Alka Garg

Factors Affecting Mechanism and Kinetics of Drug Release from Matrix-Based Oral Controlled Drug Delivery Systems

Matrix technologies have often proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form, and ease of scale-up and process validation. Technological advancements in the area of matrix formulation have made controlled-release product development much easier than before, and improved upon the feasibility of delivering a wide variety of drugs with different physicochemical and biopharmaceutical properties. This is reflected by the large number of patents filed each year and by the commercial success of a number of novel drug delivery systems based on matrix technologies.Matrix-based delivery technologies have steadily matured from delivering drugs by first-order or square-root-of-time release kinetics to much more complex and customized release patterns. In order to achieve linear or zero-order release, various strategies that seek to manipulate tablet geometry, polymer variables, and formulation aspects have been applied. Various drug, polymer, and formulation-related factors, which influence the in situ formation of a polymeric gel layer/drug depletion zone and its characteristics as a function of time, determine the drug release from matrix systems.Various mathematical models, ranging from simple empirical or semi-empirical (Higuchi equation, Power law) to more complex mechanistic theories that consider diffusion, swelling, and dissolution processes simultaneously, have been developed to describe the mass transport processes involved in matrix-based drug release. Careful selection of an appropriate model for drug release provides insight to the underlying mass transport mechanisms and helps in predicting the effect of the device design parameters on the resulting drug-release rate. Thus, a basic understanding of release kinetics and appropriate mechanisms of drug release from matrix system and their inter-relationships may minimize the number of trials in final optimization, thereby improving formulation development processes.

Development of a topical niosomal preparation of acetazolamide: preparation and evaluation.

Orally administered acetazolamide has a limited use in glaucoma due to the systemic side effects associated with its use. No topical formulation of acetazolamide is available, mainly because of it having a limited aqueous solubility and poor corneal permeation. To enhance the bioavailability of acetazolamide by the topical route and to improve the corneal permeability of the drug, niosomes of acetazolamide were prepared (employing span 60 and cholesterol) by different methods. Transmission electron microscopy (TEM) of the selected formulation was carried out to study the morphology. Niosomes were also prepared in the presence of dicetyl phosphate and stearylamine to obtain negatively and positively charged vesicles, respectively. It was found that the reverse‐phase evaporation method (REV) gave the maximum drug entrapment efficiency (43.75%) as compared with ether injection (39.62%) and film hydration (31.43%) techniques. Drug entrapment efficiency varied with the charge and the percent entrapment efficiency for the REV method was 43.75, 51.23 and 36.26% for neutral, positively charged and negatively charged niosomes, respectively. Corneal permeability studies, however, showed that the percent permeation and the apparent permeability coefficient for the charged niosomes were less than for the neutral ones. A bioadhesive niosomal formulation of acetazolamide was also prepared and compared with the positively charged formulation, considering that both of them would have a prolonged stay in the cul‐de‐sac because of their expected interactions with mucin. The formulations were also compared based on their intraocular pressure (IOP)‐lowering capacity. The positively charged niosomes (REV2), although showing good corneal permeability and pharmacodynamics, were however found to be inappropriate in terms of the corneal cell toxicity. The bioadhesive coated formulation (REV1bio) compared well with REV2 and also showed a much lesser toxicity. Further, the IOP‐lowering effect of the developed formulations was compared with that of a marketed formulation of dorzolamide 2%, a topical carbonic anhydrase inhibitor. The developed niosomal formulations of acetazolamide showed a comparable physiological effect (33% reduction of IOP in REV***1bio and 37% reduction in dorzolamide) with a duration of up to 6 h (the duration being 3 h for dorzolamide). Results of the study indicate that it is possible to develop a safe (as indicated by corneal toxicity studies) and physiologically active topical niosomal formulation of acetazolamide relative in efficiency to the newer local carbonic anhydrase inhibitor, dorzolamide. The developed formulations can form a cost effective treatment plan, which is especially important in the treatment of glaucoma, a chronic ailment affecting middle‐aged to old patients.

