Daniel P. Wermeling

Microneedles permit transdermal delivery of a skin-impermeant medication to humans

Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skins outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. Here, we present a clinical study of MN-enhanced delivery of a medication to humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications.

Bioavailability and Pharmacokinetics of Lorazepam after Intranasal, Intravenous, and Intramuscular Administration

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1‐week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7 (11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration‐time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.

Ziconotide, an Intrathecally Administered N‐Type Calcium Channel Antagonist for the Treatment of Chronic Pain

Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N‐type voltage‐sensitive calcium channels, preventing the conduction of nerve signals. N‐type calcium channels are present in the superficial laminae of the dorsal horn of the spinal cord. In various animal models of pain, intrathecal administration of ziconotide blocked nerve transmission and nociception. The United States Food and Drug Administration recently approved ziconotide intrathecal infusion for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug has a narrow therapeutic window and a lag time for the onset and offset of analgesia and adverse events. In early clinical trials, frequent and severe psychiatric and central nervous system adverse effects were associated with rapid intrathecal infusion (0.4 μg/hr) and frequent up‐titration (every 12 hrs). Therefore, patients with psychiatric symptoms are not candidates for this drug. Drug trials of external intrathecal catheters and microinfusion devices demonstrated a 3% risk of meningitis. A low initial infusion rate of 0.1 μg/hour and limiting infusion rate increases to 2–3 times/week are now recommended. Patients responsive to intrathecal ziconotide require an implanted infusion system to receive long‐term therapy.

Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients.

The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48‐hour period following intrathecal (IT) administration (1, 5, 7.5, or 10 μg) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24‐hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half‐life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose‐related analgesia was observed. Pharmacokinetic‐pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1‐hour IT infusion.

Intranasal delivery of antiepileptic medications for treatment of seizures

SummaryAcute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection.Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where care-givers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

Pharmacokinetics and Pharmacodynamics of a New Intranasal Midazolam Formulation in Healthy Volunteers

We evaluated the pharmacokinetics and pharmacodynamics of single 5-mg doses of midazolam after administration of a novel intranasal (IN) formula, IM, and IV midazolam in an open-label, randomized, 3-way cross-over study in 12 healthy volunteers. IN doses were delivered as 0.1-mL unit-dose sprays of a novel formulation into both naris. Blood samples were taken serially from 0 to 12 h after each dose. Plasma midazolam concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic parameters. The mean midazolam bioavailabilities and % coefficient of variation were 72.5 (12) and 93.4 (12) after the IN and IM doses, respectively. Median time to maximum concentration was 10 min for IN doses. Adverse events were minimal with all routes of administration, but nasopharyngeal irritation, eyes watering, and a bad taste were reported after IN doses. Our results support further development of this novel midazolam nasal spray.

Pharmacokinetics, Pharmacodynamics, and Safety of Metrifonate in Patients with Alzheimer's Disease

Metrifonate is converted nonenzymatically to 2,2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21‐day, randomized, double‐blind, placebo‐controlled trial of metrifonate in patients with Alzheimers disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75–135 mg), MD = 0.25 mg/kg (12.5–25 mg); panel 2, LD = 2.5 mg/kg (125–225 mg), MD = 0.40 mg/kg (20–35 mg); panel 3, LD = 4.0 mg/kg (200–335 mg), MD = 0.65 mg/kg (30–60 mg); and panel 4, LD = 4.0 mg/kg (200–335 mg), MD = 1.0 mg/kg (50–90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration—time curve (AUC) and maximum concentration (Cmax for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose‐independent mean values for time to Cmax (tmax) and half‐life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long‐term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimers disease.

Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access:

Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid overdose and prevention of opioid-induced mortality.

Naloxone for Opioid Overdose Prevention Pharmacists’ Role in Community-Based Practice Settings

Background: Deaths related to opioid overdose have increased in the past decade. Community-based pharmacy practitioners have worked toward overcoming logistic and cultural barriers to make naloxone distribution for overdose prevention a standard and accepted practice. Objective: To describe outpatient naloxone dispensing practices, including methods by which practitioners implement dispensing programs, prescribing patterns that include targeted patient populations, barriers to successful implementation, and methods for patient education. Methods: Interviews were conducted with providers to obtain insight into the practice of dispensing naloxone. Practitioners were based in community pharmacies or clinics in large metropolitan cities across the country. Results: It was found that 33% of participating pharmacists practice in a community-pharmacy setting, and 67% practice within an outpatient clinic-based location. Dispensing naloxone begins by identifying patient groups that would benefit from access to the antidote. These include licit users of high-dose prescription opioids (50%) or injection drug users and abusers of prescription medications (83%). Patients were identified through prescription records or provider screening tools. Dispensing naloxone required a provider’s prescription in 5 of the 6 locations identified. Only 1 pharmacy was able to exercise pharmacist prescriptive authority within their practice. Conclusion: Outpatient administration of intramuscular and intranasal naloxone represents a means of preventing opioid-related deaths. Pharmacists can play a vital role in contacting providers, provision of products, education of patients and providers, and dissemination of information throughout the community. Preventing opioid overdose–related deaths should become a major focus of the pharmacy profession.

Intranasal naloxone administration for treatment of opioid overdose

PURPOSE The pharmacology, pharmaco-kinetic properties, and clinical efficacy of naloxone injection administered intranasally for the reversal of opioid overdose are reviewed. SUMMARY Naloxone is an opioid-receptor antagonist that is used in the treatment of opioid overdose to reverse the respiratory and central nervous system-depressant effects of the opioid. Naloxone injection is traditionally given by intravenous, intramuscular, and subcutaneous routes. Paramedics also administer naloxone injection intranasally in the prehospital setting to treat suspected opioid overdose. The nasal mucosa has a rich blood supply that allows for efficient drug absorption and the avoidance of first-pass hepatic metabolism that would be seen with oral administration. Obtaining vascular access can be difficult in known drug users, prolonging the time required to administer the antidote. Patients awakening from an overdose may be agitated, confused, and even combative, thus increasing the risk of needle-stick injury to first responders. The intranasal route avoids the need for establishing vascular access and can be associated with speedier patient recovery. In two randomized controlled trials, intranasal naloxone alone was shown to be sufficient for reversing opioid-induced respiratory depression in 74% and 72% of the respective study populations of patients experiencing opioid overdose. In addition, the safety profile of intranasal naloxone appears to be no different than that of naloxone injection in the treatment of opioid overdose in the prehospital setting. CONCLUSION Intranasal administration of naloxone appears to be effective in treatment of opioid overdose when i.v. administration is impossible or undesirable.