UsesConsult your pharmacist or physician. Show Side EffectsConsult your pharmacist or physician. In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. PrecautionsConsult your pharmacist or physician. InteractionsConsult your pharmacist or physician. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Does Colistin Sulfate (Bulk) 1 Billion Unit Powder interact with other drugs you are taking? Enter your medication into the WebMD interaction checkerOverdoseIf someone has overdosed and has serious symptoms such as passing out or trouble breathing , call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Notes No monograph available at this time. Missed Dose Consult your pharmacist or physician. Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use. CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment. 1 Development Department, mibe GmbH Arzneimittel, Brehna, Germany, Find articles by Corina Pfeifer 1 Development Department, mibe GmbH Arzneimittel, Brehna, Germany, Find articles by Sylvia Noll 1 Development Department, mibe GmbH Arzneimittel, Brehna, Germany, Find articles by Hagen Gerecke 2 Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany, Find articles by Georg Fassauer 2 Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany, Find articles by Thomas Jira 3 Hospital Pharmacy, University of Leipzig, Leipzig, Germany, Find articles by Yvonne Remane 3 Hospital Pharmacy, University of Leipzig, Leipzig, Germany, Find articles by Jan Vogel 3 Hospital Pharmacy, University of Leipzig, Leipzig, Germany, Find articles by Roberto Frontini 1 Development Department, mibe GmbH Arzneimittel, Brehna, Germany, Find articles by Robert Reinhardt Received 2016 Mar 4; Revised 2016 Jun 16; Accepted 2016 Jul 5. Copyright Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ A suspension for oral use which consists of three non-absorbable antibiotics (amphotericin B, colistin and tobramycin) is often used in clinical practice for the selective decontamination of the digestive tract (SDD) of patients in intensive care. Such a therapy is a preventive tool to minimise the risk of pneumonia and bacteraemia in intubated patients. The administration and the treatment results are controversially discussed. One limiting factor for a unique SDD treatment in the hospitals is a lack of adequate data regarding batch formula and stability for such a formulation. Since no detailed procedures, specifications or stability data are available for manufacturing this formulation there may be discrepancies regarding formulation and stability of suspensions prepared in different pharmacies. The aim of this research was to collect the physicochemical and microbiological stability data of a developed, stable standard formulation under defined storage conditions. The effectiveness of the SDD suspension should be preferably proven over a long period. This would help guarantee that all patients receive the same preparation, therefore, ensuring similar efficacy and improved safety. An adequate formulation composed of the registered, marketed medicinal product Ampho-Moronal suspension (Dermapharm AG, Germany) and a buffered, preserved aqueous solution of colistin and tobramycin both as sulfates has been developed. A stability study has been performed on two batches of the formulation. During the storage, samples were taken and compatibility was verified by physicochemical and microbiological testing in stability-indicating terms of colour, odour, flavour, pH, chemical and microbiological purity as well as in vitro potency. The test methods were built and tailored to be suitable, reliable and precise for the test needs. The results show the physicochemical and microbiological stability of the described formulation for defined storage conditions. A standardised formulation with a proven stability for at least 6 months under fridge (5°C±3°C) conditions for the SDD of patients in intensive care was established. EAHP Statement 3: Production and Compounding. EAHP Statement 5: Patient Safety and Quality Assurance A suspension containing a combination of different, slightly absorbable or non-absorbable antimicrobial substances as amphotericin B, colistin and tobramycin (see table 1) is often used for the selective decontamination of the digestive tract (SDD) of artificially (mechanically) ventilated intensive care patients.1–3 Overview of the used antibiotics
