Biomedical Technology and Devices Handbook

Home , Contraceptive patch, Epidural administration

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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 discovered 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

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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 administration. 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

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•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

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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. Hydrophobic drugs have poor permeability into the CSF. One way to improve the permeability is to increase their aqueous solubility. Research into compounds such as cyclodextrins shows that combining drugs, for example sufentanil with cyclodextrin, increases its permeability into the meninges more than twofold in vitro. However, it is also possible that when used in vivo the redistribution of drugs into unintended sites might occur. Rigorous toxicology trials in animals are still necessary in this area.6,10 29.2.3.4 Intracerebroventricular Drug Delivery Invasive brain drug delivery systems have been the most widely used for circumventing the BBB drug delivery problem. This invasive strategy requires either a crainiotomy by a neurosurgeon or access to the carotid artery by an interventional radiologist. The neurosurgical-based systems include intracerebroventricular (ICV) infusion of drugs or intracerebral implants of biodegradable polymers.7 Unfortunately, drug penetration following ICV injection is minimal.5 Also, because of the one-way flow of CSF in the brain following ICV injection, the distribution of drug to both sides of the brain following ICV injection would require the placement of catheters in both lateral ventricles.5 ICV has been used primarily in three treatment areas: chemotherapy for brain tumors, treatment of infections of the central nervous system,12 and delivery of analgesics in the setting of intractable pain.8 In the case of chemotherapy, direct injection into the CNS also avoids significant systemic toxicity by limiting chemotherapy exposure to the CNS. 29.2.3.5 CNS and Drug Targeting Drug targeting describes a process for attempting site specific delivery of drugs. For drugs needing access to the CNS for their action to be exerted, the need for drug targeting and avoidance of the BBB is an obvious one. Drug targeting has been classified into three types:9 1. Delivery to a discrete organ or tissue 2. Targeting to a specific cell type (e.g., tumor cells vs. normal cells) 3. Delivery to a specific intracellular compartment in the target cells (e.g., lysosomes) Targeting can be achieved through different methodologies: Biologic agents that are selective to a particular site in the body, preparation of prodrug that becomes active once it reaches the target site, and using a biologically inert macromolecular carrier system that directs a drug to a specific site in the body. For example, 3.85% carmustine (Gliadel®) impregnated polymers consisting of CPP:SA have shown improved survival in patients with high-grade recurrent gliomas (brain tumor).7 Carmustine itself crosses the BBB; however, the polymers allow higher tissue levels to be achieved with minimal systemic side effects. The polymer wafers are placed after the surgical removal of the brain tumor itself in the cavity left behind once the tumor is removed. Drug targeting is a promising field of research to aid in drug delivery to the CNS.

29.3 Cardiovascular System: Drug Delivery

Cardiovascular disease has become an important cause of morbidity and mortality as the population ages. The new millennium holds even greater promise as genetic engineering produces new and even more effective drugs and devices to prevent and treat patients with cardiovascular disease.53 In this section the latest cardiovascular drug delivery methods will be discussed.

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29.3.1 Chronotherapeutics Chronotherapeutic medications deliver medications in concentrations that vary according to changes in physiologic need.54,55 In hypertension, chronotherapeutic medications deliver the drug in highest concentrations during the morning period, when blood pressure is the greatest, and in lesser concentrations at nighttime, when blood pressure is the lowest.54,55 Verapamil, a calcium channel blocker, has been marketed in two formulations that use novel delivery systems to provide chronotherapy: Verelan PM™ (Schwarz Pharma Inc, Milwaukee, WI) and Covera-HS™ (Pharmacia Corp, Peapack, NJ).54 Verelan PM uses chronotherapeutic oral drug absorption system (CODAS) technology, and Covera-HS uses the controlled-onset, extended-release (COER-24) delivery system.54 The CODAS delivery system incorpo- rates a 4- to 5-h delay in drug delivery followed by an extended drug release, with a peak concentration occurring approximately 11 h after administration, which is designed for bedtime dosing.54 Trough concentrations occur approximately 4 h after dosing.54 “Each capsule contains numerous pellets that consist of an inert core surrounded by active drug and rate-controlling membranes that combine water- soluble and water-insoluble polymers.”54 As the pellets lie in the gastrointestinal tract, water washes over the pellets, slowly dissolving the water-soluble polymer and allowing the drug to diffuse through pores in the coating.54 The water-insoluble polymer continues to provide a barrier that allows the drug to be dosed every 24 h.54 For the Covera-HS™ the outermost component of the (COER-24) delivery system is a semipermeable membrane that regulates absorption of water into the tablet.54 Water is absorbed from the gastrointestinal tract at a ﬁxed rate until the second layer, or delay coat, is reached.54 The second layer then absorbs water and temporarily prevents the passage of water into the inner core of the tablet.54 This process delays drug release for approximately 4 to 5 h while the patient is sleeping, when blood pressure is lower.54 When sufﬁcient moisture has been absorbed, a third layer expands by osmosis, pushing verapamil out of the tablet at a constant rate that adequately controls the patient’s blood pressure during the morning hours.54 Continued absorption of water and ongoing osmotic expansion of the third layer provide for extended release of drug and once-daily dosing.54 In conclusion, chronotherapeutic verapamil formulations provide effective 24-h control of blood pressure.54,55 The delay in drug release avoids problems with excessive blood pressure lowering during sleep and provides blood pressure control in the late morning and early afternoon hours when blood pressure is the highest.54,55

29.3.2 Grafts/Stents Since 1952, when the first vascular prostheses was constructed out of the fabric Vinyon N, many research- ers have focused upon the production of an ideal synthetic vascular graft.56 Restenosis complicates the outcome of most of the interventional cardiovascular procedures for relieving coronary artery obstruction.57 The pathogenesis of restenosis is incompletely understood, but seems to be due to a number of factors which include: acute fibrin thrombus, platelet binding, smooth muscle proliferation, and inflammation.57 Thus the search for the ideal graft that will maintain a long patency is still on. Drug-eluting vascular stents with a variety of coatings including fibrin, heparin, and polymers that contain NO donors have been tested with differing outcomes.58 NO-containing cross-linked polyethylenimine microspheres that release NO with a half-life of 51 h have been applied to vascular grafts to prevent thrombosis and restenosis. The incorporation of the NO to the polymeric matrices has shown powerful antiplatelet activity in cardiovascular grafts.58 Alternatively, liposomal drug delivery systems bearing arginine-glycine- aspartic acid (RGD) peptides on the surface could emulate the function of fibrinogen in binding GPIIb- IIIa on activated platelets, and therefore represent a means to target liposome-encapsulated anticoagulant or antiplatelet effects to discrete regions of the cardiovascular system.59 The RGD peptide utilized has demonstrated to inhibit fibrinogen binding to platelets which is one of the factors for restenosis.59 Due to their relative chemical simplicity, peptides are versatile ligands for use in liposomal drug delivery to molecular targets within the cardiovascular system.59 Poly(ethylene oxide) (PEO)-grafted phospholipids were shown to dramatically increase liposome survival in the circulation by avoiding rapid reticuloen- dothelial system uptake.59 Recently, investigators inserted silastic tubing into the peritoneal cavity of rats

