Pharmaceutical development of complex wound-healing ointment for the needs of military medicine
AbstractThis article presents experimentally proved scientific-practical methods of developing modern vulnerary medical preparations in the form of an ointment with antibacterial, anti-inflammatory and anesthetic properties for the purposes of military medicine. In pursuit of the designated goals, the authors used modern methods of research: pharmacological-technological, physical-chemical, structural-mechanical and biological methods – for proving the compound of the combined ointment including ofloxacin, nimesulide and lidocaine. On the basis of the research conducted, we proved the content and rational technique of the complex antimicrobial ointment with anti-inflammatory and anesthetic effect using ofloxacin (0.05 g), nimesulide (1.0 g) and lidocaine (4.0 g). We experimentally established the optimal content of the main component of the ointment: emulsive base of mixture of Polyethylene Oxide-400 and Polyethylene Oxide-1500 (1 : 4) and a complex of emulsifiers of the first and the second generations – cetostearylic alcohol – 3%, monoglyceryl stearate – 5% at the constant concentration of paraffin oil – 20%, which involves a certain temperature regime during preparation, a sequence of introducing active pharmacological ingredients and adjuvants to the water and oil phases, frequency and duration of mixing. Physical-chemical tests of the ointment base determined the optimum concentration of glycerine as 5%, which encourages elimination of purulent discharge from damaged tissues, causing an anti-inflammatory effect and providing a prolonged, but milder dehydrating effect. The relation between physical-chemical, rheological, biopharmaceutical properties of the developed preparation and the concentration and method of introduction of the active pharmaceutical ingredients was theoretically and experimentally proven. We conducted pre-clinical studies (in vivo) for defining the therapeutic efficiency of the ofloxacin-nimesulide composition in the compound of the developed ointment for complex treatment of the wound process. We studied the specific activity (anti-alternative – model of standard tissue wounds in rats), which allowed us to establish the optimum concentration of nimesulide, which is 1%. Biopharmaceutical studies (in vitro method) determined the optimum method of introducing ofloxacin, nimesulide and lidocaine in the ointment base as a solution in dimethyl sulfoxide. To select an anesthetic substance for the ointment, the authors conducted a comparative study on the anesthetic effect of the anesthetics most widely available in Ukraine: novocaine, dicainum, lidocaine, trimecainum and pyromecainum. The research conducted on the time it took for the anesthetic effect to occur and on the duration and extent of the effect enabled us to select a 4% concentration of lidocaine anesthetic for the preparation. The choice of the temperature regime for the ointment’s preparation was proved. The in vitro method and rheological studies determined that the optimum temperature regime for the technological process of preparing the ointment on the emulsive base is 25–30 ºС. The development and introduction of the new combined ointment on a contemporary hydrophilic ointment base into practical pharmacy would lead to an enlargement in the nomenclature of the medical preparations used for local treatment of the purulent – necrotic phase of the wound process, which is relevant for pharmaceutical technology and global medical science and practice.
Alves, M. P., Scarrone, A. L., Santos, M., Pohlmann, A. R., & Guterres, S. S. (2007). Human skin penetration and distribution of nimesulide from hydrophilic gels containing nanocarriers. Pharmaceutical Nanotechnology, 341(1–2), 215–220.
Atiyeh, B. S., Dibo, S. A., & Hayek, S. N. (2009). Wound cleansing, topical antiseptics and wound healing. International Wound Journal, 6(6), 420–430.
Barajas-Nava, L. A., López-Alcalde, J., Solà, I., Roqué i Figuls, M., & Bonfill Cosp, X. (2013). Antibiotic prophylaxis for preventing burn wound infection. Cochrane Database of Systematic Reviews, 6.
Biryukova, S. V., Tarasenko, V. A., Kolokova, A. B., & Davtyan, L. L. (2009). Vyvchennya antymikrobnoyi aktyvnosti kremu ta helyu na osnovi tseftryaksonu ta nimesulidu [Study of the antimicrobial activity of the cream and gel on the basis of ceftriaxone and nimesulide]. Farmatsevtychnyy Chasopys, 9(1), 52–56 (in Ukrainian).