There are currently no commercially available formulations on the market which are suitable for this purpose and the risk assessment of the preparation is the responsibility of the hospital pharmacists. The lack of stability data, in particular, means that hospital pharmacists have no proper instruction for the suitable storage conditions of the preparation and they are forced to prepare before use. This is an undesirable situation since processing and storage time can influence the quality of the suspension. A unique batch formula with known stability under defined storage conditions as well as a detailed manufacturing process is required to avoid differences in composition and stability between formulations prepared in different pharmacies. The assessment of the quality and the compatibility of the individual drug substances for pharmaceutical products prepared in non-industrial standards is mandatory.4 Furthermore, the knowledge acquired concerning stability and the establishment of a suitable shelf-life for the suspension allows hospital pharmacists to prepare larger quantities for storage, thus removing the necessity to prepare immediately before use. This will be a significant benefit to the pharmacists involved. Therefore, an adequate formulation has been developed based on the registered, marketed medicinal product Ampho-Moronal suspension (Dermapharm AG, Germany). The stability study was performed adapted from the stability guideline (CPMP/ICH/2736/99)5:
To perform stability studies, selective physicochemical and microbiological analysis of the relevant stability-indicating parameters in the formulation were performed. On the basis of legal guidelines (Q6A and Q3B)6 7 and the knowledge derived from the Ph.Eur.8 and United States Pharmacopoeia (USP)9 monographs of the individual drug substances an appropriate specification has been set for the investigated suspension (see table 2). Specification for the quality control of the investigated suspension
Developed and validated methods were recently published to describe the purity of each suspension active pharmaceutical ingredient and with it to assess the suspension chemical stability.10 The stability of the described formulation regarding the microbial purity and the antimicrobial preservation efficacy has been evaluated using product-specific validated methods of the Ph.Eur.8 The determination of the in vitro potency is one of several methods which can be used to characterise the performance, and therefore, the efficacy of a finished (eg, topical) dosage form.11–13 The determination of the in vitro potency is performed using the agar diffusion method, described in the pharmaceutical scientific literature as the most simple and old established in vitro technique for semisolid and liquid preparations to test the liberation of the active ingredients (eg, antibiotics) out of the matrix. The methods are in-house developed methods, only the principles of the agar diffusion test as well as the statistical testing design and equation approach are adapted from the Pharmacopeias Ph.Eur. and USP as a convenient tool.8 9 The testing approach is to determine the in vitro potency of the complete formulation. This approach had been chosen as an adequate in vivo simulation of the potency as well as for the assessment of the preparation. The suspension is prescribed for the patient as a 10 mL dose four times daily. One dose contains 118.0 mg of colistin sulfate (corresponding to 100 mg of colistin base; Xellia Pharmaceuticals), 121.75 mg tobramycin sulfate (corresponding to 80 mg of tobramycin base; Chongqing Daxin) and 500 mg amphotericin B. The following excipients of the suspension are preservatives and are therefore also required to be declared: 9.5 mg methyl parahydroxybenzoate (EP), 3.0 mg propyl parahydroxybenzoate, 10.0 mg sodium benzoate and 7.5 mg sodium metabisulfite (Azelis Deutschland Pharma GmbH). Aqua conservata is used as a standard formulation in the manufacture of the suspension.14 It contains 0.025% propyl parahydroxybenzoate and 0.075% methyl parahydroxybenzoate in water. To manufacture one dose, the declared quantities of colistin sulfate, tobramycin sulfate as well as 52.88 mg disodium phosphate dodecahydrate, 132.80 mg sodium dihydrogen phosphate (Merck dura GmbH, Germany) and 29.40 mg potassium chloride (VWR International GmbH or Kirsch Pharma GmbH) are dissolved in about 3 mL aqua conservans. The solution has to be checked for clarity. Next, 5.0 mL (corresponding to 5350 mg) of Ampho-Moronal suspension (Dermapharm AG, Germany) is added. The pH should be adjusted to between 5.3 and 5.8 with a solution of citric acid (20%) in aqua conservans. This pH range is in accordance with the buffer of Ampho-Moronal suspension and does not affect the efficacy, stability or solubility of colistin and tobramycin. The dose of suspension is finalised by dilution with 10.0 mL (10.5 g) with aqua conservans. The final suspension should be homogeneous and easily redispersible. All excipients should have Ph.Eur. quality. The prepared suspension was analytically investigated during the stability study. Details to the used physicochemical and especially chromatographic methods (reagents, sample preparation and measurements) can be found in a previous article to this topic.10 The used microbiological methods including the materials and reagents are described in the following paragraphs. First, the in vitro potency test will be illustrated as the most important quality indicator for such a suspension. The investigated formulation contains a very high concentration of all antibiotic ingredients with overlapping scope of action. The in vitro potency was tested with the complete formulation, without further dilutions. Therefore, the criterion of the selection was the converse sensitivity/resistance of the microorganisms to the investigated antibiotics—sensitive to one of the substances and not sensitive to the others (see table 3). Selected test microorganism for the in vitro potency test
