Dataset Information

Saquinavir Loaded Acetalated Dextran Microconfetti - a Long Acting Protease Inhibitor Injectable.

ABSTRACT: Since the adoption of highly active antiretroviral therapy, HIV disease progression has slowed across the world; however, patients are often required to take multiple medications daily of poorly bioavailable drugs via the oral route, leading to gastrointestinal irritation. Recently, long acting antiretroviral injectables that deliver drug for months at a time have moved into late phase clinical trials. Unfortunately, these solid phase crystal formulations have inherent drawbacks in potential dose dumping and a greater likelihood for burst release of drug compared to polymeric formulations.Using electrospinning, acetalated dextran scaffolds containing the protease inhibitor saquinavir were created. Grinding techniques were then used to process these scaffolds into injectables which are termed saquinavir microconfetti. Microconfetti was analyzed for in vitro and in vivo release kinetics.Highly saquinavir loaded acetalated dextran electrospun fibers were able to be formed and processed into saquinavir microconfetti while other polymers such as poly lactic-co-glycolic acid and polycaprolactone were unable to do so. Saquinavir microconfetti release kinetics were able to be tuned via drug loading and polymer degradation rates. In vivo, a single subcutaneous injection of saquinavir microconfetti released drug for greater than a week with large tissue retention.Microconfetti is a uniquely tunable long acting injectable that would reduce the formation of adherence related HIV resistance. Our findings suggest that the injectable microconfetti delivery system could be used for long acting controlled release of saquinavir and other hydrophobic small molecule drugs.

SUBMITTER: Collier MA

PROVIDER: S-EPMC5776024 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Saquinavir Loaded Acetalated Dextran Microconfetti - a Long Acting Protease Inhibitor Injectable.

Collier Michael A MA Gallovic Matthew D MD Bachelder Eric M EM Sykes Craig D CD Kashuba Angela A Ainslie Kristy M KM

Pharmaceutical research 20160506 8

<h4>Purpose</h4>Since the adoption of highly active antiretroviral therapy, HIV disease progression has slowed across the world; however, patients are often required to take multiple medications daily of poorly bioavailable drugs via the oral route, leading to gastrointestinal irritation. Recently, long acting antiretroviral injectables that deliver drug for months at a time have moved into late phase clinical trials. Unfortunately, these solid phase crystal formulations have inherent drawbacks ...[more]

PMID: 27154460

Similar Datasets

Project description:Medication non-adherence in patients with schizophrenia continues to be a significant problem and threatens successful treatment outcomes. Medication non-adherence is often associated with negative consequences, including symptom exacerbation, more frequent emergency room visits, re-hospitalizations and relapse. Long-acting injectable (LAI) forms of antipsychotics allow for rapid identification of non-adherence, obviate the need for the patient to take the medication on a daily basis and increase adherence to some significant degree. Eli Lilly has developed a long-acting depot formulation of olanzapine, olanzapine pamoate, which has recently been approved by the FDA for the US market, and which will be reviewed here. Olanzapine LAI appears to be an effective antipsychotic at dosages of 210 mg every 2 weeks, 300 mg every 2 weeks and 405 mg every 4 weeks in patients with acute schizophrenia, and at 150 mg every 2 weeks, 300 mg every 2 weeks and at 405 mg every 4 weeks for the maintenance treatment of stable patients. Oral supplementation appears not to be needed, particularly not at the onset of treatment with the LAI as is necessary with risperidone LAI. Its efficacy is in general comparable to the efficacy seen with oral olanzapine at a corresponding dose. The side effect profile is also comparable to the side effects observed with oral olanzapine, including lower rates of extrapyramidal symptoms, prolactin elevation and cardiovascular side effects, but significant metabolic effects. The latter include significant weight gain, lipid abnormalities and glucose dysregulation. While the injection site adverse events are overall mild, the most significant serious adverse event is the post-injection delirium sedation syndrome (PDSS). While rare, this syndrome results from inadvertent intravascular injection of olanzapine LAI and can cause a range of olanzapine overdose-type of symptoms. Olanzapine LAI needs therefore to be administered by trained personnel in settings where a post-injection observation period for at least 3 hours by medical personnel is available. The overall use of olanzapine LAI will probably be limited by the possibility of a PDSS event. Patients who have a history of good response to oral olanzapine and are in need of assured medication administration may present a good indication for its use, provided that the appropriate mental health delivery setting is available.

