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We have investigated the feasibility of administration of testosterone undecanoate （TU）-Ioaded injectable in situ-forming implant （ISFI） for contraception in adult male Sprague-Dawley rats. Male rats were treated with vehicle, TU-Ioaded ISFIs （540, 270 and 135 mg TU kg-1） or TU injections （45 mg TU kg-1 every 30 days） for 120 days. Fertility tests served for determining infertility or restoration of fertility in treated rats. Serum testosterone concentration, epididymal sperm count, motility, morphology, and histology of the testis were monitored. The TU-Ioaded ISFIs increased serum testosterone levels in rats steadily without fluctuation over 3 months. One month after TU administration, the epididymal sperm count decreased significantly in all experimental groups. After 3 months, the animals treated with 270 and 135 mg kg-~ TU-Ioaded ISFIs were 100% infertile, and no implantation sites were produced in the mated females. However, some of males treated with 540 mg kg-~ ISFI or TU injections were still fertile but numbers of implantation sites were also significantly lower than control values. TU-Ioaded ISFI at an appropriate dose has potential as a long-acting male contraceptive drug that suppresses spermatogenesis consistently over a period of 3 months.

In modern pharmaceutical technology, modified-release dosage forms, such as in situ formed implants, are gaining rapidly in popularity. These dosage forms are created based on a configurable matrix consisting of phase-sensitive polymers capable of biodegradation, a hydrophilic solvent, and the active substance suspended or dissolved in it. The most used phase-sensitive implants are based on a biocompatible and biodegradable polymer, poly(DL-lactide-co-glycolide) (PLGA). Objective: This systematic review examines the reasons for the phenomenon of active ingredient “burst” release, which is a major drawback of PLGA-based in situ formed implants, and the likely ways to correct this phenomenon to improve the quality of in situ formed implants with a poly(DL-lactide-co-glycolide) matrix. Data sources: Actual and relevant publications in PubMed and Google Scholar databases were studied. Study selection: The concept of the review was based on the theory developed during literature analysis of 12 effectors on burst release from in situ forming implants based on PLGA. Only those studies that sufficiently fully disclosed one or another component of the theory were included. Results: The analysis resulted in development of a systematic approach called the “12 Factor System”, which considers various constant and variable, endogenous and exogenous factors that can influence the nature of ‘burst release’ of active ingredients from PLGA polymer-based in situ formed implants. These factors include matrix porosity, polymer swelling, LA:GA ratio, PLGA end groups, polymer molecular weight, active ingredient structure, polymer concentration, polymer loading with active ingredients, polymer combination, use of co-solvents, addition of excipients, and change of dissolution conditions. This review also considered different types of kinetics of active ingredient release from in situ formed implants and the possibility of using the “burst release” phenomenon to modify the active ingredient release profile at the site of application of this dosage form.

Isosorbide-based aliphatic polyesters are a promising class of biodegradable polymers for biomedical applications, representing an attractive alternative to poly(α-hydroxy acids). Derived from the bio-based bicyclic diol, they combine structural rigidity, tunable hydrophilicity, and enhanced biocompatibility, making them suitable for drug delivery and sustainable medical devices. In this study, we developed novel in situ forming implant (ISFI) formulations composed of poly(isosorbide sebacate) (PISEB) and dimethyl isosorbide (DMI), and evaluated their applicability for local delivery of doxycycline hyclate (DOXY), minocycline hydrochloride (MIN), and/or eugenol (EUG). Basic characteristics of new ISFI formulations were investigated. Rheological analysis demonstrated that the liquid formulations exhibited shear-thinning behavior, which is advantageous for ISFI systems. However, the MIN-loaded formulation exhibited excessively rapid drug release, with a pronounced initial burst (86.4 ± 5.9%) within 24 h, whereas the DOXY-loaded system showed a lower burst of 41.1 ± 5.9% over the same period. The effect of EUG addition on depot morphology and antibiotic release profiles was also assessed. In vitro drug release studies demonstrated that EUG reduced the release rate of both antibiotics, increasing and prolonging their antibacterial activity. Eugenol co-released with antibiotics also reduced the pro-inflammatory effect of the released antibiotic doses by more than tenfold.

