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PubMedDate not supplied

Formulation development of frozen parenteral dosage forms.

Many of the intravenously administered drug compounds are formulated as frozen dosage forms due to lack of sufficient chemical stability at room or refrigerated temperatures. The product is stored in a freezer in the hospital pharmacy and thawed prior to its use. These products therefore, require a long-term frozen shelf-life plus a short-term room temperature and/or refrigerated temperature shelf-life. The formulation is optimized for overall stability in the frozen state as well as in the thawed state. In this paper, the significance of phase changes in the frozen state and the influence of various formulation factors such as drug concentration, diluent, buffer concentration, pH, and raw material purity on the drug stability in the frozen state is reviewed. An overview of analytical and manufacturing considerations unique to frozen products is also presented.

Buffers↗
PubMed2002

Identification of ligand-binding regions of P-glycoprotein by activated-pharmacophore photoaffinity labeling and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry.

Energy dependent efflux pumps confer resistance to anticancer, antimicrobial, and antiparasitic drugs. P-glycoprotein (Pgp, ABCB1) mediates resistance to a broad spectrum of antitumor drugs. Compounds that themselves are nontoxic to cells have been shown to act as inhibitors of Pgp. The mechanism of binding and transport of low-molecular-mass ligands by Pgp is still incompletely understood. This study introduces a series of propafenone-related photoaffinity ligands, which combine high specificity and selectivity for Pgp with high labeling efficiency. Molecules are intrinsically photoactivatable in the arylcarbonyl group, which represents a pharmacophoric substructure for this group of ligand molecules. A detailed study of the structure-activity relationship for this type of photoligand is presented. In subsequent experiments, these ligands were used to characterize the drug-binding domain of propafenone-type analogs. Matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry shows that propafenone-type ligands preferentially label fragments assigned to putative transmembrane segments 3, 5, 6, 8, 10, 11, and 12. Labeled fragments are also identified in a highly charged region of 15 amino acids in the second cytoplasmic loop. This region corresponds to the so-called EAA-like motif, which has been proposed to play a role in the interaction between transmembrane domain and nucleotide binding domain of peroxisomal ATP-binding cassette transporters. In addition, a region in cytoplasmic loop 3 and between TM12 and the N terminus of the Walker A sequence of NBD2 are labeled by the ligands. Therefore, a number of confined protein regions contribute to the drug-binding domain of propafenone-type analogs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Availability, stability, and sterility of pralidoxime for mass casualty use.

STUDY OBJECTIVE: Pralidoxime is indicated to treat patients poisoned with nerve agents. It is available in intravenous formulation for more seriously ill hospitalized patients and intramuscular formulation for field treatment and less seriously ill patients. Our study describes a method to convert the intramuscular formulation for intravenous use and determines the stability and sterility of the resulting formulation over time and under various environmental conditions. METHODS: An inventory was taken of all intravenous (Protopam) and intramuscular (Mark I Autoinjector kits) pralidoxime available in Franklin County, Ohio hospitals, and out-of-hospital stockpiles. A method was devised to safely convert the intramuscular pralidoxime to an intravenous formulation, which was then tested for stability and sterility under a variety of environmental temperatures over time. RESULTS: In Franklin County, Ohio (population 1.1 million), the 10 acute care hospitals and out-of-hospital community have 36 g of intravenous pralidoxime and 4,398 g (7,270 Mark I kits) of intramuscular pralidoxime. The reformulated pralidoxime retained greater than 90% stability and remained sterile at all environmental temperatures through day 28. CONCLUSION: Available pralidoxime in Franklin County is predominantly in the intramuscular preparation. Conversion of intramuscular to intravenous pralidoxime results in a stable and sterile solution for up to 28 days under a variety of environmental conditions and should be considered in a mass casualty situation in which additional intravenous supplies are needed.

Antidotes↗
PubMed2006

beta-carotene encapsulation in a mannitol matrix as affected by divalent cations and phosphate anion.