Project description:This multisite randomized trial addressed risks and benefits of staying on long-acting injectable haloperidol or fluphenazine versus switching to long-acting injectable risperidone microspheres.From December 2004 through March 2008, adult outpatients with a Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition diagnosis of schizophrenia or schizoaffective disorder who were taking haloperidol decanoate (n = 40) or fluphenazine decanoate (n = 22) were randomly assigned to stay on current long-acting injectable medication or switch to risperidone microspheres and followed for 6 months under study protocol and an additional 6 months naturalistic follow-up. Kaplan-Meier and Cox regression analyses were used to examine the primary outcome (time to treatment discontinuation), and random regression models were used to examine secondary outcomes.Groups did not differ significantly in time to treatment discontinuation through 6 months of protocol-driven treatment. When the 6-month naturalistic follow-up period was included, time to treatment discontinuation was significantly shorter for individuals assigned to switch than for individuals assigned to stay (10% of stayers discontinued versus 31% of switchers; P = .01). Groups did not differ with respect to psychopathology, hospitalizations, sexual side effects, new-onset tardive dyskinesia, or new-onset extrapyramidal symptoms. However, those randomized to switch to long-acting injectable risperidone microspheres had greater increases in body mass (increase of 1.0 body mass index [BMI] versus decrease of -0.3 BMI; P = .00) and prolactin (maximum increase to 23.4 ng/mL versus decrease to 15.2 ng/mL, P = .01) compared to those randomized to stay.Switching from haloperidol decanoate or fluphenazine decanoate to risperidone microspheres resulted in more frequent treatment discontinuation as well as significant weight gain and increases in prolactin.ClinicalTrials.gov identifier: NCT00044655.

Project description:OBJECTIVE:To investigate subgroup responses to long-acting injectable (LAI) medications haloperidol decanoate (HD) and paliperidone palmitate (PP) in a randomized controlled trial that found no difference between the treatments on the primary outcome of efficacy failure. METHODS:A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS) enrolled 311 participants from March 2011 to July 2013 meeting DSM-IV-TR criteria for diagnoses of schizophrenia or schizoaffective disorder at risk of relapse due to medication nonadherence or substance abuse. Participants were randomly assigned to double-blinded treatment with HD or PP and followed for up to 2 years. A committee blinded to treatment assignment adjudicated efficacy failure on the basis of participants' meeting at least 1 of these criteria: psychiatric hospitalization, crisis stabilization, increased outpatient visits, could not discontinue oral antipsychotic, discontinued assigned LAI due to inadequate therapeutic benefit, or ongoing or repeated need for adjunctive oral antipsychotic medication. Survival analyses examined modification of treatment effects on efficacy failure by age, sex, race, substance abuse, baseline symptom severity, and baseline adherence. Mixed-effect linear models and analysis of covariance examined this modification on safety outcomes. RESULTS:An interaction between age and treatment (P = .009) revealed younger participants assigned HD had longer time to efficacy failure than those assigned PP. Interactions were not significant between treatment group and sex, race, substance use disorder, baseline symptom severity, or baseline adherence. An interaction of treatment and age on akathisia (P = .047) found an advantage for PP that was larger among younger persons. An advantage for HD on serum prolactin levels was larger among younger women (P = .033). CONCLUSIONS:Among younger persons, HD was associated with lower rates of efficacy failure than PP. Age effects on adverse effects were mixed. Age-related heterogeneity of antipsychotic treatment effects warrants further investigation and consideration in clinical practice. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01136772.

Dataset Information

Saquinavir Loaded Acetalated Dextran Microconfetti - a Long Acting Protease Inhibitor Injectable.

Publications

Saquinavir Loaded Acetalated Dextran Microconfetti - a Long Acting Protease Inhibitor Injectable.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure