1140_bookreps.fm Page 1 Tuesday, July 15, 2003 9:47 AM 29 Pharmaceutical Technical Background on Delivery Methods CONTENTS 29.1 Introduction 29.2 Central Nervous System: Drug Delivery Challenges to Delivery: The Blood Brain Barrier • Indirect Routes of Administration • Direct Routes of Administration 29.3 Cardiovascular System: Drug Delivery Chronotherapeutics • Grafts/Stents 29.4 Orthopedic: Drug Delivery Metabolic Bone Diseases 29.5 Muscular System: Drug Delivery 29.6 Sensory: Drug Delivery Ultrasound • Iontophoresis/Electroporation 29.7 Digestive System: Drug Delivery GI Stents • Colonic Drug Delivery 29.8 Pulmonary: Drug Delivery Indirect Routes of Administration • Direct Routes of Robert S. Litman Administration Nova Southeastern University 29.9 Ear, Nose, and Throat: Drug Delivery Maria de la Cova The Ear • The Nose • The Throat 29.10 Lymphatic System: Drug Delivery Icel Gonzalez 29.11 Reproductive System: Drug Delivery University of Memphis Contraceptive Implants • Contraceptive Patch • Male Contraceptive Eduardo Lopez References 29.1 Introduction In the evolution of drug development and manufacturing, drug delivery systems have risen to the forefront in the latest of pharmaceutical advances. There are many new pharmacological entities discov- ered each year, each with its own unique mechanism of action. Each drug will demonstrate its own pharmacokinetic profile. This profile may be changed by altering the drug delivery system to the target site. In order for a drug to demonstrate its pharmacological activity it must be absorbed, transported to the appropriate tissue or target organ, penetrate to the responding subcellular structure, and elicit a response or change an ongoing process. The drug may be simultaneously or sequentially distributed to a variety of tissues, bound or stored, further metabolized to active or inactive products, and eventually © 2004 by CRC Press LLC 1140_bookreps.fm Page 2 Tuesday, July 15, 2003 9:47 AM 29-2 Biomedical Technology and Devices Handbook excreted from the body. A delivery system that may have an effect upon the absorption, distribution, metabolism, or excretion of a pharmaceutical entity may then affect the potency, half-life, potential for drug interactions, and side-effect profile of that specific entity. Drug delivery systems are developed to enhance the desired pharmacological effect at specific target sites, while reducing the probability of drug interactions and unwanted side effects. Other reasons for the development of new drug delivery systems include the masking of unpleasant tastes, inability of a patient to swallow a specific dosage form, protecting components from atmospheric degradation, controling the site of drug release, prolonging or delaying the absorption of the drug moiety, improving the drug’s physical appearance, and changing the physical surface characteristics of the active ingredients. The following text will present a number of pharmaceutical drug delivery systems used in the treatment of a variety of disease states. 29.2 Central Nervous System: Drug Delivery 29.2.1 Challenges to Delivery: The Blood Brain Barrier The central nervous system (CNS) consists of the brain and spinal cord. Drug delivery to the brain is challenging because of the blood brain barrier (BBB). The BBB is present in the brain of all vertebrates and is a system that protects the brain from substances in the blood. Because of the presence of the BBB over 98% of new drugs discovered for the CNS do not penetrate the brain following systemic administration. The BBB is composed of: 1. The continuous endothelium of the capillary wall 2. A relatively thick basal laminal surrounding the external face of the capillary 3. The bulbous feet of the astrocytes that cling to the capillaries The capillary endothelial cells are almost seamlessly joined all around by tight junctions making them the least permeable capillaries in the entire body. This relative impermeability of the brain capillaries constitutes most of the BBB.1 In addition, once having traversed this barrier of the capillary endothelial cell, the drug must then penetrate the glial cells that envelop the capillary structure. Cerebral endothelial cells also express ATP-dependent transmemebrane glycoproteins involved in active transport of substances to outside the cell.2 There are several theories as to what factors affect permeability into the brain. Factors such as lipophilicity, molecular size, polarity, and hydrogen bonding have been studied as methods to predict a drug’s penetration capacity into the BBB.3 The cerebral spinal fluid (CSF) is a plasma-like fluid that fills the cavities of the CNS and surrounds the CNS externally, protecting the brain and spinal cord. Passage of chemical substances into the CSF is controlled by the blood-CSF barrier. This barrier is created by the ependymal cells of the choroid plexus.4 The choroid plexus (which is located in the 3rd and 4th ventricles of the brain) has the ability to secrete substances out through an active transport system. Thus, attempts at accessing the brain through the CSF may be unsuccessful due to