Physiochemical and Microbiological Stability of Azathioprine Suspensions in PCCA Base, SuspendIt.

Azathioprine is used to treat the symptoms of rheumatoid arthritis and for the prevention of transplant rejection. A review of the therapeutic uses of Azathioprine reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of Azathioprine currently exists. Azathioprine is commercially available only as a 50-mg tablet. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded Azathioprine suspensions in the PCCA Base, SuspendIt. This base is a sugar-free, paraben free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two Azathioprine concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of Azathioprine in PCCA SuspendIt was developed and validated. Suspensions of Azathioprine were prepared in PCCA SuspendIt at 10-mg/mL and 50-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, 49, 63, 90, 119, and 182. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that Azathioprine concentrations did not go below 96.8% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. The pH values remained constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that Azathioprine is physically, chemically, and microbiologically stable in PCCA SuspendIt for 182 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for Azathioprine in a liquid dosage form, with an extended beyond-use date to meet patient needs.

Physicochemical and Microbiological Stability of Pyrimethamine in Paraben-free PCCA Base, SuspendIt.

Pyrimethamine is an antiparasitic compound available only in tablet form for oral administration. A review of the therapeutic uses of pyrimethamine reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of pyrimethamine currently exists. Pyrimethamine is available commercially only as 25-mg tablets. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded pyrimethamine suspension in PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of pyrimethamine in PCCA SuspendIt was developed and validated. Suspensions of pyrimethamine were prepared in PCCA SuspendIt at a 2-mg/mL concentration, selected to provide flexibility in customizing individual doses. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, and 42. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that pyrimethamine concentrations did not go below 96% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. pH values remained constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that pyrimethamine is physically, chemically, and microbiologically stable in PCCA SuspendIt for 42 days stored in the refrigerator and at room temperature, thus providing a viable, compounded alternative for pyrimethamine in a liquid dosage form.

Physicochemical and Microbiological Stability of Amitriptyline Hydrochloride Oral Liquid Dosage Forms in PCCA Base, SuspendIt.

Amitriptyline hydrochloride is indicated for the relief of symptoms of depression. A review of the therapeutic uses of amitriptyline hydrochloride reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of amitriptyline currently exists. Amitriptyline hydrochloride is commercially available only as 10-mg, 25-mg, 50-mg, 75-mg, 100-mg, and 150-mg tablets. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded amitriptyline hydrochloride suspensions in PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two amitriptyline hydrochloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability- indicating high-performance liquid chromatographic assay for the determination of the chemical stability of amitriptyline hydrochloride in PCCA SuspendIt was developed and validated. Suspensions of amitriptyline hydro- chloride were prepared in PCCA SuspendIt at 1-mg/mL and 5-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, 49, 63, 91, 119, and 185. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that amitriptyline hydrochloride concentrations did not go below 99.8% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. The pH values remained constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that amitriptyline hydrochloride is physically, chemically, and microbiologically stable in PCCA SuspendIt for 185 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for amitriptyline hydrochloride in a liquid dosage form, with an extended beyond-use date to meet patient needs.

Physicochemical and Microbiological Stability of Extemporaneously Compounded Hydrocortisone Oral Suspensions in PCCA Base, SuspendIt.

Hydrocortisone is indicated in the treatment of primary or secondary adrenal insufficiency. The oral dosage regimen of hydrocortisone needs to be individualized in the treatment of congenital adrenal hyperplasia, especially in pediatric patients. A review of the therapeutic uses of hydrocortisone reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of hydrocortisone currently exists. Hydrocortisone is commercially available as 5-mg, 10-mg, and 20-mg tablets. An extemporaneously compounded suspension from pure drug powder would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded hydrocortisone suspensions in PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two hydrocortisone concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of hydrocortisone in SuspendIt was developed and validated. Suspensions of hydrocortisone were prepared in SuspendIt at 1-mg/mL and 20-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially and on the following days: 7, 15, 28, 45, 60, 91, 120, and 185. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that hydrocortisone concentrations did not go below 94% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. Viscosity and pH values did not change significantly. This study demonstrates that hydrocortisone is physically, chemically, and microbiologically stable in SuspendIt for 185 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for hydrocortisone in a liquid dosage form, with an extended beyond-use date to meet patient needs.

Physicochemical and Microbiological Stability of Compounded Metronidazole Suspensions in PCCA SuspendIt.

