Vaginal and Rectal Drug Delivery (4/3/26) - Pharmaceutics II

What six main parts is the Female reproductive system composed of?

1. Uterus

2. Fallopian Tubes

3. Ovaries

4. Cervix

5. Ectocervix

6. Vagina

What three reasons explain why the Vagina is a favorable site for drug administration?

1. Avoidance of First Pass Metabolism Effect

2. Rich Vascularization

3. Relatively Low Enzymatic Activity

What two types of effects does the Vaginal Cavity have potential for noninvasive, controlled transmucosal delivery?

Local and Systemic Effects

What types of medications are given as examples of Local noninvasive, controlled transmucosal delivery options?

Antifungals

Steroids

Prostaglandins

Antimicrobials

Birth Control (Nonoxynol-9)

What types of medications are given as examples of Systemic noninvasive, controlled transmucosal delivery options?

Ovulation Inducing Activity

Urogenital Tract Infections

Hormone Replacement Therapy

Which three features of the Vagina influence the Retention, Absorption, and Drug Release of a Formulation?

1. pH

2. Enzymatic Activity

3. Microflora

What three characteristics of a Drug Formulation are affected by the pH, Enzymatic Activity, and Microflora of the Vagina?

1. Formulation

2. Absorption

3. Drug Release

What four factors can affect the Rate and Extent of Drug Absorption after Intravaginal Administration?

1. Vaginal Physiology

2. Age of the Patient

3. Stage in the Menstrual Cycle

4. Formulation Factors

What are the four main therapeutic applications for Vaginal Drug Delivery?

1. Contraceptives

2. Treatment of AIDS and HIV

3. Treatment of STDs

4. Vaginal Infections

What do Contraceptives serve as an effective route for?

Delivery of Hormones

What does AIDS stand for?

HIV?

AIDS - Acquired Immune Deficiency Syndrome

HIV - Human Immunodeficiency Virus

What are three examples of common Vaginal Infections that Vaginal Drug Delivery is used to treat?

1. Vaginosis

2. Trichomoniases

3. Candidiasis

What are three advantages to Vaginal Drug Delivery?

1. Avoidance of Hepatic First Pass Metabolism

2. Minimal Systemic Side Effects

3. Local Targeting of Drugs to the Reproductive Organs

What are three disadvantages to Vaginal Drug Delivery?

1. Patient Noncompliance

2. Local Irritation

3. Variability in Drug Absorption that is Related with Menstrual Cycle, Menopause, and Pregnancy

What two routes are Vaginal Drug forms usually absorbed into the Vagina by?

1. Transcellular

2. Paracellular

How does Transcellular absorption work in Vaginal Drug Delivery?

What type of drugs does this route typically occur with?

INTRACELLULAR - moves within the same cell, from Apical to Basal Membrane of the cell

Typically for Lipophilic Drugs

How does Paracellular absorption work in Vaginal Drug Delivery?

What type of drugs does this route typically occur with?

INTERCELLULAR - moves in between the cells via Tight Junction mediation

Typically for Hydrophilic Drugs

What are the three Key Factors that affect Vaginal Drug Delivery?

1. Physiological Factors

2. Physicochemical Factors of the API

3. Formulation Factors

What are some examples of Physiological Factors that influence Vaginal Drug Delivery?

Acidic pH (3.5-4.5)

Enzymes

- Ex. Amylases that hydrolyze Glycogen into simpler sugars and sustain bacterial populations

Microflora

Cyclic Changes

Hormone Levels

What are some examples of Physicochemical Factors of the API that influence Vaginal Drug Delivery?

Molecular Size and Weight

Partition Coefficient (Lipophilicity)

Extent of Ionization

Chemical Nature

What are some examples of Formulation Factors of the API that influence Vaginal Drug Delivery?

