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ABSTRACT: Drug-polymer solid dispersion has been demonstrated as a feasible approach to formulate poorly water-soluble drugs in the amorphous form, for the enhancement of dissolution rate and bioperformance. The solubility (for crystalline drug) and miscibility (for amorphous drug) in the polymer are directly related to the stabilization of amorphous drug against crystallization. Therefore, it is important for pharmaceutical scientists to rationally assess solubility and miscibility in order to select the optimal formulation (e.g., polymer type, drug loading, etc.) and recommend storage conditions, with respect to maximizing the physical stability. This commentary attempts to discuss the concepts and implications of the drug-polymer solubility and miscibility on the stabilization of solid dispersions, review recent literatures, and propose some practical strategies for the evaluation and development of such systems utilizing a working diagram.
Journal of Pharmaceutical Sciences 07/2010; 99(7):2941-7. · 3.06 Impact Factor
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ABSTRACT: Over the past few decades alternate routes of administration have gained significant momentum and attention, to complement approved drug products, or enable those that cannot be delivered by the oral or parenteral route. Intranasal, buccal/sublingual, pulmonary, and transdermal routes being the most promising non-invasive systemic delivery options. Considering alternate routes of administration early in the development process may be useful to enable new molecular entities (NME) that have deficiencies (extensive first-pass metabolism, unfavorable physicochemical properties, gastro-intestinal adverse effects) or suboptimal pharmacokinetic profiles that are identified in preclinical studies. This review article describes the various delivery considerations and extraneous factors in developing a strategy to pursue an alternate route of administration for systemic delivery. The various delivery route options are outlined with their pros and cons; key criteria and physicochemical attributes that would make a drug a suitable candidate are discussed; approaches to assess delivery feasibility, toxicity at the site of delivery, and overall developability potential are described; and lastly, product trends and their disease implications are highlighted to underscore treatment precedence that help to build scientific rationale for the pursuit of an alternate route of administration.
Journal of Pharmaceutical Sciences 07/2009; 99(1):1-20. · 3.06 Impact Factor
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ABSTRACT: There are many reports in the literature referring to the utilization of drug bound to ion-exchange resin (drug-resinate), especially in the drug delivery area. Ion-exchange resin complexes, which can be prepared from both acidic and basic drugs, have been widely studied and marketed. Salts of cationic and anionic exchange resins are insoluble complexes in which drug release results from exchange of bound drug ions by ions normally present in body fluids. Resins used are polymers that contain appropriately substituted acidic groups, such as carboxylic and sulfonic for cation exchangers; or basic groups, such as quaternary ammonium group for anion exchangers. Variables relating to the resin are the exchange capacity; degree of cross-linking, which determines the permeability of the resin, its swelling potential, and the access of the exchange sites to the drug ion; the effective pK(a) of the exchanging group, which determines the exchange affinity; and the resin particle size, which controls accessibility to the exchange ions. In this review, the properties of ion-exchange resins, selection of drugs that lend themselves to such an approach, selection of the appropriate resin, preparation of drug-resinate, evaluation of drug release, recent developments of drug-resinates, and applications are discussed.
Journal of Pharmaceutical Sciences 03/2009; 98(11):3886-902. · 3.06 Impact Factor
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ABSTRACT: The purpose of this study was (a) to evaluate the factors affecting the form conversion of anhydrous lactose to the monohydrate form during wet granulation using water as the granulating agent and (b) study the effect of lactose form conversion on its compaction properties. A two-level full factorial design with two center points was used to evaluate the factors affecting form conversion. The three variables evaluated were percentage of microcrystalline cellulose (low 0 and high 20), water to intragranular solids ratio (low 0.10 and high 0.18) and drying conditions (tray drying and fluid bed drying). The presence of microcrystalline cellulose in the formulation did not provide any benefit in reducing the percent lactose conversion. But, the conversion was significantly reduced by decreasing the amount of water added to the granulation and/or by decreasing the drying time, using a fluid bed dryer compared to a tray dryer. In the second part of the study, complete conversion of the anhydrous lactose to monohydrate was achieved by storing the anhydrous form under 25 degrees C/97% RH for 4 weeks. Physical characterization (compactibility, surface area and surface morphology) was performed on the form converted material and compared to the as received anhydrous lactose. The physical characterization results indicated that even though anhydrous lactose undergoes complete form conversion to monohydrate form under high humidity and/or during wet granulation, it retains its inherent higher as received material compactibility and the BET surface area and porosity of the form converted material are higher than that of the as received anhydrous lactose.
