Quality of compounded topical 2% diltiazem hydrochloride formulations for anal fissure.

AIM: To investigate the quality of topical 2% diltiazem formulations extemporaneously compounded by retail pharmacies openly offering drug-compounding services. METHODS: A participating healthcare professional wrote 12 prescriptions for compounded 2% diltiazem cream, with 2 refills allowed per prescription. The 12 sets of prescriptions were filled, at intervals of 1-2 wk between refills, at 12 different independent retail pharmacies that openly offer drug-compounding services in a major metropolitan region. The 36 resultant preparations, provided as jars or tubes, were shipped, as soon as each was filled, at ambient temperature to the study core laboratory for high-performance liquid chromatography (HPLC) analysis, within 10 d of receipt. For the HPLC analysis, 8 different samples of the topical diltiazem, each approximately 1 g in weight, were taken from prespecified locations within each container. To initiate the HPLC analysis, each sample was transferred to a 100 mL volumetric flask, to which methanol was added. The HPLC analysis was conducted in accordance with the laboratory-validated method for diltiazem in cream, ointment, and gel formulations. The main outcome measures were potency (percentage of label claim) and content uniformity of the compounded topical 2% diltiazem formulations. RESULTS: Of the 36 prescriptions filled, 30 were packaged in jars and 6 were packaged as tubes. The prescriptions were specifically for cream formulations, but 6 of the 12 pharmacies compounded 2% diltiazem as an ointment; for another pharmacy, which had inadequate labeling, the dosage form was unknown. The United States Pharmacopoeia (USP) standard for potency is 90%-115% of label claim. Of the 36 preparations, 5 (13.89%) were suprapotent and 13 (36.11%) were subpotent. The suprapotent prescriptions ranged in potency from 117.2% to 128.5% of label claim, and the subpotent prescriptions ranged in potency from 34.8% to 89.8% of label claim. Fourteen (38.9%) preparations lacked content uniformity according to the USP standard of 90%-110% potency and < 6% relative standard deviation. Of the 30 formulations packaged in jars, 12 (40%) lacked content uniformity, while of the 6 formulations packaged in tubes, 2 (33.3%) lacked content uniformity. Nine of the 12 pharmacies (75%) failed USP potency or content-uniformity specifications for at least 1 of the 3 prescription fills. For 5 of the 12 pharmacies (41.7%), the mean potency across all three prescription fills was < 90% of label claim. CONCLUSION: Patients prescribed topical 2% diltiazem for treatment of anal fissure frequently receive compounded formulations that are misbranded with respect to potency and that lack content uniformity.

Effect of surfactants and pH on naltrexone (NTX) permeation across buccal mucosa.

The objective of this pre-formulation study was to systematically investigate the effects of two surfactants (Brij 58(®) and Tween 80(®)) and change in solution pH on in vitro permeation of naltrexone HCl (NTX-HCl) across tissue engineered human buccal mucosa. For the study, 10mg/ml solutions of Tween 80(®) (0.1 and 1%, w/v) and Brij 58(®) (1%, w/v) were prepared in standard artificial saliva buffer solution (pH 6.8). For studying pH effects, solution pH was adjusted to either 7.5 or 8.2. As controls, three concentrations of NTX-HCl (2.5, 10 and 25mg/ml) were prepared. Using NTX standard solution (10mg/ml; pH 6.8), the permeation was observed between in vitro human and ex vivo porcine mucosa. It was observed that Brij 58(®) increased the permeation rates of NTX significantly. The flux of 10mg/ml solution (pH 6.8) increased from 1.9 ± 0.6 (× 10(2)) to 13.9 ± 2.2 (× 10(2))µg/(cm(2)h) (approximately 6-fold) in presence of 1% Brij 58(®). Increasing pH of NTX-HCl solution was found to increase the drug flux from 1.9 ± 0.6 (× 10(2)) (pH 6.8) to 3.0 ± 0.6 (× 10(2)) (pH 7.4) and 8.0 ± 3.5 (× 10(2)) (pH 8.2)µg/(cm(2)h), respectively. Histological analyses exhibited no tissue damage due to exposure of buccal tissue to Brij 58(®). The mean permeability coefficients (K(p)) for 2.5, 10 and 25mg/ml solutions of NTX-HCl (pH 6.8) were 5.0 (× 10(-2)), 1.8 (× 10(-2)) and 3.2 (× 10(-2))cm/h, respectively, consistent with data from published literature sources. Increase of NTX flux observed with 1% Brij 58(®) solution may be due to the effects of ATP. Increase in flux and the shortening of lag time observed by increasing in solution pH confirmed earlier finding that distribution coefficient (logD) of NTX is significantly affected by small increments in pH value and therefore plays an important role in NTX permeation by allowing faster diffusion across tissue engineered human buccal tissue.

Percutaneous permeation modifiers: enhancement versus retardation.

BACKGROUND: The use of permeation enhancers to compromise the barrier properties of skin has been ongoing for decades. However, toxicity associated with certain xenobiotics has led to the development of permeation retardants. Since both enhancers and retardants modify the surface layer of the skin, they can be collectively referred to as penetration modifiers. OBJECTIVE: This review attempts to outline a comparison of two types of penetration modifiers: enhancers and retardants. METHODS: In addition to reports of enhancement and retardation by modifiers, we also provide evidence as to why we should group these compounds together, since we have found that retardants can become enhancers in different formulation environments. CONCLUSION: Since modifiers influence drug delivery, further exploration of these compounds is required to understand their modifying action on the properties of skin.