Development and Characterization of Bioadhesive Vaginal Films of Sodium Polystyrene Sulfonate (PSS), a Novel Contraceptive Antimicrobial Agent

No HeadingPurpose.Polystyrene sulfonate (PSS) is a novel noncytotoxic antimicrobial contraceptive agent. A gel formulation of PSS was found safe for vaginal administration in phase I clinical trials. The purpose of the current study was to develop and evaluate novel bioadhesive vaginal film formulations of PSS.Methods.PSS films were prepared by solvent evaporation and optimized for various physical, mechanical, and aesthetic properties. Further, films were evaluated for various biological activities and safety.Results.Vaginal films containing 300 mg PSS per unit have been developed, using generally regarded as safe (GRAS) listed excipients. The films are colorless, transparent, thin, soft, and tough, dissolve rapidly in physiologic fluid to form a smooth, viscous and bioadhesive solution that could be retained in the vagina for prolonged intervals. Sperm function inhibition (hyaluronidase and cervical mucus penetration) and antimicrobial activities against human immunodeficiency virus (HIV) and herpes simplex virus (HSV) by PSS films were found comparable to PSS. Also, films did not inhibit normal vaginal microflora (Lactobacillus) and were noncytotoxic as indicated by negligible sperm immobilization and cytotoxicity to host cell assays.Conclusions.Rapidly dissolving bioadhesive vaginal film formulation of PSS with desired physical, mechanical, aesthetic, and biological properties is a suitable candidate vaginal microbicide for prevention of sexually transmitted disease (STDs) and is ready for toxicological and clinical evaluation.

Development Pharmaceutics of Microbicide Formulations. Part I: Preformulation Considerations and Challenges

Microbicides, the compounds and formulations that can prevent transmission of sexually transmitted diseases (STDs)/HIV are being pursued actively as a promising AIDS intervention. The drug development chain for a topical microbicide differs significantly from that of any systemic or topical compound/formulation regarding to time line, cost, activities, and milestones. This is in part because of the lack of standard in vitro models to assess efficacy, and complex ethical issues in clinical trials of microbicides. Several factors, including changes in the physiology of the cervix and vagina with age and menstrual cycle, intercourse, as well as leakage of the formulation from the vagina may affect their design, development, and performance. Selection and development of optimal microbicide delivery systems (gel/cream, pessary, film, tablet, foam, etc.), their inactive ingredients, manufacturing details, and packaging system are dependent on the properties of active drug, or their preformulation parameters (PP). The PP of the active drug substance needs to be evaluated in initial stages of drug discovery and development so that the most suitable delivery system can be selected. Some PP of microbicide agents include physical state, organoleptic properties (color, odor, appearance, taste, etc.), molecular weight, aqueous solubility, hygroscopicity, acidity/alkalinity, permeability and absorption characteristics, stability in solid/solution state, and inherent bioadhesiveness. Thus, a well-coordinated, planned, and implemented preformulation program can help in not only accelerating microbicide formulation development, but also to minimize unforeseen failures in subsequent stages of the development. The objective of this review is to highlight the significance of PP, suggesting a systematic preformulation program.

Lactobacillus Sepsis following a Laparotomy in a Preterm Infant: A Note of Caution

Probiotics for preterm infants have been shown to reduce the incidence of necrotising enterocolitis and all-cause mortality in a recent meta-analysis. It has been argued, however, that some of these results may not be applicable to specific subgroups, e.g. infants with a birth weight of <1,000 g. The specific role of probiotics in improving health outcomes in preterm and term infants following intestinal surgery is not well defined. We report a case of a premature infant diagnosed with late-onset sepsis due to Lactobacillus rhamnosus following a laparotomy. We review pertinent published cases. This case highlights the importance of considering preterm infants as being at a higher risk of systemic probiotic infection following intestinal surgery.

Development of an extemporaneous oral liquid formulation of oxandrolone and its stability evaluation

Many references exist in the literature identifying the usefulness of oxandrolone in treating muscle wasting due to various conditions including severe burns. However, there is an absence of dosage form alternatives as it is only available as tablets. The dose for children is weight based (0.1 mg/kg) which is difficult to achieve with the currently available tablets of 2.5 mg and 10 mg. The literature provides ample evidence of clinical importance but little guidance on extemporaneous oral liquid formulation of oxandrolone. In order to develop and validate an extemporaneous liquid formulation, suspensions of oxandrolone were developed using locally available (New Zealand) vehicles. Combinations of these vehicles with ethanol, as advised in some articles were also tried. Assay method was developed for oxandrolone using High Performance Liquid Chromatography (HPLC) and Mass Spectroscopy (LC-MS). The formulations were evaluated for stability as per the International Conference on Harmonization (ICH) stability guidelines. They were observed for physical and chemical stability at different time points over a period of 28 days. A stable and validated liquid formulation of oxandrolone has been developed which can be made under the hospital and community pharmacy conditions. The formula utilises commercially available oxandrolone tablets, crushed and dispersed in Simple Syrup BP or Orablend(®) vehicle. The formulation has confirmed stability for 21 days and can be easily made with locally available vehicles.

