Munir A. Hussain

Drug-polymer solubility and miscibility: Stability consideration and practical challenges in amorphous solid dispersion development.

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.

Non-invasive Systemic Drug Delivery: Developability Considerations for Alternate Routes of Administration

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.

pH-Dependent Dissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development of a Canine Model

No HeadingPurpose.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.Methods.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.Results.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 ∼2–3) as compared to famotidine (gastric pH ∼5–7.5) treatment.Conclusions.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.

Is a distinctive single Tg a reliable indicator for the homogeneity of amorphous solid dispersion

For an amorphous drug-polymer solid dispersion, a distinctive single T(g) intermediate of the two T(g) values of the two components has been widely considered as an indication of the mixing uniformity, which is critical for the stability of the amorphous drug against crystallization. In this study, two batches of amorphous solid dispersions consisting of BMS-A, a poorly water-soluble drug, and PVP-VA, were made by a twin-screw hot-melt extruder using different processing conditions. Both batches displayed an identical distinctive single T(g) that is consistent with the prediction of Fox equation assuming homogeneous mixing of the two components. Neither DSC nor PXRD detected any drug crystallinity in either batch. However, the two batches exhibited different physical stability against crystallization over time. The application of a Raman mapping method showed that the drug distributed over a much wider concentration range in the less stable solid dispersion. It is therefore experimentally demonstrated that, in the characterization of amorphous solid dispersions, a distinctive single T(g) may not always be a reliable indicator of homogeneity and optimal stability, and more examinations and new techniques may be required other than conventional studies.

Fluid bed granulation of a poorly water soluble, low density, micronized drug: comparison with high shear granulation

A 2(4-1) fractional factorial design was used to evaluate the effect of various process variables in fluid bed granulation, on the physico-chemical properties of granule and tablet containing a high dose, poorly water soluble, low density, and micronized drug. The process variables studied were inlet air temperature, inlet air flow, spray rate of the binder solution, and atomization air pressure. Tablets with identical composition, weight, size and hardness were also manufactured in a high shear granulator and their physical properties were determined and compared with those produced by the fluidized bed granulation method. Except for the granule size distribution, other physical properties of granulations and tablets produced in a fluid bed granulator are independent of the selected process variables within the study range. Both atomization air pressure and spray rate of the binder solution had strong impact on granule size distribution. Irrespective of the process conditions used in the fluid bed granulation, granules from this process were more porous, less dense and more compressible than the granules from the high shear granulation process. Comparable tablet dissolution rates to those prepared by the optimized high shear granulation method can be achieved by selecting the appropriate process conditions in fluid bed granulation. These results suggest that wet granulation tablets of a high dose, poorly water soluble, low density, micronized drug can be manufactured using a fluidized bed granulation method, with comparable tablet dissolution rates to those produced with an optimized high shear granulation method.

Ion-exchange resins as drug delivery carriers

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.

Buccal and oral bioavailability of naloxone and naltrexone in rats

Abstract The opioid antagonists naloxone and naltrexone are both known to undergo extensive first-pass metabolism after oral dosing. The buccal route was investigated as a potential alternative to oral administration. Oral and buccal bioavailabilities of naloxone and naltrexone were determined in rats. Less than 1 % of oral naloxone or naltrexone was bioavailable, but buccal administration resulted in approximately 70% bioavailability for each drug.

The Use of α-Aminoboronic Acid Derivatives to Stabilize Peptide Drugs During Their Intranasal Absorption

Abstractα-Aminoboronic acid derivatives, potent and reversible inhibitors of aminopeptidases, were tested nasally in situ in rats for stabilizing externally administered peptides. These inhibitors, at nanomolar concentrations, were found to inhibit greatly the degradation of the model peptide, leucine-enkephalin (Leu-enk), in the nasal perfusate. Enzyme inhibition was greater with boroleucine and borovaline than that observed with boroalanine. Boroleucine was more than 100 times more effective in enzyme inhibition than bestatin and more than 1000 times more effective than puromycin.

Improved Buccal Delivery of Opioid Analgesics and Antagonists with Bitterless Prodrugs

Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.

Pulmonary delivery of a GLP-1 receptor agonist, BMS-686117

Alternate delivery route of therapeutic peptides is an attractive non-invasive option to patients who must chronically self-administer their medication through injections. In recent years, much attention has centered on pulmonary peptide delivery of peptide drugs such as insulin and GLP-1 mimetic peptides in the treatment of type II diabetes. In this study, we assessed the feasibility of delivering BMS-686117, an 11-mer GLP-1 receptor peptide agonist, to the lung in rats via intratracheal administration. The pharmacokinetic profiles of three spray-dried, prototype inhaled powder formulations, 80/20 BMS-686117/trehalose (I), 100% BMS-686117 (II), and 20/80 BMS-686117/mannitol (III), as well as a lyophilized BMS-686117 powder, were compared with intravenously and subcutaneously administered peptide. The spray-dried formulations were mostly spherical particles with narrow particle size distribution between 2 to 10 microm, which are better suited for inhalation delivery than the lyophilized, irregular shape powder with a wide particle size distribution between 2 to 100 microm. Prototype III exhibited the best physical characteristics and in vivo performance, with bioavailability of 45% relative to subcutaneous administration. The T(max) for lung delivered peptide formulations were almost twice as fast as subcutaneous injection, suggesting potential for rapid absorption and onset of action. This study demonstrated that pulmonary delivery is a promising, non-invasive route for the administration of BMS-686117.