Effects of Manufacturing Conditions on Pharmaceutical Properties of Petrolatum Ointment-Distribution of Hydrocarbon.

Petrolatum ointment, which is an oleaginous ointment, is generally produced through manufacturing processes such as melting, mixing, and cooling. In this type of semisolid formulation, the manufacturing conditions of each process are empirically known to affect the quality of the resultant preparation; however, in many cases, the details of the factors are unclear. To clearly investigate the influence of the pharmaceutical properties of petrolatum ointments, we manufactured several ointments while changing the conditions of the mixing and cooling process after melting white petrolatum. As a result, the temperature at the termination was determined to influence the pharmaceutical properties of the final product. To investigate these phenomena, each petrolatum ointment sample was examined via digital microscopy and laser Raman analysis, and the distribution of the liquid-solid parts of samples was investigated. The internal structure of the ointment sample manufactured at a mixing-stop temperature of 40 °C, the needle crystals and the spherical aggregates surrounding them appropriately coexisted, while the structure exhibited a state wherein the two were linked in a semisolid phase. Meanwhile, for the ointment sample manufactured under the lowest mixing-stop temperature of 25 °C, the liquid part and the spherical aggregates were clearly separated, indicating that the liquid part was easily separated from ointments. In addition, the distribution of the hydrocarbons among the samples was measured via GC-MS; no significant difference in chemical structure was observed. In conclusion, the internal structure of the petrolatum ointment was changed by the manufacturing conditions, and this affected the pharmaceutical properties.

A Method for Measuring the Surface Free Energy of Topical Semi-solid Dosage Forms.

Our aim was to determine the surface free energy (SFE) of semi-solid dosage forms (SSDFs) by establishing a reproducible method for measuring the contact angle of liquids to SSDFs. Four SSDFs were used: petrolatum, an oil/water (O/W) and a water/oil (W/O) cream, and an alcohol-based gel. The SSDFs were evenly spread on a glass slide, and the change in contact angle over time was measured by dropping water, glycerol, diiodomethane and n-hexadecane as the test liquids. Depending on the combination of test liquid and SSDF, the contact angle was either constant or decreased in an exponential manner. Contact angles may have decreased in an exponential manner because the reaction between the test liquid and the SSDF altered the interfacial tension between the two phases and changed the surface tension of the test liquid and the SFE of the SSDF. The contact angle of the test liquid to the SSDF could be determined reproducibly using the initial contact angle immediately after dropping the liquid on the SSDF as the contact angle before reaction. Using the obtained contact angles and the Owens-Wendt-Rabel-Kaelble equation, we calculated the SFE and its component for the SSDFs tested and found that the results reflect the physicochemical properties of SSDFs. Furthermore, the work of adhesion (WA) of the SSDF to Yucatan micropig skin was calculated using the SFE for the SSDFs. Interestingly, the WA values for all SSDFs tested were comparable.

Replacing Synthetic Ingredients by Sustainable Natural Alternatives: A Case Study Using Topical O/W Emulsions.

With the increasing debate on sustainability, there is a strong market trend to formulate more sustainable products for topical application. Several studies emphasize the potential applications of natural, organic, or green chemistry-derived ingredients, but comparative studies between conventional ingredients and sustainable alternatives are lacking. This type of study is considered an excellent baseline and time-saving strategy for future studies. In addition, one of the main challenges of replacing ingredients by sustainable alternatives in topical vehicles is to maintain high-quality products. Thus, the main goal of this research study was to create a well-defined strategy supported by specific experimental data for the development of sustainable topical vehicles with high-quality standards. The study was designed to evaluate the effects of replacing conventional ingredients (e.g., hydrocarbons, silicones, and preservatives) by sustainable ones on the physical, chemical, and microbiological features of topical emulsions. Additionally, in vivo assessment studies were performed to evaluate the safety, biological efficacy, and sensorial aspects of the developed formulations. The results obtained showed that the replacement of ingredients by sustainable alternatives has an effective impact on the physicochemical and structural properties of the emulsions, mainly on their rheological behavior. However, using appropriate strategies for ingredient selection and rheological adjustment, it is possible to overcome some barriers created by the use of natural raw materials, thus developing appealing and high-quality sustainable topical vehicles.

