Bioavailability - Rapamycin

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Rapamycin's bioavailability (in raw or simple solid form) is extremely low, typically ~1–2% oral bioavailability in humans. This poor absorption is due to: * Poor aqueous solubility: Rapamycin is lipophilic and practically insoluble in water, limiting dissolution in the GI tract. * High molecular weight (~914 Da): Too large for passive diffusion through intestinal lining. * First-pass hepatic metabolism: Rapidly metabolized by CYP3A4 enzymes in the liver and intestines. * P-glycoprotein efflux substrate: Pumped back into the gut lumen by intestinal P-gp, reducing net absorption. Why SMEDDS or Microemulsions Are Needed: Without these, absorption is negligible, and the therapeutic effect would be unreliable or absent. This is why Rapamune (SMEDDS-based) was developed to raise it to a usable ~14% and allow oral administration in transplant patients and off-label longevity research. {pre} 🧠 Rapamycin Bioavailability: Route Comparison Route Approx. Bioavailability Advantages Challenges Formulation Strategies Oral (raw/standard) ~1–2% Convenient Poor solubility, extensive 1st-pass metabolism, P-gp efflux None (base compound only) Oral (SMEDDS / Rapamune) ~14% Convenient, approved, reproducible Still undergoes some 1st-pass metabolism Microemulsion: solubilization, lymphatic absorption Oral (Nanoformulations) ~10–20% (varies) Potential for higher uptake Stability, scale-up Liposomes, solid lipid nanoparticles, nanocrystals Sublingual / Buccal ~10–30% (theoretical) Bypasses liver first-pass metabolism Low water solubility, bitter taste, mucosal irritation Ethanol-based sprays, cyclodextrin complexes, mucoadhesive gels Transdermal (Topical) <1% (unformulated) / ~5–10% (enhanced) Bypasses GI/liver, localized delivery Poor skin penetration (large molecule) Ethosomes, transfersomes, nanoemulsions Intranasal ~10–20% (theoretical) Rapid absorption, avoids 1st-pass Irritation, mucociliary clearance Nanoemulsions, cyclodextrin-inclusion complexes Rectal ~5–15% (est.) Partial 1st-pass avoidance Patient acceptability, formulation variability Suppositories, lipid-based enemas {/pre} !!🧪 1. SMEDDS (Self-Microemulsifying Drug Delivery System) for Rapamycin 🧰 Materials Needed: ## Rapamycin (active drug) ## Oil phase: e.g., Capryol 90, Labrafac, or medium-chain triglycerides (MCT) ## Surfactant: e.g., Tween 80 (Polysorbate 80) ## Co-surfactant/co-solvent: e.g., Transcutol P, PEG 400, or ethanol ## Optional: Oleic acid (to help solubilize rapamycin), antioxidants (e.g., BHT) 🧪 Lab-Scale Procedure: * Determine solubility: ** First, test rapamycin solubility in each excipient to choose optimal components (oil, surfactant, co-surfactant). * Prepare SMEDDS base: ## Mix selected oil (e.g., 10–30%), surfactant (40–60%), and co-surfactant (10–30%) in a beaker. ## Stir with a magnetic stirrer or vortex until clear. * Add rapamycin: ## Add rapamycin to the above mixture (1–2 mg/mL). ## Stir at 40–45°C until fully dissolved. * Self-emulsification test: ## Add 1 mL of formulation to 100 mL of water and stir gently. ## A clear or slightly bluish nanoemulsion should form in <1 minute. ## Filter sterilize (optional): Use 0.22 µm syringe filter for sterile formulations. * Storage: ## Store in amber vials, ideally under inert gas (e.g., nitrogen) at 4°C. 💊 Administration: * Can be encapsulated into soft gel capsules or taken as a liquid. !!⚗️ 2. Oral Nanoformulations (e.g., Lipid Nanoparticles, Nanocrystals, or Polymeric Nanoparticles) Typical approach using solid lipid nanoparticles (SLNs): 🧰 Materials Needed: ## Rapamycin ## Lipid: e.g., glyceryl behenate (Compritol), stearic acid ## Surfactant: e.g., Poloxamer 188, Tween 80 ## Co-surfactant: optional (lecithin, bile salts) ## Aqueous phase: distilled water 🧪 Procedure: Hot Homogenization + Ultrasonication * Melt lipid: Heat lipid (e.g., 70–80°C) until fully melted. * Dissolve rapamycin: Add rapamycin to the molten lipid and stir. * Prepare aqueous surfactant phase: Dissolve surfactant (e.g., 1–2% w/v) in hot distilled water (same temp as lipid). * Emulsify: Add lipid-rapamycin melt into aqueous phase under high-speed homogenization (e.g., 10,000–20,000 rpm for 5–10 min). * Ultrasonication: Probe-sonicate the emulsion for 2–10 minutes in an ice bath to reduce particle size (target: ~100–200 nm). * Cooling: Let it cool to room temp. Lipid solidifies forming SLNs encapsulating rapamycin. * Characterization (optional): Measure particle size (DLS), zeta potential, and drug loading efficiency. 🧊 Storage: * Store at 4°C or lyophilize for long-term storage. {pre} 🧪 Summary Comparison: Feature SMEDDS Nanoformulation (e.g., SLNs) Size range 20–200 nm 50–300 nm Requires heat Mild (for mixing) Yes (to melt lipids) Bioavailability gain ~14% 10–20% (varies with formulation) Scale-up friendly Very Moderate (more complex) Stability Good (self-emulsifies on demand) Moderate (may need lyophilization) {/pre}
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