Transdermal, Gastroretentive & Nasopulmonary Systems
This unit explores three unique routes for controlled drug delivery. Transdermal Drug Delivery Systems (TDDS) cover skin permeation, factors affecting it, permeation enhancers, and patch components. Gastroretentive Drug Delivery Systems (GRDDS) focus on prolonging stomach residence time using floating, high-density, and mucoadhesive approaches. Nasopulmonary Drug Delivery introduces inhalers (MDI, DPI), nasal sprays, and nebulizers for both local and systemic drug delivery.
Syllabus & Topics
- 1Transdermal Drug Delivery Systems (TDDS): TDDS (Transdermal Patches): Self-contained discrete dosage forms applied to intact skin to deliver the drug through the skin at a controlled rate into the systemic circulation. Advantages: Avoids hepatic first-pass metabolism, avoids GI incompatibility (pH, enzymes), provides steady/constant plasma levels (zero-order), improves compliance (often applied once daily/weekly, e.g., fentanyl, nicotine), non-invasive, easy to terminate by simply removing the patch. Disadvantages: Skin is an excellent barrier; only highly potent drugs (dose < 20 mg/day) with specific physicochemical properties (low MW < 500 Da, moderate lipophilicity logP 1-3) can cross. Risk of contact dermatitis or skin irritation from the patch adhesive.
- 2Permeation Through Skin & Enhancers: Skin barrier: The stratum corneum (outermost dead layer of epidermis, composed of keratinocytes in a lipid matrix — ‘brick and mortar’ model) is the main rate-limiting barrier. Routes of permeation: Transcellular (across cells), Intercellular (between cells through lipid channels — most common route), Transappendageal (through hair follicles and sweat glands — minor route due to small surface area). Factors affecting permeation: Drug physicochemical properties (MW, partition coefficient, solubility), vehicle properties, skin conditions (hydration increases permeability, age, site of application). Permeation Enhancers: Agents that temporarily and reversibly decrease the barrier resistance of the stratum corneum. Chemical enhancers: Solvents (ethanol, propylene glycol), Surfactants (SDS), Azone, Terpenes, Fatty acids (oleic acid). Physical enhancers: Iontophoresis (low electrical current), Sonophoresis (ultrasound), Microneedles (physically puncture stratum corneum).
- 3Basic Components & Formulation of TDDS: Components: (1) Polymer matrix/Reservoir (holds the drug). (2) Drug (active ingredient). (3) Permeation enhancers. (4) Pressure-sensitive adhesive (PSA): Maintains contact with the skin (e.g., acrylics, silicones, polyisobutylene). (5) Backing membrane: Protects the patch from the environment, prevents drug leakage, provides structure (e.g., polyester, metallic films). (6) Release liner: Removed before application; protects the adhesive. Formulation Approaches: (1) Polymer Membrane Permeation-Controlled (Reservoir system): Rate controlling membrane between drug reservoir and adhesive. (2) Polymer Matrix Diffusion-Controlled: Drug dispersed in hydrophilic/lipophilic polymer matrix, which is mounted on a backing layer. (3) Adhesive Dispersion-Type: Drug is directly incorporated into the pressure-sensitive adhesive. (4) Microreservoir Type: Drug is suspended/solubilized in an aqueous solution, then uniformly dispersed in a lipophilic polymer matrix.
- 4Gastroretentive Drug Delivery Systems (GRDDS): GRDDS: Novel systems designed to be retained in the stomach for an extended and predictable period. Rationale/Need: Conventional oral SR dosage forms pass through the GI tract rapidly (transit time ~8-12 hours). GRDDS are essential for drugs that: (a) have an absorption window narrowly limited to the stomach or upper small intestine (e.g., levodopa, furosemide), (b) act locally in the stomach (e.g., antacids, H. pylori eradication antibiotics), (c) are degraded in the alkaline pH of the colon, or (d) are poorly soluble at alkaline pH. Advantages: Improved bioavailability, reduced dosing frequency, targeted local therapy in the stomach. Disadvantages: Requires a minimum level of gastric fluid to function, not suitable for drugs that cause severe gastric irritation (e.g., NSAIDs) or are unstable in acidic pH.