The effects of addition of divalent cations and phosphate buffer on the degree of beta-carotene encapsulation in a mannitol matrix during freeze-drying were analyzed. The degradation rate of encapsulated beta-carotene as a function of % RH and its relationship with the physical state of the matrix during storage at 25 degrees C was also studied. The presence of phosphate salts significantly delayed mannitol crystallization at a highly satisfactory degree during freeze-drying and, consequently, the degree of beta-carotene encapsulation increased. This effect was maintained over quite long time during storage of the freeze-dried samples at 25 degrees C. Unavoidable local variations in water content during 3 years storage caused the decrease of T(g) values and made the crystallization degree to increase. The divalent cations showed a synergistic effect and also modified the kinetics of beta-carotene degradation during storage, increasing its stability. The mechanism of crystallization inhibition likely includes a change in hydrogen bond network or/and change in molecular mobility in the presence of divalent cations and phosphate anions. The degradation rate of beta-carotene in a mannitol/KH(2)PO(4) matrix increased as increasing % RH until a value at which the samples collapsed (75% RH), and then the degradation rate decreased. Collapse phenomena may affect diffusion of oxygen from the surface to the inside of the matrix and increase retention of beta-carotene. Surface color was not an appropriate indicator for beta-carotene degradation, because it was mostly dependent on the optical properties of the matrix, which changed with the degree of matrix hydration and collapse.

Anions↗
PubMed2006

Transport of drugs in the kidney by the human organic cation transporter, OCT2 and its genetic variants.

The human organic cation transporter 2 (OCT2, SLC22A2) is a multispecific transporter of organic cations, including many clinically used drugs. OCT2 is primarily responsible for the uptake of organic cations across the basolateral membrane of renal tubular epithelial cells and is considered a major transporter in the active secretion of organic cations in the kidney. Uptake of organic cations by OCT2 is driven by the inside-negative membrane potential and is pH-sensitive. Regulation of OCT2 at the transcriptional level by steroid hormones and at the protein level by various protein kinases has been described. Several human genetic variants in the coding region of OCT2 have been identified and functionally characterized, including both polymorphic and rare variants. A variety of structurally diverse compounds have been shown to interact with OCT2, including endogenous compounds, drugs, and dietary supplements.

Animals↗
PubMed2005

Practical formulation and process development of freeze-dried products.

Freeze-drying science and technology continues to evolve and increase in importance because of the emergence of biotechnology drugs that are too unstable to be commercially available as ready-to-use solutions. As more new drug compounds need to be developed as freeze-dried products, this mini-review article provides practical guidance and commentary on the latest literature articles on formulation and process development of freeze-dried products. This article contains a table that provides the quantitative formulations of all commercial freeze-dried protein pharmaceutical products through 2004.

Chemical Phenomena↗
PubMed1998

New medicinal treatment for severe gingivostomatitis.

We formulated de novo a poraprezinc-sodium alginate suspension (P-AG) as a specific treatment for severe gingivostomatitis and administered it to 15 patients who had developed such inflammation while on chemotherapy. Very high utility of P-AG was demonstrated and the response was classified as excellent in 10 patients and good in 5 patients. The mechanism of the beneficial effect of P-AG in treatment of severe gingivostomatitis accompanied by hemorrhagic erosion and ulcers is considered to involve the mucosal protective effect, free radical scavenging activity and tissue repair promoting action of poraprezinc together with the hemostatic action of sodium alginate.

Adult↗
PubMed2003

An improved empirical model to calculate solute solubility in supercritical carbon dioxide.