Secondary prophylaxis of osteoporotic fractures in an orthogeriatric service.

We have recently completed an audit in the secondary prophylaxis of osteoporotic fractures in our orthogeriatric service. Counties Manukau District Health Board serves a population of nearly half a million with a busy orthopaedic service and a well-established orthogeriatric service. The mainstay of treatment of osteoporosis is bisphosphonates, alendronate in particular; however, few compliance data are available. The aims of our audit included assessing the efficacy of our initiative of identifying those eligible for starting alendronate early in their stay and the number of patients compliant with treatment at 2 years.

Compatibility of intravenous ibuprofen with lipids and parenteral nutrition, for use as a continuous infusion

There is increasing interest to administer ibuprofen as a continuous infusion instead of a traditional bolus for treating Patent Ductus Arteriosus (PDA). However, its compatibility data with commonly used drugs in the neonatal period, including parenteral nutrition (PN) and lipids is unavailable. The aim is to determine the compatibility of intravenous ibuprofen lysine with various ANZNN parenteral nutrition consensus group standard neonatal PN formulations and lipids. The PN and lipid solutions used in a tertiary neonatal unit were obtained. These included a Starter, Standard Preterm and low carbohydrate PN, and IV SMOF lipid admixture (SMOFLipid 20% 15 mL; Vitalipid N infant 4 mL, Soluvit N 1 mL) plus vitamin mixtures. 10% glucose was used as a control. 1:1 mixtures of different concentrations (1.25 to 5mg/mL) of ibuprofen lysine and each of the PN/glucose/lipid formulations were made. Samples were taken at hourly intervals for a total of 4 hours and tested for both physical (visual assessment, pH and microscopy) and chemical compatibility (High Performance Liquid Chromatography analysis). Zeta potential and particle diameter were measured for SMOF lipid admixture and ibuprofen combination to assess emulsion stability. 24 hour stability of ibuprofen dilution in 5 mL BD Luer-lok polypropylene syringes at 25°C was also assessed. Most PN formed opaque solutions when mixed with ibuprofen 2.5 and 5mg/mL solutions. However, ibuprofen dilution of 1.25mg/mL produced clear, colourless solutions with no microscopic particles when mixed with all PN/glucose/lipid formulations tested. Ibuprofen was chemically stable with all PN and SMOF lipid admixture, for a period of 4 hours. The zeta potential and particle diameter were within acceptable limits. Ibuprofen lysine was stable over 24 hours in Luer-lok polypropylene syringes. Ibuprofen 1.25mg/mL is physically and chemically compatible with 10% glucose, starter PN, standard preterm and low carbohydrate PN, and SMOF lipid admixture plus vitamins for a period of four hours, which is the maximum time they could be in an admixture during a continuous infusion.

Cetirizine - how much is too much?

Cetirizine hydrochloride is a commonly used over‐the‐counter antihistamine that may be prescribed in larger doses than are commonly used for allergic rhinitis for the management of chronic urticaria.

Penicillin stability in prefilled syringes for the purpose of skin testing for drug allergy.

