Effectiveness of topical Nigella sativa for vitiligo treatment.

Vitiligo is a pigment disease characterized by the disruption of melanocyte structure and function. Its etiology is unknown; however, genetic predisposition, biochemical factors, and neural mechanisms are thought to be effective. Although many agents are being used for its treatment, generally there is no absolute cure. The aim of the present study is to evaluate the effectiveness of topical Nigella sativa seed oil on vitiligo patients. Thirty-three vitiligo patients were included in the study. Totally 47 areas were evaluated in all patients. Cream containing N sativa seed oil was topically applied to hands, face, and genital region two times a day for 6 months. Statistically significant repigmentation was detected in hands, face, and genital region, the three treatment areas, and the p values are found .005, .001, and .004, respectively. N sativa can be used as an adjuvant therapy that can contribute to the treatment especially in sensitive skin areas like genital region.

In vitro evaluation of natural thermal mineral waters in human keratinocyte cells: a preliminary study.

We aimed to test the anti-inflammatory and angiogenic properties of two different thermal waters at the cellular level in human keratinocyte cells in the present study. Two different thermal waters, thermo-mineral BJ1 (Bursa, Turkey) and oligomineral BG (Bolu, Turkey), were tested in human keratinocyte (HaCaT) cell line. HaCaT cells were incubated for 3 days with thermal waters; RNA isolation was carried out in the treated and untreated cells. The gene expressions of TNFα, IL-1α, and VEGF were measured using the RT-qPCR. The tested thermal waters significantly decreased the expression of IL-1α (BJ1 93% p = 0.0024 and BG 38% p = 0.0303). BJ1 and BG thermal waters downregulated the expression of TNFα (59% p = 0.0001 and 23% p = 0.0238 respectively). Furthermore, BJ1 and BG significantly downregulated the gene expression of VEGF (98% p = 0.0430 and 15% p = 0.0120). The observed decrease in the gene expression of TNFα and IL1α could be interpreted as an anti-inflammatory effect of mineral waters on HaCaT cells. Moreover, the suppressed VEGF expression might be an indicator of the antiangiogenic effect on human keratinocytes. Therefore, we hypothesized that depending on their specific chemical composition such as silica (128 mg/L) in BJ1 and hydrogen sulfide (1.2 mg/L) in BG, thermal waters suppress pro-inflammatory cytokines and angiogenic growth factor. These preliminary findings might give insight on the underlying mechanisms of the therapeutic benefits observed in some skin diseases such as rosacea and psoriasis.

Evaluation of novel cosmetic shampoo formulations against Malassezia species: Preliminary results of anti-dandruff shampoo formulations.

OBJECTIVES: Malassezia species are common, clinically relevant, and lipid-dependent yeasts of humans. They are also the leading causes of the dandruff problem of humans, and the azoles are used primarily in their topical and systemic treatment. Resistance to azoles is an emerging problem among Malassezia sp., which indicates the need of new drug assessments that will be effective against dandruff and limit the use of azoles and other agents in treatment. Among them, the efficacy of various combinations of piroctone olamine and climbazole against Malassezia sp. is highly important. Here, we assessed the efficacies of various piroctone olamine and climbazole formulations against Malassezia sp. in comparison with ketoconazole. METHODS: A total of nine formulations were included in the study, where each formulation was prepared from different concentrations of piroctone olamine and climbazole and both. All formulations contained the same ingredients as water, surfactants, hair conditioning agents, and preservatives. Malassezia furfur CBS1878, Malassezia globosa CBS7874, and Malassezia sympodialis CBS9570 were tested for antifungal susceptibility of each formulation by agar diffusion method. Sizes of the inhibition zones were compared with standard medical shampoo containing 2% ketoconazole, and the data were analyzed by Dunnett's multiple-comparison test. RESULTS: For all Malassezia sp. strains, climbazole 0.5% and piroctone olamine/climbazole (0.1%/0.1% and 0.1%/0.5%) combinations were found to have the same effect as the medical shampoo containing 2% ketoconazole. Piroctone olamine/climbazole 1.0%/0.1% formulation showed the same efficacy as 2% ketoconazole on M. furfur and M. sympodialis, while 0.1%/0.5% formulation to only M. furfur. For M. globosa, none of the formulations tested were as effective as ketoconazole. CONCLUSION: The species distribution of Malassezia sp. varies depending on the anatomical location on the host. According to the results of this study, climbazole and piroctone olamine combinations seem to be promising options against the dandruff problem with their high antifungal/anti dandruff efficacy.