Metronidazole is indicated for the treatment of trichomoniasis, amebiasis, and anaerobic bacterial infections. The dosage regimen of metronidazole needs to be individualized in the treatment of trichomoniasis, in patients with hepatic impairment, and in pediatric as well as geriatric patients. A review of the therapeutic uses of metronidazole reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of metronidazole currently exists. Metronidazole is commercially available only as 250-mg and 500-mg film-coated tablets. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded metronidazole suspensions in PCCA SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two metronidazole concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating ultra-performance liquid chromatographic assay for the determination of the chemical stability of metronidazole in PCCA SuspendIt was developed and validated. Suspensions of metronidazole were prepared in PCCA SuspendIt at 25-mg/mL and 50-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5ÆC and 25ÆC). Samples were assayed initially and on the following time points (days): 7, 14, 28, 42, 59, 90, 122, and 180. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was also tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that metronidazole concentrations did not go below 97% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. Viscosity and pH values also did not change significantly. This study demonstrates that metronidazole is physically, chemically, and microbiologically stable in PCCA SuspendIt for 180 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for metronidazole in a liquid dosage form, with an extended beyond-use-date to meet patient needs.

Physicochemical Stability of Compounded Allopurinol Suspensions in PCCA Base, SuspendIt.

Allopurinol is an orally administered inhibitor of xanthine oxidase used primarily in the treatment of hyperuricemia associated with gout. Allopurinol reduces serum and urinary uric acid concentrations. Its use should be individualized for each patient. The dosage of allopurinol to accomplish full control of gout and to lower serum uric acid to normal or near-normal levels varies with the severity of the disease, and needs to be flexible to permit precise, customized dose titration for individual patients. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of allopurinol currently exists. Allopurinol is commercially available as 100-mg and 300-mg scored tablets. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of extemporaneously compounded allopurinol suspensions in the PCCA Base SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two allopurinol concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating ultra-performance liquid chromatography assay for the determination of the chemical stability of allopurinol in SuspendIt was developed and validated. Suspensions of allopurinol were prepared in SuspendIt at 10.0-mg/mL and 20.0-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially and at the following time points: 7 days, 14 days, 30 days, 45 days, 60 days, 88 days, 120 days, and 182 days. Physical data such as pH, viscosity, and appearance were also noted. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period. The study showed that allopurinol concentrations did not go below 93% of the label claim (initial drug concentration) at both temperatures studied. Viscosity and pH values also did not change significantly. This study demonstrates that allopurinol is physically and chemically stable in SuspendIt for 180 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for allopurinol in a liquid dosage form, with an extended beyond-use-date to meet patient needs.

Physicochemical Stability of Compounded Amlodipine Besylate Suspensions in PCCA Base, SuspendIt.

Amlodipine besylate is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available 2.5-mg, 5-mg, and 10-mg amlodipine besylate tablets do not provide the necessary flexibility in dosing needed for treating children. This flexibility is readily achieved using an oral, liquid dosage form. However, no commercial liquid dosage form of amlodipine currently exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of extemporaneously compounded amlodipine besylate suspensions in the PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two amlodipine besylate concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stabilityindicating high-performance liquid chromatographic assay for the determination of the chemical stability of amlodipine besylate in SuspendIt was developed and validated. Suspensions of amlodipine were prepared in SuspendIt at 0.5-mg/mL and 10.0-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and at the following time points: 7 days, 14 days, 29 days, 46 days, 60 days, 90 days, 120 days, and 180 days. Physical data such as pH, viscosity, and appearance were also noted. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period. This study demonstrates that amlodipine besylate is physically and chemically stable in SuspendIt for 90 days in the refrigerator and 7 days at room temperature, retaining 90% of the label claim (initial drug concentration) at both concentrations. The pH values did not change significantly. The viscosity of the refrigerated samples at both concentrations decreased slightly, while that of the room temperature samples showed a marked increase in viscosity. This study provides a viable, compounded alternative for amlodipine in a liquid dosage form, with an adequate beyond-use-date to meet patient needs. The study further provides stability documentation over a bracketed amlodipine concentration range of 0.5 mg/mL to 10.0 mg/mL, allowing compounding pharmacists more flexibility in customizing their formulations.

Physicochemical Stability of Compounded Naltrexone Hydrochloride Solutions in PCCA Base SuspendIt.

