Phase 1/2 Study of Topical Submicron Particle Paclitaxel for Cutaneous Metastases of Breast Cancer

Purpose: This Phase 1/2 study evaluated safety and efficacy of a topical submicron particle paclitaxel (SPP) in an anhydrous ointment base (SOR007), primarily in breast cancer patients with cutaneous metastases (CM).Methods: One of 3 concentrations of SOR007 SPP (0.15%, 1.0%, or 2.0%) was applied twice daily over an area of 50 cm2 under a 3+3 phase I design for up to 28 days, with the option for additional 28 days at the highest dose once safety was established. Efficacy was analyzed by lesion measurements and photographs to determine overall response rate (ORR), complete response (CR) and progression free survival by day 28 or 56.Results: Twenty-three subjects were enrolled, 21 with cutaneous metastases of breast cancer (CMOBC). Four subjects received SOR007 0.15%, three at a dose of 1.0% for a median of 28 days (range = 6 to 29 days), and sixteen at 2.0% for a median of 56 days (range = 42 to 60). All doses were well tolerated, and 19 subjects were evaluable for efficacy. At day 28 across all dose levels, 16% (95%CI: 3.4 to 39.6%) of subjects achieved an ORR and another 63.1% (95%CI: 34.9 to 96.8%) had stable disease (SD). The proportion of patients being progression free at 28 days across all treatments was 79% (95:CI: 54 to 94%). Conclusion: Application of SOR007 0.15%, 1.0%, and 2.0% to CM resulted in lesion stabilization or response in most subjects, with reduced lesion pain, and minimal systemic absorption of paclitaxel. A randomized, placebo-controlled trial to confirm these findings is warranted.NCT: #03101358

Optimization of the Composition of the Ointment with Phytoecdysteroids Serpisten

Introduction. Phytoecdysteroids are a group of natural compounds related in structure and physiological effect to ecdysone - the hormone of insect molting. Phytoecdisteroids have been found to have an antiflammatory effect, which suggests that they have regenerative properties. The development of a soft dosage form containing phytoecdysteroids is of interest.Aim. Improvement of ointment compositions with phytoecdysteroids by optimizing the composition of base adjuvants.Materials and methods. As an active substance was used Serpisten, containing the sum of phytoecdysteroids, the main of which is 20-hydroxyecdysone and obtained from the leaves of Serratulaecoronatae. Raw materials "Serpukhi crowned leaves" were registered by the Federal Service Rospotrebnadzor (Moscow) for the production of dietary supplements (Gr. No. 77.99.23.3.U.1922.3.08), substance Serpisten (Gr. No. 77.99.23.3.U.1923.3.08. TU 9369-002-15092611-2008). In work were used the excipients allowed for medical use: the monoglycerides distilled, T-2 emulsifier, tween 80, sodium - carboxymethylcellulose, polyvinyl alcohol, hydroxide of aluminum, aero forces, vaseline, oil vaseline, sunflower oil. Optimization of ointment auxiliary substances composition was carried out according to the Greco-Latin 4 x 4 square plan with repeated observations. The concentration of hydrogen ions from aqueous ointments was evaluated as process parameters; acid number; release of serpistene from ointment into agar gel, thermal stability of structure. The structural and mechanical properties of the optimal composition ointment composition were determined on a RV type REOTEST 2.1 rotary viscometer (RHEOTEST Medingen GmbH, Germany). Ointment Bepanten (GP Grenzach Produktions GmbH, Germany) was used as a comparison preparation.Results and discussion. During optimization of the composition of the diphilic ointment with serpistene, was found that the ratio of hydrophobic and hydrophilic phases should be 1 : 1, it is advisable to introduce into the ointment base an emulsifier T-2, aerosil and a mixture of vaseline and vaseline oil in the proportion of 1 : 1. As a result of the carried out studies on the optimization of ointment compositions, the following serpisten ointment composition is proposed: serpisten - 0.02; emulsifier T-2 - 3.0; aerosil - 3.0; vaseline - 23.0; vaseline oil - 23.0; ethyl alcohol 40 % - 1 ml; purified water to 100.0. Comparative analysis of effective viscosity showed that the proposed composition is as close as possible to the Bepanten ointment.Conclusion. A set of technological studies was carried out to optimize the composition of the Serpisten, 0.02 °% ointment on a diphilic basis. The developed composition and technology made it possible to obtain a composition with thermal stability, bring the hydrogen index of the ointment closer to the pH of human skin and achieve the parameters included in the rheological optimum for dermatological ointments (0.34-108 Pa • s).

