The use of isothermal heat conduction microcalorimetry to evaluate drug stability in tablets.

Isothermal heat conduction microcalorimetry was used to evaluate chemical stability of a solid drug in tablets. A variety of mixtures were compressed to flat faced tablets of 300 mg weight and 10 mm diameter. The content of drug amounted to 10%. Besides drug containing tablets, also placebo tablets as well as the non compressed mixtures were examined by microcalorimetry at 80 degrees C. The excipient Emcompress exhibited a substantially high exothermic heat flow that was due to a change in crystallinity. For Emcompress containing tablets this interfering signal resulted in such a way that the calorimetric data did not reflect the drug decomposition with sufficient accuracy. In the case of the other preparations the heat flow of the excipients were low, and the calorimetric data did reflect the drug decomposition. The stability increased with increasing content of CaHPO4, respectively, with decreasing content of water. Copyright     

Solubilized benzoyl peroxide versus benzoyl peroxide/clindamycin in the treatment of moderate acne

BACKGROUND: Benzoyl peroxide (BPO) is poorly soluble. A solubilized formulation of BPO has been developed to maximize its bioavailability and enhance follicular penetration. METHODS: Patients with acne vulgaris were randomly assigned to receive solubilized BPO 5% gel on one side of the face and a BPO 5%/clindamycin 1% combination product on the contralateral side, twice daily for 4 weeks. RESULTS: Of 23 patients enrolled, 100% completed the study. Reductions in lesion count with the solubilized BPO gel were at least as great as with BPO/clindamycin--and significantly greater (P< or =.05) for noninflammatory lesions at week 1 and inflammatory lesions at week 4. Both regimens were generally well tolerated and patient satisfaction was comparable. CONCLUSIONS: Solubilized BPO 5% gel monotherapy offers significantly greater efficacy, and comparable patient satisfaction, compared with BPO/clindamycin. The early reduction in lesion counts observed with the solubilized BPO gel in the absence of an antibiotic is clinically relevant.     

HPLC法测定祛痘类化妆品中的过氧化苯甲酰

目的建立高效液相色谱法测定祛痘除螨类化妆品中的过氧化苯甲酰的方法。方法采用ZORBAX C18柱,4．6×250mm．5μm;以甲醇-0．02mol·L^-1的醋酸铵溶液（80：20）为流动相;检测波长为230nm。结果过氧化苯甲酰在0．224μg·mL^-1～44．8μg·mL^-1范围内呈良好线性关系,r=0．9996．过氧化苯甲酰的平均回收率为95．94％．RSD％为2．5％。结论上述建立的方法简便易行、准确、重现性好,可用于祛痘类化妆品中禁用物质过氧化苯甲酰的检测。     

Use of isothermal heat conduction microcalorimetry to evaluate stability and excipient compatibility of a solid drug

Isothermal heat conduction microcalorimetry was used to evaluate chemical stability and excipient compatibility of a solid drug. Calorimetric data were compared with HPLC data in order to determine the origin of the thermal events. For the pure solid drug, heat flow time curves became constantly exothermic after 3–4 days in the temperature range from 60 to 80°C and were due to chemical decomposition. The activation energy calculated by both methods (microcalorimetry and HPLC) was 170±8 kJ/mol (mean±S.D.). A plot of the evolved heat Q versus the amount of degraded drug showed a linear relationship. Binary mixtures and granules led to higher exothermic signals for microcrystalline cellulose (MCC), potato starch and lactose, and indicated lower stability. In the case of MCC and lactose, physical processes were superimposed and made the interpretation of the heat flow data difficult. In the case of the other systems the exothermic heat flow was in the same range as for the pure solid drug. Neither was physicochemical interaction detected, nor was the chemical decomposition accelerated by the excipients. By combining calorimetric and HPLC data the prediction of final shelf-life at room temperature was estimated.     

The absorption of benzoyl peroxide from leg ulcers.

Absorption and clinical efficacy of a preparation containing 20% benzoyl peroxide were studied in 20 patients with leg ulcers of varying etiology. Benzoic acid formed from benzoyl peroxide on penetration through the skin cannot be demonstrated in the plasma until three days after commencing application at the earliest. This indicates a building up of deposits of benzoyl peroxide in the skin. The plasma benzoic acid levels in all patients amounted to less than 5 mumol/l and is therefore toxicologically inoffensive. Clinically, the known therapeutic effects of benzoyl peroxide were confirmed. Neither sensitization nor allergic reactions were found in the 20 patients taking part in this study.     

