RESUMEN
Objective: Some crush-resistant tablet formulations (CRTs) reduce prescription opioid abuse by nonoral routes of administration (ROAs), especially insufflation and injection, while oral abuse increases. Oral abuse involving product manipulation vs swallowing whole for CRTs and comparators was examined. Methods: Abuse by oral modes of administration (e.g., swallowing whole, chewing, dissolving in the mouth), was examined using the ASI-MV, a computerized, clinical interview for adults in substance abuse treatment from January 2009 to March 2015. CRTs (reformulated oxycodone extended-release [ER], reformulated oxymorphone ER, and tapentadol ER) were compared with non-CRT versions, morphine ER, and oxycodone immediate-release single entity. Analyses employed descriptive statistics and logistic regression. Results: Among 364,329 unique assessments, 18,135 patients reported oral abuse of the CRTs and comparators examined. CRTs had a higher prevalence of oral abuse involving product manipulation than comparators (P < 0.0001) among all abusers of product. Oral abuse involving product manipulation for CRTs was greater among the subset of patients reporting oral abuse and significantly higher than comparators (P < 0.003). CRTs were significantly less likely than comparators to be swallowed whole (P < 0.0001) and significantly more likely to be chewed (P < 0.003). CRTs were more likely to be dissolved in the mouth than most comparators. Conclusions: Results suggest the need for abuse-deterrent formulations designed to reduce abuse by oral administration with product manipulation, such as chewing. Advances in this area may reduce the overall abuse of prescription opioids and interrupt the progression from abuse by swallowing whole to oral administration involving product manipulation and other ROAs.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/química , Trastornos Relacionados con Opioides/epidemiología , Administración Oral , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Relacionados con Opioides/prevención & control , Comprimidos , Adulto JovenRESUMEN
OBJECTIVE: Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein "DETERx"). DESIGN: Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study. SETTING: Clinical research site. SUBJECTS: There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods. METHODS: The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx-administered as either a crushed intranasal (IN) or an intact oral (PO) preparation-with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control. RESULTS: For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated. CONCLUSIONS: Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested.
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Analgésicos Opioides/administración & dosificación , Trastornos Relacionados con Opioides/prevención & control , Oxicodona/administración & dosificación , Administración Intranasal , Adulto , Analgésicos Opioides/farmacocinética , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxicodona/farmacocinética , Adulto JovenRESUMEN
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.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Trastornos de Deglución/complicaciones , Oxicodona/administración & dosificación , Oxicodona/uso terapéutico , Manejo del Dolor/métodos , Adulto , Analgésicos Opioides/farmacocinética , Cápsulas , Química Farmacéutica , Dolor Crónico/complicaciones , Deglución , Preparaciones de Acción Retardada , Alimentos , Humanos , Intubación Gastrointestinal , Microesferas , Trastornos Relacionados con Opioides , Oxicodona/farmacocinéticaRESUMEN
OBJECTIVE: Oxycodone DETERx® is an extended-release (ER), microsphere-in-capsule abuse-deterrent-formulation designed to retain its extended-release properties following tampering or misuse (e.g., chewing, crushing). This study assessed the safety and pharmacokinetics of orally administered intact and crushed Oxycodone DETERx® capsules compared with intact and crushed reformulated OxyContin® tablets and crushed immediate-release oxycodone tablets (IR oxycodone). METHODS: This was a randomized, open-label, active-controlled, cross-over study. Healthy subjects received five oxycodone treatments (40 mg) with a standardized high-fat, high-calorie meal: Oxycodone DETERx® (intact or crushed), OxyContin® (intact or crushed), and IR oxycodone (crushed). Blood samples were collected for assessment of oxycodone plasma concentrations. RESULTS: Thirty-eight subjects completed the study. Both crushed and intact Oxycodone DETERx® resulted in lower peak plasma concentrations when compared with IR oxycodone. Crushed Oxycodone DETERx® was bioequivalent to intact Oxycodone DETERx® and exhibited a numerically lower Cmax . Also, median Tmax was unchanged by crushing. In contrast, mean peak plasma oxycodone concentrations for crushed OxyContin® were significantly higher compared with intact OxyContin® and were bioequivalent to IR oxycodone. Median Tmax for crushed OxyContin® was the same as IR oxycodone and 3.25 hours shorter than intact OxyContin®. CONCLUSIONS: These data demonstrate that when crushed and taken orally, Oxycodone DETERx® maintains its EXTENDED-release profile, while crushed OxyContin® shows a pharmacokinetic profile similar to an immediate-release product. These results suggest that Oxycodone DETERx® may be less attractive to illicit drug users compared with existing abuse-deterrent-formulations, while providing a safer option for patients who may unknowingly crush their medication such as those who have difficulty swallowing.