- 5Approaches for GRDDS: (1) Floating Systems (Hydrodynamically Balanced Systems – HBS): Have a bulk density lower than gastric fluid (< 1.004 g/cm³). They remain buoyant in the stomach contents without affecting the gastric emptying rate. Can be Non-effervescent (matrix-forming polymers like HPMC that swell and entrap air) or Effervescent (contain sodium bicarbonate + citric acid; gastric acid reaction produces CO₂ gas, which is trapped in the gel matrix, causing the system to float). (2) High-Density Systems: Density > 3 g/cm³ (using barium sulphate, zinc oxide). Sinks to the bottom of the stomach folds, resisting gastric emptying. (3) Gastroadhesive/Mucoadhesive Systems: Use bioadhesive polymers (Carbopol, chitosan) to stick to the gastric mucosa. Difficult due to rapid turnover of gastric mucus. (4) Inflatable/Expandable Systems: Swell or unfold to a size larger than the pyloric sphincter (> 15 mm) upon contact with gastric fluid, preventing passage into the intestine.
- 6Nasopulmonary Drug Delivery System: Nasal Delivery: Drug administered via the nasal cavity. Advantages: Rich vascularity, large surface area (nasal conchae), rapid absorption, avoids first-pass metabolism, potential for brain delivery (via olfactory pathway bypassing blood-brain barrier). Suitable for peptides/proteins (calcitonin, desmopressin) and migraine drugs (sumatriptan). Pulmonary Delivery: Delivery to the lungs for local action (asthma/COPD) or systemic absorption (huge surface area of alveoli, rich blood supply, thin barrier). Devices: (1) Metered Dose Inhalers (MDI): Pressurized devices using propellants (HFA) to deliver a precise dose (e.g., salbutamol). Require coordination between actuation and inhalation. (2) Dry Powder Inhalers (DPI): Breath-actuated; patient’s inhalation aerosolizes the fine dry powder (e.g., budesonide/formoterol Turbuhaler). Eliminate coordination issues of MDI. (3) Nebulizers: Convert liquid drug solutions/suspensions into a fine mist via compressed air (jet) or ultrasonic waves; used for young children or severe asthma attacks.
Learning Objectives
Exam Prep Questions
Q1. Why can’t all drugs be formulated as transdermal patches?
The stratum corneum is a highly effective barrier. For a drug to passively permeate the skin in therapeutic amounts, it must meet stringent criteria:
Very small dose requirement (usually < 10–20 mg/day).
Low molecular weight (< 500 Da).
Moderate lipophilicity (logP between 1 and 3) to cross both the lipid matrix and aqueous layers of the epidermis.
Non-irritating to the skin.
Drugs like insulin or antibiotics require doses too large or are too hydrophilic/large to pass.
Q2. How does an effervescent floating GRDDS work?
An effervescent floating system (gastroretentive) contains a swellable polymer matrix (e.g., HPMC) combined with an effervescent base (sodium bicarbonate and citric/tartaric acid). When the tablet reaches the stomach, the acidic gastric fluid penetrates the matrix. The acid reacts with the bicarbonate to produce carbon dioxide (CO₂) gas. The CO₂ gets trapped within the swelling polymer gel network. This trapped gas significantly reduces the density of the tablet (to less than 1 g/cm³), causing it to float on top of the gastric contents.
Q3. What is the key difference in patient usage between an MDI and a DPI?
A Metered Dose Inhaler (MDI) uses a pressurized propellant to shoot the medication into the mouth. It requires the patient to perfectly coordinate pressing the canister (actuation) with taking a slow, deep breath. Many patients struggle with this coordination, needing spacer devices.
A Dry Powder Inhaler (DPI) does not use a propellant. It is “breath-actuated.” The patient’s own rapid, forceful inhalation draws the dry powder out of the device and aerosolizes it, eliminating the need for hand-breath coordination.