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and rabbits.56 “The resulting inflammatory reaction to the silastic covered the tubes with layers of myofibroblasts, collagen matrix, and a monolayer of mesothelial cells. By withdrawing the tubing from the laminar, multicellular remains of the inflammatory response and then everting this biological tube, these investigators discovered synthetic arteries with architecture similar to that of native blood vessels.”56 The mesothelial cells mimicked endothelial cells, the myofibroblasts act as smooth muscle cells lying in a collagen bed, and the entire structure was surrounded by a collagenous adventitia.56 The vessels also developed structures similar to high-volume myofilaments that are able to respond to pharmacological agonists.56 In conclusion, the presumably higher patency rates and longer half-lives of tissue-engineered vascular prostheses and the use of liposomes as potentially advantageous targeted drug carriers for such intravascular applications will be the future for the treatment of restenosis.56,59

29.4 Orthopedic: Drug Delivery

29.4.1 Metabolic Bone Diseases The skeletal system is affected by a host of disorders including osteoporosis, osteomalacia, renal osteo- dystrophy, Paget’s disease, osteomyelitis, and numerous others. Osteoporosis, a disorder frequently encountered as bone loss associated with aging in postmenopausal women, is now recognized as a major health issue in the United States. Osteoporosis is deﬁned as a universal, gradual reduction in bone mass to a point where the skeleton is compromised.14 The majority of current treatments for osteoporosis are limited to antiresorptive therapy that slow bone turnover and loss, rather than building new bone mass. Current therapeutic prophylactic and treatment alternatives for osteoporosis include hormone replacement therapy, calcitonin, bisphosphonates, and selective estrogen receptor modulators.

29.4.1.1 Indirect Routes of Administration Indirect routes of administration include nasal, transdermal, intravenous (i.v.), oral, and subcutaneous (s.c.).

29.4.1.2 Nasal Calcitonin is a polypeptide hormone composed of 32 amino acids secreted by the parafollicular cells of the thyroid gland. Although the actions of calcitonin on bone are still not completely understood, it inhibits bone resorption by decreasing the number of osteoclasts and their resorptive activities and limiting osteocytic osteolysis.15 A synthetic nasal calcitonin formulation is available (Miacalcin“). Calci- tonin is also available for s.c. injection.

29.4.1.3 Transdermal Hormone replacement therapy (i.e., estrogen or estrogen-progestin combinations) has been shown to be beneficial in post-menopausal women at risk for osteoporosis. Women exposed to estrogen therapy for 7 to 10 years have a 50% reduction in the incidence of osteoporotic fractures.16 Estrogen therapy for osteoporosis is available as oral tablets and transdermal patches. The patch itself is usually composed of three layers: a backing layer, an adhesive layer, and protective release layer. Transdermal patches generally have one of two different designs of the drug compartment: (1) form- fill and seal design and (2) monolith design. In form-fill and seal design, drug is contained as a liquid or semisolid reservoir in shallow pouches within the backing layer. The monolith design is further subdivided into the peripheral adhesive laminate structure and solid-state laminate structure, in the peripheral adhesive design, the active delivery area is generally much less than the patch size, in the solid state laminate structure, the active delivery area is identical to the size of the patch. Monolith patches are uniform in composition throughout. They can be cut to smaller sizes without compromising their basic delivery function.16 There are numerous transdermal estrogen patches available ranging from 25 to 100 mcg of delivery per day. Generally, the patches are changed every 72 h; now several weekly patches have been introduced into the market.

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29.4.1.4 Intravenous Bisphosphonates are a class of drugs indicated to treat Paget’s disease, hypercalcemia of malignancy, and osteoporosis. They can be given orally and intravenously to humans. Clinical studies of the feasibility of bisphosphonate transdermal delivery and direct delivery to bone via prodrug are being conducted. The i.v. route, though available, is seldom used for the treatment of osteoporosis. This is because large amounts and rapid injection of i.v. bisphosphonates can result in kidney failure. 29.4.1.5 Oral Bisphosphonates are the mainstay of osteoporosis treatment in the oral setting. The mechanism of action of the bisphosphonates is based on their affinity to bone mineral hydoxyapatite. The bisphosphonates bind strongly to the calcium phosphate crystals and inhibit their growth, aggregation, and dissolution. The biological effects of the bisphosphonates in calcium-related disorders are due to their incorporation in bone enabling direct interaction with osteoclasts and/or osteoblasts.15 The oral route, as can be imagined, is the most preferred route for chronic drug therapy. The major disadvantage of the clinically utilized bisphosphonates is their poor bioavailability (less than 1%) due to their hydrophilic nature and their side effects of gastrointestinal irritation, in addition, food can further suppress absorption, as much as four- to fivefold. Therefore, these drugs are taken on an empty stomach. Attempts at circumventing the bioavailability issue have included: absorption enhancement through use of EDTA, development of prodrugs that are lipophilic, and prodrugs that would use carrier mediated transport systems.26 EDTA can improve the absorption of these compounds by directly enhancing intestinal permeability. Unfortu- nately, EDTA damages the mucosal integrity and cannot be used in humans. The other approaches are still in initial stages of research, none yet available for marketed use in humans. 29.4.1.6 Bone Infections The term osteomyelitis describes any infection involving bone. Osteomyelitis represents a difficult infection to treat for various reasons. First, it has a tendency to be chronic and recurrent and second, there is a need to deliver high concentrations of antimicrobial agents in the blood to achieve adequate levels in bone.23 Traditional therapy includes intravenously administered antimicrobials (to avoid issues with bioavailability). Since the classic organisms that infect bone are of a Gram-positive nature, the most frequently used antimicrobials are cephalosporins, extended spectrum penicillins, and vancomycin for resistant species. Three major considerations are critical in managing these infections in bone: 1. Spectrum of activity of agent chosen 2. Ability of antimicrobial to penetrate and reach the site of infection 3. Duration of therapy 29.4.1.7 Direct Routes of Administration Other treatment options used for treatment of osteomyelitis include the use of ceramic composites as implantable systems. The treatment of osteomyelitis as previously discussed is a complicated process involving surgical removal of dead bone tissue and prolonged systemic antibiotics. Hydroxyapatite cement systems have been developed to deliver drug to the skeletal tissue at therapeutic concentrations without causing systemic toxicity.18 These hydroxyapatite cement formulations are loaded with antibiotics such as cephalexin and then placed directly at the site of infection or fracture. Tricalcium phosphate and amino acid antibiotic composite ceramics and PMMA antibiotic-impregnated beads have also been used to treat osteomyelitis with success.18,19 29.4.1.8 Drug Targeting Targeting of bisphosphonate release from bone has been the subject of recent study. This drug delivery system is based on the concept of a site-specific bisphosphonate prodrug. The system, which is used only in animal trials thus far, is called the osteotropic drug delivery system. This approach is based on the chemical adsorption of the prodrug to the mineral component, hydroxyapatite.20 Also the subject of recent study was the use of the osteotropic drug delivery system to deliver diclofenac (a nonsteroidal