The Effects of Helichrysum italicum Extract on the Extracellular Matrix of the Skin.

OBJECTIVE: An in-vitro study was performed to investigate the molecular basis of the wound healing and skin protective features of Helichrysum italicum (HI), a medicinal plant from the Mediterranean basin. MATERIALS AND METHODS: A dermal fibroblast cell line culture was treated with HI hydro-alcoholic extract to detect the gene expression levels of three selected primers: FGF-2, HAS-2 and MMP-9. Cell proliferation assay was performed using a XTT reagent. RNA isolations were carried out from both the extract treated study cell group and the control cell group using a TRI reagent. GAPDH was used as the reference gene. Gene expressions were determined by real time RT-qPCR. The results were represented as 'Target/GAPDH Fold Change'. Statistical evaluation was performed by Student's t test. RESULTS: HI extract caused statistically significant upregulation of FGF-2 (P=0.0473) and HAS-2 (P=0.0335) gene expressions compared to the untreated control cells. The treatment ended with 1.74 and 3.10 fold changes for FGF-2 and HAS-2, respectively. CONCLUSION: In general, it may be considered that HI has certain anabolic effects on the extracellular matrix of the skin because of the significant increases it causes in FGF-2 and HAS-2. Therefore, it may have a promising future in anti-aging studies and cosmetic dermatology. The results obtained in this study may also partially explain the molecular basis of the health benefits of HI on skin, including improvement in wound healing, and protection against the detrimental effects of ultraviolet exposure.

In vitro evaluation of compression-coated glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu2+)-loaded microparticles for colonic drug delivery.

Glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu(2+))-loaded Zn-pectinate microparticles in the form of hydroxypropyl cellulose (HPC) compression-coated tablets were prepared and their in vitro behavior tested. GHK-Cu(2+) delivery to colon can be useful for the inhibition of matrix metalloproteinase, with the increasing secretion of tissue inhibitors of metalloproteinases (TIMPS),which are the major factors contributing in mucosal ulceration and inflammation in inflammatory bowel disease. The concentration of peptide was determined spectrophotometrically. The results obtained implied that surfactant ratio had a significant effect on percent production yield (1.25 to 1.75 w/w; 72.22% to 80.84%), but cross-linking agent concentration had not. The entrapment efficiency (EE) was found to be in the range of 58.25-78.37%. The drug-loading factor significantly increased the EE; however, enhancement of cross-linking agent concentration decreased it. The release of GHK-Cu(2+) from Zn-pectinate microparticles (F1-F8) in simulated intestinal fluid was strongly affected by cross-linking agent concentration and drug amount (50 mg for F1-F6; 250 mg for F7-F8), but not particularly affected by surfactant amount. Release profiles represented that the microparticles released 50-80% their drug load within 4 h. Therefore, the optimum microparticle formulation (F8) coated with a relatively hydrophobic polymer HPC to get a suitable colonic delivery system. The optimum colonic delivery tablets prepared with 700 mg HPC-SL provided the expected delayed release with a lag time of 6 h. The effects of polymer viscosity and coat weight on GHK-Cu(2+) release were found to be crucial for the optimum delay of lag time. The invention was found to be promising for colonic delivery.

Efficacy of two plant extracts against acne vulgaris: Initial results of microbiological tests and cell culture studies.