Influence of Manufacturing Process Variables on the Properties of Ophthalmic Ointments of Tobramycin.

PURPOSE: The main purpose of this study was to evaluate qualitative (Q1) and quantitative (Q2) equivalent oleaginous ophthalmic ointments of tobramycin (TOB) with different physicochemical properties and identify critical process/quality attributes using various in vitro methods of characterization. METHODS: Various sources of petrolatum and TOB, and two mixing methods were employed to generate Q1/Q2 equivalent ointments. Characterization studies included content uniformity, microscopy, modulated temperature differential scanning calorimetry (MTDSC), gas chromatography-mass spectrometry (GC/MS), thermogravimetric analysis (TGA) and rheology. RESULTS: The particle size distribution of TOB influenced the content uniformity of ointments. Differences in the MTDSC endothermic and exothermic peaks of TOB suggested the presence of different polymorphic forms. GC/MS revealed variations in the composition and distribution of linear and branched hydrocarbons of petrolatums. Differences were also observed in the TGA derivative weight loss peaks demonstrating differences in the composition of petrolatum that may be the source of the observed variations in the rheological parameters of the ointments. CONCLUSIONS: Source and composition of the petrolatum played a more critical role in determining the rheological properties compared to the method of preparation. Results demonstrated the impact of the source of TOB, excipients and manufacturing processes on the quality attributes of TOB ophthalmic ointments.

Perspectives on Physicochemical and In Vitro Profiling of Ophthalmic Ointments.

Ophthalmic ointments are unique in that they combine features of topical drug delivery, the ophthalmic route and ointment (semisolid) formulations. Accordingly, these complex formulations are challenging to develop and evaluate and therefore it is critically important to understand their physicochemical properties as well as their in vitro drug release characteristics. Previous reports on the characterization of ophthalmic ointments are very limited. Although there are FDA guidance documents and USP monographs covering some aspects of semisolid formulations, there are no FDA guidance documents nor any USP monographs for ophthalmic ointments. This review summarizes the physicochemical and in vitro profiling methods that have been previously reported for ophthalmic ointments. Specifically, insight is provided into physicochemical characterization (rheological parameters, drug content and content uniformity, and particle size of the API in the finished ointments) as well as important considerations (membranes, release media, method comparison, release kinetics and discriminatory ability) in in vitro release testing (IVRT) method development for ophthalmic ointments. Graphical Abstract Summary of the physicochemcial profiling and in vitro drug release testing (IVRT) for ophthalmic ointments.

The Role of Excipients in the Stability of Triamcinolone Acetonide in Ointments.

Degradation of triamcinolone acetonide (TCA) in an ointment was investigated. TCA appeared to be concentrated in propylene glycol (PG) which in turn is dispersed in a lanolin-petrolatum mixture. Two predominant degradation products were identified: a 21-aldehyde and a 17-carboxylic acid. The 21-aldehyde is formed after TCA is oxidized by O2, a reaction that is catalyzed by trace metals. Logically, the content of trace metals has a profound effect on the degradation rate. It was shown that trace metals are extracted from lanolin and petrolatum by PG, increasing the concentration in PG. In accordance with these findings, TCA degrades faster in PG that is present in the ointment formulation than in regular PG. The 21-aldehyde was confirmed to be a primary degradation product, while the 17-carboxylic acid was identified as a secondary degradation product. Based on the mechanism of degradation, the ointment can be stabilized by the addition of sodium metabisulfite which was shown to reside also in the PG phase within the ointment.

Elucidation of the variability in consistency of pharmacopoeia quality petrolatum.

The Pharmacopeia monograph for petrolatum poorly defines the material's physical properties. Indeed, differences between petrolatum grades can be substantial; yield stress varies between 65 and 280 Pa which can be compared with the consistency of respectively thin cream or thick ointment. This variation is not only due to differences in composition or refining process but also as a result of different processing; for example, thermal history influences petrolatum structure considerably. Slow cooling of petrolatum resulted in a yield stress of 26 Pa and fast cooling in 79 Pa. X-ray showed that crystallinity was 0.7% for the first cooling case and 1.5% for the second one. Crystallite size was estimated to be 20-50 nm. To investigate if this relatively small difference in crystallinity may induce the difference in consistency, 15 nm SiO2 particles were added to petrolatum. Indeed, a small increase in SiO2 concentration led to a major increase in yield stress. This was argued to be due to the small size of the particles, resulting in a large increase in absolute number of particles. The Pharmacopeia does not unambiguously define the pharmaceutical excipient petrolatum. As a consequence, the formulator has to take care of selecting the appropriate grade as well as to carefully control the processing of the material in order to achieve a consistent pharmaceutical product.

