum?
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)
What are suppositories?
Solid, single dose preparations
The shape, volume and consistency of suppositories are suitable for rectal administration
What are pessaries?
Solid, single dose preparations,
They have various shapes, usually ovoid, with a volume and consistency suitable for insertion into the vagina
What do suppositories and pessaries have in common?
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
What are the characteristics of the ideal suppository base?
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
What are the main classifications of suppository bases?
Fatty/oleaginous
Water miscible
Miscellaneous
What are examples of fatty/oleaginous base?
Theobroma oil (cocoa butter)
Hydrogenated fatty acids of vegetable oils
Witepsol
What are exmample of miscellaneous suppository bases?
Polyoxyl 40 stearate
Hydrogels
What are examples of water miscible suppository bases?
Glycerinated gelatin Polyethylene glycols (MW>1000)
What is cocoa butter?
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
What are the advantages of cocoa butter?
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
What are the disadvantages of coca butter?
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
What are examples of synthetic fatty bases?
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
What are the advantages of synthetic fat bases ?
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
What are glycero-gelatin bases?
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
What are the components of glycerol suppositories base (USP)?
Gelatin 14% w/w
Glycerol 70% w/w
Water Q.S to 100%
What are the components of glycerol-gelatin base USP?
Gelatin 20% w/w
Glycerol 70% w/w
Water Q.S to 100%
What are polyethylene glycol bases?
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
What does selection of suppository base depend on?
Formulation parameters like composition, melting behaviour, rheological properties
Drug related factors like solubility in vehicle, particle size, amount of drug
What drugs lower the melting point of suppository bases?
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
What happens if drugs are highly soluble in the vehicle?
They won’t tend to leave the vehicle so the release rate into the rectal fluid will be low
What is the relationship between melting point and drug release?
Low melting point results in a higher more rapid drug release
How much does a suppository weigh?
Typical weight is 1-4 grams but the 2g suppository is most commonly used
How much drug is commonly loaded into the suppository ?
Drug loading ranges from 0.1-40% w/w
What are the two classes of factors affecting absorption of drug from suppository ?
Physiological
Physicochemical
What are physiological factors which affect drug absorption from suppository?
Quantity of fluid available
Properties of mucous
Contents of rectum
Motility of rectal wall
What are physicochemical factors which affect absorption of the drug from the suppository?
Drug solubility
Particle size
Concentration
Surface area
What are the weight and length of suppositories containing different doses of diclofenac ?
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
How much fluid is available in the rectum?
Approximately 3mL
Dissolution of slightly soluble substances is the slowest step in the absorption process
What factors affect the colonic content and therefore affects the absorption of drug from the suppository ?
Faecal matter
Diarrhoea
Colonic obstruction due to tumorous growths
Tissue dehydration
What are the properties of the rectal mucous that should be considered when determining the absorption of drug from the suppository?
Essentially neutral in pH (7-8)
Lacks buffering capacity
What are the three main methods of preparing suppositories?
- Moulding from a melt
- Compression moulding
- Hand rolling
What is the moulding from a melt method of suppository preparation?
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
What sort of suppository bases is the moulding from a melt method suitable for?
Cocoa butter
Glycerinated gelatin
PEG bases
What is the compression moulding method of preparing suppositories?
The cold mass of the base containing the medicament is compressed into suppositories
What are the advantages of the compression moulding method for preparing suppositories?
Simple
Suppositories more elegant than hand rolling
Prevents Sedimentation of solids in the base
Suitable for heat labile medicaments as no melting required
What are the disadvantages of the compression moulding method of preparing suppositories ?
Air entrapment can take place resulting in weight variation
Drug or base may be oxidised
What is the hand rolling method of preparing suppositories ?
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
What is the main advantage and disadvantage of the hand rolling method?
+ useful for preparing a small number of suppositories as does not require specific equipment
- there is no uniformity in shape and size
What are the quality control tests regarding suppositories?
Appearance Weight Disintegration Melting range test Liquefaction/softening time Mechanical strength Content of active ingredient Dissolution (drug release)
What is Assessed in the appearance test for QC of suppositories?
Odour
Colour
Surface condition
Shape
What is assessed in the weight uniformity test for QC of suppositories?
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%
How is disintegration assessed in QC of suppositories?
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
What is the melting range test for QC of suppositories?
There are three main methods to determine melting range
- Open capillary tube method
- U-tube method
- 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
What is the liquefaction/softening time test for the QC of suppositories ?
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
What is the mechanical strength test for QC of suppositories?
- 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
What is the purpose of the mechanical strength test for suppositories?
So that we can ensure Suppositories can be transported under normal conditions and administered to the patient
What is the content uniformity of active ingredient test for QC of suppositories?
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
What is the dissolution test for QC of suppositories ?
This is required to demonstrate the release of the active substance from the dosage unit.
USP dissolution apparatus used
Compared to pharmacopoeia monograph
How should the suppositories be packed?
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
How should suppositories be stored?
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
