An injection depot formulation of buprenorphine: extended bio-delivery and effects

AIM: Buprenorphine is an effective medication for treatment of opioid dependence. An injectable depot formulation of buprenorphine has been developed using biodegradable polymer microcapsule technology. This formulation may offer effective treatment of opioid dependence and enhance treatment delivery while minimizing risks of patient non-adherence or illicit diversion of the medication. This report provides a characterization of the bio-delivery of this injectable depot in humans and of the relationship of drug blood levels to pharmacodynamic indices. METHOD AND PARTICIPANTS: The data are from two studies in which 11 opioid-dependent volunteers each received a single depot injection containing 58 mg of buprenorphine, and include previously unreported detailed plasma concentration data over a 6-week time-course following depot administration and examination of their relationship to pharmacodynamic indices. FINDINGS: Mean plasma buprenorphine increased gradually following depot administration, peaked at 2-3 days with a mean concentration of 1.25 ng/ml and then decreased gradually, approaching undetectable levels (< 0.10 ng/mL) by 6 weeks. There was substantial between-subject consistency in several aspects of buprenorphine bio-delivery, including time to first detectable blood level (4 hours), peak blood level (2 days) and undetectable blood level (6-6.5 weeks). In contrast, there was marked between-subject variability in the magnitude of peak buprenorphine concentrations, ranging from 0.17 to 3.47 ng/ml. Extent of opioid blockade was tested by weekly opioid challenges with 3 mg subcutaneous hydromorphone; subjective response and pupillary constriction were related inversely to both buprenorphine and norbuprenorphine plasma concentrations (r=0.84-0.95). CONCLUSION: The data document that this depot formulation provides effective buprenorphine delivery for several weeks and that effects persist even at fairly low buprenorphine plasma concentrations. Suggestions are offered for further research needed to develop this formulation for clinical use as a detoxification and/or maintenance pharmacotherapy for opioid dependence.     

Best practice guidelines for the administration of intramuscular injections in the mental health setting

Intramuscular injections are administered to mental health consumers in both the community and hospital settings. Medications delivered by the intramuscular route assist consumers to live in the community and enhance their ability to integrate and engage in community life. Although the practice of giving intramuscular injections is routine for mental health nurses, the process is invasive and best practice guidelines are not well developed. The aim of this study was to identify a best practice technique for the administration of intramuscular injections in the mental health setting based on: (i) the identification of 300 abstracts and a systematic review of 150 articles in the subject area; (ii) an evaluation of current practice of 93 nurses; and (iii) the use of the newly developed technique with 96 consumers. The findings add significantly to the knowledge base on administering intramuscular injections in the mental health setting. The identified best practice technique provides mental health nurses with evidence-based guidelines, thus ensuring that the medication administered by intramuscular injection provides the best possible outcomes for consumers.     

Switching long acting antipsychotic medications to aripiprazole long acting once-a-month: expert consensus by a panel of Italian and Spanish psychiatrists

ABSTRACT

Introduction: Aripiprazole long acting once-monthly (AOM) is a long acting atypical antipsychotic with proven efficacy in schizophrenia and with a pharmacological and a side effect profile that is different from other antipsychotics. These and other characteristics make AOM a possible alternative in patients requiring a change in long acting antipsychotic treatment due to issues such as lack of efficacy or persistent side effects. Both clinical and pharmacological factors should be considered when switching antipsychotics, and specific guidelines for long acting antipsychotic switching that address all these factors are needed.

Areas covered: A panel of Italian and Spanish experts in psychiatry met to discuss the strategies for the switch to AOM in patients with schizophrenia. Real life clinical experiences were shared and the clinical strategies to improve the likelihood of success were discussed.

Expert Opinion: Due to its specific pharmacological and tolerability profile, AOM represents a suitable alternative for patients with schizophrenia requiring a switch to a new LAI treatment because of lack of efficacy or persistent side effects from another LAI. Possible strategies for the switch to AOM are presented in this expert consensus paper in an attempt to provide guidance throughout the entire switching process     

Sustained Release of Human Growth Hormone from PLGA Solution Depots

Purpose. The effects of altering the dynamics of phase inversion of a polylactic glycolic acid (PLGA) solution depot on the sustained-release delivery profile of human growth hormone (hGH) were evaluated. The impact of adjusting the protein particle composition was also studied in a slow phase-inverting formulation. Methods. Protein release profiles of depots prepared from four model solvents were generated by injecting formulations into the subcutaneous space of normal rats and monitoring hGH serum levels over the course of 1 month. Scanning electron microscopy, Coulometric Karl Fischer titration, size-exclusion liquid chromatography, and reversed-phase liquid chromatography were used to observe depot morphologies, bulk water absorption, PLGA degradation, and protein particle dissolution rates, respectively. Results. An extended-release profile and significantly reduced burst effect resulted when the aqueous affinity of the depot solvent was reduced. As seen earlier in in vitro experiments, lowering the solvent's aqueous affinity slows the phase inversion rate, which in turn produces depot morphologies favorable to prolonged release. Protein burst on injection was entirely eliminated in a slow phase-inverting formulation by densifying the lyophilized protein particles. Unlike the use of metal cations to prolong release of some proteins in PLGA microsphere depots, this technique is more universal, and thus is potentially usable with any protein or highly soluble drug agent. The onset of biodegradation was observed to occur at 14 days for all depot formulations, however the bulk biodegradation rate slowed as the aqueous affinity of the depot solvent decreased. This result supports the hypothesis that, in a slow phase-inverting system, drug release over the first few weeks is governed by the diffusion rate of drug through the polymer solution. Conclusions. By taking advantage of the effects of low aqueous affinity and protein particle densification, a PLGA solution depot was produced with the capability of sustaining hGH levels in normal rats at a serum level of 10 to 200 ng/ml for 28 days.     