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anti-inﬂammatory drug). This study in rats showed that once the prodrug complex was injected into the animals it was predominantly distributed to the skeleton. This study showed hope for this approach for highly potent and nontoxic therapy of diclofenac with less frequent medication administration.21 Studies of other nonsteroidal anti-inﬂamatory drugs are also being conducted.22 Future studies will elucidate if these will be of value in humans.

29.5 Muscular System: Drug Delivery

Muscles of the skeletal system in our body have adapted to contract in order for us to carry out daily functions of motion. Contraction of these muscle fibers is achieved when these cells are stimulated by nerve impulses. Acetylcholine is the neurotransmitter released presynaptically from axon terminals at the neuromuscular junction causing an electrical activation of the skeletal fibers. The interaction of acetylcholine with receptor proteins causes a change in membrane structure that results in the opening of sodium and potassium channels leading to depolarization.45 This perfect mechanism of motion is sometimes affected by autoimmune diseases. Myasthenia Gravis is a disease characterized by episodic muscle weakness caused by loss or dysfunction of acetylcholine receptors. Current treatments for myasthenia gravis are limited to relieving the symptoms or immuno- suppressing the pathogenesis.46 Anticholinesterase muscle stimulants such as Neostigmine and Pyridostig- mine have been formulated to inhibit the destruction of acetylcholine by cholinesterase, therefore allowing constant stimulation of postsynaptic cells leading to muscle contraction.46 Access to the skeletal muscle can be gained through indirect (oral, i.v.) or direct (i.m.) routes. As it can be imagined, oral route is the preferred route for chronic drug therapy; however, the major disadvantage of these agents are the poor bioavailability (<10%). Poor bioavailability requires frequent administration of large doses leading to many gastrointestinal adverse events.47 Parenteral routes are also available. These routes of administration are most desirable for treatment when patients have difficulty swallowing or are undergoing a myasthenic crisis.47 No clinical trials have been done concluding which route of administration is preferred. If the i.v. route is chosen over the i.m., then medication should be infused slowly to be able to look for cholinergic reactions (i.e., bradycardia).49 Neostigmine and Pyridostigmine also have other therapeutic indications. Both agents can be used for the reversal of nondepolarizing muscle relaxants.47 Nondepolarizing muscle relaxants such as Mivacu- rium, Vecuronium, and Pancuronium are used in adjunct to general anesthesia to facilitate endotracheal intubation or to provide skeletal muscle relaxation during surgery or mechanical ventilation.47 These agents act by antagonizing acetylcholine by competitively binding to cholinergic site on motor endplate leading to inhibition of skeletal muscle movement.45 All nondepolarizing neuromuscular blockers are only available in injection form, intravenous use is recommended due to tissue irritation caused by i.m. administration.50 Duration of action is the only factor that sets a difference between these agents. Currently available short-acting agents include Mivacurium and Cisatricurium, intermediate acting agents are Atracurium, Rocuronium, and Vancuronium, and long-acting agents include Pancuronium and Pipecuronium. Generally, short-acting neuromuscular blockers are preferred since limited complications related to prolonged or excessive blockade are avoided.47 Numerous reports have described the use of neuromuscular blocking agents to facilitate mechanical ventilation; however, none of these reports have compared neuromuscular blockers to placebo.50 Currently, there are other pharmacological agents available that affect the skeletal muscle system. These agents are classified into centrally (i.e., Baclofen, Cyclobenzaprine) or direct acting (i.e., Dantrolene) muscle relaxants.47 Baclofen is a widely used centrally acting agent for the management of spasticity associated with multiple sclerosis or spinal cord lesion. Baclofen works by inhibiting transmission of reflexes at the spinal cord by hyperpolarization.51 Baclofen is also available in direct (intrathecal) or indirect (oral) routes of administration, intrathecal administration involves a direct injection into the CSF. This route of administration is indicated for the management of severe spasticity of spinal cord origin for patients who are unresponsive to oral Baclofen therapy or who experience intolerable CNS side effects at effective doses.51 When used intrathecally, Baclofen is given as single bolus test dose or for

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chronic use, only in an inplantable pump approved by the FDA speciﬁcally for Baclofen administration.47 Oral route is preferred for the rest of the patients because is convenient and absorption is rapid from the GI tract. Dantrolene is another muscle relaxant used for the management of spinal cord spasticity, but, as opposed to Baclofen, Dantrolene acts directly on skeletal muscle. This agent works by interfering with the release of calcium ions from the sarcoplasmic reticulum.52 Dantrolene is administered orally for the management of this condition. A major disadvantage of this route of administration is the slow and incomplete absorption from the GI tract, injections are also available, but this route of administration is reserved for the treatment of malignant hyperthermia.52

