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Influence of Additives and Storage Temperature on Physicochemical and Microbiological Properties of Eye Drops Containing Cefazolin

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Influence of Additives and Storage Temperature on Physicochemical and Microbiological Properties of Eye Drops Containing Cefazolin Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 63 No. 3 pp. 225ñ234, 2006 ISSN 0001-6837 Polish Pharmaceutical Society PHARMACEUTICAL TECHNOLOGY INFLUENCE OF ADDITIVES AND STORAGE TEMPERATURE ON PHYSICOCHEMICAL AND MICROBIOLOGICAL PROPERTIES OF EYE DROPS CONTAINING CEFAZOLIN. ANNA KODYM 1, TOMASZ ZAWISZA 2, KAMILA BUèKA 2 and HELENA KUKU£A 3 1 Department of Drug Form Technology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, 2 Department of Drug Form Technology, 3 Department of Pharmaceutical Bacteriology; K. Marcinkowski University of Medical Sciences in PoznaÒ Abstract: The purpose of the studies was to choose additives for eye drops containing cefazolin and the assess- ment of the influence of used additives and the storage temperature on the physicochemical properties and the stability of the eye drops. The drops were 1% sterile solutions of cefazolin in citrate buffer of pH 6.15-6.20. The drops were preserved with 0.002% thiomersal or 0.001% phenylmercuric borate mixed with 0.4% β- phenylethyl alcohol. Viscosity of the eye drops was increased using polyvinyl alcohol (PVAL). The pharma- ceutical compatibility test of selected additives with cefazolin showed the pharmaceutical interaction of 1% solution of cefazolin with higher than 0.003% concentration of thiomersal, 0.005% benzalkonium chloride and 0.01% chlorhexidine diacetate. The drops, protected from light, were stored at the temperature of 4∞C and 20∞C. As the criteria of the qualitative assessment of freshly prepared drops and during their storage, the following properties were considered: organoleptic analysis, sterility, pH, osmotic pressure, density, viscosity, antimicro- bial activity of cefazolin and preservation efficiency of thiomersal and phenylmercuric borate in the eye drops. The studies showed that the storage temperature did not influence the physicochemical properties of the drops or the antimicrobial activity of cefazolin in the drops, which was not influenced by the used additives either. After 30 days of storage at both temperatures, cefazolin in the eye drops retained 100% of its initial activity. Phenylmercuric borate, whose antimicrobial activity in the eye drops was compatible with the preservation assay cited in the Polish Pharmacopoeia (PPh V), can be used to preserve the drops containing cefazolin. Keywords: cefazolin, eye drops, pharmaceutical interactions of cefazolin. Cefazolin is a cephalosporic antibiotic of gen- drops (2). Cefazolin in the topical and general treat- eration I, which works efficiently against Gram-pos- ment of serious eye infections is mixed with other itive cocci i.e. staphylococci Staphylococcus aureus antibiotics e.g. gentamicin (3), tobramycin (4, 5) and (excluding MRSA) and Staphylococcus epidermidis, ofloxacin (6). and streptococci Streptococcus pneumoniae, There are no commercial forms of eye drops Streptococcus pyogenes and Streptococcus viridans. containing cefazolin available on pharmaceutical Cefazolin shows also antimicrobial activity towards market. They are prepared ex tempore by hospital some Gram-negative bacteria such as Klebsiella pharmacies for the patients of ophthalmic wards. pneumoniae and Escherichia coli and towards Commercial preparations of artificial tears (4, 7, 8), anaerobic cocci and bacilli, which are sensitive to buffer solutions such as acetate buffer of pH 4.5 and penicillin (1). 5.7 and phosphate buffer of pH 7.5, solutions of sodi- Eye drops at the concentration of 1-5% are um chloride (8, 9) and 1% glycerol (9) were used as used in the treatment of inflammations of eyelids, cefazolin solvents in the eye drops. Stability of cefa- ulcerous inflammations of eyelids, conjunctivitis, zolin in the eye drops is dependent on the storage neonatal conjunctivitis and pyogenic keratitis (2). In temperature and pH (8, 9). It is more stable in solu- case of serious infections of the eye such as intraoc- tions of acidic pH, e.g. pH 4.5 and 5.7 in comparison ular inflammation, inflammation of connective tis- with the solution of pH 7.5 (8). It retained 93% of its sue of the eye socket, and ulcerous inflammation of initial contents in the drops after 42 days of storage the corneal epithelium or with corneal perforation, at the temperature of 4∞C, while after the same time cefazolin is used systemically combined with the in the drops stored at the room temperature only 50% topical treatment in form of periocular injections or of cefazolin was left (9).The purpose of the studies injections into vitrous body and in form of 5% eye was the choice of necessary additives for the eye 225 226 ANNA KODYM et al. drops containing cefazolin and the assessment of the osmometer (Trident 800cl, Warsaw); Hˆppler vis- influence of the used additives and the storage tem- cosimeter KF10 (Pr¸fger‰te-Werk Medingen- perature on the physicochemical