Preservatives in eye drops, while not always necessary, can lead to undesirable effects. Developing preservative-free solutions demands special measures for sterility, utilizing multidose or monodose primary packaging. This review explores the merits and drawbacks of these packaging types. A literature search on PubMed, Google Scholar, and EMBASE until December 2023, using MESH terms, yielded 28 studies on multidose ampoules and 24 on monodose packaging. Heterogeneous data revealed advantages and disadvantages concerning patient use and manufacturing. Chronologically presenting the development of eye drop packaging, this study finds Droptainer® simple but unable to maintain sterility. Comod®, 3K®, ABAK®, Novelia®, and Ophthalmic Squeeze Dispenser show high sterility probability, with Comod® and ABAK® having a contamination risk. Novelia® excels with long-term sterility and better control. Ophthalmic Squeeze Dispenser, FDA-approved, boasts a smaller carbon footprint. Unit-dose systems preserve sterility and offer design flexibility. Proposing an alternative, blister technology maintains sterility, is convenient and safe, and holds promise for recycling. This comprehensive assessment aids in understanding the evolving landscape of eye drop packaging, emphasizing the importance of sterility, convenience, and environmental impact.

This study focuses on the development of a chitosan-based hydrogel incorporating polyvinylpyrrolidone and polyhexamethylene guanidine hydrochloride for the rehabilitation of damaged and contaminated skin. The thermal properties of chitosan-containing films were characterized by measuring the glass transition temperature (Tg) using differential scanning calorimetry. Due to challenges in accurately determining the Tg of chitosan from experimental and literature data, an additional method, dynamic mechanical analysis, was employed. Using the literature value for the Tg of polyhexamethylene guanidine hydrochloride, the transitions of the components were determined. The estimated sorption capacity of the developed hydrogel showed that the inclusion of polyhexamethylene guanidine hydrochloride reduced the moisture content, as expected. However, the overall behavior of the hydrogels remained similar. Vapor permeability, an important factor in wound healing, was also evaluated. Antimicrobial testing revealed no activity for the chitosan control sample despite some reports in the literature, while the samples containing polyhexamethylene guanidine hydrochloride exhibited superior antimicrobial efficacy. These findings suggest that the incorporation of polyhexamethylene guanidine hydrochloride and polyvinylpyrrolidone significantly enhances both the mechanical strength and antimicrobial potential of chitosan-based hydrogels, positioning them as promising candidates for the treatment of contaminated wounds.

Polyhexamethylene guanidine (PHMG) is a commonly used disinfectant, but safety concerns have arisen due to poisoning cases. This systematic review assesses the toxicity and safety of PHMG by inhalation, oral administration, skin contact, and ocular contact to determine its potential medical applications and acceptable concentration limits. Searches in PubMed, ScienceDirect, CENTRAL, and CyberLeninka up to January 2024 identified 11 in vitro studies with human cell lines, 28 animal studies, and 10 articles involving patients and healthy volunteers. The review found that inhalation of PHMG leads to pulmonary fibrosis and malignant neoplasms, making aerosol forms unacceptable. PHMG can also affect liver function and have adverse effects on the heart, kidneys, and hematopoietic system. For dermal use, PHMG appears to be safe at concentrations up to 3%, although practical use may limit this to 1% due to potential discomfort. Still, it is important to consider possible sensitization, especially in patients with pre-existing skin conditions. In oral hygiene, 1% PHMG-P has been used safely in periodontal treatment, suggesting its potential in dentistry. For ophthalmic use, concentrations should be carefully monitored. PHMG-P solutions below 0.13% appear to be safe for human corneal epithelium, however lower concentrations still pose a risk of corneal fibrosis, as shown in animal studies. Physicians should prefer lower concentrations and consider alternatives or formulations with reduced toxicity for sensitive applications such as eye drops. Overall, although PHMG and its derivatives show promise in a variety of medical applications, their use should be reasonable, with careful consideration of the associated risks.