29.6 Sensory: Drug Delivery

Advances in biopharmaceutical technology have led to sophisticated drug delivery devices that allow drugs to be delivered through the skin and mucous membranes of the mouth. Transdermal drug delivery requires that drug molecules have biphasic solubility.60 The transdermal drug needs lipid solubility to pass through the first layer of skin, the stratum corneum and aqueous solubility to move through the dermis.60 The drug must contain high potency, low molecular weight, and insignificant cutaneous metabolism, and the skin must be able to tolerate long-term contact with the drug.60 Most transdermal drug systems have a rate-controlling membrane that can be a disadvantage because of the slow systemic absorption of the drug.60 One method used to increase the absorption rate of drugs through the skin is that of iontophoresis.60 Iontophoresis is defined as “the introduction of ions of soluble salts into the skin or mucosal surfaces of the body by mean of an electric current.”60 Once one activates the current, electrons flow through the skin beneath the electrode being attracted by the oppositely charged electrode on the other side of the skin.60 The use of ultrasound (sonophoresis), defined as sound of frequency greater than 20 kHz, has also been considered to improve the delivery of transdermal medications.61 In addition to the elevation of skin temperature, sonophoresis is also reported to induce an increase in pore size and the formation of small gaseous pockets within cells (cavitation), which is thought to be the predominant mechanism by which low-frequency ultrasound promotes skin penetration enhancement and probably accounts for the enhanced transport of polar molecules.61 Yet another method being considered is electroporation, which uses high-voltage short duration pulses to open up new pathways through the stratum corneum, which is thought to create localized regions of membrane permeabilization by producing aqueous pathways in lipid membrane bilayers.61,62 In this section different medications and drug delivery devices will be discussed that deal with the sensation of pain.

29.6.1 Ultrasound In this particular study ultrasound was applied continuously at a frequency of 1 MHz, and at an intensity of 2 W/cm2 using an ultrasound generator to deliver radiolabeled lidocaine, a local anesthetic, through a piece of stratum corneum.63 Stratum corneum permeability was enhanced by a factor of about 9 due to ultrasound application, which led to an enhanced diffusion coefficient of most molecules, by a factor ranging from 2.6 to 15 depending on the molecule. 63 Ultrasound is thought to disrupt lipid bilayers thus allowing a higher rate of solute diffusion.63 On the other hand, ultrasound in some cases enhanced partition coefficient of some solutes by up to 60% and at the same time decreased the partition coefficient of some drugs by 30%.63 In any case the enhanced diffusion coefficients outweigh the decreases in partition coefficients.63 In another study ultrasound was used to enhance the permeability of fentanyl, a transdermal opioid agonist, in this experiment ultrasound was applied using a frequency of 20 kHz with the diameter of the ultrasound probe being 1.3 cm2, pulsed for 1 h or continuously for 10 min.64 “When ultrasound was used in pulsed mode, the diffusion flux of fentanyl was 35-fold greater than controls; however, diffusion flux calculated 7 h after the end of ultrasound exposure was not significantly different from controls.” 64 Microscopic study of the skin after ultrasound revealed no damage to the stratum corneum.64

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The administration of ultrasound to a transdermal patch might allow self-regulation of pain by the patient. Further studies will be needed to conclude the efﬁcacy and safety of ultrasound in the delivery of transdermal medications.

29.6.2 Iontophoresis/Electroporation In this study the transdermal delivery of buprenorphine, a synthetic opiate analgesic, was assisted using iontophoresis and/or electroporation.62 A current of 0.5 mA/cm2 was applied for 4 h and sampling was continued for 24 h.62 The amount delivered under anode was much higher than that delivered under cathode due to the fact that buprenorphine has a positive charge at a pH of 4.62 Electroporation alone was unable to enhance transport of buprenorphine across the skin.62 On the other hand, electroporation and iontophoresis combined produced a delivery, which was over six times higher than that achieved by electroporation alone and about twice that achieved by iontophoresis alone.62 In conclusion, the combination of iontophoresis and electroporation may be used in the future to control drug release and to increase drug permeation across the skin.

29.7 Digestive System: Drug Delivery

In general, the digestive system is made up of the stomach, small intestine, and large intestine. The fasting pH of the stomach is about 2 to 6, while in the presence of food the stomach pH is about 1.5 to 2, thus basic drugs are solubilized rapidly in the presence of stomach acid.65 Stomach emptying is inﬂuenced by the food content and osmolality. Food often slows down the gastric emptying time usually allowing an oral medication anywhere from 3 to 6 h to empty out of the stomach.65 The duodenum, the upper portion of the small intestine, is the optimum site for drug absorption.65 This is because of the unique anatomy of the duodenum which possess microvilli that provide a large surface area for drugs to passively diffuse through.65 The ileum, which is the terminal part of the small intestine, also plays a role in the absorption of hydrophobic drugs.65 On the other hand, the large intestine lacks the microvilli that the small intestine has so it is very limited in drug absorption.65 In this section new delivery methods to the digestive tract will be discussed.

29.7.1 GI Stents Expandable metal stents have been approved by the Food and Drug Administration for the treatment of gastrointestinal obstruction due to cancer and could possibly be used in other benign diseases.66 In the past, plastic stents have been used since they are relatively inexpensive when compared to these new metal stents.67 In this study by Knyrim et al., where two groups of patients either received plastic or metal stents for esophageal obstruction complications of device placement and functioning were signiﬁcantly more frequent in the plastic-prosthesis group than in the metal stent group.67 In addition, metal stents are easier to place and require less dilation than plastic stents, and are less expensive after cost analysis.67 The major problem with metal stents is tumor ingrowth, but this can be treated by laser ablation, which can be done in an outpatient setting.67 These gastric stents are made up of different metal alloys and are put in by gastroenterologists.67 The stents collapse to 3 mm in diameter at placement but can then expand up to 16 mm after positioned in the stricture.67 These metal stents are used for esophageal carcinoma, in which all other treatment options have failed to produce any relief of dysphagia.66 Dysphagia is usually relieved in up to 90% of patients who have metal stents placed and in all the patients in the Knyrim et al. trial.66,67 Esophageal expandable metal stents are also used to treat tracheoesophageal ﬁstulas due to cancer and may increase the survival of the patient, and that is why it is considered the primary treatment option.66 Stents may also be used in the upper gastrointestinal tract and for cancerous large-bowel obstruction.66 In the future, biodegradable stents could be used for benign diseases and stents that release chemotherapeutic agents or radiation can also be developed that could cause tumor regression.66