Viscosity

Penetration Enhancers

Bioadhesive / Mucoadhesive Properties

- Increase contact time between the Vaginal Mucus Membrane and given Formulations

How do Penetration Enhancers affect Vaginal Drug Delivery?

Give examples of Penetration Enhancers used in Formulations.

Promote absorption and penetration of the drug through the Vaginal Mucosa

EXAMPLE:

- Bile Salts (interact with phospholipids in cell membranes)

How do Mucoadhesive Agents affect Vaginal Drug Delivery?

Give examples of Mucoadhesive Agents used in Formulations.

Permit close contact of formulation with the Vaginal Mucosal Surface by promoting adherence

EXAMPLE:

- Hyaluronic Acid

- Cellulose Derivatives

How do Bioadhesive Formulations (Polymers) affect Vaginal Drug Delivery?

Give examples of Bioadhesive Formulations (Polymers) used in Formulations.

Capable of delivering the API for an extended period at a predictable rate

EXAMPLE:

- Carbomers

- Polycarbophil

- Prochieve TM

What is Prochieve TM?

Bioadhesive Gel used in HRT

What are the four types of Local Drug Delivery Dosage Forms used for Vaginal Drug Delivery?

1. Vaginal Suppositories

2. Vaginal Douches / Irrigation, Sprays, and Solutions

3. Vaginal Gels and Creams

4. Vaginal Films, Patches, and Rings

What are the four types of Systemic Drug Delivery Dosage Forms used for Vaginal Drug Delivery?

1. Tablets

2. Capsules

3. Injectables

4. Implants

What two types of effects does administration of pharmaceutical preparations via the Rectum allow for?

Local and Systemic

For Rectal Dosage Forms, what is the Solid Unit Dosage Form?

Liquid Unit Dosage Form?

Semi-Solid Dosage Form?

SOLID UNIT - Suppository

- Ex. Compazine, Aspirin

LIQUID UNIT - Enema

- Ex. FullWash Enteroclisma Enema

SEMI-SOLID - Ointment, Cream

For Rectal Dosage Forms, what type of Dosage Form are Suppositories?

Enemas?

Ointments and Creams?

SUPPOSITORIES - Solid Unit

ENEMAS - Liquid Unit

OINTMENTS & CREAMS - Semi-Solid

What is the main therapeutic application for Rectal Dosage Forms?

Rectal Diseases

Give three examples of Rectal Diseases that Rectal Dosage Forms are used for.

1. Perianal Abscesses

2. Hemorrhoids

3. Fissures

What are four examples of therapeutic agents delivered via Rectal Drug Delivery?

Give specific drug examples for each agent.

1. STEROIDS

- Ex. Hydrocortisone, Prednisolone

2. ANTI-INFLAMMATORY DRUGS

- Ex. Sulfasalazine, Mesalazine

3. ANTI-CANCER DRUGS

- Ex. 5-Fluorouracil, Oxaliplatin

4. NSAIDS

- Ex. Sulindac, Celecoxib

What is the only approved Rectal formulation for treatment of Early Status Epilepsy in the United States?

Diazepam

What is the Rectum?

What is the pH like in the Rectum?

Rectum is the LAST, usually empty, end portion of the Large Intestine that is located above the Anal Canal

pH is neutral in the Rectum (7.2-7.4)

How does the Surface Area for absorption of the Rectum compare to that of the Small Intestine?

Why?

SMALLER Surface Area of absorption than the Small Intestine

Lacks Villi and Microvilli

What broader classification of routes is Rectal Delivery included in?

What other delivery methods are included?

ENTERAL Routes (use digestive system)

Includes:

- Mouth

- Stomach

- Small Intestine

- Anus

What is the Rectal Route most effectively used for?

Treatment of LOCAL Diseases of the Anorectal Area

- Ex. Hemorrhoids

Delivery of drugs SYSTEMICALLY, as an alternative to Oral Route

- Ex. Antipyretic and Analgesic Drugs

What are two examples of Antipyretic and Analgesic Drugs that are given via Rectal Delivery to enter into Systemic effect?