Physicochemical Evaluation of Diploknema butyracea Seed Extract and Formulation of Ketoconazole Ointment by Using the Fat as a Base

The fat obtained from the ripened seeds of Diploknema butyracea is widely used as a vegetable oil in rural areas of Nepal. This study was aimed for the physicochemical evaluation (acid value, iodine value, saponification value, peroxide value, ester value, pH, and liquefaction point) of the Diploknema butyracea seed extract (chyuri fat) and the formulation of 2% w/w ketoconazole ointment by using it as a base. All the physicochemical parameters were determined quantitatively by using the method of Indian Pharmacopoeia (IP), volume-I. By fusion method, 3 different formulations F-A, F-B, and F-C were prepared, in which different proportions of chyuri fat, polyethylene glycol 6000 (PEG 600), Tween 80, and propylene glycol were used as an ointment base. Various quality parameters such as spreadability, extrudability, viscosity, smoothness, pH, average fill weight, assay, content uniformity, accelerated stability, and drug release profiles were determined. HPLC was used for the determination of ketoconazole content in the ointment formulations. Physicochemical evaluation of the chyuri fat ensured its suitability for industrial purpose. The active ingredient release profile of formulations F-A (87.71%), F-B (88.89%), and F-C (91.09%) after 5 hours were within acceptable range along with other parameters. Assay of the formulations F-A, F-B, and F-C were reported to be 103.01, 107.9, and 102.45%, respectively. Overall, evaluation of the formulation F-A, prepared by using chyrui fat only, gave satisfactory results and most of the parameters were statistically similar ( p > 0.05 ) to the F-B and F-C formulated by incorporating a certain proportion of synthetic base. Thus it can be concluded that chyuri fat can be the best alternative to replace the expensive synthetic base.

Development of Dermatological Ointment based on Aloe arborescens juice

The purpose of this study is to select the optimal ointment base for the creation of a soft dosage form, to develop methods for standardizing dermatological ointment based on Aloe arborescens juice and to study antibacterial activity. The choice of the optimal ointment base, ensuring the maximum therapeutic effect of the ointment, was made. Ointments were prepared in accordance with the physical-chemical properties of the components of the basics. The criterion for evaluating the effectiveness of the used ointment bases was the degree of release of the active substances (anthracene derivatives). During the studies, antimicrobial activity was determined in the in vitro experiment. The comparative determination of the antimicrobial activity of ointment bases and juice of Aloe arborescens was performed by direct diffusion into agar. To develop the method of quantitative determination, the absorption spectra of Aloe arborescens juice and ointment extraction with 60% ethyl alcohol were studied. The optical density of the solution on the spectrophotometer at a wavelength of 396nm was measured. The quantitative content of the total active substances in the ointment, calculated on barbaloin was determined by using UV spectrophotometry.

Topical Wound Healing, Antimicrobial and Antioxidant Potential of Mimosa pudica Linn root Extracted using n-Hexane Followed by Methanol, Fortified in Ointment Base