A kinetic and thermodynamic study of seratrodast polymorphic transition by isothermal microcalorimetry

The development of isothermal microcalorimetry to a study of the kinetic and thermodynamics of polymorphic transitions in seratrodast ((+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid) Form II is reported. Sieved samples of Form II were allowed to convert to Form I, in a reaction vessel of an isothermal microcalorimeter, under 13, 31, 63 and 93% relative humidity (RH) between 48 and 65 degrees C. The power (Phi, in Watts) versus time curves from the microcalorimeter were integrated into the heat output (q, in Joules) versus time curves to yield fractional extent of Form I converted versus time curves. The change in enthalpy (-5.70 kJmol(-1)) agreed very closely with that obtained by differential scanning calorimetry and solution calorimetry, which indicated that the power measured by the microcalorimeter was due only to the Form II-to-Form I transition. Application of the theoretical kinetic method [J. Am. Ceram. Soc. 55 (1972) 74] revealed that the transition took place via a two-dimensional growth of nuclei mechanism at all the studied relative humidities and temperatures. The rate constant increased with increasing RH and temperature, and with decreasing the particle size of sample. The activation energies obtained from Arrhenius plots were 292, 290, 280 and 284 kJmol(-1), and the extrapolated rate constants at 25 degrees C were also 3.01 x 10(-10), 3.11 x 10(-10), 9.65 x 10(-10) and 3.84 x 10(-9)s(-1) for 13, 31, 63 and 93% RH, respectively.     

Application of isothermal microcalorimetry in solid state drug development

Microcalorimetry is an analytical technique that has found numerous applications within the pharmaceutical environment. In the realm of pharmaceutics, especially solid state pharmaceutics, the technique has proved to be an invaluable tool. This review addresses the solid state applications of microcalorimetry within the pharmaceutical industry, with a specific focus on stability, compatibility and amorphicity determinations.     

Delayed type hypersensitivity to benzoyl peroxide

Benzoyl peroxide (BP) has been a standard and effective topical treatment for acne vulgaris for the past 35 years. Previous studies and case reports have documented benzoyl peroxide to be a strong irritant and a weak allergen, with many cases of tolerance induced with repeat use of this irritant. While less common, numerous cases of BP-induced allergic contact dermatitis (delayed type hypersensitivity reaction) have been reported in the literature. We report here an individual with an incipient edematous reaction to topical BP used for acne therapy. This under-recognized presentation is discussed in the context of published literature on BP-induced hypersensitivity and irritation.     

Dynamics of pharmaceutical amorphous solids: the study of enthalpy relaxation by isothermal microcalorimetry

The structural relaxation time is a measure of the molecular mobility involved in enthalpy relaxation, and thus, is a measure of the dynamics of amorphous (glassy) pharmaceutical solids that determines physicochemical properties and reactivity of drugs in amorphous formulations. In this article we describe a novel method for characterization of structural relaxation using isothermal microcalorimetry, which directly measures the rate of heat release during the relaxation processes. The structural relaxation time is then obtained from a fit of the power data to the derivative version of the Kohlrausch-Williams-Watts (KWW) equation. The relaxation times of quenched and lyophilized samples of saccharides were studied using an isothermal microcalorimeter, the Thermal Activity Monitor (TAM). In addition to the KWW derivative function, a derivative equation of the modified stretched exponential function (MSE) was employed to evaluate TAM data. The later (MSE) appeared to have numerical advantages over the KWW equation. The data demonstrate, as expected, that structural relaxation times of amorphous solids depend on a number of variables, including nature of material, temperature, moisture content, thermal history, etc. Isothermal microcalorimetry with the TAM provides a very fast and reliable way to characterize the dynamics of glassy materials, which in many respects is superior to the conventional DSC approach. To the extent stability and structural relaxation dynamics in the glass are correlated, structural relaxation parameters derived by isothermal microcalorimetry may provide data useful for rational development of stable peptide and protein formulations and for the control of their processing.     

过氧化苯甲酰测定方法研究

本文研究了用紫外分光光度法测定面粉及面制品中过氧化苯甲酰的方法。探讨了样品处理,还原、蒸馏、吸收光谱等条件。本法回收率:92—110%,CV6.3%.检出(?):0.02g/kg,检测范围:0—1.3g/kg。满足了正常监督监测工作的需要。     

Stability of benzoyl peroxide in aromatic ester-containing topical formulations

The chemical stability of benzoyl peroxide (BPO) was studied in solutions and gels. The solutions (1% w/v) were prepared in single solvents (alcohol USP, isopropyl alcohol USP, ethyl benzoate, C12-15 alkyl benzoate, dimethyl isosorbide, propylene carbonate, and acetone) and in binary and tertiary combinations of these solvents, with and without the addition of antioxidant(s) (BHT, BHA, eugenol, tert-butyl hydroquinone, Tenox-2, vitamin E, and vitamin C). The solutions were stored at 37 degrees C for 5 weeks, and each week were analyzed for remaining BPO. Using first-order kinetics, the stability of BPO in solution was found to decrease in the order: ternary>binary>single solvent systems. Regardless of the number of solvents present, the highest stability of BPO (t1/2>7.5 weeks) was attained in the presence of ethyl benzoate and C12-15 alkyl benzoate. The stability of BPO in solution did not change significantly with the addition of most antioxidants. The solutions in which BPO remained most stable were one in alcohol USP-ethyl benzoate-C12-15 alkyl benzoate (60:20:20; t1/2=18.15 weeks) and another in alcohol USP-C12-15 alkyl benzoate-isopropanol plus 0.1% BHT (65:20:15; t1/2=12.44 weeks). In turn, these two solutions were converted to homogeneous gels by the addition of Cab-O-Sil. The chemical stability of BPO in these gels was evaluated at 37 degrees, 45 degrees, 50 degrees, and 55 degrees C for 5 weeks. Parallel experiments were conducted with two commercial BPO products, a 2.5% tinted gel and 5% vanishing lotion. BPO was less stable in commercial products (t1/2相似文献   

Role of the benzoyloxyl radical in DNA damage mediated by benzoyl peroxide.

