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The quality-assured preparation of crushed and diluted preparations for children is a challenge. In this study, a multicenter study was conducted to validate the preparation method for the quality assurance of baclofen powder, clonidine powder, and hydrocortisone powder prepared from tablets according to a previously established method. In-hospital preparations were prepared at five medical facilities under different crushing and mixing conditions. After storage in closed bottles, in-use bottles, and laminated paper for 120 days, ingredients stability, drug elution, and content uniformity after packaging were evaluated. All three ingredients were maintained at between 90% and 110% of their initial content for 120 days under packaging conditions of 25 ± 2 °C and 60 ± 5% relative humidity, with no change in dissolution in all formulations made at all five facilities. The content uniformity was also acceptable. The established method may contribute to quality-assured pediatric dosage form modification.

Purpose Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE). There is no radiation medical countermeasure approved by the U.S. Food and Drug Administration which can be used prior to radiation exposure to protect exposed individuals. Different formulations containing synthetic genistein (BIO 300) are being developed to counter the harmful effects of radiation exposure. Materials and methods We investigated the efficacy of a BIO 300 Oral Powder (OP) formulation as a prophylactic radiation medical countermeasure against a lethal dose of cobalt-60 gamma-radiation in CD2F1 male mice while comparing to other formulations of BIO 300 and Neulasta (PEGylated filgrastim), a standard of care drug for H-ARS. Results BIO 300 OP provided significant radioprotection against ionizing radiation in mice when administered twice per day for six days prior to total-body radiation exposure. Its radioprotective efficacy in the murine model was comparable to the efficacy of a single subcutaneous (sc) injection of Neulasta administered after total-body radiation exposure. Conclusions Our results demonstrate that BIO 300 OP, which can be administered orally, is a promising prophylactic radiation countermeasure for H-ARS.

Biorelevant two-stage in vitro testing is increasingly used as a tool for various applications in drug development. Three important applications of two-stage in vitro testing are the classification of weakly basic drug compounds as part of the refined Developability Classification System, the prediction of intraluminal drug concentrations in the gastrointestinal tract and the prediction of plasma concentration profiles using physiologically based pharmacokinetic modeling. For the weakly basic, antiretroviral drug ritonavir, two-stage testing is triggered as a customized investigation in the refined Developability Classification System classification process to assess whether the drug could supersaturate and precipitate when exposed to the steep change in pH that occurs during drug transfer from the stomach into the small intestine. It was shown that for 2 Norvir® formulations, a tablet and an oral powder formulation, the two-stage test yielded similar results to the more complex “transfer” model with regard to the supersaturation and precipitation behavior of these amorphous solid dispersion formulations. Furthermore, solubility and two-stage data were mechanistically modeled in the in vitro data Analysis Toolkit and the results used as input parameters for a physiologically based pharmacokinetic model built in the Simcyp Simulator.

Background: 18β- glycyrrhetinic acid (Gly) is the major bioactive component of licorice roots and rhizomes of the Glycyrrhiza glabra species. It shows many activities such as antiviral, anti-inflammatory, antioxidant, antimicrobial, and antifungal, however, its use in the health field is very limited due to the low water solubility. Methods: This paper deals with the development of a new technological approach for Gly dissolution rate enhancement. It consists of Gly intercalation (guest) in the interlamellar spaces between the inorganic spaces (host) of the anionic clays “hydrotalcites” (HTlc) to obtain hybrids MgAl-HTlc-Gly and ZnAl-HTlc-Gly. Gly can find applications in both systemic and local therapies, thus advantages of the use of the hybrids in these two fields were investigated. Results: Gly dissolution rate from hybrids in the intestinal environment, site in which it is preferentially absorbed, resulted enhanced (ZnAl-HTlc-Gly > MgAl-HTlc-Gly) compared to the crystalline form, thereby, making them suitable for oral administration as dry powder in hard capsules. : For a local therapy, bioadhesive, vaginal emulgels loaded with the hybrids were developed. These showed suitable mucoadhesive property to the vaginal mucosa, necessary to prolong the residence time in the application site. The emulgel containing ZnAl-HTlc-Gly showed a faster and higher release profile than that containing MgAl- HTlc-Gly. Conclusions: The obtained results suggest that Gly intercalation into HTlc, especially in ZnAl-HTlc, allows to enhance Gly dissolution when the hybrids are formulated both as oral or topical products.

