34. vaginal drug delivery Flashcards
What do we currently treat using vaginal drug delivery?
Typically hormonal products of contraception (can be combined)
- Local vaginal issues→ Antifungals, Antibiotics, Steroids, Spermicides, Lubrication, Hygiene & Microbicides
- Systemic treatments→ Oestrogen, progestogens & Prostaglandins analogues
Give examples of brand name medications used to treat vaginal issues?
canesten
clotrimazole
vagsil
What are the advantages of vaginal drug delivery?
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Smaller doses are required than the oral route
- The patient may have GI tract issues
- The drug may be prone to degradation at a particular PH
- Enzymatic degradation
- Taste of the medication can not be masked & may not be favorable
- Therefore, the vaginal route is favored!
What are the disadvantages of vaginal drug delivery?
- Gender specific
- Hormonal Variations affecting drug absorption
- Varying volume of cervico-vaginal fluids can affect drug release
- Leakage likely (limited by volume of fluid and surface area)
- Physiological acidic PH may enhance drug degradation
- Systemic absorption of locally acting drugs
- Stigma of administration
What is the function of Microflora?
Transforms glycogen to lactic acid
Outline the characteristics of the Vaginal Epithelium
- he vaginal wall has a large SA of 60m2
- It has an intricate and elaborate systems of intracellular channels
- It is comprised of non-cornified stratified squamous cells (upper lining with folds which increase the SA)
- For local action→ non-absorption is desirable
- For systemic action→ drug delivery is possible via passive transport because we have a rich supply of blood (capillaries).
- Blood drains from the vaginal vein into the inferior vena cava, avoiding first pass metabolism. Achieves a higher bioavailability from local administration. In contrast…
- Rectal route → For the drug to drain into the inferior vena cava (avoiding first pass metabolism) it needs to come from the middle or inferior haemorrhoid or vein
What are the properties of an ideal vaginal dosage form?
- Long acting→ reducing administration frequency
- Stable→ In a range of climatic conditions: manufactured, stored and transferred and must survive.
- Non-irritant→ No burning or Itching
- Minimise leakage
- Not cause staining/discolouring
- Colourless and Odourless
- Have no impact on sexual activity
- Discrete
- Easy to use correctly
What are examples of Ideal drug vaginal characteristics?
- Particle size→ >50um causes mechanical irritation; >150um rapid sedimentation during manufacture
- Solubility→ Dictates the type of formulation
- Drug loading→ Difficult to maintain mechanical strength and correct melting point if very high drug concentration
- Bulk density→ May be difficult to incorporate into formulation especially if poorly soluble in the vehicle
- Surface Characteristics→ Surfactants may be required for rapid wetting after administration
Why is the particle size of the drug important? Further detail
- Particle size can affect sedimentation & agglomeration of drug particles. Large molecules can cause mechanical irritation so its important to keep the particle size low.
- Rapid sedimentation or agglormeration of particles during manufacture, which will impact drug uniformity accross the formulation
Why do these large particles cause mechanical irritation?
They are more insoluble the larger they are. A smaller particle size will increase the rate of dissolution
What is essential for drug solubility? Further detail
- The base must be immiscible with body fluid
- If we don’t have solubility of the drug in body fluid or miscibility of the base with the body fluid it can impact on the extent of drug release from the formulation.
- So, the solubility of the drug in the rectal fluid or vaginal fluid can dictate the type of formulation
What can we do to maintain mechanical strength and the correct melting point? Further detail
- High drug loading can alter the melting point of your formulation. Some drugs may lower the melting point and if this occurs pre formulation is required to change the formulation design to ensure it is not impacting drug release.
- Adding a lot of drug can reduce the frequency of administation, achieves the bioavailability we want. This can impact mechanical strength or melting range of formulation
Why is it important to check the dissolution and drug release of a drug?📌
Dissolution testing measures the extent and rate of solution formation from a dosage form, such as tablet, capsule, ointment, etc. The dissolution of a drug is importantfor its bioavailability and therapeutic effectiveness
Why is it important to check the Disintegration time of a drug?
