Microneedles: A New Frontier in Nanomedicine Delivery

This review aims to concisely chart the development of two individual research fields, namely nanomedicines, with specific emphasis on nanoparticles (NP) and microparticles (MP), and microneedle (MN) technologies, which have, in the recent past, been exploited in combinatorial approaches for the efficient delivery of a variety of medicinal agents across the skin. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and as such will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for particles and MN. Firstly, the fundamental aspects of skin architecture and structure are outlined, with particular reference to their influence on NP and MP penetration. Following on from this, a variety of different particles are described, as are the diverse range of MN modalities currently under development. The review concludes by highlighting some of the novel delivery systems which have been described in the literature exploiting these two approaches and directs the reader towards emerging uses for nanomedicines in combination with MN

Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.</jats:sec

Pharmacokinetics, safety, and tolerability of four 28-day cycle intramuscular injections for risperidone-ISM 75 mg in patients with schizophrenia: A phase-2 randomized study (PRISMA-2)

IntroductionRisperidone-ISM is a new long acting intramuscular formulation of risperidone, for monthly administration without oral supplementation.ObjectiveTo characterize the pharmacokinetic of risperidone over multiple intramuscular injections in patients with schizophrenia.MethodA multicenter, open label, two-arm, parallel design clinical trial was performed. Each patient received 4 intramuscular injections of 75 mg of risperidone-ISM in either, gluteal or deltoid muscle at 28-day intervals.ResultsA total of 70 patients were randomized, 67 received at least one dose of study medication. Preliminary data show that mean Cmax of the active moiety was achieved 24-48 hours (Tmax) after each administration and ranged over four consecutive doses from 39.6-53.2 ng/mL and 54.1-61 ng/mL, when given in gluteal or deltoid, respectively. All subjects achieved therapeutic levels (&gt; 7.5 ng/mL for the active moiety) between 2-8 hours after drug administration. The mean concentrations were maintained above therapeutic levels throughout the 4-week dosing period. No significance changes across the study were observed, either on Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 subjects (94%) experienced at least 1 Treatment Emergent Adverse Event (TEAE) during the study. One serious TEAE (dystonia) was related to study treatment. One death not related to study medication was informed. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%).ConclusionsRisperidone-ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-weeks dosing period over multiple intramuscular injections independently of the injection site. Risperidone-ISM was found to be safe and well tolerated.Disclosure of interestThe authors have not supplied their declaration of competing interest.</jats:sec

Bioequivalence of a biosimilar enoxaparin sodium to Clexane&reg; after single 100 mg subcutaneous dose: results of a randomized, double-blind, crossover study in healthy volunteers

Javier Mart&iacute;nez Gonz&aacute;lez, Mayte Monreal, Ignacio Ayani Almagia, Jordi Llaud&oacute; Gar&iacute;n, Lourdes Ochoa D&iacute;az de Monasterioguren, Ib&oacute;n Gutierro Ad&uacute;riz R&amp;D Department, Laboratorios Farmac&eacute;uticos Rovi S.A., Madrid, Spain Purpose: To demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence of a biosimilar enoxaparin to the reference drug, and to assess its safety and tolerability in healthy volunteers. Patients and methods: A randomized, double-blind, crossover, 2-sequence, single-dose study was conducted in healthy volunteers of both sexes. Participants were sequentially and randomly administered single subcutaneous injections of enoxaparin 100 mg manufactured by Rovi (test; Madrid, Spain) and Clexane&reg; (enoxaparin 100 mg manufactured by Sanofi, reference) separated by a 1-week washout period. The primary PK/PD variables were maximum activity (Amax) and area under the effect curve from time 0 to the last measured activity (T) (AUEC0&ndash;T) and AUEC from time 0 to infinity (AUEC0&ndash;inf) of anti-FXa activity, and Amax and AUEC0&ndash;T of anti-FIIa activity. Secondary variables were Amax and AUEC0&ndash;T, AUEC0&ndash;inf of tissue factor pathway inhibitor, and the ratio of AUEC0&ndash;T anti-FXa to anti-FIIa activity. Biosimilarity would be shown when the 95% CI of the ratio of geometric least squares means (95% CI RGLSMs) of primary PK/PD parameters fell within the standard range of bioequivalence, ie, 80%&ndash;125%.Results: The study sample consisted of 46 volunteers (33 males) aged 18&ndash;44 years and with body mass index ranging from 19.0 to 31.1 kg/m2. Three subjects did not complete the study. The curves of anti-FXa, anti-FIIa and tissue factor pathway inhibitor activities corresponding to administration of the test and reference products were comparable. The 95% CI RGLSMs of Amax, AUEC0&ndash;T and AUEC0&ndash;inf for anti-FXa activity were 94.6%&ndash;105.9%, 99.8%&ndash;108.0% and 100.0%&ndash;108.6% respectively; Amax and AUEC0&ndash;T for anti-FIIa activity were 94.7%&ndash;112.6% and 90.9%&ndash;117.9% respectively. In addition, the 95% CI RGLSMs of all secondary variables fell within the range 80%&ndash;125%. The incidence and types of adverse events after administration of the test and reference drugs were similar. Conclusion: The results conclusively showed that the enoxaparin manufactured by Rovi is equivalent to the reference enoxaparin in all primary and secondary PK/PD parameters, as required by the European Medicines Agency to grant marketing authorization to a biosimilar low molecular-weight heparin. Keywords: biosimilar, LMWH, pharmacodynamics, pharmacokinetics, anti-FXa, anti-FIIa, TFP