Search Results (6)

Phase-inversion in situ implants (PIISIs) represent a versatile polymer platform in which the rational choice of matrix former and solvent system directly governs the macroscopic properties of the resulting depot. This study applied a Quality by Design (QbD) approach to rationalize a bleached shellac–based PIISI, with particular focus on the physicochemical interactions between the polymer and the injection vehicle. Bleached shellac—a natural, low-cost, biodegradable oligomeric resin bearing –COOH, –OH, and ester functional groups—was selected as the matrix former and screened in seven neat solvents and five 1:1 binary combinations at 25% (m/m). Twelve formulations were evaluated against a predefined set of critical quality attributes, including injectability, phase-inversion kinetics, solvent diffusion volume, and implant structure (n = 5 per formulation; mean ± standard deviation (SD); one-way analysis of variance (ANOVA) with Tukey’s post hoc test, p < 0.05). Three lead solvent systems—propylene glycol/N-methylpyrrolidone (PG+NMP), PG/dimethyl sulfoxide (PG+DMSO), and DMSO/benzyl alcohol (DMSO+BA)—were identified as those providing an optimal balance between hydrogen-bond donor/acceptor solvation and controlled solvent extraction. In the second stage, shellac concentration (20–35%) was optimized, with 30% shellac in PG+NMP yielding the fastest phase inversion (~50 s), a structurally uniform matrix, and the lowest swelling (22%). A working mechanistic framework consistent with all observed critical quality attribute (CQA) trends in which solvent hydrogen-bond donor/acceptor balance and water miscibility govern implant architecture is proposed, and it is intended as a hypothesis-generating basis for the rational design of PIISI formulations; direct validation by spectroscopic, thermal-analytical, and biological methods is identified as the next step. The developed formulations are presented as a preliminary physicochemical platform; biological validation (in vitro cytocompatibility and inflammatory response assessment) is required before the system can be considered a validated formulation for dental drug delivery. Full article

Stimuli-sensitive (in situ) drug delivery systems are a dynamically developing area of pharmaceutical research. Over the past decade, the number of studies on such systems has doubled. Among these, phase-inversion (or phase-sensitive) formulations, which were among the earliest proposed, offer significant advantages, including enhanced stability and stimuli-responsiveness. However, phase-inversion systems have remained relatively understudied. Despite the existence of three patented technologies (Atrigel^®, BEPO^®, FluidCrystal^®) for delivery systems utilizing phase inversion for various routes of administration, the absence of unified approaches to development and standardization has significantly impeded the introduction of novel, effective drugs into clinical practice. This review examined the main polymers and solvents used to create phase-inversion compositions and discussed the feasibility of introducing other excipients to modify the systems’ physicochemical properties. The most commonly used polymers included polylactide-co-glycolide, shellac, and polylactic acid. The most frequently used solvents were N-methylpyrrolidone and dimethyl sulfoxide. Following an analysis of clinical studies of phase-sensitive drugs conducted over the past 25 years, as well as original research indexed in PubMed, ScienceDirect, and Google Scholar, the main problems hindering the broader adoption of phase-inversion systems in clinical practice were identified, and recommendations for further development in this promising area were provided. Full article

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. Full article

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. Full article

In situ forming implants (IFIs) are non-surgical approach using biodegradable polymers to treat bone fractures. The study aimed at preparing dual-drug-loaded IFIs to deliver pitavastatin (osteogenic drug) and tedizolid (antibiotic) using zein as the implant matrix via solvent-induced phase inversion method. At first, several investigations were done on pitavastatin-loaded zein IFIs, where three concentrations of zein were used (10, 20, and 30% w/v). IFIs were evaluated for their solidification time, rheological properties, injectability, and in vitro release. IFIs containing bioactive glass nanoparticles were prepared by the addition of non-doped bioactive glass nanoparticles (BGT₀; 1, 3, 5, and 10% w/v) or titanium-doped bioactive glass nanoparticles (BGT₅; 1% w/v) to the selected concentration of zein (30% w/v) and then evaluated. The optimized dual-medicated implant (D-ZIFI 1) containing pitavastatin, tedizolid, sodium hyaluronate (3% w/v), and BGT₅ (1% w/v) was prepared and compared to IFI lacking both sodium hyaluronate and BGT₅ (D-ZIFI 2). D-ZIFI 1 and 2 sustained the release profiles of both drugs for 28 days. SEM images proved the interconnected porous structure of D-ZIFI 1 due to sodium hyaluronate. In vivo studies on surgically induced bone defects in Sprague–Dawley rats signified the proper accelerated bone healing ability of D-ZIFI 1 over D-ZIFI 2. Results presented D-ZIFI 1 as a promising, effective, non-surgical approach for bone healing. Full article

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. Full article