Clinical review of a long-acting, injectable formulation of risperidone

doi:10.1016/j.clinthera.2004.12.009

Clinical Therapeutics

Volume 26, Issue 12, December 2004, Pages 1994-2002

https://doi.org/10.1016/j.clinthera.2004.12.009 Get rights and content

Abstract

Background:

A long-acting, injectable risperidone formulation is the first depot atypical antipsychotic drug to become available in the United States.

Objective:

The intent of this article is to review the efficacy and safety data available for long-acting, injectable risperidone.

Methods:

Information was identified via MEDLINE (years, 1990–May 2004) using the terms risperidone, long-acting injectable, depot, and delayed-action preparations. The manufacturer also provided information about risperidone in the form of abstracts and summaries of professional meetings.

Results:

Several 12-week studies and one 12-month study suggest that long-acting risperidone is an effective and well-tolerated treatment option for the maintenance therapy of schizophrenia. Thus far, no unexpected adverse events have been reported with the long-acting formulation. Extrapyramidal symptoms with long-acting risperidone were uncommon, dose-related, and similar to those observed with oral risperidone in short-term trials. A small, dose related weight gain occurred with long acting risperidone, again similar to that seen with oral risperidone. Pain at the injection site was uncommon and decreased with continued administration. The long-acting, injectable formulation comes in an aqueous suspension of microspheres. There is no initial drug release after injection; the main release of risperidone begins at week 2 to 3 postinjection, increases during weeks 3 and 4, is maintained during weeks 4 through 6, and declines between weeks 6 and 7. With repeated injections every 2 weeks, steady-state levels are usually reached by weeks 6 to 8. For most patients, the initial dosage should be 25 mg every 2 weeks, and oral administration should continue for the first 3 weeks after initial injection. Doses can be increased every 8 weeks to a maximum of 50 mg every 2 weeks.

Conclusion:

Long-acting risperidone offers clinicians a combination of the benefits of a depot antipsychotic drug with the therapeutic advantages of an atypical antipsychotic drug.