This study explores the impact of varying temperatures on the release behavior of Triptorelin Acetate (TA) from a PLGA-based in-situ forming implant (ISFI) and polymer degradation. Formulations were prepared using the in situ forming method in an acetate buffer (pH = 6.8) and then exposed to temperatures of 4 to 60 °C. The drug release and polymeric depot behavior were evaluated using HPLC, SEM, GPC, Rheometer, and pH measurements. A modified Gallagher-Corrigan Model-based mathematical model was applied to fit the in-vitro data, and the activation energy for peptide release in diffusional and erosional phases was calculated using the Arrhenius equation. The results revealed that matrices formed at 37, 45, and 53 °C exhibited a highly porous structure, resulting from rapid phase inversion and surface pore closing. This led to a reduction in TA burst release, observed as 38%, 27%, and 15% at 37 °C, 45 °C, and 53 °C respectively. Conversely, matrices at 4 and 25 °C demonstrated a faster initial release, followed by the formation of dense structures. The accelerated drug release profiles at 45 and 53 °C showed a shortened ultimate drug release duration and a good correlation with the real-time results at 37 °C. Due to the discernible PLGA matrices degradation at different temperatures, biphasic and tri-phasic release patterns were observed. The experimental release results aligned well with the proposed mathematical model, and the drug release kinetic parameters were estimated. Thus, in in-vitro studies, the release medium temperature plays a significant role in the drug-release behavior of ISFIs.

Breast cancer is among the most prevalent tumors worldwide. In this study, in-situ forming implants (ISFIs) containing rosuvastatin calcium were prepared using three types of poly (D, L-lactic-co-glycolic acid) (PLGA), namely, PLGA 50/50 with ester terminal and PLGA 75/25 with ester or acid terminal. Additionally, polydimethylsiloxane (PDMS) was added in concentrations of 0, 10, 20, and 30% w/v to accelerate matrix formation. The prepared ISFIs were characterized for their rheological behaviors, rate of matrix formation, and in-vitro drug release. All the prepared formulations revealed a Newtonian flow with a matrix formation rate between 0.017 and 0.059 mm/min. Generally, increasing the concentration of PDMS increased the matrix formation rate. The prepared implants’ release efficiency values ranged between 46.39 and 89.75%. The ISFI containing PLGA 50/50 with 30% PDMS was selected for further testing, as it has the highest matrix formation rate and a promising release efficiency value. Copper-selenium nanoparticles were prepared with two different particle sizes (560 and 383 nm for CS1 and CS2, respectively) and loaded into the selected formulation to enhance its anticancer activity. The unloaded and loaded implants with rosuvastatin and copper-selenium nanoparticles were evaluated for their antibacterial activity, against Gram-positive and negative microorganisms, and anticancer efficacy, against MCF-7 and MDA-MB-231 cell lines. The results confirmed the potency of rosuvastatin calcium against cancer cells and the synergistic effect when loaded with smaller particle sizes of copper-selenium nanoparticles. This formulation holds a considerable potential for efficient breast cancer therapy.

In situ forming implants (ISFI) based on poly(lactic- co -glycolic acid) (PLGA) are promising long-acting injectable depots for the treatment of human immunodeficiency virus-1 infection. One of the key parameters of depot formulations is the drug release rate which is critical for the development of optimal dosing regimens. The goal of this research is to investigate the most significant factors affecting the rilpivirine release rate from PLGA-based ISFI, including the influence of the polymer content and structure (i.e. molecular weights, lactide/glycolide ratios, and chemistry of the terminal group). Thus, the use of a low molecular weight PLGA reduces the burst-effect from 17.5 to 4.7% of the drug content and enables continuous release of rilpivirine over the period of 42 days. At the same time, a more hydrophobic PLGA with a lactide/glycolide ratio of 75/25 and a terminal ester group affects to a greater extent the rilpivirine release rate in the third phase of the release process, when destruction of the polymer matrix starts. The rilpivirine release profile from the implant, formed by using a 30% (w/w) solution of PLGA with a higher content of lactic acid (75:25) and a terminal ester group, is similar to the dissolution profile of rilpivirine nanocrystals (Rekambis ® ). Graphical abstract

Implantable drug delivery systems formed upon injection offer a host of advantages, including localized drug administration, sustained release, minimized side effects, and enhanced patient compliance. Among the various techniques utilized for the development of in situ forming drug implants, solvent-induced phase inversion emerges as a particularly promising approach. However, synthetic polymer-based implants have been associated with undesirable effects arising from polymer degradation. In response to this challenge, a novel category of drug delivery systems, known as phospholipids-based phase separation gels (PPSGs), has emerged. These gels, characterized by their low initial viscosity, exhibit injectability and undergo rapid transformation into in situ implants when exposed to an aqueous environment. A typical PPSG formulation comprises biodegradable components, such as phospholipids, pharmaceutical oil, and a minimal amount of ethanol. The minimized organic solvents in the composition show good biocompatibility. And the relatively simple composition holds promise for industrial-scale manufacturing. This comprehensive review provides an overview of the principles and advancements in PPSG systems, with specific emphasis on their suitability as drug delivery systems for a wide range of active pharmaceutical ingredients (APIs), spanning from small molecules to peptides and proteins. Additionally, we explore the critical parameters and underlying principles governing the formulation of PPSG-based drug delivery strategies, offering valuable insights on optimization strategies.