This study focused on the implementation of the stages of pharmaceutical development of a dosage form of eye drops based on the branched oligohexamethylene guanidine hydrosuccinate according to discrete and continuous optimization, followed by risk assessment and process validation. Experimental samples were developed, critical process and quality parameters were identified, technological characteristics were measured, parameters were normalized, a forecast was made, confirmatory experiments were conducted, the optimal composition was identified, risks in the production of eye drops were assessed, and partial validation was performed. During the implementation of the stages of pharmaceutical development of eye drops based on branched oligohexamethylene guanidine hydrosuccinate, three optimization cycles (discrete and continuous) were carried out, and the optimal ratio of active and auxiliary components was justified based on the results (branched oligohexamethylene guanidine hydrosuccinate 0.05%, polyvinyl alcohol 1%, phosphate-buffered saline 20%, sodium chloride 0.45%, and purified water up to 100%). After reviewing the technological process considering risk analysis, critical points were identified, and partial validation was performed, and the positive results verified and confirmed the optimal choice at this stage of pharmaceutical development. In general, a mixed type of optimization (discrete and continuous) can be used to implement pharmaceutical developments of eye drops based on branched oligohexamethylene guanidine hydrosuccinate, which is confirmed by a series of experiments and risk assessment, and the partial validation verified the data obtained. Thus, pharmaceutical development is a complex and time-consuming process, and limited functionality does not always allow quick identification of the optimal composition of a drug. As an effective solution for implementing the stages of pharmaceutical development, mathematical modeling methods and various types of optimization can be applied.

Objectives. The study set out to use mathematical modeling, in particular the method of multifactorial analysis of multicriteria optimization (MAMO), in the development of a pharmaceutical product. Methods. After carrying out experimental tests based on the proposed algorithmic sequence, the obtained data were interpreted using MAMO. Results. The possibility of using MAMO to solve the applied problem of purifying oligohexamethyleneguanidine hydrosuccinate (OHMG-HS), considered as a pharmaceutical precursor for the creation of medicines, was demonstrated. Conclusions. The expediency of using the proposed algorithm as a tool for pharmaceutical development is substantiated by identifying dependencies of the influence of purification conditions on the final content of admixtures in the target product.

Due to the growing problem of antibiotic resistance, the possibility of using alkylene guanidines as compounds exhibiting antimicrobial activity is discussed. Methods for the preparation of oligohexamethylene guanidine (OHMG) dihydrocarbonate using microfluidic technologies and the further synthesis of OHMG hydrocitrate are described. Structures of the compounds obtained were confirmed by 13 С NMR spectroscopy, and the antimicrobial activity of OHMG hydrocitrate was evaluated.

The current investigation is dedicated to the use of mathematical modeling, particularly the method of multifactorial analysis of multicriteria optimization (MAMO) in pharmaceutical development. During the investigation the algorithmic sequence was offered and the necessary tests were provided. The gained data was interpreted through MAMO. The possibility of using the MAMO for solving the applied problem of purifying the oligohexamethyleneguanidine hydrocitrate (OHMG-HC) that is considered to be as a pharmaceutical substance for formation of medicines. The dependencies of purifying conditions that have influence on the final impurities contents and the reasonability of using the suggested algorithm as a means of pharmaceutical development.

Objectives. To develop a method for the microfluidic synthesis of oligohexamethylene guanidine salts in a flow-type reactor and to evaluate its effectiveness in relation to the synthesis in a traditional capacitive reactor and compare the purities of products obtained by these methods.Methods. The synthesis of oligohexamethylene guanidine bihydrocarbonate (OHMG-BHC) was done using microfluidic hardware and the classical approach in volume. The purity and structure of the resulting product were confirmed by 13C NMR spectroscopy and high-performance liquid chromatography (HPLC).Results. The 13C NMR spectrum of OHMG-BHC in classical bulk synthesis demonstrates that the product is unbranched and contains additionally unidentifiable impurities, in contrast to the sample obtained by the microfluidic method. Furthermore, the HPLC analysis showed that the OHMG-BHC sample synthesized using microfluidic technology has a 1.5-fold lower content than the initial monomers.Conclusions. The advantage of synthesizing OHMG-BHC in a flow-type reactor compared to the traditional method of synthesis in volume is demonstrated since a product with a higher degree of purity is obtained.