International Journal of Pharmaceutics 07/2008; 357(1-2):228-34. · 3.35 Impact Factor
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ABSTRACT: The goal of this study was to evaluate biomarkers of nasal mucosal damage for rapid assessment of irritancy potential of formulations in the rat nasal lavage model, a tool to facilitate nasal formulation development prior to histopathology studies. The nasal cavity of anesthetized rats was lavaged with normal saline 20 min pos-tdose. The collected fluid was analyzed for secreted total protein and biomarkers. Solutions tested include: normal saline, buffers, benzalkonium chloride (BAC), lysophosphatidylcholine (LPC), and four marketed nasal products. Total protein, lactate dehydrogenase and interleukin-1alpha biomarkers were secreted to varying degrees. BAC (0.2%) and LPC (0.5%) exhibiting the strongest response with a signal window ranging from 3.4- to 87-fold greater levels than normal saline. Buffer treatments, excipients, and most marketed nasal products yielded levels similar to normal saline. There was a weak correlation between formulation osmolarity and surface tension with any of the biomarkers. Each nasal formulation elicited a unique protein and biomarker profile with total protein secretion correlated with IL-1alpha secretion suggesting the potential for an inflammatory response. Taken together, rapid and potentially mechanistic information on the preclinical acute irritancy potential of formulations was assessed in the rat nasal lavage model by benchmarking treatments relative to controls and marketed nasal products.
Journal of Pharmaceutical Sciences 06/2008; 98(2):495-502. · 3.06 Impact Factor
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ABSTRACT: There are many reports in the literature referring to the effect of microenvironmental pH on solid dosage form performance, particularly stability and dissolution profiles. Several techniques have been proposed for the measurement of the microenvironmental pH. Those techniques use certain assumptions and approximations and many of them employ a solution calibration curve of a probe to predict hydrogen ion activity in a substantially dry solid. Despite the limitation of the methodology, it is clear from the literature that microenvironmental pH has a significant impact on stability of compounds which demonstrate pH dependent stability in solution. Degradation kinetics of such compounds, and in some cases degradation profile as well, are dependent on the microenvironmental pH of the solid. Modulation of the microenvironmental pH through the use of pH modifiers can hence prove to be a very effective tool in maximizing solid dosage form stability. Judicial selection of the appropriate pH modifier, its concentration and the manufacturing process used to incorporate the pH modifier is necessary to enhance stability. Control of microenvironmental pH to maximize stability can be achieved without the use of pH modifier in some cases if an appropriate counter ion is used to provide an inherently optimal pH for the salt. Microenvironmental pH modulation was also shown to control the dissolution profile of both immediate and controlled release dosage forms of compounds with pH dependent solubility. The pH modifiers have been used in conjunction with high energy or salt forms in immediate release formulations to minimize the precipitation of the less soluble free form during initial dissolution. Additionally, pH modifiers were utilized in controlled release dosage forms of weakly basic drugs which exhibit diminished release in dissolution media with high pH. The incorporation of acidic pH modifiers in the controlled release formulation increases the solubility of the basic drug even as the high pH dissolution medium enters into the dosage form hence increasing drug release rate.
Journal of Pharmaceutical Sciences 06/2007; 96(5):948-59. · 3.06 Impact Factor
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ABSTRACT: Pharmaceutical blends consist of several components each with its own unique characteristics, with different size, shape, density, and particle-particle interactions. With so many degrees of complexity, prediction of segregation behavior becomes intractable. The objective of this study was to develop a segregation test method or a segregation tool that would assess the segregation potential of blends. Literature reports generally seek to predict the segregation behavior based on only one mechanism by which the segregation occurs, primarily sifting or fluidization. This study makes an attempt to combine both of these mechanisms by which segregation occurs. A test is developed and used to assess the segregation behavior of blends at large scale and compare the content uniformity results of tablets with the results of the segregation test. The segregation testing model was successful in predicting the segregation tendency of the formulation and also in rank ordering large scale formulation blends based on their segregation potential. A segregation risk classification system is proposed to assess the potential of segregation at large scale.