To provide more accurate solubility predictions in supercritical carbon dioxide (SC-CO2) using an empirical model employing density as an independent variable, the density of SC-CO2 at different temperatures and pressures has been calculated and compared with experimental densities. The average percentage deviation (APD) has been determined as an accuracy criterion and the obtained APD for the equations studied were between 1.3 (+/-1.4)-11.6 (+/-8.9)%. To show the effects of density values on solubility prediction, the solubility of 18 drug compounds in SC-CO2 has been calculated using an empirical equation with respect to temperature, pressure and density. The APD values for correlative analysis was 8.5 (+/-5.8)% for the most accurate density values calculated by BACK equation of state. A minimum number of experimental data (i.e. 6 points) has been used to train the model then the solubility at other temperatures and pressures has been predicted and the APD value for the most accurate densities obtained was 14.2 (+/-9.4)%. This prediction error could be considered as acceptable when it is compared with RSD values for repeated measurements (approximately 10%) and the proposed predictive method could be employed in industry to calculate the solubility of a drug using a limited number of experimental data.

Algorithms↗
PubMed1981

Technical problems associated with the production of technetium Tc 99m tin(II) pyrophosphate kits.

The amount of tin(II) required for adequate reduction, complexation, and stability of technetium Tc 99m pertechnetate in radiopharmaceutical kits, and methods of preventing the loss of tin(II) during formulation of these lyophilized kits are investigated. Tin(II) loss from stannous chloride solutions was studied under several conditions, including room air versus nitrogen atmospheres, during vial filling in a laminar-flow hood with samples frozen on dry ice versus samples at room temperature, during lyophilization, and during storage under refrigerated, ambient, and elevated temperatures. Various amounts of stannous chloride, ranging from 5 to 1000 microgram/ml, were used in formulating sodium pertechnetate Tc 99m kits containing 100 mCi technetium Tc 99m and 0.4 microgram total technetium. Samples were removed at various times; hydrolyzed technetium, pertechnetate, and technetium Tc 99m pyrophosphate were isolated on instant thin-layer chromatography-silica gel and quantified with a scintillation counter. The time necessary to deoxygenate distilled water by nitrogen purging was measured. Several sources of stannous chloride were assayed for tin(II) content. Tin(II) loss occurs rapidly in solution (15% in one hour) unless continuously protected with nitrogen, and during vial filling in a laminar-flow hood unless frozen with dry ice. No substantial loss of tin(II) was detected during lyophilization or during storage of lyophilized product at any of the three temperatures. A minimum of 400 microgram tin(II) was required to provide 90% technetium Tc 99m pyrophosphate at six hours after preparation. Adequate deoxygenation of small quantities (450 ml) of water was accomplished in less than one hour. Some stannous chloride salts were highly oxidized in the dry state, and only high-purity elemental tin wire gave acceptable yields of tin(II).

Chemistry, Pharmaceutical↗
PubMed1996

Comparison of HT29-18-C1 and Caco-2 cell lines as models for studying intestinal paracellular drug absorption.

PURPOSE: To compare the permeability characteristics of HT29-18-C1 colonic epithelial cell line with Caco-2, an established model of intestinal drug transport. METHODS: Cell lines were grown as epithelial monolayers. Permeability was measured over a range of transepithelial electrical resistance (Rt) using a group of drug compounds. RESULTS: HT29-18-C1 develop Rt slowly when grown in culture, allowing permeability to be measured over a wide range (80-600 Omega x cm2). In contrast, Caco-2 monolayers rapidly develop Rt of approximately equal 300 Omega x cm2 and require Ca2+ -chelation to generate Rt equivalent to human intestine (60-120 Omega x cm2). Permeability of atenolol, ranitidine, cimetidine, hydrochlorothiazide and mannitol across HT29-18-C1 decreased 4-5 fold as Rt developed from 100-300 Omega x cm2 indicating they permeate via the paracellular route. In contrast, ondansetron showed no difference in permeability with changing Rt consistent with transcellular permeation. Permeability profiles across low Rt HT29-18C1 and pulse EGTA-treated Caco-2 monolayers were the same for all 5 paracellular drugs suggesting that transient Ca2+ removal does not alter selectivity of the tight junctions. Permeabilities of cimetidine, hydrochlorothiazide and atenolol across 100 Omega x cm2 HT29-18-C1 monolayers reflect more closely those reported for the human ileum in vivo than did mature Caco-2 monolayers. CONCLUSIONS: HT29-18-C1 monolayers can be used to study drug permeability at Rt values similar to human intestine without the need for Ca2+ chelation. As such, they offer a useful alternative to Caco-2 for modelling intestinal drug absorption.