Hydrocortisone has been utilized in the management of adrenal insufficiency. For pediatric patients, the commercially available enteral form of hydrocortisone tablets (Cortoril®) is administered in powder form after being compounded by a pharmacist. However, the stability and quality of compounded hydrocortisone powder have not been verified. In this study, we formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. Stability was examined over 120 days in three storage conditions: closed bottle, in-use bottle, and laminated paper. Drug dissolution and powder X-ray diffraction analysis were conducted to assess its physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify hydrocortisone and its degradation products. Although impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage, no crystallographic and dissolution changes were noted. Hydrocortisone content was maintained between 90% and 110% of initial contents for 120 days at 25 ± 2 °C and 60 ± 5% relative humidity in all packaging conditions.

Background and importance Codeine mixed with calcium salts filled into capsules is used to treat chronic diarrhoea in transplant, oncological and geriatric patients, and in patients with irritable bowel disease. At least 11 500 hard capsules are regularly prepared from a manually blended powder mixture in the hospital pharmacy per month. Turbula 2F2 blender has been introduced into the hospital pharmacy to optimise the mixing process. Aim and objectives To establish optimal blending time and speed for mixing of codeine with the Turbula 2F2 blender and to verify homogeneity by determining the amount of codeine in the samples, a validated spectrophotometric analytical method was used. Material and methods The total amount of prepared mixture was 245.7 g containing 4.5 g of codeine phosphate (1.83%). The optimal rotation speed of Turbula was established as 49 rounds per min (RPM) based on visual analysis with colourant instead of codeine. A 2 litre polyethylene container for homogenisation was used. Calcium carbonate was premixed with colloidal silica, and codeine and tricalcium phosphate added. Five samples for analysis were taken from different places in the container after 5, 10, 15 and 20 min of mixing. Expression of relative standard deviation (RSD) was used to evaluate the homogeneity of codeine in the mixture. Results The results are summarised in table 1. Conclusion and relevance Based on the results, the optimal time of 10 min was estimated for mixing of the codeine mixture at 49 RPM. The use of the Turbula 2F2 mixer was beneficial in reducing pharmacy staff exposure to powder particles of hazardous drugs and in reducing the risk of cross contamination in the laboratory. References and/or acknowledgements No conflict of interest.

To date, the lack of age-appropriate medicines for many indications results in dose manipulation of commercially available dosage forms, commonly resulting in inaccurate doses. Various printing technologies have recently been explored in the pharmaceutical field due to the flexible and precise nature of the techniques. The aim of this study was, therefore, to compare the currently used method to produce patient-tailored warfarin doses at HUS Pharmacy in Finland with two innovative printing techniques. Dosage forms of various strengths (0.1, 0.5, 1, and 2 mg) were prepared utilizing semisolid extrusion 3D printing, inkjet printing and the established compounding procedure for oral powders in unit dose sachets (OPSs). Orodispersible films (ODFs) drug-loaded with warfarin were prepared by means of printing using hydroxypropylcellulose as a film-forming agent. The OPSs consisted of commercially available warfarin tablets and lactose monohydrate as a filler. The ODFs resulted in thin and flexible films showing acceptable ODF properties. Moreover, the printed ODFs displayed improved drug content compared to the established OPSs. All dosage forms were found to be stable over the one-month stability study and suitable for administration through a naso-gastric tube, thus, enabling administration to all possible patient groups in a hospital ward. This work demonstrates the potential of utilizing printing technologies for the production of on-demand patient-specific doses and further discusses the advantages and limitations of each method.

A novel HPLC method was developed and validated for simultaneous determination of potassium guaiacolsulfonate and sodium benzoate in pediatric oral powder. In this method, an analytical C8 column maintained at 25°C was used for chromatographic separation with a mixture of methanol and 0.02 M solution of tetrabutylammonium sulfate as the mobile phase. The composition of mobile phase was varied using a gradient program including an initial hold time of 7 minutes with methanol content maintained at 20% (v/v), followed by a linear gradient in 5.5 minutes in which methanol content was increased from 20% (v/v) to 50% (v/v) and a final hold time of 2.5 minutes with methanol content maintained at 20% (v/v). The total flow rate of mobile phase was maintained at 1.0 mL per minute. The UV detection was performed at 280 nm. Injection volume was set at 20 µl. The method was fully validated in terms of specificity, linearity, precision, accuracy, and robustness according to requirements of current guidelines and was proved as reliable and suitable for the intended application.