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The authors concluded that based on patient's history and the dosing timeline of the medications, it was proposed that the interaction between clozapine and residual risperidone, was the reason for development of the acute buccal dystonia. The steady state plasma concentration of risperidone long acting injection (LAI) can be maintained as long as 5 weeks from the last injection [25A]. It is likely that the risperidone concentration remained at sufficient amount that when clozapine was titrated, the otherwise minimal D2 antagonism of clozapine, led to development of EPS.
Antipsychotic medications are used to treat schizophrenia and other psychiatric disorders. First generation antipsychotics (FGA) are older class of drugs compared to the second-generation antipsychotics (SGA). Currently, SGA are more frequently prescribed, because of their high efficacy and fewer side effects. Extrapyramidal symptoms, neuroleptic malignant syndrome, and hyperprolactinemia are the major adverse effects associated with the FGAs. However, type 2 diabetes and metabolic adverse effects (AEs) such as dyslipidemia are more common with the SGAs. This chapter focuses on drug interactions of antipsychotics (APs) and case reports describing AEs published from January–December 2019. The APs that will be discussed in this chapter include: chlorpromazine, haloperidol, olanzapine, quetiapine, risperidone, and clozapine.
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Bioresorbable polymer microparticles are widely used to provide long-lasting drug delivery in several chronic diseases. Having fine control over the physical properties of such microparticles can improve product reproducibility, performance and process efficiency. By using an ink-jet based droplet generator device, a new approach to microparticle manufacture was explored that uses an extremely rapid phase-separation to produce highly uniform, injectable microparticles from PLGA and a PLA/PLGA blend. To demonstrate the possible pharmaceutical applicability of the microparticle printing technique, the approved peptides ciclosporin A and octreotide were formulated, producing low-density microparticles that showed between sustained release over several months. The facile scale-up of the technique was demonstrated by using an array of 256 ink-jet nozzles, allowing over 1 million discrete particles per second to be produced. The new apparatus and methods described herein could be used across a wide range of biomaterials and therapeutic compounds.
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Due to the lack of bioequivalence and low bioavailability for oral administration (Van Os et al., 2007), long-acting injectable risperidone microsphere (D’souza et al., 2013) was developed as an alternative formulation. However, it was reported that the marketed microsphere dosage form exhibited a delayed response profile and drug begun to release after 3 weeks (Knox and Stimmel, 2004). It resulted in a fact that patients had to take oral risperidone agents to stabilize the plasma level of drug during the latency.
A drug-cyclodextrin complex in liposome system was prepared in order to make a comparison with conventional risperidone-loaded liposome. Thin film hydration, reverse phase evaporation and ethanol injection methods were taken as preparation means to obtain the two types of liposome. Differential thermal analysis (DTA) and transmission electron microscopy (TEM) were used to investigate the thermal characters of inclusion complexes and morphology of liposome, respectively. Particle size, zeta potential and encapsulation efficiency were studied by light scattering analysis and ultrafiltration. In vitro release was carried out in the pH 7.4 phosphate buffer solution and samples were collected at the certain time. As a result, drug-cyclodextrin complex in liposome prepared by various methods displayed lower encapsulation efficiency than conventional liposome. However, size was larger and its stability was better than the latter. The second release phase of novel delivery system was slightly slower after initial burst release at the first phase, while the conventional liposome displayed a more regular trait. Thus, the novel liposome have potential to be developed as co-administration formulation with long-acting injection.
Design of a Drug-in-Adhesive Transdermal Patch for Risperidone: Effect of Drug-Additive Interactions on the Crystallization Inhibition and In Vitro/In Vivo Correlation Study
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To overcome the issues mentioned previously, long-acting intramuscular injection has been developed and approved for clinical use. However, many reports about the commercial injection mentioned that it showed a delay in drug release for about 3-4 weeks after the first injection.7,8 Consequently, coadministration with oral RISP was needed for at least 4 weeks at the beginning.
The purpose of this work was to develop and design an appropriate drug-in-adhesive patch for transdermal delivery of risperidone (RISP). Various formulation factors were investigated by in vitro permeation study using excised rabbit skin. Increasing the drug concentration in the pressure sensitive adhesive (PSA) was used to enhance the drug permeation. To overcome the high crystallization tendency of the patch, several crystallization inhibitors such as PVP, PEG, and surfactants and fatty acids were evaluated by microscopy study. The mechanism of crystallization inhibition was investigated by differential scanning calorimetry, nuclear magnetic resonance spectrometer, and FT-IR studies. RISP and its active metabolite were determined after topical application of the optimized transdermal patch, and the in vivo pharmacokinetic parameters were compared with the intravenous administration group. The microscopy study indicated that fatty acid greatly inhibited the crystallization of RISP in PSA. The inhibition was attributed to the drug-additive interaction between amino group of RISP and the carboxyl group of fatty acid which was further confirmed by ¹H-NMR and FT-IR studies. The optimal permeation profile was obtained with the patches containing 5% RISP and 5% oleic acid in Duro-Tak^® 87-2287. The in vivo pharmacokinetic study exhibited a sustained absorption and metabolism profile and well correlated with the in vitro permeation data.
Sustained release of risperidone from biodegradable microspheres prepared by in-situ suspension-evaporation process
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A commercial product of risperidone-loaded microspheres is an intramuscular injection administered once every two weeks, marketed as Risperdal Consta™ by Johnson & Johnson Corp., USA. The release of Risperdal Consta™ shows a sigmoidal profile, exhibiting a slight initial burst (≤3.5%) followed by a lag period of approximate three weeks and then a two-week period of fast release (Eerdekens et al., 2004; Knox and Stimmel, 2004). Risperdal Consta™ is formulated by solvent-extraction method, which is very complex and time-consuming processes composing of microsphere formation, solidification process, intermediate drying process, ethanol washing process, and complete final drying process to render an initial lag phase and a substantially sigmoidal release profile (Johnson & Johnson Pharmaceutical research & development, 2011; Lyons et al., 2002; Ramstack et al., 2003).
Risperidone-loaded poly (d,l-lactide-co-glycolide) (PLGA) microspheres were prepared with a suspension-evaporation process with an aqueous suspension containing an in situ-formed aluminum hydroxide inorganic gel (SEP-AL process) and evaluated for encapsulation efficiency, particle size, surface morphology, glass transition temperature, in vitro drug release profile, and in vivo behavior. The SEP-AL microspheres were compared with conventional oil-in-water (O/W) emulsion solvent evaporation method using polyvinylalcohol (PVA) as an emulsifier (CP-PVA process). The microspheres were spherical in shape. DSC measurements showed that risperidone crystallinity was greatly reduced due to the homogeneous distribution of risperidone in PLGA microspheres. In vitro drug release profile from the microspheres showed a sigmoidal pattern of negligible initial burst up to 24 h and minimal release (time-lag) for 7 days. After the lag phase, slow release took a place up to 25 days and then rapid release occurred sharply for 1 week. In vivo rat pharmacokinetic profile from the microspheres showed very low blood concentration level at the initial phase (up to 24 h) followed by the latent phase up to 21 days. At the 3rd week, main phase started and the blood concentration of the drug increased up to the 5th week, and then gradually decreased. The risperidone-loaded PLGA microspheres produced by SEP-AL process showed excellent controlled release characteristics for the effective treatment of schizophrenia patients.
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Also some of the very rare side effects listed in risperadone pamphlet included dysphagia and muscle weakness which may raise the possibility of unmasking undiagnosed MG in such cases among other explanations [14]. Another point is the possible drug interaction between risperidone and other drugs used in treatment of MG as its co-administration with other drugs has not been systematically evaluated in human subjects as written in the drug's pamphlet [14,17]. A search of MEDLINE and EMBASE using PubMed, EBSCOhost and Ovid search engines for relevant articles using the following search terms: myasthenia gravis, risperidone, schizophrenia and antipsychotic drugs did not reveal any previous case reports of myasthenia gravis worsening with risperidone.
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New drugClinical review of a long-acting, injectable formulation of risperidone

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Eur Neuropsychopharmacol

Lancet

Overview of partial compliance

J Clin Psychiatry

Depot neuroleptic therapy: An underutilized option

J Clin Psychiatry

Comparison of the effects of different routes of antipsychotic administration on pharmacokinetics and pharmacodynamics

J Clin Psychiatry

Risperidone

Pharmacotherapy

Risperidone in the treatment of schizophrenia

Am J Psychiatry

Pharmacokinetics of clozapine and risperidone: A review of recent literature

J Clin Psychopharmacol

Relapse and rehospitalization: Comparing oral and depot antipsychotics

J Clin Psychiatry

A randomized clinical trial of haloperidol decanoate and fluphenazine decanoate in the outpatient treatment of schizophrenia

J Clin Psychopharmacol

A survey of the attitudes of chronic psychiatric patients living in the community toward their medication

Acta Psychiatr Scand

Oral versus depot administration of neuroleptics in relapse prevention

Acta Psychiatr Scand Suppl

A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia

N Engl J Med

New drug
Clinical review of a long-acting, injectable formulation of risperidone