BACKGROUND: Acne vulgaris is a common skin disease characterized by increased sebum production, inflammation, and colonization of Propionibacterium acnes (P. acnes) on pilosebaceous follicles. AIMS: To determine the efficacy of two different plant extracts against P. acnes and to analyze the gene expression levels of IL-1α, SRD5A1, and TNFα in HaCaT cells treated with these plant extracts. METHODS: Anti-acne extract 1 (AE1) consisted of Juglans regia (walnut husk), Myrtus communis (myrtle leaves), Matricaria chamomilla (chamomilla flowers), Urtica dioica (stinging nettle leaves), and Rosa damascena (rose flowers). Anti-acne extract 2 (AE2) contained Brassica oleracea var. botrytis (broccoli) and B. oleracea var. italica (cauliflower). The antimicrobial activities of the extracts were tested on two different P. acnes strains: the reference strain of P. acnes (ATCC 51277) and the clinical isolate from a patient. The minimum inhibitory concentration (MIC) of the extracts was determined using the broth dilution method. Human keratinocyte cells were used for in vitro tests. Gene expression analyses were performed with RT-qPCR. RESULTS: The MIC values of the extracts were below 1/2048 µg/mL. In the gene expression analysis, AE1 increased the expression level of TNFα (1.1719, P < 0.0001), suppressed the expression level of IL-1α, SRD5A1 (0.0588, P = 0.0231; 0.3081, P = 0.0351), respectively. AE2 suppressed gene expression level of IL-1α, SRD5A1, TNFα (0.3815, P = 0.0254; 0.3418, P = 0.0271; 0.1997, P = 0.0623). CONCLUSIONS: Both herbal extracts demonstrated strong antibacterial and anti-inflammatory activity in this preliminary trial. In conclusion, the topical application of these botanical extracts can be good candidates for local acne treatment.

Hexagonal boron nitride as a tablet lubricant and a comparison with conventional lubricants.

The objective of this study was to investigate the lubrication properties of hexagonal boron nitride (HBN) as a new tablet lubricant and compare it with conventional lubricants such as magnesium stearate (MGST), stearic acid (STAC), and glyceryl behenate (COMP). Tablets were manufactured on an instrumented single-station tablet press to monitor lower punch ejection force (LPEF) containing varied lubricants in different ratio (0.5, 1, 2%). Tablet crushing strength, disintegration time and thickness were measured. Tensile strength of compacted tablets were measured by applying a diametrical load across the edge of tablets to determine mechanical strength. The deformation mechanism of tablets was studied during compression from the Heckel plots with or without lubricants. MGST was found to be the most effective lubricant based on LPEF-lubrication concentration profile and LPEF of HBN was found very close to that of MGST. HBN was better than both STAC and COMP. A good lubrication was obtained at 0.5% for MGST and HBN (189 and 195N, respectively). Where COMP and STAC showed 20 and 35% more LPEF compare to that of MGST (239 and 288N, respectively). Even at the concentration of 2% COMP and STAC did not decrease LPEF as much as 0.5% of MGST and HBN. Like all conventional lubricants the higher the concentration of HBN the lower the mechanical properties of tablets because of its hydrophobic character. However, this deterioration was not as pronounced as MGST. HBN had no significant effect on tablet properties. Based on the Heckel plots, it was observed that after the addition of 1% lubricant granules showed less plastic deformation.

A proprietary herbal extract against hair loss in androgenetic alopecia and telogen effluvium: a placebo-controlled, single-blind, clinical-instrumental study.

INTRODUCTION: Currently there are only a limited number of drugs available for treatment of androgenetic alopecia and telogen effluvium. However, certain plants and their standardized extracts may provide some clinical benefits against hair loss. We formulated a herbal shampoo and a solution to evaluate their efficacy, safety, and synergy in hair loss. METHODS: We conducted a randomized, placebo-controlled, single-blind, clinical and instrumental study for 6 months on 120 subjects with androgenetic alopecia and telogen effluvium, confirmed by pull test and phototricogram. Each subject was examined monthly. At the end of the study, a self-assessment test was carried out. RESULTS: Herbal formulations were found to be more effective in preventing and reducing hair loss than placebo at every assessment point. Anagen/telogen ratios improved significantly in the study group. In addition, concomitant use of the shampoo and solution were found to be more effective than single product use. CONCLUSION: We interpret this eutrophic effect for scalp hair as the final outcome of the entire content of our herbal formula, which has antiandrogenic, anti-inflammatory, antioxidative, angiogenic, and hair-stimulating features. In combination, these features help prevent hair from falling out and reducing hair loss.

Proprietary Herbal Extract Downregulates the Gene Expression of IL-1α in HaCaT Cells: Possible Implications Against Nonscarring Alopecia.

