Drug development
A technology of pharmaceutical products and pharmaceutical preparations, applied in the direction of drug delivery, antibacterial drugs, pharmaceutical formulations, etc., which can solve the problem that the preparation is not simple
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Embodiment 1
[0109] Embodiment 1: solubility test
[0110] The purpose of Example 1 is to provide a mixed pharmaceutical product containing CMS or colistin sodium mesylate and zidovudine. CMS is an inactive prodrug that, after parenteral administration, is enzymatically hydrolyzed to colistin sulfate, a salt of the antimicrobial agent polymyxin E. The antiretroviral agent zidovudine is also a prodrug that requires triphosphorylation to become effective and acts as an antibiotic resistance breaker (ARB). Colistin sulfate and zidovudine are two registered drugs that need to be combined into one antibiotic combination drug product. However, this had never been done before, and since a potential solubility difference between the two actives could not be ruled out, the inventors performed detailed solubility and stability tests to identify common compatible solvents.
[0111] A) Solubility and stability in aqueous solvent systems
[0112] To identify a common compatible solvent for the two...
Embodiment 2
[0141] Embodiment 2: freeze-drying with organic solvent system
[0142] To determine whether an organic solvent system is suitable for producing lyophilizates of C+Z, a lyophilization test was performed on a combination of C+Z dissolved in a TBA / water mixture. The formulations described in Table 4 were lyophilized:
[0143] Table 4:
[0144]
[0145] Formulations were compounded and filled into clean and heat sterilized 20R glass vials. Filled vials were then stoppered with autoclaved and dried lyophilized stoppers, sealed in lyophilized bags and loaded in a lyophilizer. Freeze dry samples using an appropriate lyophilization cycle. For each variable, 10 vials were prepared. The chamber pressure was monitored and recorded by online data acquisition to detect the end of sublimation. Samples were analyzed by degradation curves immediately after lyophilization (T0).
[0146] Material
[0147] Table 5 lists the materials used in Example 2. All were obtained from comm...
Embodiment 3
[0179] Embodiment 3: lyophilization with aqueous solvent system
[0180] Example 3 examines the possibility of freeze-drying of mixed drug products with aqueous based solvent systems. Formulations were compounded and filled into clean and heat sterilized 30R glass vials. Filled vials were stoppered with autoclaved and lyophilized stoppers, sealed in lyophilized bags and loaded in a lyophilizer. Samples were lyophilized using the same lyophilization cycle as in Example 2. For each variable, 10 vials were prepared. The chamber pressure was monitored and recorded by online data acquisition to detect the end of sublimation. Samples were analyzed immediately after lyophilization (TO) for reconstitution speed and behavior; CMS and zidovudine degradation curves were determined using the Ph. Eur method; and residual water content was determined using the universal Karl-Fischer furnace method.
[0181] Material
[0182] Table 9 lists the materials used in Example 3. All mater...
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