An abuse-deterrent, microsphere-in-capsule formulation of extended-release oxycodone: alternative modes of administration to facilitate pain management in patients with dysphagia.

BACKGROUND: Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose. OBJECTIVE: To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes. METHODS: A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration. RESULTS: There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size. CONCLUSIONS: Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.

Evaluation of an Extended-Release, Abuse-Deterrent, Microsphere-in-Capsule Analgesic for the Management of Patients with Chronic Pain With Dysphagia (CPD).

BACKGROUND: Patients who have chronic pain with dysphagia (difficulty swallowing) (CPD) often have difficulty taking oral medication and, as such, alter their medications by crushing or chewing in an attempt to make it easier to swallow. Such manipulation of currently marketed, extended-release (ER) opioid analgesics can significantly alter the pharmacokinetic (PK) properties of the formulations, resulting in poor treatment outcome or serious adverse events. There is an unmet medical need for oral ER opioid formulations suitable for patients with CPD. OBJECTIVE: The primary objectives of this study were to conduct in vitro studies to evaluate alternate means of administration of a new, extended-release (ER), abuse-deterrent, microsphere-in-capsule formulation of oxycodone for patients with CPD. Specifically, these studies investigated the in vitro equivalence of drug release rates from Oxycodone DETERx® ER intact capsules (control condition) and administration via alternate modes-opening the capsule and sprinkling the microspheres onto soft foods or administration through enteral tubes. Secondary objectives were to compare alternate modes of administration of Oxycodone DETERx® to a commercially available ER-morphine product. METHODS: Soft food study: Oxycodone DETERx® microspheres were sprinkled onto and mixed with several soft foods (ie, applesauce, vanilla pudding, strawberry jam, yogurt, and vanilla ice cream); the effect of drug contact time (0, 30, and 60 minutes) on drug release was studied. Enteral tube study: Oxycodone DETERx® microspheres were administered through varying sizes of nasogastric (10 and 12 Fr.) tubes and a 16 Fr. gastrostomy tube using 5 different delivery vehicles (ie, water, liquid nutritional feeds [Jevity®, Ensure®], and milk [whole milk and 2% milk]). Drug release rate was characterized using a standard in vitro dissolution methodology; dissolution of intact Oxycodone DETERx® capsules served as the control for both the soft food and enteral tube studies. Oxycodone concentration was measured using a standardized high-performance liquid chromatography (HPLC) assay. Similarity factor (f2) analysis was used to compare similarity of the dissolution profiles of test and control conditions. RESULTS: The mean dissolution profile of Oxycodone DETERx® microspheres sprinkled onto and mixed with each of the soft foods were similar (f2 > 50) to that of the control. Study drug-food contact time did not impact dissolution profiles. The dissolution data obtained from Oxycodone DETERx® microspheres passed through enteral feeding tubes of varying sizes were similar (f2 > 50) to that of the control. Unlike a marketed morphine sulfate ER pellet formulation, Oxycodone DETERx® did not clog any of the studied enteral tubes. CONCLUSION: A new ER, abuse-deterrent, microsphere-in-capsule formulation of oxycodone can be administered by sprinkling onto soft food without affecting the drug release profile of the formulation. The formulation can also be administered directly via enteral tubes without affecting drug release and without clogging enteral tubes. Oxycodone DETERx® may offer physicians and patients with CPD an alternate treatment option, especially in those patients who have dysphagia or an aversion to swallowing monolithic tablet/capsule formulations and for whom analgesic patches or other opioid formulations are not a viable therapeutic option.

Impact of physical manipulation on in vitro and in vivo release profiles of oxycodone DETERx®: an extended-release, abuse-deterrent formulation.

OBJECTIVE: In vitro: To assess the effect of common crushing techniques on particle size reduction (PSR) and in vitro drug-release kinetics of oxycodone DETERx® (herein DETERx) and of a commercially available oxycodone extended-release (ER) tablet. In vivo: To evaluate the impact of the most effective manipulation method identified in the in vitro study and the effect of chewing on the pharmacokinetics (PK) of DETERx relative to oxycodone solution. DESIGN: In vitro: Mechanical manipulation of dosage forms using common household utensils. In vivo: Open-label, randomized, active-controlled, crossover PK study. SUBJECTS: In vivo: Forty-four healthy male and female volunteers. METHODS: In vitro: DETERx capsule contents and marketed comparator tablets were subjected to manipulation (crushing) using 10 different household utensils. Particle size and dissolution analysis were conducted. In vivo: Subjects were randomly assigned to receive DETERx 40-mg capsules intact, crushed, or chewed or oxycodone solution. Serial blood samples were drawn for PK assessment. RESULTS: In vitro: The utensils used to manipulate DETERx capsule contents were either ineffective in reducing the particle size or produced only a small change in the median particle size and dissolution rate relative to the marketed comparator. In vivo: DETERx intact capsules provided significantly lower Cmax and longer Tmax values than oxycodone solution. Manipulation of DETERx by crushing (using the most effective method established in vitro) or chewing resulted in bioequivalent plasma concentration-time profiles to the intact dosage form. CONCLUSION: These mechanical manipulation and PK studies demonstrated that DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects.

Challenges of treating patients with chronic pain with dysphagia (CPD): physician and patient perspectives.

OBJECTIVE: Dysphagia--difficulty eating and swallowing--can significantly impair a patient's ability to maintain adequate nutritional and medication intake. There are a large number of patients with chronic pain, including pediatric, geriatric, and palliative care patients, who suffer from dysphagia and, therefore, have difficulty achieving optimal pain management with solid, oral formulations. The objective of this study was to survey physicians and patients in the US to understand their knowledge, attitudes, and clinical management/analgesic usage patterns in the treatment of patients with chronic pain with dysphagia (CPD). RESEARCH DESIGN AND METHODS: Two separate surveys were administered to physicians and patients. The physician survey design was qualitative; physicians participated in a semi-structured phone interview. The patient survey design was quantitative; patients participated in a structured online survey. Purposive sampling was used to recruit participants into both studies. Physician participants were identified based on their specialty, prescribing practices, and geographic location. Patient participants were recruited through a consumer panel of pre-identified individuals who, for 3 months or longer, had chronic pain and were taking opioids. RESULTS: Thirty-four physicians and 1021 patients were surveyed. Physicians indicated that 5-20% of their patients had difficulty swallowing. Treatment for CPD consisted of the fentanyl patch, immediate-release opioids, methadone liquid, or extended-release morphine products. Physicians were not satisfied with currently available treatment options. Twenty-nine per cent of patients surveyed had trouble swallowing or disliked swallowing pills. Eighty per cent of patients were not asked about their ability to swallow solid, oral dosage forms by their physician. To circumvent swallowing difficulties, some patients (16%) cut/crush/grind their medication to facilitate swallowing. Most of these patients (65%) did not know that altering tablets could potentially change the drug release (pharmacokinetic) characteristics of the tablet and lead to serious adverse events. LIMITATIONS: Qualitative survey research can be influenced by responder bias as well as selection bias. The number of survey participants for both the physician and patient surveys was small, thus responses may not reflect those in the general population. CONCLUSION: A proportion of patients with chronic pain have dysphagia and cannot swallow solid, oral dosage forms, which creates a serious treatment challenge for pain specialists and other healthcare providers. Currently available treatment options have limitations; new treatment options would be welcomed by both physicians and patients. Physician and patient education should be enhanced in order to promote awareness of the deleterious consequences associated with altering currently available analgesic formulations. Facilitating patient-physician communication on this topic may help to improve treatment outcomes.