Naltrexone hydrochloride is an orally active narcotic antagonist used to facilitate rapid transition from methadone maintenance. The dosing schedule of naltrexone hydrochloride in detoxification protocols needs to be flexible to permit precise, customized dose titration for individual patients. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of naltrexone hydrochloride currently exists. Naltrexone hydrochloride is commercially available as a scored, filmcoated, 50-mg tablet. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of extemporaneously compounded naltrexone hydrochloride solutions in PCCA base SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two naltrexone hydrochloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating HPLC assay for the determination of the chemical stability of naltrexone hydrochloride in SuspendIt was developed and validated. Solutions of naltrexone hydrochloride were prepared in SuspendIt at 0.5-mg/mL and 5.0-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic, amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and at the following time points: 7 days, 14 days, 29 days, 44 days, 61 days, 90 days, 120 days, and 180 days. Physical data such as pH, viscosity, and appearance were also noted. All measurements were obtained in triplicate. A stable extemporaneous preparation is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period. The study showed that naltrexone hydrochloride concentrations did not go below 94% of the label claim (initial drug concentration) at both temperatures studied. Viscosity and pH values also did not change significantly. This study demonstrates that naltrexone hydrochloride is physically and chemically stable in SuspendIt for 180 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for naltrexone hydrochloride in a liquid dosage form, with an extended beyond-use date to meet patient needs.

Stability of Compounded Ursodiol Suspensions in PCCA Base, SuspendIt.

Ursodiol (ursodeoxycholic acid) is a nontoxic, naturally occurring bile acid that constitutes 1% to 2% of human bile. It suppresses hepatic synthesis of cholesterol, aids in the desaturation of biliary cholesterol, and aids in the dissolution of cholesterol gallstones. Ursodiol is commercially available as a 300-mg capsule and a 250-mg tablet. However, no commercial liquid dosage form of ursodiol exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets/capsules would provide an alternative option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of extemporaneously compounded ursodiol suspensions in PCCA base SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. The study design included two ursodiol concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust, stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of ursodiol in SuspendIt was developed and validated. Suspensions of ursodiol were prepared in SuspendIt at 50-mg/mL and 100-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially and at the following time points: 7 days, 14 days, 30 days, 42 days, 59 days, 91 days, 120 days, and 181 days. Physical data such as pH, viscosity, and appearance were also noted. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period. The study showed that ursodiol concentration did not go below 97% of the label claim (initial drug concentration) at both temperatures studied. Viscosity and pH values also did not change significantly. This study demonstrates that ursodiol is physically and chemically stable in SuspendIt for 181 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for ursodiol in a liquid-dosage form, with an extended beyond-use-date to meet patient needs.

Physicochemical Stability of an Oral Suspension of Trimethoprim 20 mg/mL in Combination with Sulfadiazine 200 mg/mL in PCCA Base SuspendIt.

Trimethoprim is a diaminopyrimidine antibacterial agent that, like sulfonamides, inhibits bacterial folic acid synthesis, but at a different stage in the metabolic pathway. It has a similar spectrum of activity to the sulfonamides and is given by mouth or by injection, either alone or in conjunction with a sulfonamide, such as sulfadiazine. Sulfadiazine is a bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. The combination of the two drugs produces a synergistic effect against both Gram-positive and Gram-negative aerobic bacteria, by inhibiting enzymes in the folic acid pathways, which in turn inhibits bacterial thymidine synthesis. There are no published studies of the stability of the combination of trimethoprim and sulfadiazine in a liquid dosage form. An extemporaneously compounded suspension from pure drug powders or commercial tablets would provide an alternative option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of trimethoprim combined with sulfadiazine in PCCA base SuspendIt. PCCA base SuspendIt is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability-indicating high-performance liquid chromatographic assay for the simultaneous determination of trimethoprim and sulfadiazine in SuspendIt was developed and validated. This assay was used to determine the chemical stability of both drugs in SuspendIt. Samples were prepared and stored under three different temperature conditions (5°C, 25°C, 40°C), and assayed using the high-performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 0, 7, 14, 30, 45, 60, 91, 120, and 182 days at each designated temperature. Physical data such as pH, viscosity, appearance, and average particle size were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at room temperature and in the refrigerator. The pH values also did not change significantly. There was some variability in viscosity and average particle size. This study demonstrates that trimethoprim and sulfadiazine are physically and chemically stable in combination in SuspendIt for 182 days at room temperature and in the refrigerator, thus providing a viable, compounded alternative for both drugs in a liquid dosage form, with an extended beyond-use-date to meet patient needs.