the protective nature of the choroid plexus. Also, it cannot be inferred that a given drug crosses the BBB just on the basis of its distribution into the CSF.5 Access to the CNS can be gained through direct or indirect methods. For drugs with the ability to penetrate the BBB, possible routes of administration are described below as indirect routes of adminis- tration. Direct routes of administration are attempts to bypass the BBB and gain access to CNS tissue. Indirect routes of administration include: •Intravenous, intraarterial •Intraperitoneal •Digestive tract •Lung •Skin •Nasal © 2004 by CRC Press LLC 1140_bookreps.fm Page 3 Tuesday, July 15, 2003 9:47 AM Pharmaceutical Technical Background on Delivery Methods 29-3 •Intramuscular •Subcutaneous •Sublingual •Buccal •Rectal 29.2.2 Indirect Routes of Administration As previously described, access to the central nervous system can be achieved through indirect routes of administration, in addition to having to overcome the BBB, such routes of administration are subject to other bodily methods that may decrease or negate the amount of drug that penetrates the brain. For example, the drugs may be subject to being metabolized by the liver, excreted by the kidney, or acted upon by enzymes in the intestine or lung, all of which would result in a decrease in the amount of circulating drug available to the brain. These routes of administration all access the CNS through systemic absorption; in other words, access is gained to the bloodstream, which then attempts to cross the BBB. Examples of drugs that cross the BBB include clonidine and propranolol, both antihypertensives. Propranolol can be administered via the oral route or i.v. route. Extensive first pass metabolism through the liver makes the oral dose necessarily much higher than the injectable dose. Clonidine is available for administration orally, as a transdermal patch and even for epidural use for intractable pain. Other well-known drugs able to cross the BBB include the opiate analgesics such as morphine, selective serotonin reuptake inhibitors such as Prozac“, and benzodiazepines such as Valium“. These drugs are available in multiple dosage forms ranging from injectable to oral to rectal gels. Fentanyl“, a potent analgesic, is available in transdermal patches and buccal formulations and generally used to treat cancer pain. Still, the BBB and the blood-CSF barriers remain the largest challenge in developing drugs to effectively treat CNS disorders. Therefore, numerous ways to circumvent these barriers such as direct delivery to the CNS or attempted interruption of the BBB system have been researched. 29.2.3 Direct Routes of Administration 29.2.3.1 Nasal Drug Delivery The nasal route of administration bypasses the BBB. Common drugs of addiction such as cocaine or amphetamine derivative may rapidly enter the brain by the nasal route. Nasal drug intake appears to be a fast and effective route of administration, suitable for drugs that must act rapidly and are taken in small amounts. Examples include antimigraine drugs such as Imitrex Nasal Spray“ and analgesics such as Stadol Nasal Spray“. Unfortunately, frequent use of this route of administration may lead to complications such as mucosal damage that can lead to infections. Also, some patients may lose the ability to smell. 29.2.3.2 Epidural Drug Delivery Drugs administered into the epidural space in order to reach the spinal cord must traverse the dura mater, arachnoid mater, then enter the CSF to reach the spinal cord gray and white matter. This occurs through simple diffusion. Epidural infusion and anesthesia is a common tool in the U.S. for pain relief from contractions during labor. Pharmacologic means to prevent the redistribution of drug to the systemic circulation or to prolong the drug effect have been used. One such example is the addition of epinephrine to local anesthetics and epidural opioids. The addition of epinephrine has been shown to improve the quality and prolong the duration of epidural anesthesia and analgesia. Other pharmaceutical modifiers of redistribution include preparations that provide slow-release “depot” formulations, encap- sulating drugs in liposomes, embedding drugs in biodegradable polymers, or using drugs that are themselves nearly insoluble in aqueous solutions.6 © 2004 by CRC Press LLC 1140_bookreps.fm Page 4 Tuesday, July 15, 2003 9:47 AM 29-4 Biomedical Technology and Devices Handbook 29.2.3.3 Intrathecal Drug Delivery This method involves direct injection into the CSF via a spinal needle or catheter. Drug injection into the CSF results in mixing of the drug product and the CSF which does not occur with epidurally administered drugs. Drugs enter the CSF as a solution, instead of as individual molecules in the case of epidural administration. This causes the density of the solution and the patient’s position to be the most important factors with regard to where the drug initially distributes along the spinal cord. The more dense the solution, the more the tendency to move down the spinal column until complete mixture with the CSF makes the solution isobaric.