Oral pediatric formulations are either ready-to-use or require manipulation and multiuse or single-use. Strong encouragement for preservative-free pediatric formulations has resulted in fewer multiuse solutions or suspensions in favor of single-use solid oral dosage forms. This updated review covering new pediatric formulations marketed in the United States of America, Europe, and Japan spanning the years 2007 to mid-2018 identified 16 types of pediatric oral formulations of which 7 are ready-to-use and 9 require manipulation, and 51 total new pediatric oral formulations of which 21 are ready-to-use and 30 require manipulation. Ready-to-use formulations include oral solution, oral suspension, oral soluble film, tablet, scored tablets, orally disintegrating tablet, chewable tablet, and mini-tablets. Formulations requiring manipulation include sprinkle capsule, powder for oral solution, powder for oral suspension, granules for oral suspension, oral powder, oral granules, tablet, dispersible tablet, dispersible scored tablet, tablet for oral suspension, and mini-tablets (oral granules). Significant advances in packaging technology include filling mini-tablets, granules, or powders into sachets, stick packets, blisters, and 2-piece capsules. The future of pediatric oral formulations will increasingly be with user-friendly, preservative-free, taste-masked formulations including multiparticulate single-use solid dosage forms including mini-tablets, orally disintegrating tablets, and sprinkle capsules with or without a specialized package configuration.

Background Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean Cavg and individual Cavg ≥500 ng/mL and Methods A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2– Results An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted Cavg generally met PK targets. Model-predicted Cavg was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean Cavg was achieved for all but the 2– Conclusion This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food. Disclosures All authors: No reported disclosures.

Background: Phosphate binders, such as lanthanum carbonate, control elevated serum-phosphate levels in patients with end-stage renal disease (ESRD). Lanthanum carbonate is available in oral powder and tablet form. The aim of this survey was to investigate satisfaction with, preference for, and adherence to lanthanum carbonate oral powder in patients with ESRD. Scope: Patients from France and Spain who had been taking lanthanum carbonate powder for at least 4 weeks, and who had experience of other phosphate binders of any formulation, were asked to complete an online or telephone survey. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication-9; preference was measured using 5-point Likert scale agreement ratings; and adherence was measured using the Morisky Medication Adherence Scale-4. Data were evaluated using bivariate analyses. Findings: Overall, 160 patients participated (80 per country). Lanthanum carbonate powder was reported to have a higher effectiveness rating (p

A bioequivalence and pharmacokinetics profiles of two doxycycline powder formulations (Providox and Doxyvet 0-50 S ) were compared in 24 healthy chickens following administration of a single oral dose ® (20 mg/kg bw). Serial blood samples were drawn at 10 points after administration to determine doxycycline concentrations in chicken plasma by HPLC/UV. the pharmacokinetics parameters; area under plasma concentration-time curve (AUC ), maximum plasma concentration (C ) were determined for both 0-24 max formulations. The average means of AUC and C for Providox and Doxyvet 0-50 S were very close 0–24 max ® ® (62.32 ± 3.34 and 57.55 ± 4.66 μg.h/ml and 5.36 ± 0.26 and 5.08 ± 0.25 μg/ml, respectively) with no significant differences based on ANOVA. The 90% confidence intervals of the parameters AUC and C 0–24 max between two formulations were within the range 80 to 125 % of bioequivalence according to US FDA regulation. The relative bioavailability of Providox compared to Doxyvet 0-50 S was 108.24%. Therefore, the ® ® Providox and Doxyvet 0 50 S were considered to be bioequivalent. ® ®

Smokeless tobacco (ST) is widely used as chewing tobacco and as oral snuff in the world. Also, in Kahramanmaraş, a city in Southern Turkey, ST used as 'oral powder' or 'Maraş Powder' is consumed widely instead of cigarette smoking. The aim of this study was to search the effect of ST use on serum total sialic acid (TSA) and to compare the serum TSA levels in smokers and ST users. The study was performed at the Department of Chemistry-Biochemistry, University of Kahramamaraş Sutcu Imam, Turkey, in 2003. Serum samples obtained from smokers (Group I), Maraş powder users (Group II), and healthy control subjects (Group III) who were nonsmokers and nonusers ST. Individuals who were smokers and ST users were classified into subgroups with respect to amount of consumed cigarette or oral powder. Serum TSA was measured with the Denny's colorimetric method. The TSA concentrations were significantly higher in the sera of smokers (p0.001) and Maraş powder users (p0.001) than those of control subjects. The mean serum TSA level was found to be lowest in the control group and highest in the Maraş Powder users. But, there was no significant difference in serum TSA levels between smokers and Maraş powder users (p0.05). We can conclude from the results obtained that serum TSA was affected by ST use as seen in smokers. This finding may be an indication of harmful effects of ST use as Maraş powder as well as cigarette smoking.

