Mansoor Khan

Targeting to macrophages: role of physicochemical properties of particulate carriers--liposomes and microspheres--on the phagocytosis by macrophages.

Heterogeneous functions of macrophages in human immune systems have renewed interest in targeting of drugs to these cells. Various carrier systems have emerged to deliver drugs to macrophages, albeit the efficacy, reliability and selectivity of these carriers are still in question. To date, the most extensively studied carriers are liposomes and microspheres. Various physicochemical properties of these carriers can alter their efficacy and specificity to a great extent. These properties include hydrophilicity, surface charge, composition, concentration, and presence of various ligands. In this review, a comprehensive evaluation of the literature has been carried out in order to show the role of these parameters in the design of carriers for targeting of drugs to macrophages.

Polymethyacrylate based microparticulates of insulin for oral delivery: Preparation and in vitro dissolution stability in the presence of enzyme inhibitors

The purpose of this investigation was to (a) evaluate the coprecipitation technique for preparing microparticulates of insulin, (b) study the effect of variables such as addition of salts in the precipitating medium and ratio of polymeric solution to volume of precipitating medium on the dissolution and encapsulation efficiency of insulin microparticulates, and (c) evaluate the in-vitro enzymatic dissolution stability of insulin microparticulates in the presence of chicken ovomucoid (CkOVM) and duck ovomucoid (DkOVM) as inhibitors. Insulin dissolved in 0.01 N HCl was mixed with alcohol USP to get a final concentration of 32% v/v. Eudragit L100, a representative polymethyacrylate polymer, was then dissolved in this solution which was transferred to a beaker containing cold water with homogenization to obtain microparticulates. Dissolution studies were carried out in pH 6.8 phosphate buffer using a 100-ml conversion kit in a standard dissolution assembly. Dissolution stability of microparticulates was evaluated in the presence of 0.5 microM trypsin and 0.l microM chymotrypsin at various ratios of CkOVM and DkOVM. The results indicated that insulin microparticulates could be prepared using the coprecipitation technique with high encapsulation efficiency by proper selection of experimental conditions and amount of polymer. Presence of salts in the precipitating medium decreased the dissolution of insulin from the microparticulates. As the ratio of precipitating medium with respect to the polymeric solution was increased, the encapsulation efficiency increased. In dissolution stability experiments, insulin was not detected in the presence of enzymes alone. When CkOVM and DkOVM were incorporated, the stability of insulin increased significantly in a concentration dependent fashion.

Permeability of Chemical Delivery Systems Across Rabbit Corneal (SIRC) Cell Line and Isolated Corneas: A Comparative Study

The purpose of this study was to investigate the corneal permeability of phenylephrone chemical delivery systems (CDS) across isolated cornea and to evaluate the utility of the SIRC cell line (epithelial cells originating from rabbit cornea) as an in vitro model for predicting the ocular permeability. The effect of benzalkonium chloride (BAC) on the drug permeability through SIRC cell layers was also studied. The transport of phenylephrone CDS across the isolated cornea of the albino rabbit was measured at various pH values using a two-chamber glass diffusion cell, and the results were compared with the reported permeability values across SIRC cells of rabbit origin. Corneal membranes showed lower flux values for compounds, especially for hydrophilic compounds, than the SIRC cell line. A significant correlation was observed between the permeability coefficients through corneal membranes and SIRC cells. When the pH of the transport medium was increased, the permeability coefficients increased and lag times decreased in both in vitro models. Furthermore, both in vitro models showed significant correlation between permeability coefficients and lipophilicities of the drugs. The three esters, having higher lipophilic characteristics, showed higher permeability than phenylephrine HCl. The phenylacetyl ester of phenylephrone showed a three-fold increase in penetration across SIRC cell layers in the presence of 0.01% BAC. These results suggest that the use of SIRC cell layers can reasonably predict the permeability of ophthalmic drugs across corneal membranes.

Transport studies of insulin across rat jejunum in the presence of chicken and duck ovomucoids.

Our aim was to evaluate the transport of insulin across rat jejunum in the presence of ovomucoids and to assess the effect of ovomucoids on intestinal tissue by studying the permeation of a lipophilic and a hydrophilic marker. Rat jejunal segments were mounted in a side‐by‐side diffusion chamber filled with Krebs bicarbonate buffer, bubbled with 95% O2/5% CO2 at a fixed flow rate and maintained at 37°C. The permeation of insulin, a lipophilic marker ([7‐3H] testosterone) and a hydrophilic marker (D‐[1‐14C] mannitol) was evaluated in the presence of 0.5–1.5 μM duck ovomucoid (DkOVM) or chicken ovomucoid (CkOVM). For stability and permeation of insulin in the presence of α‐chymotrypsin, an enzyme‐to‐inhibitor ratio of 1:1 and 1:2 was used. In the absence of α‐chymotrypsin, the permeability coefficient (Papp) of insulin at pH 7.4 was 0.922 ± 0.168 times 10−7 cm s−1, which decreased with increasing concentrations of DkOVM or CkOVM. Conversely, the permeation of the hydrophilic and lipophilic marker increased with increasing concentrations of CkOVM and DkOVM. In stability studies, the percentage of drug remaining was found to be 2‐fold higher at the 1:2 ratio than with the 1:1 ratio of enzyme to inhibitor. This was in agreement with the 2‐fold increase in flux values of insulin in the presence of α‐chymotrypsin and DkOVM at the 1:2 ratio of enzyme to inhibitor. The decrease in permeation of insulin in ovomucoids was unexpected. Marker transport studies indicated that ovomucoids have the potential to modulate transcellular and paracellular permeability. The flux enhancement of insulin in the presence of α‐chymotrypsin and DkOVM is encouraging. The use of ovomucoids offers potential to enhance oral delivery of insulin and warrants further investigation.

