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.

Thermosensitive systems based on poloxamer 407 are widely used in targeted drug delivery; however, the stability of the phase transition temperature remains insufficiently studied. This article presents the results of a study on the effect of adding polyethylene glycols (PEG) with different molecular weights and some classical gel-forming polymers on the gelation temperature of thermoreversible compositions based on poloxamer 407 in a long-term experiment. The study showed a positive effect of PEG addition with average molecular weights at concentrations of 1.5–2.0%, as well as gelling agents at a concentration below the critical gelation concentration. The proposed rheological test for studying the samples’ adhesion can give an indirect forecast of the composition adhesive rate. Based on the conducted studies, three experimental binary systems based on poloxamer 407 were selected, with the addition of HPMC 0.5%, sodium alginate 0.5%, and PEG 1500 1.5%. These systems are the most promising for the further development of in situ targeted drug delivery systems.

Xyloglucan is a highly promising ‘green’ polymer that has found its application in the food and pharmaceutical industries. Due to its molecular structure similarity to mucin, it has remarkable mucoadhesion properties, which has led to a high research interest in this excipient for the development of transmucosal delivery systems. Thermosensitivity is another promising property of xyloglucan derivatives, which is mainly exhibited by synthetic block copolymers such as pluronics and PLGA derivatives. Delivery systems whose mechanism of active ingredient release is based on temperature sensitivity are widely used in many medical fields, ranging from antitumour therapy to intranasal delivery. Thus, conducting research on the possibility of obtaining and using a new mucoadhesive, fully biocompatible and affordable polymer—xyloglucan—is a promising task.

This review presents a comprehensive analysis of modern thermosensitive polymer systems for in situ systems (ISSs) which are used for targeted drug delivery in situ. The main classes of polymers used to create “smart” hydrogels that undergo a “sol–gel” phase transition in response to a temperature stimulus in the physiological range are considered. Key representatives of thermosensitive matrices are described in detail: synthetic block copolymers (poloxamers, block copolymers of polylactic-co-polyglycolic acid with polyethyleneglycol, etc.) and natural, modified natural, and semi-synthetic polymers (chitosan, including in combination with β-glycerophosphate, xyloglucan, etc.). This paper systematizes the advantages and disadvantages of various thermosensitive systems and highlights the key risks in their pharmaceutical development, including the influence of the nature and concentration of the active pharmaceutical ingredients and excipients on the rheological properties and phase transition temperature. Particular attention is paid to the difference between thermoreversible and irreversible gel-forming systems. Modern in vitro, ex vivo, and in vivo methods for evaluating critical quality parameters of thermosensitive systems, such as gelation temperature and time, gel strength, mucoadhesive properties, and release kinetics, are discussed. The need to develop standardized and biologically relevant methods to improve the reproducibility and success of preclinical studies is emphasized. The review is intended to help researchers to make informed choices about polymer matrices and optimize compositions for successful pharmaceutical development.

Aim to consider the potential prospects of using Poly(l-lactide-co-glycolide) (PLGA) and shellac to obtain phase-dependent in situ implants. Material and methods. The study required two stages: stage I was the evaluation of NMP-polymer compositions, and stage II was the evaluation of NMP-polymer-PEG compositions. We used PLGA with various ratios of lactide and glycolide units (75:25, 50:50), dewaxed bleached shellac, N-methylpyrrolidone (NMP) as a solvent, and PEG-1500 at a concentration of 5% (wt/vol) as a co-solvent. The experimental formulations contained matrix formers at a concentration of 33%. The formulations were screened for polymer solubility in NMP, homogeneity and permeability through the needle of the resulting polymer-NMP system, the implant formation rate during the liquid-liquid extraction in a phosphate buffer solution (pH=6.8), and the implant morphology. The rate of implant formation and the diffusion of the dye from the delivery systems were also studied using the in vitro agar gingiva model, previously developed in the laboratory of the A.P. Nelyubin Institute of Pharmacy. Results. The first stage of the study showed that the NMP-PLGA system (75:25) formed a solid implant in 1 hour, and the NMP-shellac system in 2 hours. The formulations were positively assessed according to the presented criteria, despite the very different diffusion volumes 1414 l for NMP-shellac and 1065 l for NMP-PLGA (75:25) which indicates the possibility of their use without the introduction of additional excipients. The NMP-PLGA system (50:50) had not completely precipitated after the critical time (3 hours) and was considered as requiring an adjustment due to the insufficient implant formation rate. In the stage II, a less intense diffusion of the dye from the implants into agar was observed. For example, for NMP-PLGA(50:50) 641 l, and for NMP-PLGA(50:50)-PEG 25 l. At the same time, there was the positive dynamics in the time of their precipitation both in phosphate buffer medium (instantaneous precipitation without the need for shaking) and in the in vitro agar gingiva model after 3 hours, the composition of NMP-PLGA (50:50)-PEG, in contrast to NMP-PLGA (50:50), had formed a semi-solid implant. Conclusion. In the course of the experiments, the compositions of NMP-shellac and NMP-PLGA (75:25) were selected as the most promising for further development of a phase-sensitive in situ dental implant. The addition of PEG was found to be rational in terms of increasing the rate of implant precipitation and reducing the initial diffusion of the solvent.