Pharmaceutical Development and Technology 02/2007; 12(5):457-62. · 1.36 Impact Factor
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ABSTRACT: The purpose of the study was to investigate the specific mechanism by which elevated gastric pH reduces the absorption of BMS-561389, a factor Xa inhibitor, and to develop a solid formulation strategy to overcome this gastric pH interaction.
A dissolution method in an acetate buffer at pH 5.5 was used to evaluate the dissolution behavior of the tablet formulation. A precipitation model was used to screen different excipients for their potential to minimize the pH-dependent absorption of BMS-561389. Excipients that showed promise in the precipitation model were incorporated in modified tablet formulations. Dissolution rate of the modified tablets was also determined by the acetate buffer method. A canine model for pH-dependent absorption was subsequently used to evaluate the tablet formulations.
Dissolution studies suggested that the reduced absorption of the original formulation was the result of the precipitation of the poorly water-soluble free base during the initial dissolution of the salt. Modified tablets containing organic acids, sulfobutylether-beta-cyclodextrin, or povidone showed enhanced dissolution as compared with the original formulation. Drug absorption from the tablet containing tartaric acid was substantially independent of gastric pH in the canine model.
A multitier approach was successful in identifying a solid dosage form that minimizes the pH-dependent absorption of this drug candidate.
Pharmaceutical Research 06/2006; 23(5):989-96. · 4.09 Impact Factor
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ABSTRACT: The aim of this study was to investigate the mechanism of the effect of wet granulation process on the compaction properties of microcrystalline cellulose (MCC).
MCC alone and with hydroxypropyl cellulose (HPC) as a binder were wet granulated by a high-shear process using different granulation parameters (over- and undergranulated). Overgranulated batches were also ball milled after drying and compared to the unmilled material. MCC starting material and granulation were characterized for particle size distribution, surface area, porosity, and isothermal moisture uptake. Compaction behavior of the MCC and granulations was also studied using a compaction simulator.
In all cases, the wet granulation process decreased MCC primary particle porosity. Wet granulation also reduced compactibility of MCC to different degrees. Overgranulated batch with HPC showed the lowest compactibility and was less compactible than the batch without HPC granulated using the same parameters. Ball-milled material showed an increase in porosity and was significantly more compactible than the unmilled granulation from the same batch.
The decrease in MCC compactibility after granulation is associated with the decrease in MCC primary particle porosity and in some cases with the formation of large dense granules as well. Under certain conditions, milling seems to counteract the effect of wet granulation on MCC compactibility.
Pharmaceutical Research 04/2006; 23(3):634-40. · 4.09 Impact Factor
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ABSTRACT: The aim of this research was to develop a pH-dependent canine absorption model for studying pH effect on both dissolution in vitro and pharmacokinetics in vivo using the weak bases ketoconazole and dipyridamole as model drugs.
Ketoconazole and dipyridamole pH-dependent dissolution profiles in vitro were determined by dissolution test at different pH values using USP apparatus II and an Opt-Diss Fiber Optic UV System. In vivo absorption studies for ketoconazole and dipyridamole were performed with crossover design in three groups of beagle dogs under control (no treatment), pentagastrin, and famotidine treatments. Ketoconazole and dipyridamole plasma concentrations were quantified by gradient high performance liquid chromatography mass spectroscopy (HPLC MS/MS). Pharmacokinetic parameters were determined from individual plasma concentration vs. time profiles.
Ketoconazole and dipyridamole displayed pH-dependent dissolution. Increasing the pH of the dissolution medium from 1.2 to 6.8 reduced the extent of dissolution of ketoconazole and dipyridamole at 1 h by 96% and 92%, respectively. In vivo studies in dogs under control (no treatment), pentagastrin, and famotidine treatments show marked differences in systemic ketoconazole and dipyridamole exposure. Area under the concentration-time curve (AUC) increased more than 4-fold as compared to control group, whereas it increased nearly 30-fold for ketoconazole and 9-fold for dipyridamole with pentagastrin (gastric pH approximately 2-3) as compared to famotidine (gastric pH approximately 5-7.5) treatment.
This work demonstrates a pH-dependent dissolution in vitro and absorption in vivo for the weak bases ketoconazole and dipyridamole independent of food effects. This model is useful to examine pH-dependent effects on oral drug absorption and for screening formulations to overcome the pH dependency.