Development of Orally Administered γ-Tocotrienol (GT3) Nanoemulsion for Radioprotection.

The purpose of this study was two-fold: (1) to formulate γ-tocotrienol (GT3) in a nanoemulsion formulation as a prophylactic orally administered radioprotective agent; and (2) to optimize the storage conditions to preserve the structural integrity of both the formulation and the compound. γ-tocotrienol was incorporated into a nanoemulsion and lyophilized with lactose. Ultra performance liquid chromatography-mass spectroscopy (UPLC-MS) was used to monitor the chemical stability of GT3 over time, the particle size and ζ potential, and scanning electron microscopy (SEM) were used to study the physical stability of the nanoemulsion. Radioprotective and toxicity studies were performed in mice. The liquid formulation exhibited GT3 degradation at all storage temperatures. Lyophilization, in the presence of lactose, significantly reduced GT3 degradation. Both the liquid and lyophilized nanoemulsions had stable particle size and ζ potential when stored at 4 °C. Toxicity studies of the nanoemulsion resulted in no observable toxicity in mice at an oral dose of 600 mg/kg GT3. The nano-formulated GT3 (300 mg/kg) demonstrated enhanced survival efficacy compared to GT3 alone (200 and 400 mg/kg) in CD2F1 mice exposed to total body gamma radiation. The optimal long-term storage of formulated GT3 is as a powder at -20 °C to preserve drug and formulation integrity. Formulation of GT3 as a nanoemulsion for oral delivery as a prophylactic radioprotectant shows promise and warrants further investigation.

Stability of Clindamycin Hydrochloride in PCCA Base SuspendIt.

Clindamycin is an effective antibiotic in the treatment of infections caused by certain gram-positive and gram-negative anaerobic microorganisms. While manufactured forms of the drug for pediatric use are available, there are instances when a compounded liquid dosage form is essential to meet unique patient needs. The purpose of this study was to determine the chemical stability of clindamycin hydrochloride in the PCCA base SuspendIt, a sugar-free, paraben- free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability-indicating high-performance liquid chromatographic assay for the determination of clindamycin hydrochloride in SuspendIt was developed and validated. This assay was used to determine the chemical stability of the drug in SuspendIt. Samples were prepared and stored under three different temperature conditions (5°C, 25°C, and 40°C), and assayed using the high-performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 7, 14, 30, 45, 60, 91, 120, and 182 days at each designated temperature. Physical data such as pH, viscosity, and appearance were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at all three temperatures studied, barring isolated experimental errors. Viscosity and pH values also did not change significantly. Some variations in viscosity were attributed to the thixotropic nature of the vehicle. This study demonstrates that clindamycin hydrochloride is physically and chemically stable in SuspendIt for 182 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for clindamycin hydrochloride in a liquid dosage form, with an extended beyond-use date to meet patient needs.

A second-generation inhaled insulin for diabetes mellitus.

PURPOSE: The pharmacologic properties of a recently approved inhaled insulin product, its unique delivery system, and the results of clinical safety and efficacy trials are reviewed. SUMMARY: Afrezza (also called Technosphere Insulin, MannKind Corporation, Valencia, CA) is a novel ultrarapid-acting insulin formulation indicated for use in improving glycemic control in selected patients with type 1 or type 2 diabetes mellitus. Afrezza is not intended as a substitute for traditional basal therapy with injectable long-acting insulin but may be used to provide prandial insulin coverage; it must be used in combination with long-acting insulin in patients with type 1 diabetes. Administered before meals using a dry-powder inhalation device, Afrezza is formulated with a novel excipient (fumaryl diketopiperazine) that dissolves instantly in lung fluid and releases recombinant human insulin for absorption. In clinical trials, rates of hypoglycemia in Afrezza-treated patients were significantly lower than rates reported in comparator groups receiving injectable insulin products. The most commonly reported adverse effect of Afrezza is coughing, which tends to occur shortly after inhalation and is typically mild. Afrezza is not recommended for use in patients who smoke (or have recently stopped smoking) and those with a chronic lung disease such as asthma or chronic obstructive pulmonary disease. Afrezza is not recommended for the treatment of diabetic ketoacidosis. CONCLUSION: Afrezza is a safe and effective treatment for selected adults with type 1 or type 2 diabetes, potentially providing an alternative to injectable insulin for prandial blood glucose control.

