Non-Oral Routes of Drug Administration Reading: Ansel 9 th edition, p. 161-170 Routes of Drug Administration Over the next series of lectures, we will talk about the biopharmaceutics of several non-oral routes of drug administration and related drug delivery devices. Biopharmaceutics is defined as the study of physiological and formulation factors affecting the release and subsequent absorption of drugs from drug delivery systems as relate to the onset, duration, and intensity of drug action For each of the routes of drug administration or delivery strategy that we will discuss, it is helpful to keep in mind the following basic but important thoughts (among others). The design of the formulation/device governs or controls how the drug is released from the formulation/device at the site of administration and how the drug product is used or applied at the site of administration (brief or long exposure) When intended for systemic therapy, the drug must move from the formulation/device at the site of administration to the intended site of drug action, requiring drug absorption and drug distribution When targeted for local action, there may be unintended drug absorption causing systemic side effects 1. Parenteral Administration General types of injectable formulations: Injection: Liquid preparation that is a solution of a drug in a liquid vehicle For injection: Dry solids that upon addition of a vehicle become an injection solution PCEUT 531P Page 1
Injectable emulsion: Liquid preparation of a drug dissolved or dispersed in an emulsion medium (e.g., propofol) Injectable suspension: Liquid preparation of a solid drug suspended in a liquid vehicle (betamethasone sodium phosphate and betamethasone acetate, Celestone Solupan ) For injectable suspension: Dry solid that upon addition of vehicle yields a an injectable suspension (e.g., octreotide acetate, Sandostatin LAR Depot) Any of the above may contain buffers, preservatives, and other excipients. Parenteral (injection) routes (we will cover some in more detail than others) Intravenous within a vein Intra-arterial within an artery Intraosseous into the bone marrow (as an alternative to intravenous access) Intra-cardiac within one of the chambers of the heart Intra-articular within the cavity of a joint Intrasynovial within the synovial sac of a joint or a synovial tendon sheath Intra-spinal - within the vertebral canal or spinal cord Intrathecal within either the subarachnoid (middle of the three coverings of the central nervous system) or the subdural space (between the dura mater and the arachnoid mater) Epidural on (or outside) the dura mater Intracutaneous/intradermal within the substance of the skin, particularly the dermis Subcutaneous within the tissue under the skin Intramuscular within muscle Note: all parenteral routes are vulnerable to risk of infection PCEUT 531P Page 2
INTRAVENOUS (IV) can provide rapid action potential for significant adverse effects invasive (risk of infection) rate of injection/volume of injection: bolus in less than a minute or two; small injection volume (1 to 10 ml) short-term infusion from minutes to few hours; decrease peak concentration; larger injection volume, up to several hundred ml long-term infusion to achieve steady-state plasma drug levels; may need IV bolus loading dose to achieve therapeutic levels sooner antecubital vein (in front of elbow) is usually used; access via central vein (internal jugular, subclavian or femoral) catheter may be required for drugs that are caustic or prone to cause phlebitis 100% systemic availability of the dose not suitable for insoluble materials, unless drug particle size is sufficiently small to avoid formation of emboli microemulsions of fat-like or fat-soluble materials (e.g., propofol) and other heterogeneous formulations (e.g., Abraxane albumin-bound paclitaxel injectable suspension) are sometimes used poorly water soluble drugs may precipitate if injected too rapidly or into a vein with low blood flow; classic examples: diazepam solubility 66 mg/l or μg/ml dose 5 to 10 mg (5 mg/ml in 40% propylene glycol + 10% alcohol in water at ph 6.6) should be administered slowly (2 to 5 mg per minute) into a large lumen vessel, such as an antecubital vein rapid injection or injection into small vein carries the risk of syncope, hypotension, apnea and thrombophlebitis phenytoin solubility 32 mg/l or μg/ml dose 10 to 20 mg/kg or 700 to 1400 mg (50 mg phenytoin sodium/ml in 40% propylene glycol + 10% alcohol in water at ph 12) recommended infusion rate 40-50 mg/min PCEUT 531P Page 3
a dose of a poorly water soluble drug can be slowly administered by using short-term infusions of the drug dissolved in a sufficient volume of vehicle and administered immediately to avoid precipitation issue INTRA-ARTICULAR injected directly into the joint space for local effect (for example, antiinflammatory corticosteroids or steroids into a painful, inflamed arthritic joint) range of injection volumes: 0.1 to 2 ml for elbow, ankle, knee, shoulder 2 to 3 ml for hip INTRA-ARTERIAL injection volume varies, usually from 10 to 50 ml over time (infused) invasive (risk of infection) used for specific access to a vascular bed, often to deliver chemotherapy to a particular organ or tumor site floxuridine (FUDR) for hepatic tumor FUDR has a high hepatic extraction ratio (94-99%) administration into the hepatic artery achieves very high hepatic levels and relatively low systemic levels degradable starch microspheres (40 μm) have been injected into the hepatic artery to retard flow of the blood through the arteriolar-capillary bed of the liver and lead to increased local drug deposition INTRADERMAL between the layers of the skin for local purpose usual injection volume up to 0.1 ml often given in the inner palm-side surface of the forearm often used for conducting skin allergy tests and testing for antibody formation PCEUT 531P Page 4