BACKGROUND: Currently while, topical minoxidil and oral finasteride are the only medications approved in androgenetic alopecia (AGA), the cause oriented treatment and immunsupressive treatment are being performed in telogen effluvium (TE) and alopecia areata (AA) respectively. Considering the inflammatory factors in the pathogenesis of these three nonscarring alopecia forms, we have formulated a mixture for topical usage composed of six different herbal extracts (HE) which have already known antiinflammatory and antioxidant features. MATERIALS AND METHODS: In addition to performing the phytochemical analysis of HE, we detected the gene expression level of IL-1α, the crucial hair loss mediator, for the putative efficacy in nonscarring alopecia. Cell proliferation assay was performed by XTT reagent. After determination of non-cytotoxic concentration, HaCaT cells were treated with HE. RNA isolations were carried out from both non-treated and treated cell groups by using TRI-reagent. Gene expressions of IL-1α and as control GAPDH were determined by RT-qPCR analysis. RESULTS: Results were represented as "IL-1α/GAPDH Fold Change". HE solution caused statistically significant downregulation of IL-1α gene expressions (p<0.0001), compared to untreated control cells. HE treatment ended up with 0.1900 fold change for IL-1α. CONCLUSION: IL-1α is a direct growth inhibitory agent in hair follicles and an important actor in the pathogenesis of AGA , TE, and AA. Considering together the vitamins, flavonoids, and trace elements identified in the phytochemical analyses and downregulation of IL-1α in HaCaT cells, our HE may be an auxiliary agent in the therapy of these three nonscarring alopecia forms.

Minoxidil Downregulates Interleukin-1 Alpha Gene Expression in HaCaT Cells.

INTRODUCTION: Minoxidil has been used topically to stimulate hair growth for male androgenetic alopecia (AGA) for more than 3 decades. It is currently being used for female AGA and alopecia areata (AA) as well. Although much time has passed since its first use, our understanding of its mechanism of action is highly limited. Therefore, we examined the inflammatory properties of AGA and AA, two entities in which minoxidil is being used as a therapeutic agent. We investigated the in vitro expression levels of cytokine interleukin-1 alpha (IL-1α), a potent inhibitor of hair growth, in minoxidil-treated human keratinocyte (HaCaT) cells to determine whether this molecule exerts anti-inflammatory effects. MATERIALS AND METHODS: Cellular proliferation was examined using the Cell Proliferation Kit II (XTT) reagent. After determining a noncytotoxic concentration, HaCaT cells were treated with minoxidil. RNA was isolated from both untreated and treated cells with TRI Reagent®. Expression of the IL-1α gene was determined by reverse transcription quantitative polymerase chain reaction analysis and is reported relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which served as a control. RESULTS: Results are presented as IL-1α/GAPDH fold change. Minoxidil treatment downregulated IL-1α expression by 0.3433-fold compared with untreated cells (P = 0.001). CONCLUSION: This anti-inflammatory effect of minoxidil, as evidenced by significant downregulation of IL-1α gene expression in HaCaT cells, may represent one of its mechanisms of action in alopecia.

Colonic delivery of compression coated nisin tablets using pectin/HPMC polymer mixture.

Nisin containing pectin/HPMC compression coated tablets were prepared and their in vitro behavior tested for colonic delivery. Nisin is a 34-amino-acid residue long, heat stable peptide belonging to the group A lantibiotics with wide antimicrobial activity against Gram-positive bacteria. The invention can be useful for treating colonic infectious diseases such as by Clostridium difficile, and also by colonization of vancomycin-resistant enterococci. In this study, each 100mg core tablet of nisin was compression coated with 100% pectin, 90% pectin-10% HPMC, 85% pectin-15% HPMC, 80% pectin-20% HPMC, 75% pectin-25% HPMC, 100% HPMC at a coat weight of 400mg. The concentration and the activity of nisin were quantified using Well Diffusion Agar Assay. Drug release studies were carried out in pH 3.3 buffer solution. System degradation/erosion experiments were carried out in pH 1.2, 3.3, and 6.8 buffers using a pectinolytic enzyme. The biological activity and NMR studies were performed to assess the stability of nisin during the processing and after the in vitro tests. It was found that pectin alone was not sufficient to protect the nisin containing core tablets. At the end of the 6h 40% degradation was observed for 100% pectin tablets. HPMC addition required to control the solubility of pectin, a 5% increase in HPMC ratio in pectin/HPMC mixture provided a 2-h lag time for nisin release. Eighty percent pectin-20% HPMC appeared to be an optimum combination for further evaluation. Tablets maintained their integrity during the 6-h dissolution test, approximating the colon arrival times. Nisin was found to be active/stable during processing and after in vitro tests. Effect of polymer hydration on pectin degradation was found to be crucial for the enzyme activity. Sufficiently hydrated pectin degraded faster. The pectin/HPMC envelope was found to be a good delivery system for nisin to be delivered to the colon.