Up to 10% of the patients attending hospitals report an allergy to penicillin, though only about 6% to 10% of these have a true IgE-mediated allergy, proven by cutaneous tests and drug provocation. A label of penicillin allergy when a true allergy is not present often leads to lifelong avoidance of penicillin and related drugs. This leads to the use of less specific, more expensive antibiotics, contributing to increased adverse effects and antibiotic resistance. The negative predictive value for penicillin skin testing for immediate reaction is close to 100%, whereas the positive predictive value is between 40% and 100%. Diagnosis is currently confirmed using cutaneous tests (skin prick testing [SPT] and intradermal testing [IDT]) with penicilloyl poly-L-lysine (PPL) as the major determinant of benzylpenicillin and minor determinant mixture (MDM) containing benzylpenicillin, benzylpenicilloate, and benzylpenilloate. SPT and IDT, using penicillin dilutions and PPL and MDM, are widely recommended for testing immediate hypersensitivity to penicillin class antibiotics. In Europe, both PPL and MDM are available with Diater DAP (Madrid, Spain). In the United States, only PPL is available as PRE-PEN (AllerQuest LLC, Plainville, Conn). Traditionally, test reagents, including drug dilutions and allergic determinants, are made at the bedside by the allergist because there is no evidence of their stability in the syringes these are prepared in. This is a time-consuming, labor-intensive practice and limits the number of patients who can be tested at one time. Also, with multiple antibiotics, at multiple dilutions, errors can be made. If these dilutions could be prepared in advance in pharmacy under aseptic conditions and labeled appropriately, it would not only improve safety of testing but also contribute significantly to improving the workflow of allergy testing clinics and facilitate more patients being tested. There would be financial gains in terms of less drug wastage and time saved in preparing syringes for multiple patients together rather than one at a time. Table I details the reagents used for SPT for penicillin class antibiotics. Other drugs can be included on the basis of individual patient requirements. Pharmacy at Women’s and Children’s Hospital in Adelaide makes these dilutions within 24 hours of testing, so that patients do not have to wait while these dilutions are being made. However, there is no literature regarding the stability of these dilutions in the syringes in which they are prepared in advance. Recent information from Diater (available in Australia) confirms the stability of PPL and MDM after reconstitution to be 15 days in refrigerated conditions (Sanchez J, 2013; unpublished data). The aim of this study was to carry out validated stability testing of penicillin class drugs commonly used for SPT and IDT in syringes to enable their preparation before the tests. HPLC analytical methods were developed for benzylpenicillin sodium (Penicillin G sodium salt, Sigma, Sydney, Australia), amoxicillin sodium (Amoxil, GlaxoSmithKline, Uxbridge, UK), and flucloxacillin sodium (DBL Flucloxacillin sodium, Hospira Australia, Melbourne, Australia) to ensure that they were adequate and repeatable. The assay methods were validated for linearity, specificity, precision, and stability in the analytical solution. Analysis was carried out using HPLC (Shimadzu, Kyoto, Japan) and Phenomenex Kromasil C-18 column. The mobile phases included acetonitrile, potassium dihydrogen phosphate, and sodium hydroxide for amoxicillin HPLC analysis; methanol, potassium dihydrogen phosphate, and orthophosphoric acid for benzypenicillin HPLC analysis; and acetonitrile, potassium dihydrogen phosphate, and sodium hydroxide for flucloxacillin HPLC analysis. Dilutions of benzylpenicillin sodium (0.6 mg/mL, pH 7.06, and 6 mg/mL, pH 6.98), amoxicillin sodium (2 mg/mL, pH 8.6, and 20 mg/mL, pH 8.66), and flucloxacillin sodium (0.5 mg/mL, pH 6.05, and 5 mg/mL, pH 5.24) were aseptically prepared in sterile water for injection and packed in 1-mL Leurlock polycarbonate syringes with “Combi” syringe caps. This was done in a sterile pharmacy manufacturing facility by aseptically validated pharmacists. Water for injection was used to further dilute to the required concentrations. Three batches for each dilution were prepared, and 2 sample replicates were drawn from each batch for each sampling point and each temperature. The syringes were transferred to the analytical testing laboratory immediately postproduction, maintaining the cold chain, and placed in stability chambers (Newtronic, Mumbai, India) at 25 C, 4 C, and 20 C (Refrigerator/freezer; Samsung, Seoul, South Korea). Samples were withdrawn at different time points ranging from 0 to 7 days and assessed for physical (color change, precipitation) and chemical (drug recovery 90% by HPLC) stability. No color change or precipitation was observed for the 3 penicillins tested at all temperatures throughout the stability study. All drug dilutions were thereby deemed physically stable at all temperatures tested. Figure 1, A to F, depicts the chemical stability of the tested penicillins (percent drug recovery with respect to time). Based on these results, new shelf life was determined for the dilutions in syringes of the penicillin class antibiotics tested, as detailed in Table II.