Methods of Drug Delivery, Lecture notes of Chemistry

Download Methods of Drug Delivery and more Lecture notes Chemistry in PDF only on Docsity! Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Prof. Robert Langer R. Langer/HST-151 1 Methods of Drug Delivery Professor Robert Langer, D. Sc. I. Introduction: The means by which a drug is introduced into the body is almost as important as the drug itself. Drug concentration at the site of action must be maintained at a level that provides maximum therapeutic benefit and minimum toxicity. The pharmaceutical developer must also consider how to transport the drug to the appropriate part of the body and, once there, make it available for use. As the name implies, a controlled-release drug delivery system serves two functions: 1. orally, by implantable reservoir, etc. 2. Drug delivery, involves the absorption and transport of the drug to a particular part of the body. This may be accomplished intravenously, transdermally, Controlled release governs the rate at which the drug is made available to the effect site once it has been delivered. Traditionally, delivery systems have not incorporated means of controlled release. This means that the concentration of most drugs peaks and declines rapidly after each dose and will often be above or below the desired therapeutic range. Time l Desi Pl as m a D ru g Le ve red Range Next Dosage R. Langer/HST-151 2 II. Sustained Release Sustained release is an incremental improvement. It provides prolonged but not uniform release of drug and reduces the need for repeated dosing. Once the maximal level is reached, the amount of drug in the body decreases slowly so it will take longer to drop below the therapeutic range. Sustained release technologies in current use include 1. Complexes 2. Slowly dissolving coatings 3. Suspensions 4. Emulsions 5. Compressed tablets Release rates are strongly influenced by environmental conditions Release rarely lasts longer than 12 hours; so the benefits are limited. l i Pl as m a D ru g Le ve Des red Range Time R. Langer/HST-151 5 DCm • Flux − = D DX Release rate for a cylindrical reservoir: dM 2πHDK Cs − 0)( = dT ⎞ ln ⎛ ⎜ Ro ⎟ ⎝ RI ⎠ Where dM/dT = release rate H = height D = diffusion coefficient of drug in polymer K = partition coefficient Cs = drug solubility in surrounding media Ro = outer radius RI = inner radius II. Non-erodable Matrix Drug Dispersed in Polymer Time 0 Drug Dispersed in Polymer Time T 1. Advantages: • No leakage • Easily made • High MW compounds can be delivered 2. Disadvantages: • Not zero-order • Must be removed R. Langer/HST-151 6 III. Bioerodable Systems Drug Dispersed in Polymer Time 0 Drug Dispersed in Polymer Time T 1. Zero-order if only surface erosion occurs and surface area does not change with time 2. Examples include poly-lactic acid, polyaminoacids, polyorthoesters, and polyanhydrides 3. Advantages • removal is not a problem 4. Disadvantages • there are few biodegradable materials • release kinetics are often hard to control • by-products of degradation may cause toxicity or tissue damage IV. Polymers with Pendant Drugs Polymer Backbone Drug Time 0 Polymer Backbone Water or Enzyme Time T 1. Drug covalently attached to polymer 2. Advantage: very high drug loading R. Langer/HST-151 7 3. Disadvantage: new chemical entity - expense V. Swelling Controlled Matrix di l l Drug sso ved in po ymer Swollen Polymer from which drug has been released Time 0 Time T 1. Drug is dissolved in polymer and is released when polymer swells 2. Advantage • no burst effect • reformulation of vehicle not necessary for different drugs 3. Disadvantage • Experimental systems—generally do not have water as permeant VI. Osmotically Controlled System di Drug ssolved in polymer Porous openings which permit release Time 0 Time T 1. Drug is dissolved in polymer and porous openings permit entry of fluid and release of drug along osmotic gradient R. Langer/HST-151 10 100 80 60 P ilo ca rp in e R el ea se R at e (µ g/ hr ) 40 20 0 0 1 2 3 4 5 6 7 Time (Days) 40 µ 20 µ g/hr Therapeutic System g/hr Therapeutic System Occusert Advantages: • Control of intraocular pressure with less drug and fewer side effects • Convenience of once-a-week application • Improved compliance • Assurance of round-the-clock medication Occusert Disadvantages: • Retention • Discomfort • Leakage • Expense • Low