properties and Dresden); apparatus for membrane filtration ñ antimicrobial activity of cefazolin in the drops. Sartorius; air sterilizer type S.P.W. 65M (SpÛ≥dzielnia Pracy Marki); autoclave EIMI type EXPERIMENTAL ESS-105 (SpÛ≥dzielnia Pracy MechanikÛw, Warsaw); densitometer (Mettler Toledo DA-110M); Materials electronic analytical scales: up to 0.1 mg ñ type KefzolÆ (Cefazolinum natricum), Eli Lilly WPS 36/S and up to 0.002 g type WPS 720/C Italia, vials a 1.0 g, dry substance for intramuscular (Radwag, Radom). and intravenous injections; eye drops containing cefazolin, prepared under aseptic conditions accord- Methods ing to the formulary composition showed in Table 1; Preparation of sterile solutions of additives sterile solutions: cefazolin, citrate buffers, polyvinyl Citrate buffers I and II, solution of polyvinyl alcohol (PVAL), preservatives: benzalkonium chlo- alcohol (PVAL), 0.5% solution of benzalkonium ride, thiomersal, phenylmercuric borate and chloride, 2% solution of thiomersal, 0.04% solution chlorhexidine diacetate. of phenylmercuric borate and 1% solution of chlorhexidine diacetate. The solutions of additives Reagents mentioned above were prepared and examined using Citric acid monohydrate, sodium citrate p.a. methods described in other publications (10, 11). P.P.H. POCH Gliwice, polyvinyl alcohol 72000 (PVAL) P.P.H. POCH Gliwice, Thiomersal BP Preparation and studies of physicochemical stability 1998 ñ Caesar & Loretz GmbH, phenylmercuric of sterile buffered solutions of hydroxyethylcellu- borate Pharma Cosmetic s.c. Cracow, chlorhexidine lose (HEC), hydroxypropylmethylcellulose (HPMC) diacetate monohydrate ñ Fluka Biochemika, benza- and polyvinyl alcohol (PVAL). lkonium chloride NF, β-phenylethyl alcohol (2- 50.0 g of the solutions containing 0.7 g of phenylethanol) Merck-Schuchard. HEC, 1.0 g of HPMC and 4.0 g of PVAL were pre- pared in separate flasks. The weight of the solution, Apparatus after the filtration through a fritted glass funnel pH-meter (CyberScan 500, Singapore); Schott G-1, was supplemented up to 100.0 g with Table 1. Formulary composition of the eye drops containing cefazolin. Formulary versions Constituents (per 100 g of the eye drops) I II III IV V VI 12 12 Cefazolin 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Citrate buffer I Constituents of the buffer: Sodium citrate 3.0 99.0 99.0 99.0 - - - 99.0 - Citric acid 0.15 Water 96.85 Citrate buffer II Constituents of the buffer: Sodium citrate 6.0 - - - 49.5 49.5 49.5 - 49.5 Citric acid 0.30 Water 93.70 Solution of polyvinyl alcohol (PVAL) viscosity η = 17.11 mPa∑s - - - 49.5 49.5 49.5 - 49.5 Thiomersal - 0.002 0.02 - 0.002 0.02 - - Phenylmercuric borate - - - - - - 0.001 0.001 β-Phenylethyl alcohol - 0.4 0.4 - 0.4 0.4 0.4 0.4 Influence of additives and storage temperature on physicochemical... 227 the preserved solution of citrate buffer, which was HEC (0.25%), HPMC (0.5%), PVAL (2.0%), thio- filtered through Schott G-3 and contained sodium mersal (0.002%-0.02%), phenylmercuric borate citrate (6%), citric acid (0.3%), phenylmercuric (0.001%), benzalkonium chloride (0.005%), borate (0.002%) and β-phenylethyl alcohol (0.5%). chlorhexidine diacetate (0.01%), sodium pyrosulfite The solutions were poured into infusion bottles (0.01%), disodium EDTA (0.03%). Solutions of cefa- and sterilized at the temperature of 120OC ± 2OC for zolin containing the additives, protected from light, 20 min. The freshly prepared solutions of hydrogels were stored at the temperature of 4∞C and 20∞C for 14 and those stored for 12 months at the temperature of days and were examined for their color and clarity. 20OC were submitted to physicochemical evalua- The following examined additives were not compati- tion, during which the following parameters were ble with 1% solution of cefazolin: Thiomersal at the determined: color and clarity, pH, osmotic pressure concentration over 0.003%: sediment appeared after and viscosity. The solutions of selected hydrogels, 6 days of storage at the temperature of 20∞C and after both freshly prepared and stored for 12 months, 10 days at the temperature of 4∞C. were colorless and clear. Benzalkonium chloride at the concentration of HEC solutions. 0.005% caused opalization immediately after mix- Freshly prepared solution: pH 6.10 ± 0.1, osmotic ing with 1% solution of cefazolin. pressure 369.00 ± 2.10, viscosity 29.24 ± 0.4 mPa∑s. Chlorhexidine diacetate at the concentration of After 12 months of storage: pH 6.11±0.1, osmotic 0.01%, opalization appeared immediately after mix- pressure 371.12 ± 3.20, viscosity 23.09 ± 0.3 mPa∑s, ing with 1% solution of cefazolin, which was fol- viscosity loss 21.04%. lowed by precipitation during the storage at the tem- HPMC solutions. perature of 20∞C and 4∞C. Freshly prepared solution: pH 6.25 ± 0.2, osmotic pressure 372.20 ± 4.40, viscosity 11.21 ± 0.3 mPa∑s. Preparation of the eye drops containing cefazolin After 12 months of storage: pH 6.23 ± 0.2, osmotic Under sterile conditions cefazolin was dissolved pressure 368.00 ± 2.50, viscosity 10.18 ± 0.2 mPa∑s, in the recommended volume of citrate buffer I or II viscosity loss 9.19%.
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