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1.  Dissolution Testing of Sublingual Tablets: A Novel In Vitro Method 
AAPS PharmSciTech  2011;12(2):544-552.
In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.
doi:10.1208/s12249-011-9615-0
PMCID: PMC3134647  PMID: 21523516
custom-made dissolution apparatus; development and validation; dissolution testing; novel in vitro dissolution method; sublingual tablets
2.  An Electronic Tongue: Evaluation of the Masking Efficacy of Sweetening and/or Flavoring Agents on the Bitter Taste of Epinephrine 
AAPS PharmSciTech  2010;11(2):550-557.
An epinephrine (E) tablet is under development for sublingual (SL) administration for the first-aid treatment of anaphylaxis; however, the inherent bitterness of E may hinder acceptability by patients, especially children. To assess the degree of E bitterness and to predict the masking effects of sweetening and/or flavoring non-medicinal ingredients (NMIs), the potential usefulness of an electronic tongue (e-Tongue) was evaluated. The e-Tongue sensors were conditioned, calibrated, and tested for taste discrimination. Six standard active pharmaceutical ingredients were used to build and validate a bitterness model which was then used to assess E bitartrate (EB) solutions from 0.3–9 mM. Taste-masking efficiency of aspartame (ASP), acesulfame potassium (ASK), and citric acid (CA) each at 0.5 mM was evaluated. Using EB 9 mM, the bitterness score was 20 on a scale of 20 (unacceptable) down to 1 (not detected). When NMIs 0.5 mM were added, neither ASK (17.2, unacceptable) nor was ASP (14.0, limit acceptable) effective in masking the bitter taste. When the combination of ASK and ASP was used, the bitterness score was reduced to 9.2 (acceptable). However, the addition of CA alone resulted in the best reduction of the bitterness score to 3.3 (not detected). Using the e-Tongue, the incorporation of a variety of sweetening and/or flavoring NMIs into a SL tablet of E could be shown to mask its bitter taste by up to 80%. These results should be confirmed by in vivo studies.
doi:10.1208/s12249-010-9402-3
PMCID: PMC2902344  PMID: 20352537
anaphylaxis; artificial sweeteners; electronic tongue; epinephrine; sublingual tablet
3.  H1 Antihistamines: Current Status and Future Directions 
In this review, we compare and contrast the clinical pharmacology, efficacy, and safety of first-generation H1 antihistamines and second-generation H1 antihistamines. First-generation H1 antihistamines cross the blood-brain barrier, and in usual doses, they potentially cause sedation and impair cognitive function and psychomotor performance. These medications, some of which have been in use for more than 6 decades, have never been optimally investigated. Second-generation H1 antihistamines such as cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine cross the blood-brain barrier to a significantly smaller extent than their predecessors. The clinical pharmacology, efficacy, and safety of these medications have been extensively studied. They are therefore the H1 antihistamines of choice in the treatment of allergic rhinitis, allergic conjunctivitis, and urticaria. In the future, clinically advantageous H1 antihistamines developed with the aid of molecular techniques might be available.
doi:10.1186/1939-4551-1-9-145
PMCID: PMC3650962  PMID: 23282578
H1 antihistamines; second-generation H1 antihistamines; nonsedating H1 antihistamines; allergic rhinitis; allergic conjunctivitis; urticaria; atopic dermatitis; cetirizine; desloratadine; fexofenadine; levocetirizine; loratadine
4.  Fast-disintegrating sublingual tablets: Effect of epinephrine load on tablet characteristics 
AAPS PharmSciTech  2006;7(2):E72-E78.
The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9∶1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content uniformity, hardness, disintegration time, wetting time, and friability were measured for each formulation at each compression force. All 4 tablet formulations at each compression force were within the United States Pharmacopeia (USP) limits for weight variation and content uniformity. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times of A, and an exponential increase in disintegration and wetting times of B, C, and D. At a mean±SD hardness of ≥2.3±0.2 kg, all tablet formulations passed the USP friability test. At a mean±SD hardness of ≤3.1±0.2 kg, all tablet formulations resulted in disintegration and wetting times of <10 seconds and <30 seconds, respectively. Tablets with drug loads from 0% to 24% epinephrine can be formulated with hardness, disintegration times, and wetting times suitable for sublingual administration.
doi:10.1208/pt070241
PMCID: PMC2750292  PMID: 16796358
sublingual; transmucosal drug delivery; fastdisintegrating tablets; epinephrine; anaphylaxis
5.  Cetirizine from topical phosphatidylcholine-hydrogenated liposomes: Evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model 
The AAPS Journal  2004;6(3):7-12.
Cetirizine, an effective, minimally sedating, second-generation H1-antihistamine is widely used orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of cetirizine from liposomes applied to the skin. Cetirizine was incorporated into small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) prepared using L-α-phosphatidylcholine hydrogenated (HPC), and into Glaxal Base (GB) as the control. In a randomized, crossover study, each formulation, containing 10 mg of cetirizine, was applied to the depilated backs of 6 rabbits (3.08±0.05 kg). Histamine-induced wheal tests and blood sampling were performed before cetirizine application and at designated times for up to 24 hours afterwards. Compared with baseline, histamine-induced wheal formation was suppressed by cetirizine in SUV only at 24 hours, in MLV from 0.5 to 24 hours, and in GB from 0.5 to 8 hours (P<.05). Wheal suppression by cetirizine in SUV at 24 hours (91.7%±5.2%) and in MLV from 1 to 24 hours (93.8%±2.2% to 76.2%±6.5%) was greater than in GB (36.5%±7.4% to 60.6%±14.2%) from 1 to 24 hours (P<.05). Faster onset, as well as greater and more persistent suppression was obtained from cetirizine in MLV. Plasma cetirizine concentrations from MLV (area under the curve [AUC] of 221.2±42.3 ng.hr/mL) were lower than from GB (AUC of 248.3±34.6 ng.hr/mL). In this model, cetirizine from MLV had excellent topical H1-antihistamine activity, while systemic exposure was reduced, compared with cetirizine from GB.
doi:10.1208/aapsj060318
PMCID: PMC2751243  PMID: 18465266
cetirizine; L-α-phosphatidylcholine hydrogenated; liposomes; antihistamine; rabbit's skin
6.  Hydroxyzine from topical phospholipid liposomal formulations: Evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model 
AAPS PharmSci  2003;5(4):41-48.
Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-α-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08±0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1±20.8 and 78.4±33.9 ng/mL/h, respectively, were lower than that from GB, 492±141 ng/mL/h (P<.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765±50, 1035±202, and 957±227 ng/mL/h, respectively (P<.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.
doi:10.1208/ps050428
PMCID: PMC2750990  PMID: 15198516
hydroxyzine; L-α-phosphatidylcholine; liposomes; antihistamine; skin; rabbit

Results 1-6 (6)