Branched oligohexamethyleneguanidine hydrochloride (branched OHMG-HC) possesses high biocidal activity. This study aimed at evaluating the pharmacokinetics of branched OHMG-HC and is mandatory for obtaining permission to conduct clinical studies. The thermal activation method was used to obtain radioactive-labeled drugs for the investigation of substance distribution in various tissues of experimental animals (rats and rabbits). Substance administration was carried out both orally (a dose was split into two equal volumes that were applied to buccal zones of the oral cavities of the animals) and intravenously to get a clear pharmacokinetic profile. In this research, the drug was applied in the concentration of 0.77 mg/kg with the addition of 0.037 mg/kg H-3-OHMG for rats, and 0.42 mg/kg with the addition of 0.015 mg/kg H-3-OHMG for Chinchilla rabbits. The selected samples of blood, organs, and urine underwent alkaline mineralization. A quantitative determination of H-3-OHMG was carried out using a liquid beta-, gamma-counter according to the level of scintillation in the sample. Branched OHMG-HC displayed uniform distribution within all main organs and tissues upon oral administration. The highest concentrations were found in liver and kidney tissues, whereas the lowest in blood, cardiac muscle tissue, and brain. The closeness of the f(abs) values obtained from different animals (24.5% for rats and 29.0% for rabbits) demonstrated the absence of the species specificity in response to the pharmaceutical substance. The main parameters of excretion were established, and the half-life time was estimated to be 15 h.

This paper reports the synthesis of branched alkylene guanidines using microfluidic technologies. We describe the preparation of guanidine derivatives at lower temperatures, and with significantly less time than that required in the previously applicable method. Furthermore, the use of microfluidics allows the attainment of high-purity products with a low residual monomer content, which can expand the range of applications of this class of compounds. For all the samples obtained, the molecular-weight characteristics are calculated, based on which the optimal condensation conditions are established. Additionally, in this work, the antiviral activity of the alkylene guanidine salt against the SARS-CoV-2 virus is confirmed.

Objectives. Given that microorganisms can become resistant to certain groups of drugs and considering also their ability to form biofilms, the development of new drugs that are active against adapted microflora is required. This study focused on the development of a new method for the synthesis of a promising compound, the branched hydrosuccinate oligohexamethylene guanidine (OHMGsucc), with high purity that meets the standards of the 14th edition State Pharmacopeia of the Russian Federation (SPRF). Previously proposed methods have managed to isolate this product, which, however, complies with the requirements of the outdated SPRF. Therefore, the main aim of this study was to update the regulatory framework for the indicated OHMG salt for its further use in the pharmaceutical industry according to modern standards.Methods. To control the residual impurities of hexamethylenediamine (HMDA) and guanidine hydrochloride (GHC), high-performance liquid chromatography (HPLC) was applied using a Thermo Scientific Dionex UltiMate 3000 chromatograph, and the chromatographic signals of the test solution with those of a standard sample solution obtained by a previously published conventional method were compared.Results. The HPLC experimental data indicated a significant difference in the quantitative content of HMDA and GHC observed for the new and older preparation method of the branched OHMGsucc, suggesting that the method disclosed in this article can be used to obtain highly pure OHMGsucc.Conclusions. The specified compound was standardized with the parameter “related impurities” according to the current (14th) edition of the SPRF. The effectiveness and reproducibility of the proposed method was experimentally confirmed. In addition, a process diagram for the preparation of the indicated OHMG salt was prepared.