To explore the mechanism of drug release and depot formation of in situ forming implants (ISFIs), osthole-loaded ISFIs were prepared by dissolving polylactide, poly(lactide-co-glycolide), polycaprolactone, or poly(trimethylene carbonate) in different organic solvents, including N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and triacetin (TA). Drug release, polymer degradation, solvent removal rate and depot microstructure were examined. The burst release effect could be reduced by using solvents exhibit slow forming phase inversion and less permeable polymers. Both the drug burst release and polymer depot microstructure were closely related to the removal rate of organic solvent. Polymers with higher permeability often displayed faster drug and solvent diffusion rates. Due to high polymer-solvent affinity, some of the organic solvent remained in the depot even after the implant was completely formed. The residual of organic solvent could be predicted by solubility parameters. The ISFI showed a lower initial release in vivo than that in vitro. In summary, the effects of different polymers and solvents on drug release and depot formation in ISFI systems were extensively investigated and discussed in this article. The two main factors, polymer permeability and solvent removal rate, were involved in different stages of drug release and depot formation in ISFI systems.

Objectives: Lower urinary tract symptoms (LUTSs) related to benign prostatic hyperplasia (BPH) are common in older men, and alpha-adrenoceptor blockers continue to be a key part of managing these symptoms. This study aimed to formulate injectable poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants (ISFIs) loaded with silodosin (SLD) to address symptoms associated with BPH. This method, which ensures prolonged therapeutic effects of SLD, is intended to decrease dosing frequency and improve treatment outcomes, leading to better patient adherence. Methods: An appropriate solvent with favorable PLGA solubility, viscosity, and in vitro release profile was selected. Additionally, an I-optimal design was employed as an optimization technique. An in vivo study in albino male rats was conducted to investigate prostate-specific antigens (PSAs), prostate weight and prostatic index, histopathology, and SLD pharmacokinetics. Results: The optimized formulation showed experimental values of 29.25% for the initial burst after 2 h and 58.23% for the cumulative release of SLD after 10 days. Pharmacokinetic data revealed that the SLD–ISFI formulation had lower Cmax and higher AUC values than subcutaneous (SC) pure SLD and oral commercial SLD capsule, indicating the controlled-release impact and improved bioavailability of the ISFI systems. SLD–ISFI produced a marked drop in the prostatic index by 2.09-fold compared to the positive control. Serum PSA level decreased significantly from 0.345 ± 0.007 to 0.145 ± 0.015 ng/mL after SLD–ISFI injection compared to the positive control. Conclusions: This study indicated that the optimized SLD–ISFI formulation proved its efficacy in managing BPH.

PLGA-based in situ forming implants (ISFI) often require a high amount of potentially toxic solvents such as N methyl-Pyrrolidone (NMP). The aim of the present study was to develop lipid in-situ-forming oleogels (ISFOs) as alternative delivery systems. 12-Hydroxystearic acid (12-HSA) was selected as the oleogelling agent and three different oleoformulations were investigated: (a) 12-HSA, peanut oil (PO), NMP; (b) 12-HSA, medium-chain triglycerides (MCT), ethanol; (c) 12-HSA, isopropyl myristate (IPM), ethanol. The effects of the 12-HSA concentration, preparation method, and composition on the mechanical stability were examined using a texture analysis and oscillating rheology. The texture analysis was used to obtain information on the compression strength. The amplitude sweeps were analyzed to provide information on the gel strength and the risk of brittle fractures. The frequency sweeps allowed insights into the long-term stability and risk of syneresis. The syringeability of the ISFOs was tested, along with their acute and long-term cytotoxicity in vitro. The developed ISFOs have the following advantages: (1) the avoidance of highly acidic degradation products; (2) low amounts of organic solvents required; (3) low toxicity; (4) low injection forces, even with small needle sizes. Therefore, ISFOs are promising alternatives to the existing polymer/NMP-based ISFIs.