Minoxidil Acts as an Antiandrogen: A Study of 5α-reductase Type 2 Gene Expression in a Human Keratinocyte Cell Line.

Although more than three decades have passed since the first use of minoxidil in androgenetic alopecia (AGA), its mechanisms of action have still not been comprehensively understood. 5α-reductase (5α-R) has an active role as the predominant enzyme in both AGA and female pattern hair loss (FPHL), which are also the main therapeutic indications of topical minoxidil. But there is insufficient literature data regarding the interaction of minoxidil and the enzyme 5α-R. Herein, we studied the in vitro expression levels of 5α-R type 2 (5α-R2) in a minoxidil-treated human keratinocyte cell line (HaCaT) in order to elucidate the relation of these two parameters. Cell proliferation assay was performed by a XTT reagent (a yellow tetrazolium salt). After determination of non-cytotoxic concentration, HaCaT cells were treated with minoxidil. Ribonucleic acid (RNA) isolations were carried out from both non-treated and treated cell groups using a TRI reagent (an RNA, DNA, and protein isolation reagent). Gene expressions of 5α-R2 as study material and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the control were determined by real time-quantitative polymerase chain reaction (RT-qPCR) analysis. Results were represented as 5α-R2 / GAPDH fold change. Minoxidil treatment resulted in a 0.22 fold change for 5α-R2 (p < 0.0001). This antiandrogenic effect of minoxidil, shown by significant downregulation of 5α-R2 gene expression in HaCaT cells, may be one of its mechanisms of action in alopecia.

Effect of Ficus carica leaf extract on the gene expression of selected factors in HaCaT cells.

BACKGROUND: Ficus carica Linn. (Fc), common fig, has been traditionally used for many metabolic, cardiovasculary, respiratory, gastrointestinal, and skin disorders. Several studies were performed showing its anti-inflammatory, anti-angiogenic, anticancerogenic, and tissue-protective effects. In all of those studies, the positive effects of Fc were concluded as the result of its antioxidant and anti-inflammatory features due to the polyphenols it contains. AIMS: To study the phenolic compounds of Fc extract and to investigate the molecular basis of anti-inflammatory, anti-angiogenic, antimitotic, and anti-androgenic effects of Fc leaf extract in vitro. MATERIALS AND METHODS: The gene expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-a), interleukin 1-alpha (IL-1a), and 5 alpha-reductase type II (SRD5A2) were tested in human keratinocyte cells (HaCaT) by RT-qPCR. RESULTS: The gene expression analysis showed that the plant extract caused statistically significant downregulation of VEGF, TNF-a, IL-1a, and SRD5A2 compared to the untreated cells. DISCUSSION: These preliminary results of this in vitro study may partially explain the clinical success of Fc in the traditional medicine. CONCLUSION: Topical Fc leaf extract may be beneficial for some inflammatory disorders and androgen-dependent disorders of the skin such as androgenetic alopecia.

Chondroprotective effects of a new glucosamine combination in rats: Gene expression, biochemical and histopathological evaluation.