Atenolol↗
PubMed2006

Stabilisation of deoxyribonuclease in hydrofluoroalkanes using miscible vinyl polymers.

A mix of biocompatible macromolecules (poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP)) has been shown previously to enhance the physical stability of non-aqueous pharmaceutical suspensions. The aim of this work was to assess the feasibility of employing such a combination to facilitate the formulation of deoxyribonuclease I (DNase I) in a metered dose inhaler (MDI) using hydrofluoroalkane (HFA) propellants. DNase I was combined with the selected excipients and formed into an inhalable microparticle by spray-drying. When spray-dried alone DNase I lost almost 40% of its original biological activity, but stabilising DNase I with trehalose and PVA (DTPVA) retained 85% biological activity and trehalose, PVA and PVP (DTPVAPVP) retained 100%. Suspending the DTPVAPVP microparticles within a HFA pMDI for 24 weeks led to no further reduction in the biological activity of DNase I and the formulation delivered almost 60% of the dose expelled to the second stage of a twin-stage impinger. The solubility of PVP in HFA propellants suggests that the enhanced physical stability observed with PVA and PVP may partially be as a result of steric stabilisation. However, the large zeta potential associated with the suspensions suggested that charge stabilisation may also influence the pMDI physical stability.

Algorithms↗
PubMed2004

[Therapeutical strategies in hypertensive patients presenting heart failure symptoms].

In the last decade the number of patients with congestive heart failure has increased noticeably and today heart failure is one of the major problems in civilized countries. While in earlier decades arterial hypertension was the main reason for developing heart failure, today coronary artery disease has become the focus of attention. However, arterial hypertension, diabetes and hyperlipidemia are also main risk factors for developing coronary artery disease. In addition to non-pharmacological management with reduced fluid intake and periodical exercise training particularly in stable heart failure, in the last decade some special drug compounds have demonstrated a significant reduction in mortality in great double blind randomized trials. ACE-inhibitors and betablockers are essential components in treating congestive heart failure. Angiotensin-II-receptorblockers are indicated if ACE inhibitors and/or beta-blockers are not tolerated. The combined use of all three compounds was shown to result in a further reduction of mortality in the recently presented CHARM study. In progressive heart failure the use of diuretics is necessary and effective especially when fluid overload exists. Not treating heart failure is followed by high mortality, as we know, and so adequate and uncompromising treatment of hypertension is the most important approach to prevent the further development of heart failure.

Adrenergic beta-Antagonists↗
PubMed1998

1,5-Bis(4-amidinophenoxy)pentane (pentamidine) is a potent inhibitor of [3H]idazoxan binding to imidazoline I2 binding sites.

The aromatic diamidine 1,5-bis(4-amidinophenoxy)pentane (pentamidine) is used for treatment and prophylaxis of Pneumocystis carinii pneumonia in patients with Acquired Immune Deficiency Syndrome. Clinical use of pentamidine has been restricted by significant toxicity, that includes hypotension, and hypoglycemia. Although clinical toxicity is well described, the mechanisms are still poorly understood. Competitive binding analyses using [3H]idazoxan as the radioligand, and cirazoline to define non-specific binding, demonstrate that pentamidine binds to an imidazoline I2 binding site on rat liver membranes with a Ki of 1.4+/-0.22 nM. The Ki indicates that pentamidine inhibits radioligand binding at imidazoline I2 sites with an affinity approximating the most potent known ligands and may be related to pentamidine toxicity. Moreover, pentamidine analogs inhibit radioligand binding with a range of affinities that vary according to their structure. Two candidate drugs, Compounds 5 and 6, are more active than pentamidine in the corticosteroid-suppressed rat model of P. carinii pneumonia, yet have different affinities for the imidazoline I2 site (Ki 5 = 50.1+/-1.06 nM and Ki 6 = approximately 3500 nM). Affinity for this site does not correlate with antimicrobial activity (r = 0.60; p = 0.09) or the calculated log of the octanol:water partition coefficient (ClogP) (r = -0.38; p = 0.22).