Temperature-Induced Collapse, and Arrested Collapse, of Anisotropic Endoskeleton Droplets.

Micron-scale rod-shaped droplets with a range of aspect ratios are produced using extrusion of oil containing a soft wax crystal network to permit shape customization. A physical model of the droplet shape stability is developed based on balancing interfacial stresses with the internal crystal network yield stress. The model predicts the mechanical properties required for particular droplet size stability, in a given physicochemical environment, and is tested by microscopic observations of droplets over a range of relevant applied temperatures. The time-dependent response to temperature of individual rods is monitored and used to identify the collapse temperature based on structural yielding. Precise temperature control allows variation of the droplet endoskeleton yield stress and direct determination of the droplet stability as a function of size, by observing the onset of collapse by interfacial compression, and enables validation of the model predictions. Mapping the regions of droplet stability and instability for various-sized droplets yields a basis for designing droplet shapes for multiple applications using easily measured physical variables. The phenomenon of arrested collapse is also explored as a means of transforming simple rod-shaped starting materials into more complex shapes and enhancing adhesion to targeted solid surfaces, enabling exploitation of the hybrid solid-liquid nature of these droplets.

Effects of mixing procedure itself on the structure, viscosity, and spreadability of white petrolatum and salicylic acid ointment and the skin permeation of salicylic acid.

White petrolatum is a mixture of solid and liquid hydrocarbons and its structure can be affected by shear stress. Thus, it might also induce changes in its rheological properties. In this study, we used polarization microscopy to investigate how different mixing methods affect the structure of white petrolatum. We used two different mixing methods, mixing using a rotation/revolution mixer and mixing using an ointment slab and an ointment spatula. The extent of the fragmentation and dispersal of the solid portion of white petrolatum depended on the mixing conditions. Next, we examined the changes in the structure of a salicylic acid ointment, in which white petrolatum was used as a base, induced by mixing and found that the salicylic acid solids within the ointment were also dispersed. In addition to these structural changes, the viscosity and thixotropic behavior of both test substances also decreased in a mixing condition-dependent manner. The reductions in these parameters were most marked after mixing with a rotation/revolution mixer, and similar results were obtained for spreadability. We also investigated the effects of mixing procedure on the skin accumulation and permeation of salicylic acid. They were increased by approximately three-fold after mixing. Little difference in skin accumulation or permeation was detected between the two mixing methods. These findings indicate that mixing procedures themselves affect the utility and physiological effects of white petrolatum-based ointments. Therefore, these effects should be considered when mixing is required for the clinical use of petrolatum-based ointments.

EPR STUDIES OF THERMALLY STERILIZED VASELINUM ALBUM.

Electron paramagnetic resonance (EPR) spectroscopy was used for examination of free radicals in thermally treated vaselinum album (VA). Thermal treatment in hot air as sterilization process was tested. Conditions of thermal sterilization were chosen according to the pharmaceutical norms. Vaselinum album was heated at the following conditions (T--temperature, t--time): T = 160°C and t = 120 min, T = 170°C and t = 60 min and T = 180°C and t = 30 min. The aim of this work was to determine concentration and free radical properties of thermally sterilized VA. EPR analysis for VA was done 15 min after sterilization. EPR measurements were done at room temperature. EPR spectra were recorded in the range of microwave power of 2.2-70 mW. g-Factor, amplitudes (A) and line width (ΔBpp) of the spectra were determined. The shape of the EPR spectra was analyzed. Free radical concentration (N) in the heated samples was determined. EPR spectra were not obtained for the non heated VA. EPR spectra were detected for all thermally sterilized samples. The spectra revealed complex character, their asymmetry depends on microwave power. The lowest free radicals concentration was found for the VA sterilized at 180°C during 30 min. EPR spectroscopy is proposed as the method useful for optimization of sterilization process of drugs.