The goal of the screening was to find preferably primary resistant species/strains. It was necessary to perform a very expanded screening of scientific literature sources and of different species and strains for the detection of suitable microorganisms.15–21 The established testing methods are specific according to the type of the examination (determination of the in vitro potency of the complete formulation) and the selected test microorganisms. The in-house developed agar diffusion method has been applied as an adequate test tool. The statistical study design of the in-house agar diffusion method follows the USP, chapter <81>, item cylinder-plate assays.9 Accordingly, suitable media, incubation temperature and duration had been defined experimentally in-house, too. For details, see table 3. The specificity and selectivity of the used test method have been confirmed in preliminary tests. Any influence of both other antibiotics as well as the influence of the containing preservatives—methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium benzoate, sodium metabisulfite—to the specific test strain has been excluded experimentally. Preparations containing various combinations of the relevant ingredients were tested for this purpose with the agar diffusion method using the selected test microorganisms. The in-house method uses an unconventional testing approach, because the goal of the test is the comparison of the in vitro potency of the complete formulation (without any analytical sample preparation) at different time points. This special parameter cannot be expressed in activity units as usual for results of antibiotic assays according to Pharmacopeias. Therefore, the principle of the method here is the comparison of the diameters of inhibition zones, which are given by the quantities of the antibiotics in the formulation in relation to a constant value (=inhibition zones, induced by five defined concentrations of the appropriate reference standard) at each stability time point. Different steps during the development were done for the above described approach. First, the range of the five concentrations of the reference standard solutions giving inhibition zone diameters equal to those of the described fresh prepared original formulation was determined. Second, adequate quantities of the inoculum for each microorganism to be incorporated into an appropriate volume of the used agar media were defined. The quantity was chosen to allow sufficient growth within the incubation period and to give acceptable inhibition zones. For testing, the inoculum was added to the agar medium that had been melted and cooled up to 45°C–50°C. Afterwards the inoculated agar medium was poured immediately into standard Petri dishes to generate uniform layer. Then, seven cavities of 6 mm diameter each were prepared in the agar layer of each plate using sterile punches of stainless steel. The testing solutions were applied in these cavities in the order given in the USP, chapter <81>, see above.9 After the incubation time for each microorganism (see table 3) the diameters of the inhibition zones were measured with a precision of 0.1 mm using a calibrated digital calliper. The single ‘relative value of potency’ of the formulation was calculated by interpolation from the standard curve using the log-transformed straight-line method with the least-squares fitting procedure according to USP.9 That means the inhibition zone diameters have been compared between the reference standard and the tested formulation. Microbial determinations of antibiotics potency are subject to interassay as well as intra-assay variables; therefore, two or more independent assays are required for reliable estimation of the potency of a given sample. So, eight separate determinations for each antibiotic have been accomplished at each testing time point during the stability time accordingly. Statistical evaluation of the results of the in vitro potency has been performed using the test of equivalence (TOST: two one-sided tests).9 22 The tests were conducted at a significance level of α=0.05. Using this statistical method it is important to define ‘sufficiently similar (equivalent)’ for the purpose of the study. The acceptance limits were carefully set to accept the results in a 15% variation range δ from the start value. This difference δ had been set on the basis of real specification limits of a typical antibiotic assay and the difference is also acceptable for reason of the unconventional approach of performing this test in opposite to the conventional antibiotic assay techniques. All statistical analyses have been performed using Microsoft Excel 2010. Beside the determination of the in vitro potency further microbiological tests were done to demonstrate the stability of the formulation. The test