Animals↗
PubMed1996

Therapeutic effect of glibenclamide in a fixed combination with metformin or phenformin in NIDDM patients.

The combination of a sulfonylurea with a biguanide improves the pancreatic beta-cell insulin secretion and the insulin utilization in peripheral tissues in NIDDM. This open, crossover, randomised and prospective study was designed to compare the effects of the fixed combination glibenclamide-metformin (GL-METF)-2.5 and 400 mg respectively, with the fixed combination glibenclamide-phenformin (GL-PHEN)-2.5 and 25 mg respectively, on NIDDM diabetes control. Thirty NIDDM patients, in ideal metabolic control, who were being treated with GL-PHEN were divided in two groups. One group received GL-PHEN for 12 weeks followed by 12 weeks treatment with GL-METF and the reverse treatment was given to the second group. A statistically significant decrease of post-prandial blood glucose (p = 0.034) and glycosylated haemo-globin (p < 0.02) values was observed under GL-METF treatment compared to those with GL-PHEN. The values of lactic acid were within normal limits during both treatments. The insulin secretion after breakfast was similar with both drug compounds. The BMI of the patients remained the same during a follow-up study of 24 weeks. Lipid metabolism did not change significantly during the trial and the safety parameters (renal and liver function, full blood count) remained unchanged. In conclusion, the administration of GL-METF leads to better diabetes control in NIDDM patients compared to that of GL-PHEN.

Aged↗
PubMed1999

Comparison of turbulent-flow chromatography with automated solid-phase extraction in 96-well plates and liquid-liquid extraction used as plasma sample preparation techniques for liquid chromatography-tandem mass spectrometry.

Turbulent flow chromatography (TFC) combined with the high selectivity and sensitivity of tandem mass spectrometry (MS-MS) is a new technique for the fast direct analysis of drugs from crude plasma. TFC in the 96-well plate format reduces significantly the time required for sample clean-up in the laboratory. For example, for 100 samples the workload for a technician is reduced from about 8 h by a manual liquid-liquid extraction (LLE) assay to about 1 h in the case of TFC. Sample clean-up and analysis are performed on-line on the same column. Similar chromatographic performance and validation results were achieved using HTLC Turbo-C18 columns (Cohesive Technologies) and Oasis HLB extraction columns (Waters). One 96-well plate with 96 plasma samples is analyzed within 5.25 h, corresponding to 3.3 min per sample. Compared to this LLE and analysis of 96 samples takes about 16 h. Two structurally different and highly protein bound compounds, drug A and drug B, were analyzed under identical TFC conditions and the assays were fully validated for the application to toxicokinetics studies (compliant with Good Laboratory Practices-GLP). The limit of quantitation was 1.00 microg/l and the linear working range covered three orders of magnitude for both drugs. In the case of drug A the quality of analysis by TFC was similar to the reference LLE assay and slightly better than automated solid-phase extraction in 96-well plates. The accuracy was -3.1 to 6.7% and the precision was 3.1 to 6.8% in the case of drug A determined for dog plasma by TFC-MS-MS. For drug B the accuracy was -3.7 to 3.5% and the precision was 1.6 to 5.4% for rat plasma, which is even slightly better than what was achieved with the validated protein precipitation assay.

Animals↗
PubMed1984

Plasma levels of opioid analgesics determined by radioreceptor assay.