initial acceptance, particularly by older patients 2. Artificial tears: Goals: ƒ A wetting agent to stabilize the tear film and improve adherence to the corneal surface Merck: ƒ Hydroxypropylcellulose Advantages: ƒ Comfort Disadvantages: ƒ Poor retention ƒ Discomfort ƒ Blurred vision ƒ Difficulty in insertion R. Langer/HST-151 11 B. Contraceptive Systems: • Non-erodible subdermal implants o Norplant – silicone capsules containing Levonorgestrel. Implanted by trocar injections into forearm ƒ 2 capsules, release rate = 3.8 µg/cm length/day = 70 µg/day TOTAL ƒ Plasma level: 0.3ng/ml, 2-3 times higher in arm containing device ƒ Effective with few side effects; perception in 3rd world that injection more effective than oral ƒ Reasons for discontinuation: • Menstrual irregularity • Other factors: pain, appearance, feel • Erodible subdermal implants: o Alza – Levonorgestrel and norethindrone : limited studies on norethindrone in humans shows zero-order release (allergic reactions observed) o Poly (ε-caprolactone): 6-month constant release o Injectable microcapsules – lactic/glycolic acid copolymer and rods • Steroid releasing iuds (intrauterine device) – o Advantages: Less menstrual bleeding, improved compliance, and comparable pregnancy and expulsion o Disadvantages: Intrauterine inflammation, increased incidence of ectopic pregnancies • Vaginal rings C. Periodontal Disease • Percent with evidence of periodontal disease – 25% • Percent requiring surgery – 2-3% Current Therapy None Surgery Oral Tetracycline Problems Tooth Loss Pain, Expense Nausea, diarrhea 1. Tetracycline hollow fibers: • Are effective with less than 1/1000th of the dose • Can be applied in less than 3 min. per tooth • Barely visible, no local irritation • Caused elimination of spirochetes R. Langer/HST-151 12 Pl ll ll l l i l Si i l i ingi acement of the drug-fi ed ho ow fibers for oca treatment of per odonta disease. ngle strands of tetracycline-filled hollow f bers are placed around the tooth and gent y pressed around the marg n of the g va. 1 cm µ200 25 µ Volume = 0.3 µ /cm D. Coated intracoronary stents: Problems to solve: atherosclerosis, restenosis Polymers: ethylene-vinyl acetate, Pluronics Drugs: Heparin, antisense DNA Good initial results in animal models • JOHNSON & JOHNSON o Drug- Sirolimus (Rapamune) ƒ A lactone approved for renal transplant rejection ƒ Polymer blend- acrylates used in bone cements, ocular lenses, and IUDS -poly(ethyl acrylate), n - butyl methacrylate R. Langer/HST-151 15 Aerosol insulin: l S er um In su lin C on ce nt ra tio n, n g/ m l 10 1 Inhaled Injected (sc) Untreated S er um G lu co se C on ce nt ra tio n, m g/ d 0 20 40 60 80 100 120 Time (hours) 90 20 30 40 50 60 70 80 Inhaled Untreated 0 20 40 60 80 100 Time (hours) Implanted Pumps 1. Advantages: • Can release drug directly into venous or arterial blood • Large volumes possible • Some are refillable • Releases drugs independently of the drugs’ properties R. Langer/HST-151 16 2. Disadvantages: • Expense • Need for surgical implantation • Contents are in solution • Difficult to reformulate Transdermal Systems 1. Skin generally impenetrable (principal resistance is stratum corneum) 2. Permeability correlates with drug’s water solubility, molecular weight, and oil/water partition coefficient 3. Useful for drugs with low dose requirement, high skin permeability 4. Permeability can be enhanced by certain compounds 5. The system provides simple localization. It is easy to apply and remove. 6. Reduces first pass metabolism 7. Drawbacks: lag time to achieve effect (2-6 hours or more) in some cases; drug in skin may sustain effect even if device is removed General rules for transdermal product: 1. Water solubility > 1 mg/ml 2. Oil solubility > 1 mg/ml 3. Molecular weight < 1000 4. Dose < 10 mg/ml 5. No requirement for rapid onset i ir Mi i Skin Surface Back ng Membrane Drug Reservo Rate-Controlling croporous Membrane Skin Contact Adhes ve Drug Molecules Blood Capillary R. Langer/HST-151 17 i ilOrdered Lip d B ayers Make Stratum Corneum Impermeable M ax im um F lu x (µ g/ 20 c m 2 – H r) 100,000 1,000 100 Ephedrine Dcarbamazineiethyl Nitoglycerin Scopolamine Fentanyl Estradiol Atropine Ouabain Digitoxin 10,000 10 1,000 1 100 0.1 10 0.01 1 0.001 0.1 0.0001 0 50 100 150 200 250 300 Drug Melting Point (°C) D evice R elease R ate (µg/20 cm 2 –D ay)