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29.7.2 Colonic Drug Delivery There are many different designs of colonic delivery systems and targeting has been achieved in several ways: coating drugs with pH-sensitive polymer, coating drugs with bacterial degradable polymers, using prodrugs, and delivering drugs through bacterial degradable matrixes.68 The colon-targeted delivery capsule was recently developed at Tanabe Co. Ltd., and was designed by making three different layers along with an organic acid that is used as a pH adjusting agent along with the medication.68 The three different layers are an enteric-coated layer, a hydrophilic layer, and an acid-soluble layer.68 Using this system, the drug does not release until at least 5 h without regard to fed or fasted patients.68 Electrostatic interaction between polyanions and polycation led to the formation of polyelectrolyte complexes (PECs), which can provide a greater barrier to drug release in the upper GIT than either material alone.69 Thus pectin, a polyanion, and chitosan, a polycation, can be used together to better improve drug delivery to the colon.69 In this study the optimum ratio of PEC was 10:1 weight ratio of pectin to chitosan.69 Another study found that the ratio of pectin to chitosan to hydroxypropyl methylcellulose of 3:1:1 also had the potential of colonic selective delivery.70 The delivery to the colon would ultimately occur when the bacterial enzymes commence to breakdown the pectin and the medication is released.69,70 In another study using 5-aminosalicylic acid (5-ASA), which is used to treat ulcerative colitis, it was found that using an 80:20 pectin-hydroxypropyl methylcellulose (HPMC) coating mixture provided an intermediate erosion pattern for the colonic delivery of 5-ASA tablets.71 This is promising to patients who have ulcerative colitis, whose current treatment options include rectally applied foams, suppositories, and enemas.71

29.8 Pulmonary: Drug Delivery

Inhalation is one of the oldest modes of drug delivery dating back to the earliest days of medical history. Medications were added to boiling water for patients to inhale.26 Many advances have come from the renewed interest in this form of drug delivery. Direct administration using inhalation as a method of drug delivery to the respiratory tract has become well established in the treatment of lung disease. This route has several advantages. Medication is delivered directly to the tracheobronchial tree allowing for rapid and predictable onset of action; the first-pass effect is circumvented; degradation within the gastrointestinal tract is avoided; much lower dosages than by the oral route can be administered with equivalent therapeutic efficacy, minimizing the potential for undesired side effects; and it can be used as an alternative route to avoid potential drug interactions when two or more medications are used concurrently. For many years theophylline was the gold standard for the treatment of asthma. It is now known that asthma is an inflammatory process best treated on a chronic basis with corticosteroids. Nonetheless, theophylline continues to be used to treat asthma. It is available as an injectable to be administered via i.v. infusion, as controlled-release tablets, and liquid suspensions and rectal suppositories. Bronchodilators and corticosteroids are the mainstay of treatment for asthma and chronic obstruc- tive pulmonary disease (COPD). Administration via inhalation reduces systemic exposure of these compounds and unwanted systemic side effects. Bronchodilators exert their action by relaxing airway smooth muscle. Numerous compounds are available on the market with varying degrees of duration of action. Some bronchodilators are available for injectable use such as terbutaline, isoproterenol, and epinephrine. Others are available as oral solutions or tablets such as albuterol. Unfortunately, systemic use of these drugs to treat respiratory conditions results in unwanted systemic side effects. These side effects include such conditions as tachycardia; therefore, direct administration into the lungs is desirable. Corticosteroids affect the inflammation that is present in these airway diseases. Corticosteroids are available for injectable use as intravenous or intramuscular depot injections, as oral solutions and tablets. Again, systemic use of corticosteroids can lead to many undesirable side effects including osteoporosis, hyperglycemia, and electrolyte imbalances.

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29.8.1 Indirect Routes of Administration Indirect routes of administration for agents available to treat the respiratory system include i.v., i.m., oral, and rectal. A discussion of direct methods of administration follows.

29.8.2 Direct Routes of Administration Direct routes of administration through the mouth and into the lungs can be categorized in the following manner: 1. Nebulizers (ultrasonic or jet) 2. Metered dose inhalers 3. Dry powder inhalers 4. Administration through chest tube into the pleural cavity The respiratory tract consists of multiple generations of branching airways (pharynx, larynx, trachea, bronchi, bronchioles, and alveoli) that progressively decrease in diameter but increase in number and total surface area. The large surface area of bronchioles and alveoli facilitates the rapid absorption of inhaled drugs.31 29.8.2.1 Jet Nebulizers Jet nebulizers use compressed gas (air or oxygen) from a compressed gas cylinder, hospital air-line, or electrical compressor to convert a liquid into a spray. The aerosol leaving the nebulizer is diluted by atmospheric air and inhaled through a face mask or mouthpiece. The ability of an aerosol to penetrate the respiratory tract is directly related to its efficacy. The most important property to possess that governs penetration and deposition in the respiratory tract is particle size. Particles must be less than 5 mm and preferably less than 2 mm for alveolar deposition.27 For the most part, drugs are in aqueous solution form when available for nebulization. There are multidose preparations available, but most nebulizer formulations are packaged as sterile, isotonic preservative-free unit doses. Examples include albuterol, n- acetylcysteine, and cromolyn sodium, all drugs used in the treatment of asthma. 29.8.2.2 Ultrasonic Nebulizers In ultrasonic nebulizers, the energy required to atomize a liquid comes from a piezoelectric crystal, usually a man-made ceramic material, vibrating at high frequency.31 Commercially available ultrasonic nebulizers produce aerosol droplets that are often significantly larger than those produced by jet nebulizers. The absence of droplets with size less than 2 mm suggests that such nebulizers may be inappropriate for applications requiring that the drug penetrates to the most peripheral lung regions.28 As previously mentioned, most solutions for nebulization are aqueous; however, drugs poorly soluble in water can be formulated as suspensions. For example, Pulmicort Respules“ consists of a suspension of the corticosteroid budesonide; in general, ultrasonic nebulizers are less efficient and more variable in delivering suspensions than jet nebulizers.28 Nebulizers are established devices for the delivery of therapy to the lungs. They have advantages over other systems in the elderly and pediatric population. This advantage stems from the fact that the drug may be inhaled during normal tidal breathing through a mouthpiece or face mask. Other delivery methods require coordination of inhalation and activation of the device, which would be unsuitable for the very elderly or the very young. 29.8.2.3 Metered Dose Inhalers The metered dose inhaler (MDI) is currently the most widely used inhalation delivery device. This is due to its portability, durability, long shelf life, cost-effectiveness, and relative ease of use. Unlike nebulizers, MDIs require metering and dispensing in coordination with the patient’s inspiratory cycle. There- fore, successful lung delivery depends on a patient’s ability to operate the inhalation device properly. Current improvements include the use of spacer devices. One of the biggest challenges with MDIs is to