Plasma levels of opioid drugs, Mr 1268 MS (3-(2-methyl-3-furylmethyl)-1,2,3,4,5,6-hexahydro-6 alpha,11 alpha-dimetyl-2,6-methano-3-benzazocin-8-ol methane sulfonate), Mr 2033 CL ( [2 alpha, 3(S*), 6 alpha, 11 R*]-(+/-)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-[(tetrahydro-2-furanyl) methyl]-2,6-methano-3-benzazocin-8-ol hydrochloride), MRZ 2549 BR ( (2-methoxypropyl)-1,2,3,4,5,6-hexahydro-6 alpha, 11 alpha-dimethyl-2,6-methano-3-benzazocin-8-ol hydrobromide), and pentazocine, have been determined by a radioreceptor assay after enteral and parenteral administration to human volunteers as well as to laboratory animals (monkeys and dogs), using [3H]dihydromorphine as radioligand and freshly prepared membrane homogenates of rat brains. The concentration of parent compound drug has been evaluated after a specific extraction from plasma. The method described presents a universal possibility for the determination of opioid drugs of different structures in plasma and other body fluids.

Analgesics↗
PubMed2004

Improving medication safety in a neonatal intensive care unit.

PURPOSE: A revision of the medication-use process intended to reduce errors on a neonatal intensive care unit (NICU) is described. SUMMARY: A multidisciplinary team conducted a systematic review and implemented multifaceted changes to improve the NICU's medication-use process. These changes were made to improve safety and consistency and make the system more user-friendly. A distinct, unit-specific formulary was created for the drug products used on the NICU. Rules were built into the order-entry computer system for these NICU formulary items to identify doses outside the documented range on the basis of body weight. A unit-specific reference was developed detailing all formulary mnemonics, oral drug compounding and i.v. admixture procedures, and guidelines for appropriate product selection. Emergency medication sheets listing the calculated doses by weight for critical or urgent medications were developed; these sheets are provided for every new admission and are updated weekly. End-product-testing procedures for i.v. admixtures and a medication-checking process for the unit's automated dispensing machine were implemented. CONCLUSION: Systematic changes in the medication-use process designed to reduce the opportunity for errors were implemented on an NICU.

Dose-Response Relationship, Drug↗
PubMed2005

Preparation and in vitro evaluation of thiolated chitosan microparticles.

The objective of this study was to prepare a microparticulate drug delivery system being based on a new thiomer, namely a chitosan 2-iminothiolane conjugate (chitosan-TBA conjugate). Due to thiol groups being immobilized on chitosan, chitosan-TBA conjugate exhibits improved mucoadhesive and permeation enhancing properties. Because of these features microparticulate drug delivery systems based on chitosan-TBA conjugate might be a promising tool for the non-invasive administration of hydrophilic macromolecular drugs. Chitosan-TBA conjugate microspheres were prepared by the emulsification/solvent evaporation method. Fluorescein-isothiocyanate labelled dextran (FITC-dextran) was chosen as a model hydrophilic drug. Microspheres have been characterized by morphological analysis, thiol group content, swelling behaviour, polymer degradation drug load determination, dissolution test and mucoadhesion studies. Results reported in this work demonstrated the possibility to obtain stable microspheres without cross-linking agents. Thiolated chitosan microspheres seem to be more stable in aqueous media with respect to unmodified chitosan. The degradability by lysozyme appears quite similar for both polymers, showing that chemical modification does not influence the biodegradable properties of chitosan. Microspheres were able to control the drug release for at least 1 h, exhibiting comparatively strong mucoadhesive properties. The chitosan-TBA conjugate microparticles remain on the mucosa in a 2.5-fold higher concentration with respect to unmodified chitosan microparticles. These data suggest that chitosan-TBA conjugate microspheres have the potential to be used as a mucoadhesive drug delivery system.

Adhesiveness↗