Disintegration testing measures the ability of a tablet to break down into smaller particles or granules to allow the active drug to be absorbed into the body. Its important that the drug disintegrates at the required time to have an effect on the patient.
Disintegration testing can be affected by: binders, lubricants, surfactants and hardness
Why is the Uniformity of content test performed/important?
Content uniformity is particularly important where tablet splitting is used. “The active ingredient needs to be evenly distributed throughout the tablet to ensure that if the tablet is split in half, each half of the tablet has an equal dose
Why is the Uniformity of mass test performed/important?
If the weight variations are too high the level of active ingredient in each tablet might be too high or too low and then the tablets don’t comply with the specifications any more
What Quality control of vaginal (&rectal) dosage forms must we complete?
- Uniformity of mass (single and multidose) → weight tolerance
- Uniformity of content (single and multidose)
- Disintegration time (tablets/capsules)
- Dissolution and drug release
- Microbial quality→ testing contamination
- Melting behaviour→ must have an ideal range characteristic, amplification of the product to the site will keep it intact. So it will not disintegrate or dissolve, drug will not be released and absorption is inhibited. If the melting behaviour is not good you can test different ratios of components to increase/decrease melting point
- Organoleptic assessment (colour, odour, surfaces, shape) → Is it mixed properly? Are all the shapes the same?
- Mechanical strength → during transportation and packaging
Give examples of vaginal dosage forms?
Pessaries, Ointments, Creams, Gels, Vaginal films, Vaginal tablets/capsules, Vaginal rings, Vaginal solutions/emulsions/suspensions
Outline the main characteristics of Pessaries
- [ ] Single dose preparations for vaginal insertion (1g)
- [ ] Contain one or more active ingredients dispersed in a suitable base which either disperses in water or melts at body temperature:
Outline the main characteristics of ointment, creams and gels
- [ ] For both local and systemic drug release (dependent on indications)
- [ ] Often developed from topical formulations rather than specifically on the spreading, volume, pH, osmolarity, retention time etc in the vagina (they typically take a topical formulation and alter it)
- [ ] Stability issues (e.g. hydrolysis)→ Aqueous environment drugs suceptible to hydrolysis (so degregation or introduction to water) bring stability issues
- [ ] Packaged formulations
- Multidose tubes with applicator
- Pre-syringe filled single applications
Define Drug Levigation
Levigation is the process of decreasing the particle size of powders via triturating them with a mortar and pestle along with a small amount of liquid wherein the substance is insoluble to.
This specific liquid is called a levigating agent and is viscous in nature with a low surface tension to easily wet the solid particles. Such agents also act as a lubricant as they also allow a smoother incorporation of solids in the preparation.
Outline the main characteristics of Vaginal films
- [ ] Thin layers of polymeric material designed to dissolve in the vaginal fluids
- [ ] Single dose and no need for applicator
- [ ] Film composition
- polymer (dissolve), plasticizer and solvent (provide flexibility)
- disintegrating agents (aids dissolution and disintegration), colourants, antimicrobial agents (prevents contamination), stabilizers (for polymeric formulation)
Outline the main characteristics of Vaginal tablets
- [ ] Similar formulation and manufacture to oral tablets
- [ ] Can be coated or uncoated
- Inclusion of bioadhesive polymers (carbopol, xanthan gum) providing a thick bioadhesive dispersion.
- Aids in adhesion of formulation during dispersion. If drugs are breaking up and disintergrating (not adhering to the mucosal membrane) we can have a potential reduction bioavailbility so add bioadhesives
- Improves retention and minimises leakage
- [ ] Should rapidly disintegrate:
- Can use biocarbonate + organic acid = CO2 release
- Filler – lactose (naturally converted to lactic acid by flora) → bulks up formulation
Why is the filler ideal for the vaginal membrane?
Lactose is ideal because the presence of the microflora naturally converts lactose to lactic acid. So fillers are broken down easily and will not be irritant.
