Vaginal Drug Delivery PDF

4.3 Vaginal Drug Delivery Vaginal drug delivery is typically self-administered. The drug is intended to distribute throughout the vaginal cavity. There are two main purposes of vaginal drug delivery: ○ Local effects: This is the most common purpose. Some example...

4.3 Vaginal Drug Delivery Vaginal drug delivery is typically self-administered. The drug is intended to distribute throughout the vaginal cavity. There are two main purposes of vaginal drug delivery: ○ Local effects: This is the most common purpose. Some examples of local effects include: Vaginal infections Lubrication Contraception ○ Systemic absorption: While the vagina is a good route for systemic absorption, there aren't many products designed for this purpose. However, there is ongoing research in this area. Dosage Forms for Vaginal Drug Delivery Liquids: These can include douches. Semisolids: This category encompasses: ○ Creams ○ Gels ○ Ointments ○ Foams ○ These dosage forms will be covered in detail in topical drug delivery lectures. Solids: This is one of the more common dosage forms, particularly suppositories. ○ Students will be making vaginal suppositories in the spring. ○ Other solid forms can include compressed tablets shaped like suppositories. ○ Other terms for vaginal suppositories include: Pessary (more common in Europe) Ovule Insert Films: ○ Similar to oral and buccal films, the drug is evenly distributed within a rapidly disintegrating polymer sheet. ○ The polymer is usually a cellulose derivative. Anatomy and Physiology of the Vagina Length: The vagina is approximately 6 to 10 centimeters long, extending from the cervix. Mucosa: This mucus membrane is vital as it's the primary site of drug absorption. ○ Like the mouth and rectum, it is coated with mucus, which keeps the epithelium moist.  ○ It's composed of a stratified squamous epithelium, making it more similar to skin than the GI tract. This means the drug needs to pass through multiple cell layers for absorption. Rugae: These folds in the vaginal wall offer several advantages: ○ Increased surface area: This can enhance drug absorption if systemic effects are desired. ○ Product retention: The folds help keep the drug product in place. Microflora: The vagina has a natural microflora that's essential for a healthy mucosa. This microflora should not be disrupted by drug formulations. Epithelium: The stratified squamous epithelium of the vagina has several key features: ○ The outermost layer consists of flattened squamous cells, much like the skin. ○ The stratum corneum, like that of the skin, is made up of dead corneocytes and intercellular lipids. ○ Key difference from skin: The intercellular lipids in the vaginal stratum corneum do not form an impermeable layer. This makes the vaginal stratum corneum more permeable than the skin's, allowing for easier drug passage. Vaginal Fluid Limited amount: Similar to the rectum, the vagina has a limited amount of fluid. Complex composition: Vaginal fluid is a mixture of various components, including: ○ Cervical secretions ○ Transudates from between cells ○ Exfoliated cells ○ Leukocytes Low pH: The vaginal fluid is typically acidic due to the presence of lactobacilli. ○ These bacteria convert glycogen into lactic acid, contributing to the acidic environment. ○ The acidic pH has a bacteriostatic effect, which is crucial for a healthy vaginal environment. ○ Important for formulation: Manufacturers need to consider the acidic pH when designing vaginal drug products to avoid disrupting this natural defense mechanism. Enzymes: Vaginal fluid contains enzymes that may impact the stability of certain drugs. Formulators need to be aware of these enzymes and their potential interactions with the drug being administered. Systemic Absorption from the Vagina Limited surface area: While the rugae do increase surface area, the vagina has a relatively limited surface area compared to the GI tract, which can limit systemic absorption. No hepatic first-pass effect: Like buccal administration, drugs absorbed through the vagina bypass the hepatic portal system, avoiding first-pass metabolism in the liver. This makes it an advantageous route for drugs with a high first-pass effect.  Variability: The vaginal mucosa can vary significantly between patients, affecting drug absorption. Factors influencing this variability include: ○ Amount and composition of vaginal fluid ○ Consistency of vaginal fluid ○ Menstrual cycle ○ Age (pH is generally higher in prepubescent girls, postmenopausal women, and during certain stages of the menstrual cycle) ○ Epithelial thickness (thinner after menopause) Good absorption for some drugs: Studies show that certain drugs, even large molecules that struggle to penetrate the skin, can be well-absorbed vaginally. ○ This is because the vagina lacks the continuous intercellular lipid barrier found in the skin. Limited systemic absorption for most current products: Several factors contribute to this: ○ The multi-layered stratified squamous epithelium, while more permeable than skin, still poses a barrier. ○ Short residence time of many vaginal products, limiting absorption time. ○ Significant interpatient variability in absorption due to differences in the vaginal mucosa. Considerations for Vaginal Drug Product Design Product pH: ○ Formulators should consider the natural acidic pH of the vagina and its importance in infection resistance. ○ Ideally, products should be formulated to match the vaginal pH. ○ However, pH adjustments might be necessary for drug solubility or stability. In such cases, a weak buffer should be used to allow vaginal fluids to readjust the pH after administration. Microbial presence: ○ Products must be free from any microorganisms, including yeast and molds, to prevent infections and disruption of the natural microflora. Residence time: ○ Products should remain in the vagina long enough for adequate drug distribution. ○ Factors affecting residence time include: Rheology (viscosity): More viscous products are less likely to leak out. Level of insertion: High insertion typically leads to better retention. Dosage form: Solid dosage forms should liquefy, disintegrate, or melt within minutes. Distribution: ○ Ideally, the product should spread evenly throughout the vaginal cavity. ○ Liquids and foams tend to spread better than disintegrating tablets or suppositories.  Leakage: Products should be designed to minimize leakage. Administration aids: Most vaginal products come with applicators to facilitate high insertion. Examples of Vaginal Drug Products Inserts (suppositories): ○ While suppository formulations are usually simple, some, like IMVEXXY, can have complex formulations with multiple excipients. Creams: ○ Example: Tramizol vaginal cream, which contains benzoyl alcohol (likely as a preservative). Ointments: ○ Often have simple formulations. ○ Example: An ointment containing butylated hydroxyanisole (BHA) as an antioxidant. Suppositories with fatty acid base: A classic type of suppository. Gels: ○ Can be formulated with gelling agents like carbomer (also known as carbopol). ○ Bioadhesive gels, containing excipients like polycarbophil, can enhance residence time by adhering to the vaginal mucosa. Films: ○ Example: VCF contraceptive film, a fast-dissolving polymer film containing Nonoxynol-9. General Administration of Vaginal Suppositories The sources provide general advice on administering vaginal suppositories. Important: Always refer to the manufacturer's specific information for the particular product being used, as administration instructions can vary. The information on general administration will be covered in the exam.