Pharmaceutical Research 03/2005; 22(2):188-92. · 4.09 Impact Factor
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ABSTRACT: The use of metered-dose inhalers for the delivery of albuterol, a beta2-selective adrenergic agonist, is associated with drawbacks, especially in children and the elderly. This investigation was designed to assess the effectiveness of albuterol delivered intranasally and to compare this delivery route with intratracheal and intravenous delivery. Three parameters of pulmonary function (peak maximal expiratory flow, maximal expiratory flow at 50% vital capacity, and total lung capacity) in anaesthetized, artificially ventilated guinea pigs were used to determine the degree of protection produced by albuterol against bronchoconstrictor responses provoked by acetylcholine. The heart rate was also measured. Although intranasal albuterol induced a slower protective action during the very initial phase of absorption, the drug was shown to be equally effective when administered either intranasally or intratracheally. In contrast, despite a significant effect initially in the case of intravenous albuterol, its ability to influence pulmonary function faded rather rapidly. No statistically significant differences in heart rate could be detected among the different treatment groups. In conclusion, intranasal albuterol may offer an alternative to metered-dose inhalers for the treatment of acute bronchospasm and for prevention of exercise-induced asthma, especially for children and the elderly.
Journal of Pharmacy and Pharmacology 11/2004; 56(10):1211-5. · 2.17 Impact Factor
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ABSTRACT: The effect of anhydrous lactose particle size distribution on its performance in the wet granulation process was evaluated. Three grades of anhydrous lactose were used in the study: "as is" manufacturer grade and 2 particle size fractions obtained by screening of the 60M lactose. Particle growth behavior of the 3 lactose grades was evaluated in a high shear mixer. Compactibility and porosity of the resulting granules were also evaluated. A uniaxial compression test on moist agglomerates of the 3 lactose grades was performed in an attempt to explain the mechanism of particle size effect observed in the high shear mixer. Particle growth of anhydrous lactose in the high shear mixer was inversely related to the particle size of the starting material. In addition, granulation manufactured using the grade with the smallest particle size was more porous and demonstrated enhanced compactibility compared with the other grades. Compacts with similar porosity and low liquid saturation demonstrated brittle behavior and their breakage strength was inversely related to lactose particle size in the uniaxial compression test, suggesting that material with smaller particle size may exhibit more pronounced nucleation behavior during wet granulation. On the other hand, compacts prepared at higher liquid saturation and similar compression force exhibited more plastic behavior and showed lower yield stress for the grade with smallest particle size. The lower yield stress of compacts prepared with this grade may indicate a higher coalescence tendency for its granules during wet granulation.
AAPS PharmSciTech 06/2004; 5(3):e38. · 1.43 Impact Factor
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ABSTRACT: Drug 'developability' assessment has become an increasingly important addition to traditional drug efficacy and toxicity evaluations, as pharmaceutical scientists strive to accelerate drug discovery and development processes in a time- and cost-effective manner. The fraction of drug absorbed and the maximum absorbable dose (MAD) can be estimated from in vivo clinical pharmacokinetics, mass balance studies or in vivo drug permeability in humans by different calculation methods. Unfortunately, in vivo data are usually unavailable at the early stages of drug discovery and development, and in vitro screening for the permeability, solubility, activity and toxicity of a drug has become a routine measurement in drug discovery and development. These in vitro data could be used to predict drug 'developability' with different calculation methods before selecting candidates for clinical evaluation. The fraction of drug absorbed in human could be predicted by in vivo human permeability or in vitro Caco2 permeability. For example, if drug permeability in Caco2 cells reaches 13.3 to 18.1 x 10(-6) cm/s, its predicted in vivo permeability in humans would reach 2 x 10(-4) cm/s, and its predicted fraction of drug absorbed would be > 90%, which is defined as highly permeable. The MAD could also be predicted with in vitro permeability, or calculated absorption rate constant. In addition, in vitro solubility and permeability data can also be used for the biopharmaceutics classification system (BCS) and, subsequently, to direct formulation optimization strategies. If drug 'developability' becomes an obstacle for drug delivery based on these in vitro data and predictions at the early stages of drug discovery and development, options such as prodrug approaches could be explored to enhance drug 'developability', in addition to different formulation methods. Therefore, in vitro absorption testing is a highly valuable tool in the decision-making process to select candidates for in vivo clinical studies at early-stage drug discovery and development.