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Analgésicos Opioides/farmacocinética , Trastornos Relacionados con Opioides/tratamiento farmacológico , Oxicodona/farmacocinética , Administración Oral , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Química Farmacéutica/métodos , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxicodona/administración & dosificación , Oxicodona/uso terapéutico , Equivalencia Terapéutica , Adulto JovenRESUMEN
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RESUMEN
BACKGROUND AND OBJECTIVE: Extended-release (ER) opioids are associated with high rates of abuse. Recreational opioid users often manipulate ER formulations to achieve a high plasma concentration in a short amount of time, resulting in a more rapid and intense high. Patients may also manipulate ER tablets to facilitate swallowing, without recognizing that manipulation could increase release rate. The goal of this study was to assess the ability of oxycodone DETERx (Xtampza® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA) and other commercially available ER opioid formulations with and without physicochemical abuse-deterrent characteristics to be manipulated by crushing in an in vitro setting. METHODS: In vitro dissolution techniques were used to compare the opioid release from a variety of ER opioid formulations. Dissolution was assessed for intact and crushed dosage forms. Opioid release was quantified using high-performance liquid chromatography. RESULTS: Intact formulations exhibited drug release rates characteristic of 12- or 24-h dosage forms. After crushing using commonly available household tools, only Xtampza ER maintained ER of opioid. CONCLUSIONS: Xtampza ER maintained its ER characteristics after crushing, unlike many other commercially available opioid formulations, including some formulated with abuse-deterrent properties. As such, Xtampza ER may be less appealing to abusers and offer a margin of safety for patients who manipulate dosage forms to facilitate swallowing.
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Analgésicos Opioides/administración & dosificación , Liberación de Fármacos , Oxicodona/administración & dosificación , Administración Oral , Analgésicos Opioides/química , Cromatografía Líquida de Alta Presión , Preparaciones de Acción Retardada/administración & dosificación , Humanos , Trastornos Relacionados con Opioides , Oxicodona/química , ComprimidosRESUMEN
AIM: To further characterize the pharmacokinetics of Xtampza® ER. SUBJECTS & METHODS: This was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContin® (intact or crushed) or immediate-release (IR) oxycodone (crushed). Blood samples were collected to assess oxycodone concentrations. RESULTS: Crushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR. CONCLUSION: This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606.
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Oxicodona/administración & dosificación , Oxicodona/farmacocinética , Administración Oral , Adulto , Estudios Cruzados , Preparaciones de Acción Retardada/farmacocinética , Composición de Medicamentos , Femenino , Humanos , Masculino , Oxicodona/efectos adversos , Oxicodona/sangreRESUMEN
Oxycodone DETERx® (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended-release, microsphere-in-capsule, abuse-deterrent formulation designed to retain its extended-release properties after tampering (eg, chewing/crushing). This randomized, double-blind, placebo-controlled, triple-dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate-release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high-fat, high-calorie meal and fasted), chewed oxycodone DETERx (high-fat, high-calorie meal and fasted), crushed immediate-release oxycodone (fasted), and placebo (high-fat, high-calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty-eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate-release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (Emax ) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .01). The time to Emax was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate-release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate-release oxycodone.