Silicones as nonocclusive topical agents.

BACKGROUND/AIMS: Silicone excipients are commonly used ingredients because of their emollient and skin-conditioning effects, and their ability to form uniform, water-resistant, yet permeable films. Based on comparisons with organic materials and conflicting knowledge from silicones used in scar treatment, the misconception still exists that silicone topical excipients are occlusive substances that may block the passive loss of water through the upper skin layers. Therefore, 3 types of common silicone excipients and 3 water-in-(oil-plus-silicone) or W/(O + Si) creams, containing 10% (w/w) of the respective silicones, were investigated as a function of time and compared to petrolatum. METHODS: Transepidermal water loss (TEWL) and skin hydration measurements were carried out after a single topical application on forearm skin of 26 healthy young female volunteers. RESULTS: Both petrolatum and silicones significantly decreased TEWL 15 min after application, but the measurements for the silicones were not significantly different from the untreated control values. The tested silicones did not moisturize the skin. Petrolatum formed an occlusive layer, creating an increase in skin hydration for more than 4 h. The results measured for the W/(O + Si) creams indicated that they moisturized the skin, without any effect on TEWL. CONCLUSION: A clear difference was shown between the skin occlusive properties of petrolatum and the water vapor permeability of the common silicone excipient materials.

A technique to eliminate subgingival cement adhesion to implant abutments by using polytetrafluoroethylene tape.

Residual excess cement adhered subgingivally to an implant abutment has the potential to cause periimplant mucositis or periimplant disease. This article describes a procedure in which polytetrafluoroethylene (PTFE) tape is used to protect dental cements from adhering to the implant abutment. This technique ensures complete removal of cement from the implant abutment after seating of the crown.

pH and effects on Streptococcus mutans growth of denture adhesives: an in vitro study.

OBJECTIVES: To evaluate the pH and effects on Streptococcus mutans growth of denture adhesives. BACKGROUND: There is little information regarding the pH of contemporary adhesives and their influences on S. mutans growth. MATERIALS AND METHODS: The adhesives tested were Polident® cream, Protefix® cream and Protefix® powder. Samples of each adhesive were added to deionized water to produce solutions of 10.0, 5.0, 2.5 and 1.0% w/v (cream formulations) or 5.0, 2.5,1.0 and 0.5% (powder formulation). The pH values were measured immediately after preparation and at 1-, 2-, 3-, 6-, 12-, and 24-h intervals using a digital pH meter. Streptococcus mutans UA159 was inoculated in the Brain Heart Infusion medium with or without the adhesive extracts (control). Bacterial growth was observed by measuring absorption at 600 nm every 1 h for 12 h using a spectrophotometer. RESULTS: The tested adhesives generally remained relatively pH-stable over 24 h, ranging from 5.5 to 7.0. There were no statistically significant differences in S. mutans growth rates between the extract-treated and control cultures (p>0.5). CONCLUSIONS: Some adhesives produce a pH below the critical pH of hydroxyapatite and may not be suitable for patients with natural teeth. None of the tested adhesives significantly affect S. mutans growth.

Impact of active pharmaceutical ingredient variables and oleaginous base on the in vitro drug release from ophthalmic ointments: An investigation using dexamethasone as a model drug.

The present study systematically investigates the impact of active pharmaceutical ingredient (API) variables and oleaginous base characteristics on the in vitro release (IVR) performance of ophthalmic ointments, utilizing dexamethasone as a model drug. The interplay between selected attributes (i.e., particle size distribution, crystallinity, and polymorphic form for API, and rheological factors for compendial-grade white petrolatum) and IVR performance was investigated. APIs from different vendors exhibited variations in crystallinity and polymorphism. Ointments containing amorphous dexamethasone presented higher release amounts/rates compared to crystalline counterparts, emphasizing the role of physical state in release kinetics. Variations in particle size of this lipophilic API (5.4 - 21.2 µm) did not appear to impact IVR performance significantly. In contrast, white petrolatum's rheological attributes, which varied substantially within USP-grade petrolatum, were found to critically affect the drug release rate and extent of the ointment. The study's comprehensive analysis establishes a coherent connection between the quality attributes of both API and petrolatum and IVR, delineating their intricate interdependent effects on ophthalmic ointment performance. These findings provide reference to formulation design, quality control, and regulatory considerations within the pharmaceutical industry, fostering a robust foundational understanding of commonly overlooked quality attributes in ophthalmic ointments.