Background POS, a triazole antifungal approved for prophylaxis and treatment of adults with invasive fungal infections, is available as an IV solution and 2 oral formulations: an oral suspension and a tablet with improved bioavailability. A novel powder for oral suspension (PFS) has been developed to offer the bioavailability of the tablet in a formulation optimized for weight-based dosing in children. The objective of this study is to evaluate the safety, tolerability, and PK of POS IV and POS PFS in pediatric patients (patients) aged 2 to 17 y with documented or expected neutropenia. Methods This is an ongoing, nonrandomized, multicenter, open-label, sequential dose-escalation study evaluating POS IV and POS PFS. Pts are divided into 2 age groups: 2 to Results 57 of 66 patients (86%) who received POS IV were PK evaluable; 35 patients (53%) received POS PFS, of whom 30 (86%) were PK evaluable. Table 1 shows Cavg and proportion in target range of PK-evaluable patients by dose cohort and age group. The safety profiles of POS IV and PFS were similar to those previously reported for adults treated with oral/IV POS. Conclusion POS PFS resulted in lower POS exposure than IV across age groups at both dose levels. POS exposure was substantially lower in the younger age group for both IV and PFS. At 4.5 mg/kg, the patients in this study achieved the predefined target but did not achieve systemic exposures (mean Cavg) comparable to those seen in adults with POS IV or tablet. These results suggest that study of POS IV and PFS dosing >4.5 mg/kg/d is warranted. Disclosures A. H. Groll, Merck Sharp & Dohme: Consultant, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. T. Lehrnbecher, Merck/MSD: Scientific Advisor and Speaker’s Bureau, Speaker honorarium. Astellas: Scientific Advisor and Speaker’s Bureau, Speaker honorarium. Basilea: Scientific Advisor, Consulting fee. Gilead: Investigator, Scientific Advisor and Speaker’s Bureau, Research grant and Speaker honorarium.Pfizer: Speaker’s Bureau, Speaker honorarium. W. Steinbach, Merck: Consultant, Consulting fee. Astellas: Consultant, Consulting fee. Gilead: Consultant, Consulting fee. R. Murray, Merck: Employee, Salary. A. Paschke, Merck: Employee, Salary. E. Mangin, Merck: Employee, Salary. G. A. Winchell, Merck: Research Contractor, Consulting fee. C. J. Bruno, Merck: Employee and Shareholder, Salary and Stock.

FDA on July 7 approved l-glutamine oral powder to reduce acute complications of sickle cell disease in patients age 5 years or older. Emmaus Life Sciences, Inc., of Torrance, California, announced that it will market the product, possibly in the fourth quarter of this year, under the brand name

Background A novel ritonavir oral powder formulation has been developed to eliminate the alcohol and propylene glycol contents in the current ritonavir oral solution for paediatric use. Two clinical studies were conducted to assess the bioequivalence of the powder formulation to the marketed oral solution and to evaluate the effect of food and vehicles on bioavailability. Methods Study 1 was a randomized, partial-crossover, 4-period study in 48 subjects. Regimens included: oral solution under moderate-fat conditions, powder formulation in water under fasting, moderate-fat or high-fat conditions, and powder formulation in chocolate milk or pudding under moderate-fat conditions. Study 2 was a randomized, crossover, 4-period study in 24 subjects. Subjects were randomized to a sequence of the oral solution and powder formulation in water, infant formula and apple sauce, all under moderate-fat conditions. Bioavailability comparisons were assessed by the 90% CIs for the geometric least-squares mean ratios. Results Ritonavir powder formulation in water was found to be bioequivalent to the marketed oral solution. Ritonavir powder formulation administered in chocolate milk, pudding, infant formula or apple sauce was bio-equivalent to the powder formulation administered in water. Compared with fasting conditions, moderate-fat and high-fat meals were associated with approximately 25–40% and 35–50% reduction in ritonavir concentrations, respectively. Conclusions The novel ritonavir powder formulation is bioequivalent to marketed ritonavir oral solution under moderate-fat conditions with a similar effect of meals. None of the vehicles tested negatively affected the bioavailability, which suggests the potential for use of a broad range of vehicles for dose preparation.