Pharmaceutical Technical Background on Delivery Methods 29-13

reduce the amount of drug that is deposited in the oropharyngeal area instead of the lungs. Spacer devices have the ability to reduce the speed of the emitted aerosol cloud and reduce the deposition of drug in the throat by as much as 45%.29 Drugs available for delivery through these devices include b-agonists for smooth muscle relaxation, corticosteroids, and mast cell stabilizers. MDIs available on the market containing these products are numerous. As previously mentioned, all these drugs treat asthma and COPD. 29.8.2.4 Dry Powder Inhalers Prior to 1987, aerosolized MDIs were delivered via systems that relied on chlorofluorocarbon (CFC) propellant systems. There was a subsequent ban on all nonmedical uses of these CFC products that could deplete the ozone layer. Pharmaceutical manufacturers were encouraged to investigate other propellant systems, in addition to researching new propellants following the ban on CFC, pharmaceutical companies began to develop inhalable drugs in new forms such as dry powders.30 There are several different designs for dry powder inhalation devices (DPIDs). One such design is the Spinhaler“, in this device a gelatin capsule filled with drug and excipient is mounted in a rotor upon which are several small fan blades. The capsule is pierced by two small needles by sliding the outer casing of the inhaler relative to the inner casing. When the patient inhales, the capsule rotates rapidly and empties its content.31 Some devices such as the Diskhaler“ make it possible for the patient to know how many doses remain. This is an advantage over the MDI, which does not have this capacity. As with MDI, these devices rely on the patient’s inspiratory effort; in frail, elderly patients or small children this can be an issue with adequate drug delivery. The drug formulations for these devices exist as capsules or disks. The majority of the drug formulations again consist of b-agonists, corticosteroids, and mast cell stabilizers. A novel formulation being investigated with these devices is the use of vaccines by inhalation. It is postulated that there is potential for enhanced biological efficacy since pulmonary delivery may produce mucosal immunity superior to that produced by parenteral administration of vaccines. Studies have shown the safety and efficacy of measles vaccine delivered as a liquid aerosol from a nebulizer. A powder formulation of measles vaccine has been formulated for aerosol delivery in feasibility study. Challenges remain such as the development of appropriate delivery technology and reduction in the hygroscopic nature of the formulation.32 29.8.2.5 Chest Tube Administration Malignant pleural effusions are a common complication in advanced malignancy. Metastatic lung and breast cancer account for 75% of the cases.33 In this procedure a small bore thoracostomy tube is placed under local anesthesia. Then a sclerosing agent is instilled through the tube. Agents that have been used with success include bleomycin, doxycycline, and talc poudrage. The sclerosing agent instillation, if successful, will stop the accumulation of the fluid in the lung.

29.9 Ear, Nose, and Throat: Drug Delivery

29.9.1 The Ear Diseases of the ear, most commonly infections, are very prevalent in children. Extensive use of antibiotics for this indication has lead to marked antimicrobial resistance. Recently, the American Academy of Otolaryngology convened to set consensus on the treatment of common ear ailments. These included chronic suppurative otitis media, otitis externa, and tympanostomy tube otorrhea. The consensus was that in the absence of systemic infection or serious underlying disease topical antibiotics alone should constitute ﬁrst line treatment.34 29.9.1.1 Indirect Routes of Administration Indirect routes of administration include oral, i.v., and i.m. antibiotics. Using these routes the antibiotic reaches the systemic blood circulation, which then enters the middle and inner ear.

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29.9.1.2 Direct Routes of Administration Direct administration includes the use of antibiotic and anti-inﬂammatory ear drops such as Cipro HC Otic Suspension“ or Otobiotic Otic“ (which contains a mixture of antibiotic and anti-inﬂammatory). Solutions such as Otocain“ contain topical analgesics (benzocaine) to alleviate ear pain. Novel direct delivery devices being studied in animals include a biodegradable support matrix incor- porating a therapeutically releasable amount of antibiotic. This device is then inserted into the middle ear and is capable of drug delivery for 3 months. Progression into human studies may show potential for this device to be used as a source of inner ear drug delivery.35 Intratympanic therapy for Meniere’s disease has also been studied. Gentamicin solution of 0.5 ml has been injected transtympanically using a tuberculin syringe and a 27-gauge long needle. Patients treated in the study had good response to treatment with over 50% having complete control of their vertigo.36

29.1.2 The Nose Drugs have been administered nasally for both topical and systemic action. Common ailments that affect the nose and are treated with topical therapy include: allergic rhinitis, congestion, and sinusitis. Acute sinusitis is a condition manifesting inﬂammation and infection, usually of the frontal and maxillary sinuses. Goals of therapy are to improve drainage in the blocked sinuses and resolve the infection. Steam inhalation can cause vasoconstriction and help with drainage as can topical vasocontrictors such as phenylephrine spray.

29.1.2.1 Indirect Routes of Administration Indirect routes of administration include oral and i.v. use of antibiotics.

29.1.2.2 Direct Routes of Administration Direct routes of administration include the use of nasal sprays and, for more accurate dosing, mechanical pumps and pressurized aerosol systems. Allergic rhinitis is a condition that is prevalent in our society. Frequently present in patients who also have asthma, it is best treated by nasal corticosteroids. The use of these medications directly to the nasal mucosa avoids exposing the body to systemic levels of corticosteroids and their potential side effects. One of the simplest and oldest methods of nasal drug delivery is the use of a device to administer solutions via dropper. This system, while cost-effective and easy to manufacture, has the disadvantage of not accurately measuring drugs because of the inability to control the exact volume delivered. Squeezed nasal bottles are mainly used as a delivery device for decongestants, such as Afrin Spray“. They function by pressing the bottle and pushing air inside the bottle through a simple jet, which atomizes a certain volume of ﬂuid. Metered-dose pump sprays (MDPSs) allow for the application of a deﬁned dose with a high dosing accuracy. These systems consist of the container, the pump with the valve, and the actuator.37 Powder dosage forms are understudy and include inhaled insulin. Although dry powders have advantages over liquid formulations, they are infrequently used in nasal drug delivery. Nasal gels have also been studied as a means of prolonging drug contact with the nasal mucosa. One product is marketed as vitamin B-12 (Nasocobal gel“).

