VAGINAAAAAAAl and rectal formultions

Why chose the rectal route?

GI problems

unconsious

very old/young

drug can’t be taken orally (ph, first pass, unaccaptable organoleptic properties)

What are the disadvantages of rectal administration?

* people don’t like stuff in their butts
* inter/intra subject varition
* proctitis (inflammation of rectum- bleeding, pus, mucous)
* short shelf life
* large scale manufactuse cuks

Is rectal administrtion systemic/ local?

both

What’s the anus

Circular muscle

Describe the rectal wall?

one layer thick

cyckindrical cells

goblet cells

no villi

How much mucus in the rectum

3ml

Whats the surface area of the rectum

300cm

Does the rectum buffer?

Not really

ph 7.5

What are the 3 vessels @ rectum

inferior haemorrhoidal vein

middle haemorrhoidal vein

superior haemorrhoidal vein

where does superior haemorrhoidal vein drain to?

Liver

where do inferior and middle haemorrhoidal veins drain to?

Systemic circulation

Does first pass metabolism happen at the rectal route?

Soemtimes

depends where the drug is absorbed

if high up→ superior haemorrhoidal vein→ liver

Where should the drug be absorbed to avoid FPM?

Lower rectum

Is the 3ml of mucous bad or good for drug absorption?

Bad!

dissolution= rate limiting step

viscosity= barrier

What are the advantageous bits of the rectal physiology?

Motiloty (muscular contractions= spreading of drug=absorbtion)

goood blood supply

no enzymes= no peptidases/esterarses (peptide like drugs??)

What can happen to the suppository base after insertion?

* dissolve in rectal fluids
* 3ml small volume
* complete dissolution unlikely
* extra water required
* painful

\
* melt on the mucus layer at 37C

\

What will the drug have to do first if its in a vehicle before getting absorbed?

Leave the water immmiscible vehicle (gravity or motility will do that)

What layers does the drug have to pass before getting absorbed?

Mucus layer

Epithelial

What kind of transport will get the drug through the epithelia?

Passive diffusion

Are there active transporters in the rectum?

No

What are the two main classes of suppository bases

1. Fatty bases (glyceride)
2. Water soluble bases

What are themelting properties of an ideal base?

Lower range offers better particle seperation which leads to better absorption

\
Higher range is better for the manufacturing process (won’t melt due to machines)

What are the viscosity properties of an ideal base?

Good flow, diffusion , spreading

Will allow seperation of particles

What are the properties of a base that facilitate easy removal from the mold?

will contract upon solidification

Give examples of water soluble bases for suppositories

1. polyethylene glycols (macrogols)
2. glyco-gelatin

Give an example of a fatty base?

Theobroma oil

Semisynth bases

What chemicals is theobroma oil?

* it’s cocoa butter
* a mixture of triglycerides
* 2-oleopalmitostearin and 2-oleodistearin

What’s good about cocoa butter?

Will melt

Non-irritating

Solidifies quick

Why isnt theobroma oil used anymore?

* polymorphism
* insuffient contraction
* low softening point
* chemical instability
* poor water absorbtion
* oxidation
* leaks from the body
* expensive

What are the semi-synth fatty bases now used?

SATURATED FATTY ACIDS

What fatty acids are used now?

C12-C18 fatty acids

mixed triglycerides

Why are the semisynthetic bases now used less prone to oxidation than theobroma oil?

Theobroma oil = unsaturated

Semisynth= saturated (dont get oxidised as easily)

What are the melting point ranges for semi-synth bases?

33-37.5C

Why are semi-synth bases better at absorbing water?

high hydroxyl number

Give examples of semi-synth bases?

Massuppol

Suppocire

What are the disadvantages of semi-synth bases?

brittle if cool quick

less viscous than theobroma oil= sedimentation

If water soluble bases have a melting point higher than body temp, how are the drug particles released?