Oral Delivery of Proteins: Effect of Chicken and Duck Ovomucoid on the Stability of Insulin in the Presence of α-Chymotrypsin and Trypsin

The in-vitro stability of insulin in the presence of α-chymotrypsin and trypsin has been evaluated in the presence of different concentrations of chicken and duck ovomucoid (CkOVM and DkOVM), a new class of enzyme inhibitor derived from the egg white of avian species. The inhibitory effect was compared with that of aprotinin. The effectiveness of DkOVM was also determined in the presence of agents that accelerate α-chymotrypsin-mediated degradation of insulin in solution by deaggregation. n n n nInsulin solutions (18μM) were incubated at 37°C with 0.1 μM chymotrypsin and 0.5 μM trypsin in lOOmM Tris buffer containing 1 mM calcium chloride and different concentrations of CkOVM and DkOVM. Samples were treated with cold Tris containing 1% (v/v) trifluoroacetic acid to stop the enzyme action and analysed by reversed-phase high-performance liquid chromatography. Similar studies were performed with aprotinin, EDTA (0.05 mM) and sodium glycocholate (30mM) in the presence of α-chymotrypsin and DkOVM. DkOVM was effective against α-chymotrypsin-mediated degradation of insulin at enzyme-to-inhibitor ratios of 1:0–5, 1:1 and 1:2. CkOVM was ineffective against α-chymotrypsin even at an enzyme-to-inhibitor ratio of 1:4. In contrast, both DkOVM and CkOVM were completely effective against trypsin-mediated degradation of insulin at an enzyme-to-inhibitor ratio of 1:1. This effect was comparable with that of aprotinin at an enzyme-to-inhibitor ratio of 1:1. Inhibition of the enzyme was reduced in the presence of sodium glycocholate and EDTA. n n n nDkOVM effectively stabilized insulin against degradation for a study period of 1 h in the presence of α-chymotrypsin and trypsin. Because insulin is extensively degraded by α-chymotrypsin, DkOVM might be used to enhance the oral delivery of insulin.

Biodegradable Microparticulates of Beta-Estradiol: Preparation and In Vitro Characterization

ABSTRACT Beta-estradiol has been recommended for the long-term therapy of osteoporosis and its oral formulations are subjected to intensive first pass metabolism. The present investigation was aimed at preparing and characterizing biodegradable microparticles of beta-estradiol with polymers such as PLA, PLGA 85/15, PLGA 75/25, and their mixtures. The microparticles were prepared by solvent evaporation method using methylene chloride as a solvent and polyvinyl alcohol as a surfactant. The drug-polymer ratios were 1:3, 1:5, and 1:7. The prepared microparticles (twelve formulations) were tested for encapsulation efficiency and in vitro drug release in 50% methyl alcohol/phosphate buffer pH 7.4. The results showed that the encapsulation efficiency varied from 81 to 100% and the formulation fabricated from PLGA 85/15 (1:3) showed less burst and consistent long time release. This formulation when further characterized displayed irregular spherical shape with an average particle size of 72 µm. The crystallinity of the drug was reduced when investigated using X-ray diffractometry. No chemical interaction between the drug and the polymer was observed as evidenced by FT-IR analysis. The results indicated that beta-estradiol biodegradable microparticles with PLGA 85/15 (1:3) could be a suitable approach for long term therapy of osteoporosis.

