A novel echinocandin, CD acetate CD; Figure 1 , is presently being developed as a once-weekly i. Characteristic of the echinocandins, CD is a cyclic hexapeptide with a lipophilic tail. It displays potency and spectrum of activity in vitro typical of the echinocandins.
Solubility data are also presented. The stability and solubility features of CD not only provide advantages for manufacturing and storage, but also enable expansion of echinocandin use to include weekly i. Structures of CD 1 and anidulafungin 2. The primary means of elimination in vivo for anidulafungin is chemical degradation that occurs initially at the hemiaminal region shown in the box. For CD, the hemiaminal is replaced with a choline aminal ether that imparts greater stability and solubility to the product compound.
All solvents and modifiers were HPLC grade. HPLC analyses were performed using an Agilent Series LC with an autosampler, thermostatted column compartment and multi-wavelength detector. The synthesis of CD will be described elsewhere. All quantitative assays and purity assessments were performed using two reversed-phase HPLC methods.
Method 1 was used to assess the purity of CD and to identify the formation of any degradation products. Quantitation was performed by comparison of peak areas of test samples to the peak areas of external reference standards, analyzed in separate HPLC injections within the same set of samples. The reference standards for these studies were solutions of known concentration of previously purified and characterized lots of anidulafungin and CD Each respective matrix was mixed separately with 1.
The sample volume for each solution was 5. No stabilizers or other excipients were added to the lyophilisate. Stability was monitored over a period of 9 months using reversed-phase HPLC methods 1 and 2. Appearance was also monitored. CD 3. The dextrose formulation solution was stored in an infusion bag at room temperature.
The saline formulation solution was stored in a sealed, clear glass vial. Both were unprotected from light for up to 15 months. No stabilizers were added to the solutions. Stability was monitored using HPLC methods 1 and 2. The assay values were reported in comparison with a reference standard and are an indication of the amount of CD in solution.
CD stock solutions acetate buffer, lactate buffer and USP sterile water were made at concentrations of 3. No stabilizers or other excipients were added. The sterile water and some acetate-buffered solutions were kept at room temperature and unprotected from light.
Stability was monitored up to 18 months using HPLC methods 1 and 2. The assay values were reported in comparison with a reference standard. No solubilizers or other excipients were added. The solution samples were analyzed by HPLC method 1. The time curves for CD in the various matrices are shown in Figure 2a. These results were in good agreement with an earlier report demonstrating rapid chemical degradation of anidulafungin in human plasma.
The time curves for anidulafungin in the various matrices are shown in Figure 2b. Degradation of CD a and anidulafungin b in plasma from different species and in phosphate-buffered saline PBS buffer.
No stabilizers were used in the reactions. In contrast to anidulafungin, CD showed very little degradation in the matrices that were tested. The results from stability studies under accelerated conditions of two lots of CD lyophilisates are presented in Table 1. Values reported for individual lots are the percent area under the curve for CD and for the total of all impurities and degradation products. Averages for purity, impurity and degradation products and percent degradation are also presented.
The average chromatographic purity after 9 months was The results from stability studies of CD in two different i. Purities are reported as the percent area under the curve for CD out of the total chromatogram. Degradation was minimal in each solution over the course of the study.
The results from stability studies of CD in different aqueous solutions at varying pH in the absence of stabilizers are presented in Table 3. In contrast, degradation was extremely low at room temperature in acetate buffers pH 4. No epimerization of the hemiaminal ether was observed in any of the samples. The solubility of CD was evaluated in various aqueous solutions, buffered solutions pH range from 4. Anidulafungin was also evaluated under many of the same conditions.
The solubility results are displayed in Table 4. Solubilities for CD were noticeably lower in phosphate and citrate buffers in comparison with the other media evaluated.
Chemical degradation marked by cleavage of the cyclic echinocandin core is common to the currently approved echinocandins and occurs in both plasma and buffered solutions, resulting in inactive degradants that are subject to further reaction and degradation.
As illustrated in Figure 3 , the ring-opening step that initiates the chemical degradation cascade of anidulafungin and other echinocandins is disfavored in CD because of the presence of the hemiaminal ether moiety. Whereas the hemiaminal hydroxyl of anidulafungin leads to a highly reactive, open-chain aldehyde, the corresponding step with the hemiaminal ether of CD would result in an oxonium ion, which is disfavored energetically.
This explanation is further supported by prior work from Damle et al. The primary degradation product was itself reactive, undergoing further transformation. During in vivo studies utilizing a radioactive tag, they found that degradation products of anidulafungin persist in the body until eventual elimination in the feces. In our studies, formation of such a degradation product was not observed with CD We used anidulafungin as the comparator in these studies not only because of the structural similarity to CD, but also because anidulafungin has the longest plasma half-life of the approved echinocandins across species.
Proposed mechanism of the first step of the chemical degradation pathway for echinocandins at physiologic pH. The cyclic anidulafungin can undergo a ring-opening event in which the hemiaminal cleaves to form a linear peptide having a terminal amide and an aldehyde from the C5 hydroxyl of the ornithine residue.
This open-chain degradant is then subject to further degradation. In addition, the reactive aldehyde that is generated is then available for covalent reaction intra- or intermolecularly. This pathway is disfavored for CD, as the first step would result in an oxonium ion. This oxonium formation is likely further discouraged by the proximity of the quaternary ammonium cation of the choline.
Should the site be taken down, which we fully expect to happen we have attached a screenshot below. While CD told The Other Paper that this is merely a contract dispute between the programmers and the owners of the frequency, it looks more and more as though the end result will be Salem taking over the operations of A sale of the station would not affect the LMA, and WWCD looks forward to continuing to provide independent radio to central Ohio listeners for years to come.
Instant Insight: What is telling about the statement is that CD acknowledges a sale of the station could be taking place. Based on a pair of domain registrations it appears the station may soon come under the control of Salem Media. The question now becomes will Salem be purchasing Will CD move to another frequency in the market, or is it at the end of its journey?
Remember Me. Recent Headlines. Ralphie Aversa Joins Got News? Let us know at News RadioInsight. Login Membership Account. November 17, The WWCD brand has always been a strong partner of Columbus non-profit organizations, providing arts, culture, and social service organizations promotional support to reach key target audiences. The WWCD brand was established in in Columbus as an independently owned and operated, alternative rock radio station.
For 30 years, it has maintained its alternative format and its independence, funded solely by commercial advertising revenue. Tune in now to When I tune in to Depending on where you live, you may have an easier time picking us up once construction on the Huntington building is complete and our new antenna is running at full power. Construction is expected to be completed by mid-December, although we continue to hope for an earlier completion date.
If all else fails, you can still tune in to the stream!
0コメント