for microbial purity has been carried out at the beginning and at the end of the stability study period. The described non-sterile formulation has been classified as aqueous preparation for oral (and oromucosal) use according to the Ph.Eur. chapter 5.1.4. The microbiological examination has been performed in accordance with Ph.Eur. chapter 2.6.12 (microbial enumeration tests) and 2.6.13 (test for specified microorganisms), respectively.8 The plate-count method (pour plate method) has been applied for the quantitative enumeration of the mesophilic bacteria and fungi that may grow under aerobic conditions. Ten grams of the formulation has been used as a sample for the test. The sample has been suspended in buffered sodium chloride-peptone solution pH 7.0 containing neutralising agents for interfering preservatives. The recommended mediums, Casein soya bean digest agar and Sabouraud 4% dextrose agar have been used for the tests. Casein soya bean digest broth has been mixed with a quantity of the prepared sample corresponding to 1 g sample for the determination of the absence of specified microorganisms and further processing as described in the Ph.Eur.8 MacConkey broth and agar as well as cetrimide agar and mannitol salt agar has been applied as selective media for the test of the absence of specified microorganisms (here Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli). The compositions of the used media follow the Ph.Eur.8 and they have been supplied by Merck/Millipore (Merck KGaA, Darmstadt, Germany). The antimicrobial preservation efficacy test has been conducted with a sample of the test formulation with reduced content of preservatives simulating the potential decrease of these ingredients during the shelf-life. The test of the preserved formulation in the multidose container has been performed according to Ph.Eur. 5.1.3.8 The compliance with the acceptance criteria for oral (and additionally oromucosal) preparations has been checked. The test consists of challenging the preparation with a prescribed inoculum of test microorganisms (here S. aureus ATCC 6538, P. aeruginosa ATCC 9027, E. coli ATCC 8739, Candida albicans ATCC 10231, Aspergillus brasiliensis ATCC 16404), storing the inoculated preparation at temperature range of 20°C–25°C (protected from light), withdrawing samples from the container at specified intervals of time and determine the microbiological quality in the samples. The recommended media, Casein soya bean digest agar and Sabouraud 4% dextrose agar has been used for the tests by using the pour plate method (see test of microbial purity). Colour, odour and flavour as well as pH values (5.3–5.8) were unaltered during the storage time of 6 months under the defined storage conditions (2°C–8°C and 25°C, 60% RH). The assessment of the chemical stability of the three individual active ingredients is preformed regarding the defined specification (see table 2). ColistinThe stability of colistin in the investigated suspension is exemplarily shown in figure 1 and under different storage conditions. According to the Ph.Eur. monograph any impurity (excluding the sum of five colistin analogues) should not be <4% and the sum of unknown impurities should not be <23%.8 These two parameters can be used for the stability assessment of colistin in the investigated suspension. TobramycinFor the assessment of the purity profile of tobramycin during the stability study several impurities were considered and the specification limits were set according to the Ph.Eur. and USP monograph.8 9 Potential impurities of tobramycin are known: kanosamine, nebramine (impurity B, EP), deoxystreptamine and deoxystreptamine-kanosaminide which may be formed by hydrolysis in acidic and basic solutions as well as through oxidation.8 9 23 In table 4, the results for the purity profile of tobramycin for one batch under different storage conditions is exemplary shown. Stability of tobramycin at 25°C and 2°C–8°C (batch: 120214A, 40 mL glass bottle)
These data are representative for the stability of colistin and tobramycin for all investigated batches and packing forms (glass bottle and prefilled syringe). AmphotericinThe judgement of the impurity profile from the third active substance amphotericin B was also done in accordance to the limits of the Ph.Eur. monograph.8 Commercially available amphotericin B is manufactured by fermentation, which may produces biologically active analogue impurities as by-products like heptaenes and tetraenes. The acceptable content of total impurities is limited by 15%. All impurity profiles measured (data shown in table 5 and figure 2) demonstrate only small deviations in comparison to the used active substance and in any case the content of heptaenes and tetraenes achieve the acceptance limits of the Ph.Eur. monograph.8 Purity of amphotericin B at 25°C and 2°C–8°C (batch: 120214A, 40 mL glass bottle)
The in vitro potency of the described formulation is demonstrated as an example in table 6 for one batch. Stability parameters at 25°C and 2°C–8°C (batch: 120214A, 40 mL glass bottle)