AIMS: This study investigates the effect of a new combination of glucosamine hydrochloride, chondroitin sulfate, methylsulfonylmethane, Harpagophytum procumbens root extract (standardized to 3% harpagoside) and bromelain extract (GCMHB) on formalin-induced damage to cartilage tissue in the rat knee joint and evaluates this combination in comparison with another combination of glucosamine hydrochloride, chondroitin sulfate and methylsulfonylmethane (GKM). MATERIALS AND METHODS: Animals in the control group were injected with formalin into the knee joint (FCG). Animals in the GCMHB-500 group were given 500mg/kg GCMHB+formalin, and those in the GKM-500 group were given 500mg/kg GKM+formalin. Finally, a healthy group (HG) was also used. GCMHB and GKM were administered to rats orally once a day for 30days. At the end of this period, the rats were sacrificed and the levels of MDA, NO, 8-OH/Gua, and tGSH in the knee joint tissue were measured. Analysis of IL-1ß and TNF-α gene expression was done and the tissue was evaluated histopathologically. KEY FINDINGS: MDA, NO and 8-OH/Gua levels and IL-1ß and TNF-α gene expression were significantly lower in the GCMHB-500 group compared to the FCG group, whereas tGSH was significantly higher in the GCMHB-500 group than in the FCG group. No significant difference was found for the IL-1ß, TNF-α and oxidant/antioxidant parameters between the GKM and FCG groups. The histopathological analysis showed that GCMHB could prevent damage to the cartilage joint, whereas GKM could not. SIGNIFICANCE: GCMHB may be used clinically by comparing with GKM in the treatment of osteoarthritis.

In vitro evaluation of pectin-HPMC compression coated 5-aminosalicylic acid tablets for colonic delivery.

In this study, we report pectin-HPMC compression coated core tablets of 5-aminosalicylic acid (5-ASA) for colonic delivery. Each 100 mg core tablet contained 5-ASA and was compression coated at 20 kN or 30 kN using 100% pectin, 80% pectin-20% HPMC, or 60% pectin-40% HPMC, at two different coat weights as 400 or 500 mg. Drug dissolution/system erosion/degradation studies were carried out in pH 1.2 and 6.8 buffers using a pectinolytic enzyme. The system was designed based on the gastrointestinal transit time concept, under the assumption of colon arrival times of 6 h. It was found that pectin alone was not sufficient to protect the core tablets and HPMC addition was required to control the solubility of pectin. The optimum HPMC concentration was 20% and such system would protect the cores up to 6 h that corresponded to 25-35% erosion and after that under the influence of pectinase the system would degrade faster and delivering 5-ASA to the colon. The pectin-HPMC envelope was found to be a promising drug delivery system for those drugs to be delivered to the colon.

Tableting and stability evaluation of enteric-coated omeprazole pellets.

In this study, fluidized-bed manufactured enteric-coated omeprazole pellets were compressed into tablets. The stability of the pellets and those of compressed tablets were evaluated for remaining omeprazole and for degradation products under an accelerated stability protocol. The data were analyzed using the artificial neural network (ANN) and analysis of variance (ANOVA). It was found that enteric-coated omeprazole pellets could be compressed into quickly disintegrating tablets using microcrystalline cellulose granules as the pressure absorbing matrix. The ANN, using the multilayer perceptron model, predicted that there was a positive correlation between tablet crushing strength and microcrystalline cellulose concentration. Microcrystalline cellulose matrix showed a strong plastic deformation and all the pellets inside the tablet maintained their integrity with no significant change in their surface properties. Omeprazole degradation in acid medium was mainly dependent on microcrystalline cellulose concentration. A 90-day accelerated stability test in brown glass bottles with a desiccant showed that all prototype formulations would result in an acceptable stability profile for both remaining omeprazole, and also for the increase of impurity concentrations.

Evaluation of hexagonal boron nitride as a new tablet lubricant.

In this study, hexagonal boron nitride (HBN) was evaluated as a new lubricant for pharmaceutical tablet manufacturing. The other conventional lubricants such as magnesium stearate (MGST), stearic acid (STAC), and glyceryl behenate (COMP) were also tested along with HBN. Tablets were manufactured on an instrumented single-station tablet press to monitor and quantify the lower punch ejection force (LPEF). The force ratio, tablet crushing strength, disintegration time, and thickness were measured. The lubricant film formation and lubricant distribution in tablets were studied using the scanning electron microscopy (SEM) and electron probe micro analyzer (EPMA). Based on the force ratio, a good lubrication was obtained at 1% for MGST and HBN; in contrast, STAC and COMP did not show a good lubrication. After 1%, all lubricants performed well. MGST was found to be the most effective lubricant based on LPEF-lubricant concentration profile. HBN provided a 50% decrease in LPEF at 2% lubricant concentration and was rated as an effective tablet lubricant. HBN was better than either STAC or COMP. Unlike MGST, HBN had no significant prolongation effect on tablet disintegration times.