Measurement depth enhancement in terahertz imaging of biological tissues.

We demonstrate the use of a THz penetration-enhancing agent (THz-PEA) to enhance the terahertz (THz) wave penetration depth in tissues. The THz-PEA is a biocompatible material having absorption lower than that of water, and it is easily absorbed into tissues. When using glycerol as a THz-PEA, the peak value of the THz signal which was transmitted through the fresh tissue and reflected by a metal target, was almost doubled compared to that of tissue without glycerol. THz time-of-flight imaging (B-scan) was used to display the sequential glycerol delivery images. Enhancement of the penetration depth was confirmed after an artificial tumor was located below fresh skin. We thus concluded that the THz-PEA technique can potentially be employed to enhance the image contrast of the abnormal lesions below the skin.

Dermal uptake study with 4,4'-diphenylmethane diisocyanate led to active sensitization.

BACKGROUND: To investigate the dermal uptake of 4,4'-diphenylmethane diisocyanate (4,4'-MDI), a study was performed in which 2 female volunteers were exposed to 10 and 25 mg, respectively, of 4,4'-MDI by applying 2.0% 4,4'-MDI in petrolatum over areas where the surface concentration corresponded to 800 µg/cm(2) . Ten days later, they developed eczematous dermatitis at the area of application. OBJECTIVES: To investigate whether the dermal application caused active sensitization to 4,4'-MDI. METHODS: Chemical analysis of the 4,4'-MDI preparation used in the application and the amount of 4,4'-MDI not absorbed by the skin was performed with liquid chromatography-mass spectrometry. The volunteers were tested with serial dilutions of 4,4'-MDI and the potentially cross-reacting substances 4,4'-diaminodiphenylmethane (4,4'-MDA), p-phenylenediamine (PPD), and dicyclohexylmethane-4,4'-diisocyanate (DMDI). RESULTS: Patch test results suggested that the volunteers were actively sensitized to 4,4'-MDI following the dermal uptake study, as they reacted positively to 4,4'-MDA, a marker for 4,4'-MDI allergy. No positive reactions were seen to PPD or DMDI. Chemical investigation confirmed that the correct concentration had been used for the dermal uptake study, and showed that about 70% of the applied 4,4'-MDI was not absorbed. CONCLUSIONS: A dermal uptake study with 4,4'-MDI in 2.0% pet. with an occlusion time of 8 hr induced active sensitization to 4,4'-MDI and subsequently to 4,4'-MDA.

Development and Evaluation of Biocompatible Topical Petrolatum-liquid Crystal Formulations with Enhanced Skin Permeation Properties.

Transdermal administration represents a major advancement over traditional pharmaceutical dosing methods. However, a frequent issue is inadequate penetration of the active medicinal component through the skin. As a result, in the current research, we assessed the utility of newly developed petrolatum-liquid crystal (LC) ointment formulations and characterized their biocompatibility and function in the transdermal drug delivery system. To begin, we made petrolatum-LC formulations using p-aminobenzoic acid (PABA) as a hydrophilic model molecule. The viscosity, small-angle X-ray scattering (SAXS), particle diameters, and z-potential were measured to assess the physicochemical properties of the formulations. A dialysis release technique was used to evaluate medication release from petrolatum-LC formulations. In vitro testing was performed to determine the potential to enhance skin penetration. The biocompatibility of the produced formulations was further tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and single-cell gel electrophoresis. According to the results, the novel petrolatum-LC formulations are biocompatible and effective in forming hexosomes. PABA skin penetration was significantly enhanced by the new petrolatum-LC formulations. According to this study, petroleum-LC formulations are more efficient than commercial petrolatum in terms of skin permeability improvement and PABA skin concentration.

The effects of height and surface roughness of abutments and the type of cement on bond strength of cement-retained implant restorations.