Effect of squalane on mebendazole-loaded Compritol® nanoparticles.

The objective of this study is to develop nanostructured lipid formulations of Compritol for the delivery of mebendazole. The formulations were prepared with Compritol 888 ATO, squalane, and Pluronic F68. Nine batches with different amounts of modifier, squalane, and drug were prepared. The formulations were characterized by evaluating particle size, morphology, and zeta potential. The thermal properties of the formulations were analyzed by differential scanning calorimetry (DSC). The encapsulation efficiency of each formulation and the drug release rates from each formulation were quantified by UPLC. The particles were spherical and had median particle sizes between 300 and 600 nm (50th percentile). A linear relationship was observed between Compritol/squalane composition and the melting point of the mixture. The DSC scans of the formulations revealed some recrystallization of the drug from the formulations, and the amount of recrystallization correlated with the amount of squalane in the formulation. Approximately, 70% efficiency of encapsulation was observed in the formulations with 30% (w/w) squalane, and these formulations also had faster dissolution rates compared to the other formulations. Overall, the formulations with 30% squalane are the preferred formulation for future testing.

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide.

Fenretinide is an anticancer drug with low water solubility and poor bioavailability. The goal of this study was to develop biodegradable polymeric nanoparticles of fenretinide with the intent of increasing its apparent aqueous solubility and intestinal permeability. Three biodegradable polymers were investigated for this purpose: two different poly lactide-co-glycolide (PLGA) polymers, one acid terminated and one ester terminated, and one poly lactide-co-glycolide/polyethylene glycol (PLGA/PEG) diblock copolymer. Nanoparticles were obtained by using an emulsification solvent evaporation technique. The formulations were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and particle size analysis. Dissolution studies and Caco-2 cell permeation studies were also carried out for all formulations. Ultra high performance liquid chromatography coupled with mass spectrometry (UPLC/MS) and ultraviolet detection was used for the quantitative determination of fenretinide. Drug loading and the type of polymer affected the nanoparticles' physical properties, drug release rate, and cell permeability. While the acid terminated PLGA nanoparticles performed the best in drug release, the ester terminated PLGA nanoparticles performed the best in the Caco-2 cell permeability assays. The PLGA/PEG copolymer nanoparticles performed better than the formulations with ester terminated PLGA in terms of drug release but had the poorest performance in terms of cell permeation. All three categories of formulations performed better than the drug alone in both drug release and cell permeation studies.

Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles.

Fenretinide is an effective anti-cancer drug with high in vitro cytotoxicity and low in vivo systemic toxicity. In clinical trials, fenretinide has shown poor therapeutic efficacy following oral administration - attributed to its low bioavailability and solubility. The long term goal of this project is to develop a formulation for the oral delivery of fenretinide. The purpose of this part of the study was to prepare and characterize hydrophilic nanoparticle formulations of fenretinide. Three different ratios of polyvinyl pyrrolidone (PVP) to fenretinide were used, namely, 3:1, 4:1, and 5:1. Both drug and polymer were dissolved in a mixture of methanol and dichloromethane (2:23 v/v). Rotary evaporation was used to remove the solvents, and, following reconstitution with water, a high pressure homogenizer was used to form nanoparticles. The particle size and polydispersity index were measured before and after lyophilization. The formulations were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The effectiveness of the formulations was assessed by release studies and Caco-2 cell permeability assays. As the PVP content increased, the recovered particle size following lyophilization became more consistent with the pre-lyophilization particle size, especially for those formulations with less lactose. The DSC scans of the formulations did not show any fenretinide melting endotherms, indicating that the drug was either present in an amorphous form in the formulation or that a solid solution of the drug in PVP had formed. For the release studies, the highest drug release among the formulations was 249.2±35.5ng/mL for the formulation with 4:1 polymer-to-drug. When the permeability of the formulations was evaluated in a Caco-2 cell model, the mean normalized flux for each treatment group was significantly higher (p<0.05) from the fenretinide control. The formulation containing 4:1 polymer-to-drug ratio and 6:5 lactose-to-formulation ratio emerged as the optimal choice for further evaluation as a potential oral delivery formulation for fenretinide.