INTRATHECAL OR EPIDURAL ADMINISTRATION primarily used to administer analgesics and anesthetics for regional effects morphine (or other opioids) by this route intraoperative or postoperative use also for the control of chronic pain activity is through spinal opioid receptors increased duration of effect, and a lower incidence of respiratory depression and other CNS effects if respiratory depression is observed by this route, it often is observed hours after the administration of the drug as it spreads rostrally via the CSF or via systemic redistribution to supra-spinal sites SUBCUTANEOUS (SC) needle penetrates the epidermal and dermal layer to deposit drug into the loose subcutaneous fatty tissue usual injection volume of about 0.5 ml; range 0.5 to 1.5 ml, 2 ml injections may cause a feeling of painful pressure injected formulation volume produces the drug delivery site within the interstitial fluid larger volumes may be administered (over longer time) by SC infusion large number of potential injection areas on the body to choose from (see accompanying figure) readily self-administered by patient (and patient acceptance may be increased with prefilled syringe) good route for multiple dosing or continuous infusion muscle mass is not an issue in cachectic or elderly patients risk of infection is present because the needle breaks the protective barrier of the skin PCEUT 531P Page 5
systemic bioavailability for a given drug may be 100% or < 100%, mainly related to formulation factors and drug stability at the SC injection site bioavailability information is difficult to find for the SC route small molecule drugs are generally rapidly absorbed following SC injection; rate of absorption depends on drug dissolution if formulation is a suspension or if drug precipitates out of solution at the injection site absorption involves diffusion through interstitial fluid and tissues, and passage across vascular membranes into surrounding blood capillaries generally, it is thought that the blood supply to SC site is poorer than to muscle tissue and, consequently, small molecule drug absorption may be slower than IM absorption rate may be influenced by massage, exercise (such as running) and heat (as in a sauna or hot tub), because of the increase in blood flow vasoconstrictors are used to slow dissipation of local anesthetics; e.g., lidocaine hydrochloride and epinephrine injection for infiltration and nerve block protein drugs have the following issues stability in the sc site; proteolysis slow absorption depending on size: small proteins (insulin ~6 kd) are taken up into the interstitial capillaries larger protein >16 kd (Mabs ~150kd) are absorbed indirectly via the lymphatic system (see accompanying figure), which is a slow process occurring over some hours (tmax >24 hours) PCEUT 531P Page 6
INTRAMUSCULAR (IM) range of injection volumes: 0.5 to 2.0 ml for deltoid 1 to 5 ml for gluteus maximus 1 to 5 ml for vastus lateralis as with SC injection, formulation volume that is injected IM produces the drug delivery site within the interstitial fluid drugs irritating to SC tissue may be given IM risk of infection is present as the protective barrier of the skin is broken considerations of rate and extent of absorption are generally the same as for SC administration (see above) absorption rate for lipophilic small drug molecules is generally in the order of deltoid > vastus lateralis >> gluteus maximus, because of blood perfusion and amount of fatty tissue at the injection site poorly soluble small molecule drugs can precipitate on administration and actually form crystals at the site of injection can cause of pain at the injection site and at times muscle injury crystals may dissolve very slowly and apparently incompletely, possibly resulting in less than 100% bioavailability phenytoin (see solubility, solution ph and dosing details above) o IM administration of may be required by the clinical situation (but is not very common), postoperatively or in comatose patients o sufficient dose (higher dose compared to oral dose) must be administered IM to maintain the plasma level within the therapeutic range IM route for diazepam should be avoided if practicable because of precipitation absorption rate for small drug molecules can be decreased or at least compromised when the injection does not actually reach the muscle, but is instead deposited in the subcutaneous fat lower blood flow in fat more sequestration and slower release of lipid soluble drug from fat PCEUT 531P Page 7
muscle site, length of needle and angle of injection are important determinants of the likelihood of deposition in fat deltoid and thigh are less likely to result in this problem, more likely with injection into the buttocks absorption in infants and young children may be unpredictable due in part to insufficient muscle tone and vascularity of muscle tissue decreased muscle mass of many older adults may result in faster small drug molecule absorption; approximate 25% decline in muscle strength occurs between the ages of 20 and 60 years, and a decline in muscle strength corresponds with a decrease in muscle mass protein drugs are usually slowly absorbed (depending on size), again as with SC absorption, because of lymphatic involvement PCEUT 531P Page 8