Search Results (5)

Background: TV-46000 (Uzedy, Teva), a long-acting subcutaneous antipsychotic, is an injectable formulation of risperidone and is approved by the FDA for the treatment of schizophrenia in adults. Its innovative copolymer-based drug delivery depot technology (licensed from MedinCell, Jacou, France) allows for plasma concentrations of the total active moiety of risperidone (TAM) to reach clinically relevant levels within 6–24 h and the maintenance of these therapeutic levels with monthly and bimonthly dosing regimens. Objective: As part of the development program for TV-46000, the effect of extrinsic factors of manipulation on the site of injection, and on the pharmacokinetic (PK) profile of TAM following TV-46000 administration was evaluated. Methods: Studies were conducted assessing the effect of heat and rubbing with male Gottingen minipigs and the effect of rubbing with male beagle dogs. A pilot clinical study in healthy volunteers was performed to evaluate the effect of rubbing. Results: These investigations showed that heating or rubbing of the TV-46000 sc injection site immediately post-injection had no clinically meaningful impact on safety and no burst or uncontrolled release was evident. Furthermore, no impact of injection site manipulation on TAM exposure was observed after depot formation (≥0.5 h post-injection). Conclusions: The observed similarity in findings between the animal and human studies supports the suitability of animal models for evaluation of the effect of extrinsic factors on injection sites and its translatability to clinical settings. Full article

In recent years, stimulus-sensitive drug delivery systems have been developed for parenteral administration as a depot system. In situ systems incorporate smart polymers that undergo a phase transition at the site of administration. All parenteral and ocular dosage forms must meet sterility requirements. Careful selection of the sterilization method is required for any type of stimuli-sensitive system. Current sterilization methods are capable of altering the conformation of polymers or APIs to a certain extent, ultimately causing the loss of pharmacological and technological properties of the drug. Unfortunately, the issues of risk assessment and resolution regarding the sterilization of stimuli-sensitive systems, along with ways to stabilize such compositions, are insufficiently described in the scientific literature to date. This review provides recommendations and approaches, formulated on the basis of published experimental data, that allow the effective management of risks arising during the development of in situ systems requiring sterility. Full article

In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months. Full article

Developing prolonged antigen delivery systems that mimic long-term exposure to pathogens appears as a promising but still poorly explored approach to reach durable immunities. In this study, we have used a simple technology by which His-tagged proteins can be assembled, assisted by divalent cations, as supramolecular complexes with progressive complexity, namely protein-only nanoparticles and microparticles. Microparticles produced out of nanoparticles are biomimetics of secretory granules from the mammalian hormonal system. Upon subcutaneous administration, they slowly disintegrate, acting as an endocrine-like secretory system and rendering the building block nanoparticles progressively bioavailable. The performance of such materials, previously validated for drug delivery in oncology, has been tested here regarding the potential for time-prolonged antigen release. This has been completed by taking, as a building block, a nanostructured version of p30, a main structural immunogen from the African swine fever virus (ASFV). By challenging the system in both mice and pigs, we have observed unusually potent pro-inflammatory activity in porcine macrophages, and long-lasting humoral and cellular responses in vivo, which might overcome the need for an adjuvant. The robustness of both innate and adaptive responses tag, for the first time, these dynamic depot materials as a novel and valuable instrument with transversal applicability in immune stimulation and vaccinology. Full article

This article describes the utilization of (methoxy)poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) ((m)PEG–PTMC) diblock and triblock copolymers for the formulation of in situ forming depot long-acting injectables by solvent exchange. The results shown in this manuscript demonstrate that it is possible to achieve long-term drug deliveries from suspension formulations prepared with these copolymers, with release durations up to several months in vitro. The utilization of copolymers with different PEG and PTMC molecular weights affords to modulate the release profile and duration. A pharmacokinetic study in rats with meloxicam confirmed the feasibility of achieving at least 28 days of sustained delivery by using this technology while showing good local tolerability in the subcutaneous environment. The characterization of the depots at the end of the in vivo study suggests that the rapid phase exchange upon administration and the surface erosion of the resulting depots are driving the delivery kinetics from suspension formulations. Due to the widely accepted utilization of meloxicam as an analgesic drug for animal care, the results shown in this article are of special interest for the development of veterinary products aiming at a very long-term sustained delivery of this therapeutic molecule. Full article