Cardinal, M. M., Eisenbud, D. E., & Armstrong, D. G. (2009). Serial surgical debridement: A retrospective study on clinical outcomes in chronic lower extremity wounds. Wound Repair and Regeneration, 17(3), 306–311.
Chan, B. A., Xuan, S., Li, A., Simpson, J. M., Sternhagen, G. L., Yu, T., Darvish, O. A., Naisheng, J., & Zhang, D. (2017). Polypeptid polymers: Synthesis, characterization, and properties. Biopolymers, e23070.
Chauhan, N. P. S., Pathak, A. K., & Bhanat, K. (2016). Encyclopedia of biomedical polymers and polymeric biomaterials. Taylor & Francis, New York.
Davtian, L. L. (2009). Tekhnolohichnyy sposib vvedennya diyuchykh rechovyn do osnovy preparatu [Technological method of introduction of active substances to the basis of the preparation]. Military Medicine of Ukraine, 12(4), 61–63 (in Ukrainian).
Debjit, B., Harish, G., Pragati, K. S., Duraivel, K. P., & Sampath, K. (2012). Recept advances in novel topical drug delivery system. The Pharma Innovation, 1(9), 12–31.
Dohmen, P. M. (2008). Antibiotic resistance in common pathogens reinforces the need to minimize surgical site infections. Journal of Hospital Infection, 70(2), 15–20.
Farooq, U., Rishabh, M., Bansal, V., & Pragati, K. S. (2014). Characterization of some polymers as pharmaceutical excipient. Advances in Biological Research, 8(3), 123–126.
Gullapalli, R. P. (2010). Soft gelatin capsules (softgels). Journal Pharmaceutical Science, 99(10), 4107–4148.
Haag, R., & Kratz, F. (2006). Polymer therapeutics: Concepts and applications. Angewandte Chemie International Edition in English, 45(8), 1198–1215.
Healy, B. M., & Freedman, A. M. (2010). ABC of wound healing infections. British Medical Journal, 332, 838–841.
Hotz, B. V., Visekruna, A. A., Buhr, H. J., & Hotz, H. G. (2010). Beyond epithelial to mesenchymal transition: A novel role for the transcription factor snail in inflammation and wound healing. World Journal of Gastrointestinal Surgery, 14(2), 388–397.
Hryzodub, O. I. (ed.), (2015). Derzhavna farmakopeya Ukrayiny [State pharmacopoeia of Ukraine]. Ukrayins’kiy Naukoviy Farmakopeyniy Tsentr Yakosti Likars’kykh Zasobiv, Kharkiv (in Ukrainian).
Isaac, V. L. B., Chiari-Andreo, B. G., Marto, J. M., Moraes, J. D. D., Leone, B. A., Correa, M. A., & Ribeiro, H. M. (2015). Rheology as a tool to predict the release of alfa-lipoic acid from emulsions used for the prevention of skin aging. BioMed Research International, 2015, 1–8.
Islam, M. T., Rodríguez-Hornedo, N. P., & Ciotti, S. E. (2014). Rheological characterization of topical carbomer gels neutralized to different pH. Journal Pharmaceutical Research, 7(21), 1192–1199.
Janis, J. E., & Harrison, B. (2016). Wound healing: part I. Basic science. Plastic and Reconstructuctive Surgery, 138(3), 9–17.
Kadajji, V. G., & Betageri, G. V. (2011). Water soluble polymers for pharmaceutical applications. Polymers, 3(4), 1972–2009.
Kiamahalleh, M. V., Mellati, A., Madani, S. A., Pendleton, P., Zhang, H., & Hadi Madani, S. H. (2017). Smart carriers for controlled drug delivery: Thermosensitive polymers embedded in ordered mesoporous carbon. Journal of Pharmaceutical Science, 106(6), 1545–1562.