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Trastornos Relacionados con Opioides/sangre , Trastornos Relacionados con Opioides/diagnóstico , Oxicodona/administración & dosificación , Oxicodona/sangre , Administración Oral , Adolescente , Adulto , Estudios Cruzados , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/metabolismo , Método Doble Ciego , Composición de Medicamentos , Femenino , Humanos , Masculino , Masticación/fisiología , Persona de Mediana Edad , Oxicodona/química , Adulto JovenRESUMEN
OBJECTIVE: Abuse of prescription analgesics is a well-recognized problem, with nearly 2 million people aged 12 years or older initiating nonmedical use of pain relievers in 2012. The prevalence of opioid abuse via intravenous (IV) injection has led to the development of dosage forms designed to deter abuse using different inactive ingredients and formulation strategies. This study evaluated the IV abuse potential for a novel, microsphere-encapsulated abuse-deterrent formulation of oxycodone, Xtampza™ ER (referred to as "oxycodone DETERx"). METHODS: The extraction of oxycodone DETERx and two comparators, extended-release oxycodone (oxycodone ER) and immediate-release oxycodone (oxycodone IR), was evaluated in small volumes (5 and 10 mL) of water after manipulation of the dosage forms. The syringeability and injectability of these products were evaluated to determine the feasibility of using these products via IV injection. RESULTS: The extraction of oxycodone from oxycodone DETERx was nominal, with <12 percent extracted under any test condition. Oxycodone ER and oxycodone IR had as much as 83 and 98 percent oxycodone extracted, respectively. Injectability and syringeability analyses showed that injection of oxycodone DETERx microspheres in suspension is not feasible. In contrast, oxycodone ER and oxycodone IR suspensions were more easily drawn into and expelled from a syringe. Furthermore, injection of molten oxycodone DETERx microspheres was also shown to be ineffective. CONCLUSION: The chemical and physical properties of oxycodone DETERx provide barriers to manipulating the microspheres for the purpose of IV injection.
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Analgésicos Opioides/administración & dosificación , Trastornos Relacionados con Opioides/etiología , Oxicodona/administración & dosificación , Química Farmacéutica , Humanos , Inyecciones Intravenosas , Microesferas , TemperaturaRESUMEN
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.
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Analgésicos Opioides , Dolor Crónico , Trastornos de Deglución/complicaciones , Oxicodona , Manejo del Dolor/métodos , Administración Oral , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapéutico , Dolor Crónico/complicaciones , Dolor Crónico/tratamiento farmacológico , Ensayos Clínicos como Asunto , Humanos , Oxicodona/administración & dosificación , Oxicodona/efectos adversos , Oxicodona/farmacocinética , Oxicodona/uso terapéuticoRESUMEN
Opioid analgesics are commonly used for the treatment of chronic low back pain (CLBP); however, abuse potential is a major concern. This study used a randomized, double-blind, placebo-controlled, enriched-enrollment randomized-withdrawal study design to evaluate the safety, tolerability, and analgesic efficacy of an abuse-deterrent formulation of extended-release oxycodone, Xtampza ER, in opioid-naive and opioid-experienced adults with moderate-to-severe CLBP. Patients entered an open-label titration phase (N = 740); those who were successfully titrated on Xtampza ER (≥40 to ≤160 mg oxycodone hydrochloride equivalent per day) were randomized to active drug (N = 193) or placebo (N = 196) for 12 weeks. Primary efficacy results showed a statistically significant difference in average pain intensity from randomization baseline to treatment week 12 between the Xtampza ER and placebo groups (mean [±SE], -1.56 [0.267]; P < 0.0001). All sensitivity analyses results supported the primary result of the study. Secondary efficacy outcomes indicated that Xtampza ER vs placebo had more patients with improvement in patient global impression of change (26.4% vs 14.3%; P < 0.0001), longer time-to-exit from the study (58 vs 35 days; P = 0.0102), and a greater proportion of patients with ≥30% (49.2% vs 33.2%; P = 0.0013) and ≥50% (38.3% vs 24.5%; P = 0.0032) improvement in pain intensity. There was less rescue medication (acetaminophen) use in the Xtampza ER treatment group than in the placebo group. Xtampza ER had an adverse event profile consistent with other opioids and was well tolerated; no new safety concerns were identified. In conclusion, Xtampza ER resulted in clinically and statistically significant efficacy in patients with CLBP.