Benzoyl peroxide (BzPO) is both a tumor promoter and progressor in mouse skin; however, BzPO is neither an initiator nor a complete carcinogen in this tissue. Although not mutagenic, BzPO has been observed to produce strand breaks in DNA of exposed cells. These actions are presumed to be mediated by free-radical derivatives of BzPO. Previous studies suggested that the metabolism of BzPO in keratinocytes proceeds via the initial cleavage of the peroxide bond, yielding benzoyloxy radicals which, in turn, can either fragment to form phenyl radicals and carbon dioxide or abstract H atoms from biomolecules to yield benzoic acid. Benzoic acid is the major stable metabolite of BzPO produced by keratinocytes. In the present study we have investigated the role of BzPO and its metabolites in the generation of strand scissions in a cell-free system using phi X-174 plasmid DNA. In this system BzPO produced DNA damage that was dose-dependent over a concentration range of 0.1-1 mM and required the presence of copper but not other transition metals. By contrast, benoic acid did not produce DNA damage in this system, either in the presence or in the absence of copper. The inclusion of spin trapping agents, such as N-tert-butyl-alpha-phenylnitrone (PBN), 3,5-dibromo-4-nitrosobenzenesulfonate, and nitrosobenzene, in incubations was found to significantly reduce the extent of DNA damage generated via the copper-mediated activation of BzPO. Electron paramagnetic resonance spectroscopy studies suggested that the primary radical trapped by PBN following copper-mediated decomposition of BzPO was the benzoyloxy radical.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of topical nadifloxacin and benzoyl peroxide versus clindamycin and benzoyl peroxide in acne vulgaris: A randomized controlled trial

Background:

Topical therapy with comedolytics and antibiotics are often advocated for mild and moderate severity acne vulgaris. Nadifloxacin, a new fluoroquinolone with anti-Propionibacterium acnes activity and additional anti-inflammatory activity, is approved for use in acne. This randomized controlled assessor blind trial compared the clinical effectiveness and safety of eight weeks therapy of nadifloxacin 1% versus clindamycin 1% as add-on therapy to benzoyl peroxide (2.5%) in mild to moderate grade acne.

Materials and Methods:

The efficacy parameters were changes in the total, inflammatory and non-inflammatory lesion counts, Investigator Global Assessment (IGA), and Cardiff Acne Disability Index (CADI) scales from baseline to study end (eight weeks). All treatment emergent dermatological adverse events were evaluated for safety assessment.

Results:

Out of 84 randomized subjects (43-nadifloxacin arm) and (41-clindamycin) 42 in nadifloxacin group, 37 in clindamycin group completed the study. Reduction from baseline of total, inflammatory and non-inflammatory lesion counts were highly significant in both the groups (P<0.0001), but between group differences were not significant. Significant improvement in CADI and IGA scales were noted in both groups. Between-group comparison showed no significant differences. The safety and tolerability profile of both regimens were good and statistically comparable.

Conclusions:

Topical nadifloxacin, a new fluoroquinolone is effective, tolerable, and safe for mild o moderate facial acne. Its clinical effectiveness is comparable to clindamycin when used as add-on therapy to benzoyl peroxide.KEY WORDS: Acne vulgaris, clindamycin, nadifloxacin, randomized controlled trial     

The use of isothermal microcalorimetry in the study of changes in crystallinity of spray-dried salbutamol sulphate

Isothermal microcalorimetry has been used to monitor the recrystallisation of spray-dried salbutamol sulphate. The drug recrystallises in water vapour, by a cooperative process. The cooperative nature demonstrates that the water must first absorb to saturate the entire powder bed before recrystallisation occurs. Consequently, recrystallisation is slower for low humidities, due to a slower arrival of water vapour. The data have been compared with previous data for recrystallisation of spray-dried lactose. The heat change for the crystallisation was significantly lower for salbutamol sulphate than for lactose. In terms of apparent enthalpy of crystallisation, the large exothermic responses are indicative of the fact that the crystal form is the thermodynamically stable state. The salbutamol which had been recrystallised at the lower humidities showed that the process, whilst being rapid, was discontinuous. In each case, the exothermic recrystallisation was followed by an endothermic response for the expulsion of water as the amorphous region recrystallised. There was a repeating sequence of crystallisation, followed by water expulsion, followed by further recrystallisation. With each repeat of the cycle the responses decreased in size. This ability to follow crystallisation in real time provides a novel insight into the process.