29.1.3 The Throat Infection of the throat is a common ailment as is cough. Many throat infections are self-limiting and require treatment only with analgesics. Streptococcal throat infections, however, do require antimicrobial treatment because of their potential to damage the heart valves. Treatment for these infections consists of systemic oral antibiotics; the drug of choice is a simple penicillin. Cough is another common ailment that is treated with different medications depending on the cause of the cough. For cough from the common cold and allergic rhinitis, oral antihistamines and decongestants along with ipratropium nasal spray can be used. If the cough is due to COPD, a 2-week trial of oral corticosteroids can be utilized.38

Pharmaceutical Technical Background on Delivery Methods 29-15

Other over-the-counter treatment modalities include liquid sprays that contain topical anesthetics for throat pain, such as Orasept Throat Spray“, or lozenges such as Cepacol“. A novel treatment in throat disorders involves the use of botulinum toxin to treat spasmodic dyspho- nias. This condition is a disorder that results in the patient having either a strained or strangled voice or a breathy, whispery voice. The toxin, injected directly into the posterior cricoarytenoid muscle, paralyzing the muscle that is causing the spasm and resulting in relief of the condition.39

29.10 Lymphatic System: Drug Delivery

The human body is exposed to a wide variety of diseases of benign and malignant origin. These diseases affect the lymphatic system at the early stages of the process. Cancers, as well as many infections (viral, bacterial, or fungal), spread by lymphatic dissemination.40 The high prevalence of lymph node involve- ment in these diseases is not surprising because the primary function of the lymphatic tissue is to provide the body’s immune response. Appropriate diagnosis and treatment of diseases affecting the lymph nodes depend on the availability of drugs that are retained by the lymph nodes. Effective accumulation of drugs into the lymph nodes can be achieved by intralymphatic or interstitial administration.41 Since there is a high variability of lymphatic networks and drainage routes, systemic administration would always be preferred and currently represents a focus in lymphotropic drug design.42 The interstitial space constitutes a significant barrier to the diffusion of macromolecules and particulates and may limit the rate and extent of drainage from site of administration. Macromolecules dissolved in the interstitial fluid are readily drained by lymphatics; therefore, the limiting factor to macromolecular transfer from blood capillary to lymph is capillary permeability. The rate of macromolecule and particle extravasation depends on size and structure. Macromolecules may be transferred in liquid phase, while some proteins are transported by transcytosis-associated receptors. The nature and size of lymphatic vessels vary along the route.41 Access routes to the lymph nodes can be accomplished through lymphatic vessels or blood vessels. Drug delivery through the lymphatic vessels is highly efficient; interstitial macromolecules are cleared from the injection site almost exclusively by lymphatics, but do not return to blood capillaries. Direct drug delivery through blood vessels to intranodal tissue is not very effective unless homing receptors are utilized.40 Different local administration routes have been utilized to deliver diagnostic or therapeutic drugs to the lymph nodes. For intralymphatic administration, a peripheral lymphatic vessel has to be cannulated by surgical cut- down. This method results in high concentration of drug in the lymph nodes, but it is only limited to draining lymph nodes leading to an uneven drug distribution. This method has been used for x-ray lymphography and CT. Agents used include iodized oils.41 Interstitial administration does not require cannulation of a lymphatic vessel, and therefore is easier to perform. Agents can be injected at any accessible anatomical site, where they penetrate from the interstitial space into small lymphatic vessels through intercellular gaps of lymphatic endothelium. The agents are then transported through the network of lymphatic vessels to peripheral lymph nodes. The disadvantage of the interstitial route is that it provides low, unreliable drug delivery to mediastinal and abdominal lymph nodes, which are involved in the majority of carcinomas.44 Oral delivery of lipophilic drugs to the lymph nodes is associated with the formation and transport of lipoproteins, which are formed after the adsorption of lipid digestion products. Lymphatic transport of polar drugs after intestinal absorption is lower because of their preferential absorption by blood. Intra-arterial injections of drugs carrying particulates that are too large to pass through capillary vessels result in high local tissue concentration of the released drugs, which can then diffuse to local lymph nodes. This method is used to chemoembolize tumors rather than to treat metastatic diseases.41 In addition to locally administered drugs, there are systemic agents that can be injected intravenously and can accumulate in the lymph nodes by different mechanisms.

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Low molecular weight compounds such as gallium citrate accumulates in normal lymphatic tissue and lymphomas; however, because its nonspecific biodistribution, it is not used very often except for imaging of lymphomas, tumor recurrence, or sarcoid imaging. Metalloporphyrins also have been used for selective lymphatic imaging and MRI of human colon carcinoma.43 Radiolabeled lymphocytes are another source for clinical use in detecting sites of inflammation and lymphoreticular malignancies. Usually, lymphocytes are incubated with an Indium oxide complex and the resulting labeling efficiency is 50 to 60%.42 Homing receptors of lymphocytes are responsible for cell accumulation in lymphatic tissue and inflammations (where homing molecules are also expressed). Because the homing process is highly selective, it is possible that the future availability of vector molecules with specificity to lymphocyte adhesion glycoproteins will allow efficient drug delivery. Colloidal iron oxide particles have been studied as diagnostic MR contrast agents. It has been found that after i.v. administration, some dextran-coated colloids accumulate in lymph nodes in much higher concentrations than any other particulate.43 Lymph nodes are an easy target for drug delivery through intralymphatic or interstitial administration with local concentrations achievable. These administration routes are rarely used because of the unreliable and highly variable delivery to different lymph node groups. Because of these factors, system carriers are being developed for lymph node delivery. The two classes of agents are (1) agents that have long circulation times and are able to extravasate into interstitium and then are cleared by lymphatics (i.e., dextran- covered particles of dextran-based graft copolymers); (2) agents targeting lymph node-specific lymphocyte homing receptors or antigens.40

29.11 Reproductive System: Drug Delivery

The female reproductive tract is divided into external and internal genitalia. Parts of the female anatomy include the pelvis, bladder, urethra, and vagina.72 For reproduction, the human endometrium must receive hormonal signals that prepare it for implantation.72 When conception does not occur, these signals initiate mechanisms that lead to menses and controlled regeneration of this tissue, and the cycle repeats itself again.72 In contrast, the male reproductive system is composed of the scrotal sac, testes, genital ducts, accessory glands, and penis.73 The scrotal sac performs an important role in maintaining the testes at a temperature about 2°C below the temperature of the internal organs so that spermatogenesis can occur.73 In this section new reproductive system drug delivery methods will be discussed.

