Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

Abstract

Abstract. Cilostazol (CLZ), an anti-platelet agent, is primarily used following the onset of cerebral infarction. However, as CLZ is only marginally soluble in water, a strategy for patients with serious secondary conditions, such as impaired consciousness or aphagia, is required. In the present study, topical formulations containing CLZ nanocrystals (CLZ nano ) were designed to enhance percutaneous absorption. In addition, the mechanism of penetration of CLZ nano through rat skin was investigated. A topical formulation containing CLZ nanoparticles (CLZ nano gel patch) was prepared using a combination of recrystallization and ball milling of an aqueous gel. The particle size of CLZ nano was 74.5±6.2 nm (mean ± standard deviation). The concentration of permeated CLZ nano and penetration mechanism of the nanocrystals were measured in a percutaneous absorption experiment. The amount of penetrated CLZ, the penetration rate (J c ), the penetration coefficient through the skin (K p ) and the skin/preparation partition coefficient (K m ) for the CLZ nano gel patch were all significantly higher than those of the CLZ powder (CLZ micro ) gel patch, the CLZ nano ointment and the CLZ micro ointment. In in vitro percutaneous penetration experiments on the CLZ nano gel patches, there was a positive correlation between the number of CLZ nano . Following the application of the CLZ nano gel patch on rat skin, 98% of penetrated CLZ was observed in nanoparticle form; for the CLZ micro gel patch, this figure was 9%. In addition, the CLZ concentrations in the plasma of rats administered the CLZ nano gel patches were significantly higher than those of rats administered the CLZ nano CP gel and PEG ointments. It was suggested that CLZ nano (diameter <100 nm) were transferred through the intracellular spaces in the skin and then into peripheral blood vessels. To the best of our knowledge, this is the first report to elucidate the mechanism of the percutaneous penetration of nanocrystal medicines.

A Systematic Approach to the Development of Cilostazol Nanosuspension by Liquid Antisolvent Precipitation (LASP) and Its Combination with Ultrasound

“…On the other hand, the descriptions of cilostazol nanosuspensions in the available literature do not report PVA use. Instead, among the used polymers, surfactants and their combinations, the following are mentioned: HPC+DOSS [14], low substituted MC+DOSS [15,16], Poloxamer [18,24], HPMC [28], HPMC+Tween 80 [17], and SDS (+Tween 80 or Kolliphor RH40) [19]. The current results apparently do not confirm the optimal potential of HPMC, HPC or PX for the particle size reduction of cilostazol.…”

“…The most popular, as well as industrially feasible, methods of nanocrystals production are top-down techniques, where large particles are mechanically fragmented into nanoparticles [12]. There are several examples of cilostazol nanosuspensions obtained with wet milling [13][14][15][16][17][18][19]. On the other hand, top-down methods are often relatively expensive and time-and energy consuming.…”

Biosynthesis of Zinc Oxide Nanoparticles from Acacia nilotica (L.) Extract to Overcome Carbapenem-Resistant Klebsiella Pneumoniae

“…H and E was used to stain the tissues collected from the wound areas and morphological and histological assessments [ 41 , 42 , 43 , 44 , 45 ]. Tissue sections were checked under a light microscope (Nikon, Eclipse i80), and images were taken at different magnifications using a Nikon mounted digital camera (OXM 1200C; Nikon, Japan).…”

<p>Potential of Nanoparticles as Permeation Enhancers and Targeted Delivery Options for Skin: Advantages and Disadvantages</p>

“…The most important advantages of chitosan nanoparticles are biocompatibility, low toxicity, and low immunogenicity. 87 The most common technique used for • Production from pure active pharmaceuticals 84 • Avoidance of the use of organic solvents 84 • Increment of saturation solubility and the concentration gradient of active pharmaceuticals from nanocrystal formulation to skin layers 84 • Enhancement of drug dissolution rate 82,84 • High surface adhesion properties 79,84 • Increment of skin bioactivity 84 • Increase in skin permeation 84 • Excellent skin retention of active pharmaceuticals 85 • Potential trans-dermal drug delivery properties 85 • High (100%) drug loading 77 • Long-term physicochemical stability 77 • Reducing the need for surfactants in nanoformulations 77 • Safe in topical applications 77 • Ease of formulation manufacturing process 77 • Enhancement of drug bioavailability 77 • Aesthetically pleasant topical sensation 77 • Improvement of dose proportionality 77 • Ease of process scale-up 77 • The possibility of agglomeration and flocculation of nanocrystals 85 • The faster skin penetration rate in comparison to conventional and other topical nanoparticulate formulations 82 • The need for more frequent dose administration 82 • Enhancing the risk of systemic absorption and systemic adverse reactions 82 • Not suitable for water-soluble drugs 79 polymeric nanoparticle preparation is the nanoprecipitation method. Other less useful methods are in situ polymerization, emulsification diffusion, solvent extraction, and salting-out technique.…”