Suppository breaks up by the rectal fluid

Why are water soluble bases used more rarely ?

the volume of rectal fluid is small , dissolution difficult

What’s the problem that arises with the water soluble bases being hydroscopic?

They draw out water which is painful

What’s in glycerol suppositories BP?

14% gelatin

70% glycerol

List the types of gelatin used in glycerol suppositories

type a

type b

Are type a acidic or basic?

Acidic

Are type b anionic?

yes

(they’re basic, OH- is an anion and a base)

What are the problems with a glycogelatin base?

* microbial growth
* laxative


* irritant
* unpredictable dissolution time
* hydroscopic
* lubricating of moulds is vital
* long prep time

What are macrogol bases?

Mixtures of polyethylene glycols of varying m.w.

What is the melting point of macrogols?

50C typically

different m.w. have diff melting points= use a blend to get what you want

What’s the advantage of macrogols over glycogelatin base?

No laxative effect

Why is the contraction of macrgols upon cooling beneficial?

You don’t need to add a lubricant to the base like with glucogelatin bases

Are macogols more or less viscous than theobroma oil?

More viscous= less leakage

What dictates maximum attainable concentration?

Drug solubility in rectal fluids

What will happen if the vehicle to water partition co-eff is high?

Means drug has a high affinity for vehicle

= drug has a low tendency to leave vehicle

What form of base is suitable is the drug is highly soluble in fats?

an aqueous base

\

What do surface properties determine?

How drug transfers from one phase (base) to another (rectal fluids)

Why is a small particle size important?

1. less irritation’
2. less sedimentation
3. faster dissolution

What is the general thumb of rule for particle size ?

Less than 150 micrometers will prevenent sedimentation

Less than 50 micrometers will prevent irritation

What can happen to really small particles?

Agglomeration (mass or collection)

Describe the suppository quality control test for uniformity of weight

* 20 samples
* 2 max can deviate by 5%
* none can deviate by over 10%

Describe the suppository quality control test for uniformity of content?

* suitable analytical method
* 10 suppositories
* one max can be in 85-115% range
* none can be in 75-125% range

When can the uniformity of content test be redone?

If there’s no more than 3 in the 115-85% range

\
* none can be outside 85% -125% range

How to retake the uniformity of content test?

Analise additional 20 samples

What are the methods to measure the melting range of suppositories?

Open capillary tube

u tube

drop point

What should be the melting point for fatty acids?

less than 37C

Describe the suppository quality control test for disintegration

* placed in a liquids medium
* checked if they disintegrate in an okay time

What is considered as a pass of the disintegration test?

* completely dissolve
* separated into its components
* become soft/disfigured

What are the times for disintegration?

less than 30mins for fatty bases

less than 60mins for aqueous bases

What are rectal capsules?

* shell suppositories
* lubricating coating
* single dose
* solid
* elongated
* smooth

What can be the solvents for rectal solutions?

glycerol/macrogol/ water

What excipients are particularly important in powders and tablets that are used to prepare rectal solutions?

Excipients to prevent aggregation of particles

* faciltates dispersion

What monograph do rectal semi-solids go under?

Semi-solids for cutanous use

What monograpgh to rectal foams go under ?

Medicated foams monograpgh

What are rectal tampons?

* solid
* single dose
* INSERTED ONLY FOR A LIMITED TIME

What monograpgh do rectal tampons go under?

Medicated tampons

What materials are used to make medicated tampons?

Celluouse

Collagen

Sillicone

(impregnated w/ api)

Can intravaginal drug delivery be used for systemic effects?

YES

but primarly for local effect

What is the vagina?

Muscular tube

How much fluid produced by the vagina daily?

6ml

How much vaginal secretions present at any given time?

0\.5-0.75ml

What’s the pH of the vagina?

4\.5

Are enzymes present in the vagina?

Low enzymatic activity

What’s great about the vagina?

* vascularised well


* prolonged retention

What are the disadvantages of the vagina?

* menstrual cycle causes changes
* local side effect
* variable permeability