These data are representative regarding the stability for all investigated batches and packaging forms (glass bottle and prefilled syringe). The in vitro potency can be shown as equivalent after storage of 6 months at 2°C–8°C for the three active ingredients. The formulation with reduced content of preservatives has been fulfilled the acceptance criteria for oral (and oromucosal) preparation as result of the test of antimicrobial efficacy of the preservation according to Ph.Eur. 5.1.3. The unchanged pH values as well as no organoleptic changes support good stability and compatibility of the active substances in the investigated suspension under all conditions. In contrast to this the purity profiles and the in vitro potency of the individual substances show differences. It is obvious from figure 1 that colistin, a cyclic heptapeptide, in the investigated suspension is not stable at 25°C. Deamination, hydrolysis and racemisation are well known possible reactions for the degradation of polypeptides. Orwa et al 24 identified the most degradation products of colistin solution at neutral or acid conditions as isomers through racemisation. On the other side at 2°C–8°C temperature range the acceptance limits for the assessment of colistin stability are fulfilled during the whole testing period (6 months) and no change in the purity profile (fingerprint) is observed. The in vitro potency has been changed during the stability time in different way for the examined antibiotic substance. There is a significant reduction at 6 months storage at 25°C, 60% RH for colistin. The equivalence test is not passed using the acceptable difference of δ ≤15% but at 2°C–8°C δ was calculated well below 15%, and therefore, the test criterion is fulfilled. The in vitro potency results for colistin correlate well with the results of chemical stability. The chemical stability of tobramycin is still ensured at 25°C after storage over 6 months. The values obtained (see table 4) for the known degradation products are still in accordance with specification limits for the desired Ph.Eur. quality of tobramycin. After 6 months at 2°C–8°C temperature range storage condition there are only small variations in comparison to the impurity values at the beginning (0 month). Brandl and Gu23 reported rapid degradation of tobramycin under drastic pH values and at neutral pH extremely slow reactions in the absence of oxygen even at high temperatures.25 The in vitro potency values have been reduced for tobramycin in comparison to the initial values. These tobramycin results support the previously reported incompatibilities of tobramycin with the anion excipient, especially carmellose sodium. A precipitation of tobramycin can be occurring in the presence of this substance at pH values <7.5. Because of the acceptable tobramycin purity levels the precipitant probably leads to decreased in vitro potency.8 14 26 But the defined acceptance equivalence criteria of δ ≤15% for the in vitro potency test for tobramycin is still accomplished under storage conditions of 2°C–8°C and 25°C. Although polyene macrolide antibiotics are known to be chemical and photosensitive amphotericin B is very stable in the investigated suspension.25 No degradation and only small variation in the impurity profile has been observed. As described in the literature the oxidation process for the heptaene is weakened at neutral pH value.27 This physicochemical stability of amphotericin B is in good correlation with the unchanged values observed in the in vitro potency test. Additionally, it could be shown that the described formulation is stable regarding the microbiological purity for 6 months at 2°C–8°C and 25°C, storage in both types of primary containers. This study established the physicochemical and microbiological stability of the described standardised formulation—suspension consisting the three antibiotics, amphotericin B, colistin and tobramycin, which is often used in clinical practice for SDD of patients in intensive care. The developed standardised formulation contain Ampho-Moronal suspension (Dermapharm) and a buffered, preserved aqueous solution of colistin and tobramycin both as sulfates. To prepare the suspension the quantities of colistin sulfate, tobramycin sulfate as well as the buffer substances sodium phosphate dodecahydrate, sodium dihydrogen phosphate and potassium chloride were dissolved in aqua conservans. Next, Ampho-Moronal suspension is added. The pH should be adjusted to between 5.3 and 5.8 with a solution of citric acid. The dose of suspension is finalised by dilution with aqua conservans. The formulation can be manufactured in the clinical pharmacies in a simple way and stored at least for 6 months at the temperature range of 2°C–8°C. The preparation should be applied in further clinical trials for analysing the efficacy of SDD procedures due to the standardised formulation can ensure the comparability of the study results. What this paper adds?What is already known on this subject?
What this study adds?
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