Summary Background and objective: To compare content uniformities between different sizes of extemporaneously compounded nifedipine oral powders and capsules, in order to find out if capsules could be used instead of oral powders as paediatric medications. Methods: Actual content and content uniformity of extemporaneously compounded 1-mg nifedipine oral powders and capsules were evaluated by a high performance liquid chromatographic assay. Capsules and powders were prepared by triturating 10-mg nifedipine tablets with different amounts of lactose or microcrystalline cellulose with a mortar and pestle using a standard geometric dilution technique. Oral powders were weighed individually and capsules were filled by a hand-operated capsule-filling machine. Four different sizes of powders (500, 300, 100 and 50 mg) and three different sizes of capsules (numbers 1, 3 and 4) were prepared. Ten oral powders and 10 capsules from each batch were randomly selected and individually assayed for nifedipine amount. Results and discussion: The extemporaneously prepared nifedipine oral powders and capsules were within acceptable limits for content uniformity, as defined by the European Pharmacopoeia, but the results indicate that the loss of nifedipine during the preparation process may be considerable for both preparations. The concentration on nifedipine decreased while the total mass of the oral powder decreased. These results demonstrate that nifedipine oral powders can be replaced by capsules, whose contents are emptied for use, in paediatric medications. Compounding small capsules, such as size number 3 or 4, is acceptable when considering the average drug content. The total weight of the oral powder should be at least 300 mg. Conclusion: The preparation of nifedipine in all studied capsule sizes was safe with either lactose monohydrate or microcrystalline cellulose as excipients. Thus, emptied capsules seem to be a good choice for delivering a paediatric medication. The loss of nifedipine was considerable in oral powders with low total weight.

Chronic kidney disease (CKD) is associated with very high mortality rates, mainly of cardiovascular origin. The retention of phosphate (P) and increased fibroblast growth factor-23 levels are common, even at early stages of CKD, due to disturbances in normal P homeostasis. Later, hyperphosphatemia appears, which has also been strongly associated with high mortality rates linked to P-mediated cardiovascular and procalcifying effects. Treatment guidelines for these patients continue to be poorly implemented, at least partially due to the lack of adherence to a P-restricted diet and P-binder therapy. Calcium-free P binders, such as lanthanum carbonate, have been associated with a decreased progression of vascular calcification, rendering them an important therapeutic alternative for these high cardiovascular risk CKD patients. Lanthanum carbonate has typically been available as chewable tablets, and the new presentation as an oral powder may provide a useful alternative in the therapeutic armamentarium. This powder is a tasteless, odorless, and colorless semisolid compound miscible with food. In a recent study in healthy individuals, the safety and efficacy of this novel form were evaluated, and it was concluded that it is well tolerated and pharmacodynamically equivalent to the chewable form. In the long run, individualization of preferences and treatments seems an achievable goal prior to final demonstration of improvements in hard outcomes in wide clinical trials in CKD patients.

Rheumatism is a painful joint disease. It is more frequent in female, due to an abnormal uric acid metabolism. The cause is raised serum uric acid level and deposition of uric acid crystal in cartilage of joints, resulting in recurrent attacks of pain and inflammations. Modern medicines do not have any cure for this disease, except their prevention and temporary relief. However, traditional herbal remedies do have a cure. A decoction, oral powder, herbal oil or hot formulation prepared from some household herbs is an excellent remedy for rheumatism, which is discussed in the present paper.

A number of flavors were screened for their ability to mask the bitterness of an oral powder of potassium penicillin G with triple sulfonamides. The powder, when restored with sufficient water to yield 5 ml. of suspension, contained 100,000 to 250,000 units of penicillin and a mixture of sulfamerazine, sulfadiazine, and sulfamethazine totaling 0.5 Gin. The flavored powders thus selected were subjected to an accelerated penicillin stability test of heating at 100° for four days. Several flavors were selected on the basis of the accelerated test and were used to formulate preparations for long-term stability studies.