ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
The experiment was conducted on 10 Wistar rats, male and female, with initial body weight 270-280 g (males) and 250-260 g (females). The drug was administered using a spray cap in 10 doses of 0.1 mg at 45 min intervals. The average cumulative dose of the drug per naloxone hydrochloride was 36.6 mg/kg for males and 39.4 mg/kg for females. The animals were monitored for 2 weeks after the exposure and then euthanized by a gentle decapitation.We noticed that after each drug administration the animals showed a decrease in motor activity. During the observation period there were no animal deaths or signs of abnormalities in their general state or behavior. Beginning on day 7 a significant increase in body weight of the animals was noted in comparison with the initial data. The relative mass of the internal organs of the treated rats remained within the physiological norm.We conclude that naloxone hydrochloride after an intranasal administration at 36.6 mg/kg for males and 39.4 mg/kg for females does not cause death of animals and or have a toxic effect on their general state, does not change their protein metabolism characteristics or the appearance of the internal organs and their mass.