29.11.1 Contraceptive Implants Norplant™ (The Population Council) and Jadelle are the only subdermal implants currently available in the United States, even though there are several more that are currently being used in other countries.74 Norplant consists of six capsules that release the progestin, levonorgestrel for at least 5 years; after this time there is still 69% of the original steroid load left in the silastic capsules to act as a safety margin for women who don’t remove the implants after the recommended 5 years.74–76 The system consists of six silastic capsules, 34 mm long and 2.4 mm in diameter.75 Jadelle™ (The Population Council) also uses levonorgestrel just like Norplant.76 The only difference between the products is that Jadelle uses two silastic rods instead of six capsules, thus making insertion and removal easier for the Jadelle implant.76 Each Jadelle implant is 4.4 cm long and is composed of a polydimethylsiloxane elastomer covered by silicone rubber tubing.74 Jadelle is approved by the FDA for 3 years of use, but has been shown to be effective for up to 5 years.74 The next implant that is currently used in other countries is the Implanon™ (NV Organon, Oss, The Netherlands).76 Implanon is a single-rod implant that is 4 cm long and 2 mm in diameter.74 It contains 68 mg of 3-keto-desogestrel (etonogestrel) in an ethylene vinyl acetate (EVA) polymer core surrounded by an EVA membrane with a contraceptive dose maintained for 3 years.74,75 Its contraceptive efﬁcacy is excellent since there has not been one report of a single pregnancy in over 5000 woman-years of experience with this product.76 Yet another implant used in other countries is the

Pharmaceutical Technical Background on Delivery Methods 29-17

Uniplant™. Uniplant is a single silastic 3.5-cm-long, 2.4-mm-diameter capsule containing 55 mg nome- gestrol acetate developed as a single 1-year contraceptive implant.74–76 An alternative approach to resolving the difﬁculties of implant removal which is considered a minor surgery and usually takes about 20 min, is to eliminate the need for removal altogether.74–76 Capronor™ is a 40-mm rod containing levonorgestrel in an E-caprolactone polymer.74 The polymer releases levonorgestrel about ten times faster than silastic and thereby one implant can achieve adequate serum concentrations, instead of normally two implants.74 The implant is biodegradable and it appears to remain for about 1 year.74 Another form of biodegradable implants is pellets.74 These pellets are expected to dissolve within 2 years of application, but are impossible to take out after several months of implantation.74 In conclusion, some of the advantages of progestin implants are long unattended use, efﬁcacy, no compliance issues, and lower levels of progestin when compared to oral contraceptives.76 Disadvantages are that minor surgery is required for insertion and removal and there is a high cost associated with the method if early removal is performed.76

29.11.2 Contraceptive Patch Ortho Evra/Evra™ (Janssen Pharmaceutica, NV Belgium) is the only available female contraceptive transdermal patch in the market. The matrix patch which is 20 cm2 is thin and consists of three layers: an outer protective layer of polyester; a medicated, adhesive middle layer; and a clear, polyester release liner that is removed prior to patch application.77,78 The patch is designed to deliver 150 µg of norelgestromin and 20 µg of ethinyl estradiol daily to the systemic circulation.77–79 The patch can be applied to the buttocks, upper outer arm, lower abdomen, or upper torso (excluding the breast).77 Because the patch is replaced weekly on the same day of the week for 3 consecutive weeks (followed by 1 week patch- free) and the next patch cycle begins on the same day, it makes patient compliance easier when compared with oral contraceptives.79

29.11.3 Male Contraceptive Androgen therapy is predominantly used for replacement in primary hypogonadism but may be used for male contraception.80 Desogestrel DSG (300 µg daily) and transdermal testosterone (T0) (5 mg daily) patches were given to male patients for 24 weeks.81 Using this regimen 71% of the patients were azoosper- mia (no sperm) by the end of week 12.81 This regimen wasn’t as effective as using IM T enanthate.81 The lower efﬁcacy of the transdermal T is likely to be due to failure of the transdermal T system in maintaining circulating T levels consistently in the required range.81 In conclusion, the use of desogestrel and IM T enanthate might lead to male contraception in the near future.

References 1. Marieb, E., The central nervous system, in Human Anatomy & Physiology, 4th ed., Fox, D., Ed., Benjamin/Cummings Science Publishing, Menlo Park, CA, 1997, pp. 405–455. 2. Minn, A. et al., Drug metabolism in the brain: beneﬁts and risks, in The Blood-Brain Barrier and Drug Delivery to the CNS, Begley, D., Bradbury, M., and Kreuter, J., Eds., Marcel Dekker, New York, 2000, pp. 145–170. 3. Bradbury, M., History and physiology of the blood-brain barrier in relation to delivery of drugs to the brain, in The Blood-Brain Barrier and Drug Delivery to the CNS, Begley, D., Bradbury, M., and Kreuter, J., Eds., Marcel Dekker, New York, 2000, pp. 1–8. 4. Madaras-Kelly, K. et al., Central nervous system infections, in Pharmacotherapy: A Pathophysiologic Approach, 3rd ed., Dipiro, J. et al., Eds., Appleton-Lange, Norwalk, CT, 1997, pp. 1971–1993. 5. Partridge, W.M., Invasive brain drug delivery, in Brain Drug Targeting: The Future of Brain Drug Development, Cambridge University Press, New York, 2001, pp. 13–35. 6. Bernards, C.M., Epidural and intrathecal drug movement, in Spinal Drug Delivery, Yaksh, T., Ed., Elsevier, New York, 1999, pp. 239–252. 7. Haroun, R.I. and Brem, H., Local drug delivery, Curr. Opin.Oncol., 12, 187, 2000.

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