Kopenkin, S. S., & Talitsky, K. A. (2013). Mestnoye primeneniye nesteroidnykh protivovospalitel’nykh sredstv v travmatologii i ortopedii [Local use of non-steroidal anti-inflammatory drugs in traumatology and orthopedics]. Visnyk Ortopedii, Travmatologii i Protezuvannya, 1, 77–80 (in Ukrainian).
Lindley, L. E., Stojadinovic, O., Pastar, I., & Tomic-Canic, M. (2016). Biology and biomarkers for wound healing. Plastic and Reconstructive Surgery, 138(3), 18–28.
Maisch, T. (2007). Anti-microbial photodynamic therapy: Useful in the future. Lasers in Medical Science, 22(2), 83–91.
Maitz, M. F. (2015). Applications of synthetic polymers in clinical medicine. Biosurface and Biotribology, 1(3), 161–176.
Mastropietro, D. J., Nimroozi, R., & Omidian, H. (2013). Rheology in pharmaceutical formulations – A perspective. Journal of Developing Drugs, 2(2), 108.
Merkle, H. P. (2015). Drug delivery’s quest for polymers: Where are the frontiers? European Journal Pharmaceutical Biopharmaceutics, 97, 293–303.
Mincer, О. P., Voronenko, Y. V., & Vlasov, V. V. (2003). Obroblennya klinichnykh i eksperymental’nykh danykh u medytsyni [Treatment of clinical and experimental data in medicine]. Vishha Shkola, Кyiv (in Ukrainian).
Nishio, N. S., & Suzuki, I. H. (2009). Antibodies to wounded tissue enhance cutaneous wound healing. Immunology, 128(3), 369–380.
Owens, C. D., & Stoessel, K. P. (2008). Surgical site infections: Epidemiology, microbiology and prevention. Journal of Hospital Infection, 70(2), 3–10.
Puoci, F., Piangiolino, C., Givigliano, F., Parisi, O. I., Cassano, R., Trombino, S., Curcio, M., Iemma, F., Cirillo, G., Spizzirri, U. G., Restuccia, D., Muzzalupo, R., & Picci, N. (2012). Ciprofloxacin-collagen conjugate in the wound healing treatment. Journal of Functional Biomaterials, 3, 361–371.
Rudenko, V. V., Vlasenko, I. O., & Vashchuk, V. A. (2013). Vyvchennya osmotychnoyi aktyvnosti kombinatsiy hidrofil’nykh nevodnykh rozchynnykiv dly modelyuvannya preparatu, dlya likuvannya I fazy ranovoho protsesu [Study of osmotic activity of combinations of hydrophilic non-aqueous solvents for modeling a drug for treatment of phase I of the wound process]. Pharmaceutical Journal, 1, 46-49 (in Ukrainian).
Sheskey, P. J., Cook, W. G., & Cable, C. G. (2017). Handbook of pharmaceutical excipients. APhA/Pharmaceutical Press, London.
Stefanov, O. V. (ed.), (2001). Doklinichni doslidzhennya likars’kih zasobiv [Preclinical studies of medicines]. Avicena, Kyiv (in Ukrainian).
Trostrup, H., Bjarnsholt, T., Kirketerp-Moller, K., Hoiby, N., & Moser, C. (2013). What is new in the understanding of non-healing wounds epidemiology, pathophysiology and therapies. Ulcers, 2013, ID 625934.
Victorov, О. P., & Kashuba, О. V. (2014). Nimesulid: Otsinymo perspektyvy [Nimesulide: Assessment of the prospects]. Mystetstvo Likuvannya, 5, 20–22 (in Ukrainian).
Vyas, K. S., & Vasconez, H. C. (2014). Wound healing: Biologics, skin substitutes, biomembranes and scaffolds. Healthcare, 2(3), 356–400.
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