Pharmaceutical and Clinical Calculations

Prerequisite Mathematics Review Numbers and Numerals Arabic and Roman Numerals Fractions Decimals Ratio and Proportion Percentage Percent Concentration Expressions Dilution and Concentration Density and Specific Gravity Systems of Measurement The Metric System Apothecaries System The Avoirdupos System The Household System Interconversions Prescription and Medication Orders Types of Prescriptions Components of Prescriptions Label on the Container Medication Order Common Latin Terms and Abbreviations Medications and Their Directions for Use Prescription Problems Errors and Omissions Principles of Weighing and Measuring Prescription Balance and Sensitivity Requirement Aliquot Method for Solids Liquid Measurements Aliquot Method for Liquids Calculations Involving Oral Liquids Calculations Associated with Bulk Preparations Calculation of Doses Percentage Strength Calculations of Oral Liquids Dilution and Concentration Milliequivalent Calculations of Oral Electrolyte Solutions Dosage Calculations Involving Milliequivalents Calculations Involving Capsules, Tablets, and Powder Dosage Forms Strength of Dosages Extemporaneous Filling of Capsules Compounding Tips and Calculations for Filling Powder Prescriptions Calculations Involving Ointments, Creams, and Other Semisolids Compounding Tips Calculations Associated with Bulk Preparations Percentage Strength Calculations of Semisolid Preparations Dilution and Concentration Calculations Involving Topical Ophthalmic, Nasal, and Otic Preparations Isotonicity Calculation of Dissiociation (I) Factor Sodium Chloride Equivalents of Drug Substances Isotonicity Adjustments by Sodium Chloride Equivalent Methods Tonicity Agents Other Than Sodium Chloride Isotonicity Adjustments by Cryoscopic Method Volumes of Iso-Osmotic Solutions pH Adjustment Conversion of Hydrogen Ion Concentration to pH Conversion of pH to Hydrogen Ion Concentration Buffers Calculations Involving pH Value of a Buffer Molar Ratio of Buffer Components in a Buffer Calculations Involving Suppositories Displacement Value Preparation of Suppositories with Cocoa Butter Calculations Involving Injectable Medications Rate of Flow of Intravenous Fluids Insulin Dosage Heparin Dosage Calculations Involving Reconstitution of Dry Powders Milliequivalents and Milliosmoles Calculations Involving Nutrition Calculations of Calories Parenteral Hyperalimentation Resting Energy Expenditure (REE) Calculations Geriatric Nutrition Pediatric Nutrition Calculation of Doses and Dose Adjustments Plasma Concentration versus Time Profile Some Pharmacokinetic Parameters Fraction of Drug Absorbed and the Dosing Interval Clearance Loading and Maintenance Doses Dose Adjustments in Renal Failure Dose Adjustments in Hepatic Failure Pediatric and Geriatric Dosing Dosage Calculations Based on Age Dosage Calculations Based on Body Weight Dosage Calculation Based on Body Surface Area Dosage Regimen in Patients Using Aminoglycosides Critical Care Pediatric Critical Care Calculations Involving Immunizing Agents and Vaccines Bacterial Vaccines Viral Vaccines Toxoids Calculations Involving Radiopharmaceuticals Units of Radioactivity Half-Life of Radiopharmaceuticals Mean Life Radioactive Decay of Radioisotopes Percentage Activity Dispensing of Radiopharmaceuticals Review Problems Answers to Practice Problems Answers to Review Problems Appendices A-E Suggested Readings Index

Response Surface Methodology to Obtain β-Estradiol Biodegradable Microspheres for Long-Term Therapy of Osteoporosis

The purpose of this work was to evaluate the main and interaction effects of formulation factors on the drug encapsulation efficiency of β-estradiol biodegradable microspheres by applying response surface methodology. A secondary purpose was to obtain an optimized formula for long-term therapy of osteoporosis. A three factor, three level Box-Behnken experimental design was used to get 15 experimental runs. The independent variables were drug/polymer ratio (X1), dispersing agent concentration (X2), and deaggregating agent concentration (X3). The dependent variables were percentage encapsulation efficiency (Y1), cumulative percent drug released (Y2), and percentage yield of the microspheres (Y3). The formulations were prepared by emulsion solvent evaporation technique using ethyl acetate as organic solvent. The optimized formulation was maximized for encapsulation efficiency and further characterized for the particle size distribution, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR). The mathematical relationship obtained between X1, X2, X3, and Y1 was: Y1 = −129.85 + 29.35X1 + 129.99X2 + 64.82X3 − 3.2X1X2 − 0.29X1X3 − 35.83X2X3 − 2.05X12 − 13.23X22 − 5.92X32 (R2 = 0.99) The equation showed that X1, X2, and X3 affect Y1 positively but interaction between any two of these factors affects Y1 negatively. The most significant interaction was between X2 and X3. The finding indicated that controlled releases β-estradiol biodegradable microspheres with high encapsulation efficiency and low pulsatile release can be prepared and the quantitative response surface methodology applied helped in understanding the effects and the interaction effects between the three factors applied.

Nanotechnology-based drug products

Abstract A sponsor must submit data for a review to US Food and Drug Administration (FDA) in order to market nanotechnology-based prescription drug products. An application to submit data for a brand and generic version of drug product are NDA (new drug application) and ANDA (abbreviated NDA), respectively. FDA basic requirements of safety and efficacy for approval have not changed, even for nanomedicines; the onus rests on the sponsor to provide evidence of safety and efficacy. Oftentimes, a sponsor must provide additional safety and efficacy information of nanomedicines due to presence of nanoscale materials in them which are responsible for high reactivity, and unique mechanical and magnetic properties. For example, safety evaluation of nanotechnology-based drug products may include environment and toxicological assessment. In terms of pharmaceutical quality, particle size characterization is a major challenge as there is no consensus on sizing technique. To ensure consistency in product quality, hence clinical performance, it is also important to understand the product and process variables that can affect the quality of products, especially particle size. Quality by design approach provides a mean to link material attributes and process variables to critical quality attributes of the nanomedicines. This chapter provides scientific and regulatory aspects of nanotechnology-based drug products.