The acquisition of resistance to the antibiotics and antibacterial agents used by microorganisms sets the task of finding new active disinfectants. It is known that compounds of the oligoguanidine class possess pronounced antibacterial properties, low toxicity, and can exhibit a prolonged biocidal effect, causing destruction of biofilms formed by pathogenic microflora. One of these compounds is branched oligohexamethylene guanidine hydrosuccinate (OHMG succ). The specified compound can be used as an active component in the development of a drug that acts on microbial dehydrogenases for the prevention and treatment of conjunctivitis of an infectious nature. In this regard, the purpose of this work is to study and visualize the mechanism of action of OHMG succ in relation to microbial dehydrogenases of Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa by colorimetric methods, to study its effect on the formation of biofilms and mature biofilms of E.coli, on its cell wall by scanning electron microscopy, as well as experimental evidence of the influence of OHMG succ on the morphology of several types of bacteria, yeasts, and molds that cause conjunctivitis, by atomic force microscopy. In addition, it was necessary to identify the dependence of cell segregation disturbance on the increasing concentration of OHMG succ. Thus, it was proved that OHMG succ affects not only the microbial dehydrogenases of certain Gram-negative bacteria, the mature biofilm of E.coli, but also its cell wall. The effect of OHMG succ on the morphology of several types of bacteria, yeast and mold fungi was also revealed. The indicated information shows that the creation of an antimicrobial drug based on OHMG succ is of interest, and this work may serve as the basis for the development of an innovative pharmacological drug for the treatment of conjunctivitis of an infectious nature.

Objectives . Given that microorganisms can become resistant to certain groups of drugs and considering also their ability to form biofilms, the development of new drugs that are active against adapted microflora is required. This study focused on the development of a new method for the synthesis of a promising compound, the branched hydrosuccinate oligohexamethylene guanidine (OHMGsucc), with high purity that meets the standards of the 14th edition State Pharmacopeia of the Russian Federation (SPRF). Previously proposed methods have managed to isolate this product, which, however, complies with the requirements of the outdated SPRF. Therefore, the main aim of this study was to update the regulatory framework for the indicated OHMG salt for its further use in the pharmaceutical industry according to modern standards. Methods . To control the residual impurities of hexamethylenediamine (HMDA) and guanidine hydrochloride (GHC), high-performance liquid chromatography (HPLC) was applied using a Thermo Scientific Dionex UltiMate 3000 chromatograph, and the chromatographic signals of the test solution with those of a standard sample solution obtained by a previously published conventional method were compared. Results . The HPLC experimental data indicated a significant difference in the quantitative content of HMDA and GHC observed for the new and older preparation method of the branched OHMGsucc, suggesting that the method disclosed in this article can be used to obtain highly pure OHMGsucc. Conclusions . The specified compound was standardized with the parameter “related impurities” according to the current (14th) edition of the SPRF. The effectiveness and reproducibility of the proposed method was experimentally confirmed. In addition, a process diagram for the preparation of the indicated OHMG salt was prepared.

There is an outline of the problem of oral diseases treatment arising due to exposure to pathogenic organisms in the review. The article contains classification of existing antimicrobials used as pharmaceutical substances; the analysis of advantages and disadvantages of different active substances within it’s basic structural elements and it’s mechanisms of action. The article also represents the information about existing dosage forms used for the treatment of oral diseases, with a description of the pros and cons of application in each case. Special attention is paid to the adjuvants which are available in existing products, and providing various properties of the preparations: ease of application, a corrective effect, stability of the drug during the claimed shelf life, etc. The information provided in the review fully depicts modern approaches of drug products development for the treatment of oral diseases and can serve as an auxiliary material for creating new medicines in this area.

The review presents data regarding the main classes of substances applied in pharmaceutics for long-term control of pathogenic microflora. The problems of application of these substances caused by the resistance of pathogenic microflora to the main classes of the biocides are discussed. Mechanisms of action of antimicrobial agents and possible mechanisms of adaptation of pathogenic microflora to these substances are considered. Guanidine-containing cationic polyelectrolytes with different structures affecting their features, as well as the main stages of their mechanism of action, are described. Comparative information on the range of antimicrobial action of representatives of this class based on the results of studies conducted in different periods of time is presented. Analysis of the literature data demonstrated that branched oligohexamethyleneguanidine hydrochloride is a promising compound for the development of pharmaceutical substance.

The aim of this investigation was to estimate the influence of composition of dihydroquercetin and lipoic acid on the hemostasis of rats model of lower limbs chronic venous insufficiency. In this model the disturbance of external coagulation pathway was detected. It reflected in significant shorting of a prothrombin time on 3,2 s in comparison with sham operated animals. Corse i.g. administration of antioxidant composition (dihydroquercetin and lipoic acid) during 14 days suppressed the prothrombin time change.