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Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Oxicodona/uso terapéutico , Adulto , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Controlled release delivery of carmustine from biodegradable polymer wafers was approved as an adjunct to surgical resection in the treatment of recurrent glioblastoma multiforme after it was shown in clinical trials to be well tolerated and effective. Given the localised nature of the drug in the brain tissue, no direct pharmacokinetic measurements have been made in humans after implantation of a carmustine wafer. However, drug distribution and clearance have been extensively studied in both rodent and non-human primate brains at various times after implantation. In addition, studies to characterise the degradation of the polymer matrix, the release kinetics of carmustine and the metabolic fate of the drug and polymer degradation products have been conducted both in vitro and in vivo. GLIADEL wafers have been shown to release carmustine in vivo over a period of approximately 5 days; when in continuous contact with interstitial fluid, wafers should degrade completely over a period of 6 to 8 weeks. Metabolic elimination studies of the polymer degradation products have demonstrated that sebacic acid monomers are excreted from the body in the form of expired CO(2), whereas 1,3-bis-(p-carboxyphenoxy)propane monomers are excreted primarily through the urine. Carmustine degradation products are also excreted primarily through the urine. Pharmacokinetic studies in animals and associated modelling have demonstrated the capability of this modality to produce high dose-delivery (millimolar concentrations) within millimetres of the polymer implant, with a limited penetration distance of carmustine from the site of delivery. The limited spread of drug is presumably due to the high transcapillary permeability of this lipophilic molecule. However, the presence of significant convective flows due to postsurgical oedema may augment the diffusive transport of drug in the hours immediately after wafer implantation, leading to a larger short-term spread of drug. Additionally, in non-human primates, the presence of significant doses in more distant regions of the brain (centimetres away from the implant) has been shown to persist over the course of a week. The drug in this region was presumed to be transported from the implant site by either cerebral blood flow or cerebrospinal fluid flow, suggesting that although drug is able to penetrate the blood-brain barrier at the site of delivery, it may re-enter within the confines of the brain tissue.
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Antineoplásicos Alquilantes/farmacocinética , Neoplasias Encefálicas/metabolismo , Carmustina/farmacocinética , Simulación por Computador , Glioma/metabolismo , Animales , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/metabolismo , Carmustina/uso terapéutico , Implantes de Medicamentos , Glioma/tratamiento farmacológico , Semivida , Humanos , Modelos Biológicos , Compuestos de Nitrosourea/farmacología , Ratas , Distribución TisularRESUMEN
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.
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Analgésicos Opioides/farmacocinética , Masticación , Trastornos Relacionados con Opioides/prevención & control , Oxicodona/farmacocinética , Administración Oral , Adolescente , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/sangre , Analgésicos Opioides/química , Disponibilidad Biológica , Química Farmacéutica , Estudios Cruzados , Preparaciones de Acción Retardada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxicodona/administración & dosificación , Oxicodona/sangre , Oxicodona/química , Tamaño de la Partícula , Solubilidad , Comprimidos , Adulto JovenRESUMEN
Low water solubility and rapid elimination from the brain inhibits local delivery via implants and other delivery systems of most therapeutic drugs to the brain. We have conjugated the chemotherapy drug, camptothecin (CPT), to poly(ethylene glycol) (PEG) of molecular weight 3400 using previously established protocols. These new conjugates are very water-soluble and hydrolyze at a pH-dependent rate to release the active parent drug. We have studied the uptake of these conjugates by cells in vitro and quantified their cytotoxicity toward gliosarcoma cells. These conjugates were loaded into biodegradable polymeric controlled-release implants, and their release characteristics were studied in vitro. We implanted similar polymeric disks into rat brains and used a novel sectioning scheme to determine the concentration profile of CPT in comparison to conjugated CPT in the brain after 1, 7, 14, and 28 days. We have found that PEGylation greatly increases the maximum achievable drug concentration and greatly enhances the distribution properties of CPT, compared to corelease of CPT with PEG. Although only one percent of CPT in the conjugate system was found in the hydrolyzed, active form, drug concentrations were still significantly above cytotoxic levels over a greater distance for the conjugate system. On the basis of these results, we believe that PEGylation shows great promise toward increasing drug distribution after direct, local delivery in the brain for enhanced efficacy in drug treatment.