[Homogeneity of Two Semisolid Formulations Using Simple In-tube Mixing Method].

To accelerate therapeutic effects, the mixtures of two or more topical pharmaceutical products having different medicinal purposes are often applied in the medical field. In this study, we aimed to develop a simple mixing method/procedure to achieve excellent homogeneity in the mixture of two topical products, a steroidal ointment and a skin moisturizer. To assess an in-tube mixing method as a simple mixing procedure, we injected both topical products into an empty resin tube, a flexible hollow tube with an open end that can be closed on one side, and a closed end on the other, removed as less air as possible inside the tube, and then thermocompressed (sealed) the open end to close it. The two topical products were then mixed uniformly by repeated finger pressure along the longitudinal axis of the tube. The homogeneity of the two topical products in the tube was evaluated by measuring the content of methyl paraoxybenzoate (MP), an additive loaded in the skin moisturizer. In addition, the mixability was qualitatively evaluated from the distribution of white petrolatum, another additive loaded in the steroid ointment, using Raman spectroscopy. As a result, the measured value of MP relative to the label claim was in the range of 100±12%, and the coefficients of variation value was also less than 12%. These results indicate that the in-tube mixing method using two topical products is approximately hologenetic preparations that do not cause therapeutic problems.

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.

Effects of Manufacturing Conditions on Pharmaceutical Properties of Petrolatum Ointment.

Oleaginous white petrolatum ointment (WP ointment) is one of the most commonly used dosage forms in the preparation of topical products. In general, WP ointments containing medium chain fatty acid triglycerides (MCT) are manufactured through a process of melting, mixing, agitating, and cooling. To investigate the pharmaceutical properties of WP ointments in greater detail, we examined manufacturing factors which could potentially influence the pharmaceutical properties of the finished product. WP ointment samples containing 10% MCT were stirred with a homogenizer and a paddle mixer at 65°C, then the homogenizer was stopped. Next, the paddle-mixer was stopped at several planned temperature points at which different samples were taken. Each sample was then cooled under the following planned conditions: rapid-cooling [-50°C/h] and slow-cooling [-7.5°C/h]. The pharmaceutical properties of each WP ointment sample, along with the appearance (Optical/digital microscope), hardness (Rheometer), and bleeding ability (100 Mesh wire-net cone) were measured. Then, release profiles were performed with a WP ointment using the model active ingredient Vitamin D. As a result, high hardness, low bleeding ability and low release profile were observed in the WP ointment samples that were manufactured under the condition of stopping the paddle-mixer at 40°C. However, the influence of cooling speed was observed to affect only hardness. Through optical microscopic observation, it was found that the appearance of WP ointment samples differed depending on the conditions under which they were manufactured. In this study, it was clear that the pharmaceutical properties of WP ointment samples were particularly influenced by the paddle-mixer stopping temperature.

Formulation study of topically applied O/W lotion containing vitamin D3 derivative, focusing on skin permeability of the drug.

Permeation of 22-oxacalcitriol-1α, 25-dihydroxyvitamin D(3) (OCT) through excited hairless mouse skin was determined after application of OCT as solutions and O/W lotions consisted of different polarities of solvents: medium-chain fatty acid triglyceride (MCT), myristate isopropyl (IPM), 1,3-butylene glycol (1,3-BG), and propylene glycol (PG). OCT concentration in skin was also followed after applying these formulations. A two-layer diffusion model was composed to analyze dermatopharmacokinetic profiles of OCT for each vehicle. In the OCT solutions, skin permeation profile of OCT differed depending on solvent polarity. The O/W lotion with a high MCT content led to a low amount of OCT in skin. On the other hand, the O/W lotion with a high 1,3-BG content led to a high amount of OCT in skin. This dermatopharmacokinetic analysis indicated that addition of MCT to the formulation decreases the skin/vehicle partition coefficient of OCT and increases the diffusion coefficient of OCT in skin. However, the opposite effects on these two parameters were found in the case of 1,3-BG. Thus, skin permeability of OCT differed depending on the solvents used in the formulation. These results indicate that skin permeability of OCT is influenced by the physicochemical properties (i.e. polarity) of OCT, solvent, and skin. Our findings on the solvent effects of the skin permeability of OCT are thus useful for designing topical drug formulation, especially in aiming for bioequivalent dosage formulas.