OBJECTIVES: To evaluate the effects and interactions between cement type, abutment height and surface roughness on bond strength of cemented implant restorations. MATERIALS AND METHODS: One hundred and sixty metal copings were fabricated and divided into 16 groups of 10 samples each. Copings were cemented on 4 and 6 mm height Alfa-Gate(®) abutment, using four types of cements: zinc phosphate (ZNP), glass ionomer (GI), and zinc oxide eugenol (ZOE) with or without 15% vaseline. Copings were removed using a universal testing machine and bond strengths were recorded. All abutments were sandblasted with 50 µm aluminum oxide and the experiment was repeated. Results were analyzed using univariate analysis, Games-Howell, and Bonferroni's pairwise comparisons tests at P≤0.05. RESULTS: Bond strengths were significantly different according to cement type, abutment height, and surface roughness (P=0.001). The cement ranking from highest to lowest was: ZNP>GI>ZOE>zinc oxide eugenol with 15% vaseline (ZOEV). An increasing abutment height showed a significant increase in bond strength for permanent cements only (P≤0.05). Sandblasting abutment surface significantly the increased bond strength for all cement except the ZOEV at 4 mm abutment, and for only ZOE and GI cements at the 6 mm abutment (P≤0.05). CONCLUSIONS: ZP was the strongest cement and required using one of the variables (height, surface roughness) for maximum bond strength. GI bond strength was increased by both variables but sandblasting was more effective. ZOE required using both variables to be as effective as some of the permanent cement subgroups. ZOEV was the weakest and bond strength was not improved by either variables.

Oregano extract ointment for wound healing: a randomized, double-blind, petrolatum-controlled study evaluating efficacy.

BACKGROUND: Wound healing is a dynamic and complex process affected by tissue hydration, the presence of bacteria, inflammation, and other variables. Oregano has potent antibacterial, antifungal, antioxidant, and anti-inflammatory properties. Studies of oregano ointment on wound healing are lacking. OBJECTIVE: To determine the efficacy of 3% oregano extract ointment on wound healing. METHODS: An investigator initiated, randomized, double-blind, petrolatum-controlled study was performed to determine the effects of oregano ointment on wound healing. Forty patients who underwent surgical excision were enrolled and randomized. Cultures were obtained on day 12 and scars were evaluated using the Patient and Observer Scar Assessment tool on day 12, 45, and 90. RESULTS: The oregano ointment group had 19 percent of cultures test positive for Staphlococcus aureus compared to 41 percent in the petrolatum group. One patient in the oregano ointment group developed a cellulitis compared to three patients in the petrolatum group. The oregano group had a statistically significant improvement over petrolatum in scar color, pigmentation, and pliability. CONCLUSION: Oregano extract ointment decreased bacterial contamination and subsequent infection on post-surgical wounds and had equivalent overall scar appearance compared to petrolatum.

Determination of formaldehyde in formaldehyde-releaser patch test preparations.

BACKGROUND: Positive patch test reactions to formaldehyde-releasers in patients co-reacting to formaldehyde are often ascribed to formaldehyde allergy. However, the formaldehyde content of patch test materials has not been investigated. OBJECTIVES: To demonstrate and quantify free formaldehyde in commercial patch test materials and in prepared aqueous solutions of formaldehyde releasers. MATERIALS: Free formaldehyde was measured by (13)C NMR Spectroscopy in (i) all formaldehyde-releasers in water available from Chemotechnique and Brial, (ii) 5 releasers in petrolatum, (iii) 12 prepared aqueous solutions of formaldehyde-releasers and (iv) water that had been in contact with petrolatum test samples. RESULTS: In none of the five petrolatum test substances was free formaldehyde found. In all nine commercial aqueous patch test substances and 9 of the 12 prepared solutions, free formaldehyde was demonstrated with concentrations ranging from 0.019% to 0.37% (detection limit 0.01%). Contact of the petrolatum test samples with water resulted in the release of formaldehyde. CONCLUSIONS: Most aqueous solutions of formaldehyde-releasers contain free formaldehyde. Petrolatum-based patch test materials with formaldehyde-releasers do not contain free formaldehyde, but probably start releasing it upon contact with water. Therefore, in future studies, determination of free and releasable formaldehyde may be preferable.