1. Paracetamol

2. Diclofenac

Under what circumstances can systemic delivery be useful for certain drugs?

Useful for drugs that:

- Possess limited absorption in upper GI Tract

- Are unstable to Proteolytic Enzymes

- Exhibit high hepatic first pass effect

- Cause irritation to the Gastric Mucosa

- Need high doses and cannot easily be formulated in oral dosage forms

What are the two main advantages to Rectal Drug Delivery?

1. Secondary choice after Oral and IV administration

2. First choice and favorable in certain conditions

During what conditions does Rectal Drug Delivery become the first choice for drug administration?

Nausea and / or Vomiting

Objectionable Taste

Unconsciousness during Post-Operative Treatments

Difficulty in Swallowing with Motility Issues in the GI Tract (ex. Dysphagia)

Inflammation at Site of Intramuscular Administration

What are five main disadvantages to Rectal Drug Delivery?

1. Poor Patient Compliance

2. Neglected due to Erratic Absorption

3. Limited SA for Absorption

4. Dissolution Problems due to small fluid content of Rectum

5. Drug Metabolism via Superior Hemorrhoidal Vein drains into the Portal System

What is the composition of the Epithelia in the Rectum like?

What does this make it comparable to?

Made up of a single layer of Columnar or Cuboidal Cells and Goblet Cells

Gives it comparable abilities to the GI Tract for digesting drugs

What is the Surface Area of the Rectum?

What is it without?

How does this compare to the GI Tract and Nasal / Buccal Routes?

200-400 cm2

Is without Villi and Microvilli

SMALLER than upper GI Tract

LARGER than Nasal and Buccal Surfaces

Where should Rectal Dosage Forms be inserted?

Why?

Inserted into LOWER Part of Rectum

This is to avoid having the drug be absorbed by the Upper Hemorrhoidal Vein, which supplies to the Portal Vein

What is the Rectal Region drained by?

How does this affect absorption?

Extensively drained by Lymphatic Circulation

Increases systemic absorption of some highly Lipophilic Drugs

What does an Empty Rectum provide for drug delivery?

Provides a constant and static environment, compared to the Upper GI Tract

What is the Lower Rectum drained by?

How does this affect absorption?

Drained by the Lower and Middle Hemorrhoidal Veins (and bypasses Liver)

Avoids Hepatic First Pass Effect, allowing RAPID ABSORPTION and systemic effect prior to Metabolism in Liver

Why do Middle and Lower Hemorrhoidal Veins enter Systemic Circulation?

They bypass the liver

Where do the Superior Hemorrhoidal Veins drain?

How does this effect where things are metabolized after processing through these veins?

Drain into the Portal System

Things processed through these veins are therefore metabolized by the Hepatic Portal System (first pass effect)

What type of diffusion does Rectal Drug Delivery use for absorption?

Passive Diffusion

What four main categories of factors affect Rectal Drug Delivery?

1. Drug-Associated Factors

2. Formulation-Associated Factors

3. Pathology-Associated Factors

4. Physiology-Associated Factors

What are four examples of Drug-Associated Factors that affect Rectal Drug Delivery?

1. Partition Coefficient

2. Solubility

3. Degree of Ionization

4. Particle Size

What are three examples of Formulation-Associated Factors that affect Rectal Drug Delivery?

1. Liquid Dosage Forms

2. Solid Dosage Forms

3. Semi-Solid Dosage Forms

What are three examples of Pathology-Associated Factors that affect Rectal Drug Delivery?

1. Inflammatory Bowel Disease

2. Hemorrhoids

3. Gastrointestinal Infections

What are four examples of Physiology-Associated Factors that affect Rectal Drug Delivery?

1. Rectal Fluid Volume and pH

2. Presence of Rectal Contents

3. Rectal Mucous

4. Motility