An ultra-high performance chromatographic method for the determination of artemisinin.

OBJECTIVE: The goal of this study is to develop an ultra-high performance liquid chromatographic method for the quantitative determination of artemisinin at very low concentrations using selective ion mass spectroscopic detection. MATERIALS AND METHODS: Separation was conducted using a C4 100 mm× 2.1 mm column, and the mobile phase consisted of an isocratic two-component system consisting of 60% of a 0.1% aqueous solution of formic acid and 40% acetonitrile at a flow rate of 0.4 ml/min. The drug was detected by means of an electrospray mass spectrometer with selective ion monitoring of the [M-H2O+H](+) with m/z of 265.3 in positive ion mode. RESULTS: The calibration curves of artemisinin obtained from the UPLC/MS system were linear in the three ranges analyzed, with a correlation coefficient of no less than 0.9996 for all sets of standards. The peak tailing factor for all measurements were ≤1.7. The method proved to have good repeatability and linearity. DISCUSSION: The described analytical method reached a LOQ of 0.010 µg/ml with an isocratic system and enables an analysis rate of 20 samples per hour. The linearity of the standards was excellent for all sets of standards analyzed. CONCLUSION: The method presented in this study provides a rapid and suitable means for the determination of artemisinin at very low concentrations. This is especially significant when performing dissolution studies where, due to the low solubility of artemisinin, a method that can measure the drug at nanogram levels is necessary.

Cellular delivery of PEGylated PLGA nanoparticles.

OBJECTIVES: The objective of this study was to investigate the efficiency of uptake of PEGylated polylactide-co-gycolide (PLGA) nanoparticles by breast cancer cells. METHODS: Nanoparticles of PLGA containing various amounts of polyethylene glycol (PEG, 5%-15%) were prepared using a double emulsion solvent evaporation method. The nanoparticles were loaded with coumarin-6 (C6) as a fluorescence marker. The particles were characterized for surface morphology, particle size, zeta potential, and for cellular uptake by 4T1 murine breast cancer cells. KEY FINDINGS: Irrespective of the amount of PEG, all formulations yielded smooth spherical particles. However, a comparison of the particle size of various formulations showed bimodal distribution of particles. Each formulation was later passed through a 1.2 µm filter to obtain target size particles (114-335 nm) with zeta potentials ranging from -2.8 mV to -26.2 mV. While PLGA-PEG di-block (15% PEG) formulation showed significantly higher 4T1 cellular uptake than all other formulations, there was no statistical difference in cellular uptake among PLGA, PLGA-PEG-PLGA tri-block (10% PEG), PLGA-PEG di-block (5% PEG) and PLGA-PEG di-block (10% PEG) nanoparticles. CONCLUSION: These preliminary findings indicated that the nanoparticle formulation prepared with 15% PEGylated PLGA showed maximum cellular uptake due to it having the smallest particle size and lowest zeta potential.

A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp) derived from the receptor binding region of human apolipoprotein E (apoE) inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

Preparation and in-vitro/in-vivo evaluation of surface-modified poly (lactide-co-glycolide) fluorescent nanoparticles.

OBJECTIVE: The aim was to develop biodegradable nanoparticles suitable for cellular delivery of chemotherapeutic drugs. METHODS: Poly (lactide-co-glycolide) (PLGA) nanoparticles were prepared using a modified solvent evaporation method. Chitosan and calcium chloride were tested as surface modifiers. Coumarin-6 was incorporated into some formulations as a fluorescent marker. KEY FINDINGS: The median size of the particles was between 400 nm and 7 microm, and scanning electron microscope pictures showed that the particles were smooth and spherical. The zeta potentials of the particles with and without surface modifier ranged between -25.7 mV and -7.0 mV, respectively. Fluorescence microscopy and flow cytometry (FACS) analysis showed that smaller surface-modified particles were efficiently internalised by neoplastic 4T1 cells. Image analysis of frozen tissue sections from Balb/c mice given nanoparticles via the tail vein showed that the particles were distributed preferentially into the lungs, followed by the liver, spleen, kidney and heart. CONCLUSIONS: Chitosan-modified PLGA nanoparticles showed significant uptake by neoplastic 4T1 cells, and were distributed to several major organs frequently seen as sites of cancer metastasis in mice.