Mimosa pudica Linn is an ornamental perennial herb belonging to the taxonomic group of Magnoliopsida and family Leguminaceae. Besides its ornamental use, Mimosa pudica is also a popular plant among folk healers to treat several diseases including bleeding disorders such as menorrhagia, dysentry with blood, mucus and piles, and wound healing. In this study, roots of Mimosa pudica was successively extracted with hexane, ethyl acetate, and methanol to evaluate the folkloric assert of plant in view of antioxidant, antibacterial, and wound healing potential. Methanolic extract showed concentration dependent elevation in inhibition for radical scavenging assay following dpph with maximum effect of 73.43% against standard ascorbic acid equivalent to 250 µg/ml, however IC50 of extract with n-hexane and ethyl acetate exhibited relatively poor antioxidant efficacy. Minimum inhibitory concentration demonstrated higher inhibitory action in range of 1.25-0.625 mg/ml against tested gram positive Staphylococcus aureus -MTCC737, and Bacillus subtilis-MTCC110 and 2.5 mg/ml for gram negative Salmonella typhi-MTCC15442, Escherichia coli-MTCC118 micro-organism for methanolic extract compared to ethyl acetate extract, however hexane extract showed MIC > 2.5 mg/ml. Among the tested solvent system for column chromatography, fractionation with diethyl ether: methanol (1:4) demonstrated single clear spot with Rf value 0.72 for methanolic extract indicated presence of flavonoid as major phytoconstituents. The results of spectral analysis following fourier transform spectroscopy, nuclear magnetic resonance, and mass spectroscopy for purified isolated compound confirmed identity of isolated flavonoid from methanolic fraction with chemical name 7,8,3’,4’-tetrahydroxy-6-methoxy-flavone. Thus, overall results demonstrated that Mimosa pudica root extract have potential antioxidant and antimicrobial efficacy. Furthermore, the Mimosa pudica root extracted with n-hexane followed by methanol fortified in a pharmaceutical formulation ointment base demonstrated excellent wound healing efficacy compared to marketed povidone-iodine ointment. Therefore, traditional claim for the use of Mimosa pudica root as potential antioxidant, antimicrobial, and wound healer in topical drug delivery have been proven by the present study.

Temporal Effects of Different Vehicles on Wound Healing Potentials of Quercetin: Biochemical, Molecular, and Histopathological Approaches

Development of novel drugs or formulations to accelerate the wound healing process is the need of current era. Quercetin (Q), a bioflavonoid, at 0.3% concentration has showed some wound healing potential in our preliminary studies. The present study was aimed to explore the wound healing potential of 0.3% quercetin formulated in 3 different vehicles, that is, dimethyl sulfoxide (DMSO; 10%), ointment base, and corn oil. Ninety experimentally wounded rats were grouped in 6 groups. The 0.3% quercetin mixed with DMSO, ointment base, and corn oil was topically applied once daily for 21 days on the wounds of groups 2, 4, and 6, respectively. DMSO, ointment base, and corn oil alone was applied similarly in groups 1, 3, and 5, respectively. Gross evaluation and wound contraction results revealed accelerated wound closure in all quercetin-treated groups. The mRNA expressions of vascular endothelial growth factor, transforming growth factor-β1, and interluekin-10 were markedly upregulated in healing tissues of quercetin-treated groups. Tumor necrosis factor-α mRNA expression and protein levels were lowered by quercetin treatment. Quercetin-treated groups also showed increased activities of SOD (superoxide dismutase) and catalase, and levels of total thiols in wound tissues on day 7. Levels of superoxide anion radicals and malondialdehyde were markedly lower in quercetin-treated groups. Histologically, wound sections of quercetin-treated groups showed early dominance of fibroblasts, increased blood vessels, marked collagen deposition, and regenerated epithelial layer. The significant effects were more pronounced in ointment + Q group among all the quercetin-treated groups. In conclusion, 0.3% quercetin mixed in ointment base produced the fastest and better wound healing in rats.

Effects and Characterization of Some Topical Ointments Based on Vegetal Extracts on Incision, Excision, and Thermal Wound Models

The present paper aims to formulate and characterize four phytotherapeutic ointments based on Hippophae fructus, Calendulae flos, Bardanae folium, and Millefolii herba, which are included in a novel ointment base. In order to investigate the healing properties of the ointments, in vivo experimental wound models of linear incision, circular excision, and thermal burn were performed on Wistar rats. Topical treatment was performed daily for 21 days. Determination of the wound contraction rate (WCR), the period of reepithelization, and histopathological examination were achieved. Additionally, for the tested ointments, oscillatory and rotational rheological tests were carried out, and for the extracts, HPLC analysis was performed. The results demonstrate that the tested novel ointments are safe for use and the most effective ointment proved to be the one based on Arctium lappa, followed by that of Calendulae flos.