Hematopoietic Stem Cell Antigen-1 (Sca-1) Expression in Different Lymphoid Tissues of Female Mice Treated With GnRH Agonist

PROBLEM : Our earlier studies have demonstrated a general suppression of leukocyte maturation upon GnRH agonist treatment in mice and suggested a potential effect at an early stem cell stage of leukocyte development. METHOD : Three-week old Balb/c and C57BL/6 female mice received 50 μlg injections of Lupron depot or placebo. Sequential changes in Sca-1⁺ cells in the bone marrow, thymus, blood and spleen were studied by flow cytometry. RESULTS : In bone marrow, the absolute numbers of Sca-1⁺ cells were significantly decreased at 2 weeks in C57BL/6 mice whereas a decreasing trend was noted in Balb/c mice following agonist administration. Concomitantly, thymocytes expressing Sca-1⁺ cells were significantly increased at 2 weeks in C57BL/6 mice, but were significantly decreased in Balb/c mice. Significant decreases in Sca-1⁺ cells were also observed in spleen and blood in Balb/c mice whereas no significant differences were observed in C57BL/6 mice. CONCLUSIONS : These data suggest GnRH agonists affect hematopoietic stem cell development in mice. The effects observed vary with different genetic backgrounds. In Balb/c mice these effects are more pronounced, and appear to result in the inhibition of stem cell maturation. In contrast, GnRH agonist enhances stem cell maturation in C57BL/6 mice.     

Supramolecular approaches for insulin stabilization without prolonged duration of action

Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics. The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol(CB[7]-PEG) has been shown to stabilize insulin formulations by reducing aggregation propensity. Yet prolonged in vivo duration of action, arising from sustained complex formation in the subcutaneous depot, limits the application scope for meal-time insulin uses and could increase hypogly...     

GnRH Agonist Induces Suppression of Lymphocyte Subpopulations in Secondary Lymphoid Tissues of Prepubertal Female Mice

PROBLEM: Gonadotropin-releasing hormone (GnRH) agonists are playing an increasing role in the medical management of a variety of diseases. Recent evidence also indicates GnRH immune system interactions. METHOD: The present study investigated the sequential changes in lymphocyte subpopulations in secondary lymphoid tissues of prepubertal female mice in vivo following Lupron depot administration. A direct two-color immunofluorescence staining followed by flow cytometric analysis was employed. RESULTS: Following agonist administration, white blood cell counts decreased significantly with decreases in both granulocyte and lymphocyte counts. Blood T-cell and B-cell subsets were also reduced although B cells decreased more markedly. In the spleen, B cells were again reduced more than T cells. There was no selective loss of either CD4 or CD8 subpopulations at any time point, in both spleen and blood. There were no differences in the percentage of lymph node subsets except that B cells decreased in the second week. CONCLUSION: These data indicate that GnRH agonist alters specific lymphocyte subpopulations and, therefore, have the potential for affecting immune system function in vivo.     

Depo-Provera: use of a long-acting progestin injectable contraceptive in Turkish women

OBJECTIVE: To assess the demographic and clinical characteristics and experience of Turkish women treated with depot medroxyprogesterone acetate (DMPA). STUDY DESIGN: This prospective clinical study was carried on 9262 subjects, treated with DMPA at Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey, between 1996 and 2004. RESULTS: The mean age of study population was 28.4+/-4.6 years; 1759 (19%) subjects were breast-feeding at the time of the first injection. Eight (0.08%) pregnancies occurred, within 3 months of injection in 9262 women. Of 9262 cases, irregular bleeding occurred in 80% (7410) of the women. Discontinuation rate with this contraceptive method was recorded as 71% (6576) of the subjects. The rate of other predominant side effects was observed as follows: 8% for increase in weight, 8% for breast engorgement, 7% for mastalgia, 5% for headache. CONCLUSION: The results of this study suggest that DMPA may be an attractive contraceptive choice for both the patient and the physician in some clinical situations, especially in women at risk for complications with oral hormonal contraceptives and women who have had low compliance with other contraceptive methods. Moreover, DMPA contraception might be particularly appropriate in some cases such as in the postpartum period and in lactating women.