Current opinion in drug discovery & development 01/2004; 7(1):75-85. · 4.20 Impact Factor
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Journal of Pharmaceutical Sciences 10/2003; 92(9):1735-8. · 3.06 Impact Factor
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ABSTRACT: [corrected] To evaluate the in vivo disintegration behavior of tablets and capsules of a bile acid sequestrant, DMP 504, in beagle dogs and to assess the significance of the in vitro disintegration of the dosage forms on subsequent in vivo behavior in order to draw possible in vitro-in vivo correlations.
Tablet and capsule formulations of a bile acid sequestrant, DMP 504, were formulated with samarium oxide and neutron activated to produce radioactive 53Sm to noninvasively evaluate their in vivo behavior in beagle dogs by gamma-scintigraphy. A four-way crossover design was completed (n = 4) in which (a) tablets from two different batches were administered under the fasted condition and manufactured using different lots of drug substance where one batch exhibited relatively faster in vitro disintegration time (30 min) than the other tablet batch, which resulted in slower disintegration (45 min), (b) a capsule formulation was administered to fasted beagles, and (c) the tablet having slower in vitro disintegration was also administered in the fed state, and its in vivo disintegration was compared to that observed in the fasted state.
Tablets manufactured using a lot of DMP 504 having relatively fast in vitro disintegration (approximately 30 min) resulted in relatively rapid in vivo disintegration time (15 min) in the fasted condition. This in vivo disintegration time was comparable to the in vivo disintegration of the capsules (17 min) even though the in vitro capsule disintegration time was considerably faster (2 min). Tablets prepared using a drug substance that provided a longer in vitro disintegration time (approximately 45 min) resulted in a slower in vivo disintegration (63 min). There was no difference observed in the in vivo disintegration behavior in fasted and fed dogs for the tablets that provided slower in vitro disintegration.
In vivo disintegration of tablets of the bile acid sequestrant DMP 504 correlated with in vitro disintegration times. Gamma-Scintigraphy continues to be a good tool to use during early stages of product development to investigate in vivo performance of dosage forms. The results of this study provided evidence that the physical chemical specifications of the drug substance may not always be indicative of in vitro or in vivo performance of tablet dosage form, even when formulation and process are not changed.
Pharmaceutical Research 04/2003; 20(3):460-4. · 4.09 Impact Factor
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ABSTRACT: The purpose of this study was to examine the potential of the nasal route for the systemic delivery of the poorly water-soluble drug testosterone (TS) using a water-soluble prodrug, TS 17beta-N,N-dimethylglycinate hydrochloride. The physicochemical properties of the prodrug, in vitro hydrolysis in human liver homogenate, and in vivo nasal and intravenous experiments were performed in rats. The aqueous solubility of the prodrug was more than 100 mg/mL, compared with 0.01 mg/mL for TS, and its log partition coefficient between 0.05 M, phosphate buffer (pH 6) and octanol was 2.4. The prodrug was found to generate TS in 33% human liver homogenate and was absorbed from the nasal cavity rapidly and quantitatively. The bioavailabilities of both the prodrug and TS after nasal administration of the prodrug were similar to that after equivalent intravenous doses. These studies in rats suggest that this water-soluble prodrug of TS may have therapeutic utility for the management of TS deficiency.
Journal of Pharmaceutical Sciences 04/2002; 91(3):785-9. · 3.06 Impact Factor
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ABSTRACT: The purpose of this study was to examine the potential of the nasal route for the systemic delivery of the poorly water-soluble drug testosterone (TS) using a water-soluble prodrug, TS 17β-N,N-dimethylglycinate hydrochloride. The physicochemical properties of the prodrug, in vitro hydrolysis in human liver homogenate, and in vivo nasal and intravenous experiments were performed in rats. The aqueous solubility of the prodrug was more than 100 mg/mL, compared with 0.01 mg/mL for TS, and its log partition coefficient between 0.05 M, phosphate buffer (pH 6) and octanol was 2.4. The prodrug was found to generate TS in 33% human liver homogenate and was absorbed from the nasal cavity rapidly and quantitatively. The bioavailabilities of both the prodrug and TS after nasal administration of the prodrug were similar to that after equivalent intravenous doses. These studies in rats suggest that this water-soluble prodrug of TS may have therapeutic utility for the management of TS deficiency. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 785–789, 2002
Journal of Pharmaceutical Sciences 02/2002; 91(3):785 - 789. · 3.06 Impact Factor