Prolonged anti-inflammatory action of DL-lactide/glycolide copolymer nanospheres containing betamethasone sodium phosphate for an intra-articular delivery system in antigen-induced arthritic rabbit.

PURPOSE: The objective of the present study was to develop prolonged anti-inflammatory action of DL-lactide/glycolide copolymer (PLGA) nanosphere incorporating a water-soluble corticosteroid (betamethasone sodium phosphate; BSP). Another aim was to demonstrate the biocompatibility and biologic efficacy of these BSP-loaded nanospheres directly administered into ovalbumin-induced chronic synovitis in the rabbit. METHODS: BSP-loaded nanospheres were prepared by an emulsion solvent diffusion method in oil (caprylate and caprate triglyceride). The drug releasing properties of the nanospheres were measured in vitro in phosphate buffer saline (PBS: pH7.4), and in vivo in rat air-pouch (pseudo synovial fluid). The BSP-loaded nanosphere suspensions were administered into the joint cavity in a model of antigen-induced arthritic rabbit and evaluated by measuring the joint swelling, and the biocompatibility was appraised by histologic microscopy. RESULTS: The BSP-nanospheres were a unimodally-dispersed particulate system with a mean diameter ranging from 300 to 490 nm, and BSP was efficiently entrapped in the lipophilic copolymer (PLGA), although its hydrophilic properties. The drug release-rate from the nanospheres in PBS was controlled by the molecular weight and the lactic/glycolic acid (LA/GA) ratio of the polymers. The in vitro releasing study demonstrated that sustained drug release occurred for over three weeks. In the antigen-induced arthritic rabbit, the joint swelling decreased significantly by administering BSP-loaded nanospheres during a 21-day period after intra-articular challenge. With regards to the prolonged anti-inflammatory efficacy, serum antibody to ovalbumin showed a sustained reduction during the period, and the steroidal effect appeared by the degradation of the polymer in the synovium. The BSP-nanosphere administered was phagocytosed by the synovial activated-cells and the cartilage degradation was almost prevented. CONCLUSIONS: Direct intra-articular injection of a PLGA nanosphere system with a water-soluble steroid provided a prolonged pharmacological efficacy in the joints of arthritic rabbits. The local anesthetic in the knee-joints was evaluated to be safe and without biologic damage.

Size-dependency of DL-lactide/glycolide copolymer particulates for intra-articular delivery system on phagocytosis in rat synovium.

PURPOSE: The present study evaluated the size-dependency of DL lactide/glycolide copolymer (PLGA) particulates for an intra articular delivery system on phagocytosis in the rat synovium after administering directly into the joint cavity. We also investigated the biocompatibility of PLGA particulate systems administered directly into the joint cavity of the rat. METHODS: Fluoresceinamine bound PLGA (FA-PLGA) nanospheres and microspheres were prepared by the modified emulsion solven diffusion method. The suspension of these particulate systems was administered into the rat-joint cavity and the biological action of the synovium was evaluated by histological inspection and fluorescence microscopy. RESULTS: A colloidal suspension of the FA-PLGA nanospheres, with a mean diameter of 265 nm, was phagocytosed in the synovium by the macrophages infiltrated through the synovial tissues. The phagocytosed nanospheres were delivered to the deep underlying tissues. An aqueous suspension of the FA-PLGA microspheres, with a mean diameter of 26.5 microm, was not phagocytosed in the macrophages. The macrophages slightly proliferated in the epithelial lining synovial-cells and the microspheres were covered with a granulation of multinucleated giant cells. The molecular weights of the polymer in these particulate systems were slowly reduced in the synovium. Localize inflammatory responses were almost undetected. CONCLUSIONS: PLGA nanospheres should be more suitable for delivery to inflamed synovial tissue than microspheres due to their ability to penetrate the synovium. PLGA particulate systems with biocompatibility in the joint can provide local-therapy action in joint disease in a different manner depending on the size of the system.