Nose-to-Brain Delivery by Nanosuspensions-Based in situ Gel for Breviscapine

Abstract

Purpose Nose-to-brain drug delivery is an effective approach for poorly soluble drugs to bypass the blood–brain barrier. A new drug intranasal delivery system, a nanosuspension-based in situ gel, was developed and evaluated to improve the solubility and bioavailability of the drug and to prolong its retention time in the nasal cavity. Materials and Methods Breviscapine (BRE) was chosen as the model drug. BRE nanosuspensions (BRE-NS) were converted into BRE nanosuspension powders (BRE-NP). A BRE nanosuspension in situ gelling system (BRE-NG) was prepared by mixing BRE-NP and 0.5% gellan gum (m/v). First, the BRE-NP were evaluated in terms of particle size and by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Subsequently, the critical ionic concentration of the gellan gum phase transition, influence of the deacetylated gellan gum (DGG) concentration on the expansion coefficient (S%), water-holding capacity, rheological properties and in vitro release behaviour of the BRE-NG were investigated. The pharmacokinetics and brain distribution of the BRE-NG after intranasal administration were compared with those of the intravenously injected BRE-NP nanosuspensions in rats. Results The rheology results demonstrated that BRE-NG was a non-Newtonian fluid with good spreadability and bioadhesion performance. Moreover, the absolute bioavailability estimated for BRE-NG after intranasal administration was 57.12%. The drug targeting efficiency (DTE%) of BRE in the cerebrum, cerebellum and olfactory bulb was 4006, 999 and 3290, respectively. The nose-to-brain direct transport percentage (DTP%) of the cerebrum, cerebellum and olfactory bulb was 0.975, 0.950 and 0.970, respectively. Conclusion It was concluded that the in situ gel significantly increased the drug retention time at the administration site. Therefore, the nanosuspension-based in situ gel could be a convenient and effective intranasal formulation for the administration of BRE.

Polymeric long-acting drug delivery systems (LADDS) for treatment of chronic diseases: Inserts, patches, wafers, and implants

“…The use of the intranasal route to bypass the bloodbrain-barrier and deliver drugs directly to the central nervous system (CNS) is indeed of interest. Deacetylated gellan gum has been used to enhance intranasal retention of a nano-suspension of Breviscapine, a flavonoid glycoside used mainly as an anticoagulant [14]. Gellan gum is also used in delivering Flibanserin loaded nanostructured lipid carriers via the intranasal route to the brain [15].…”

“…Other polymer combinations used in the formulation of in situ gelling systems for intranasal administration include poloxamer 407/poloxamer 108 [16], poloxamer/chitosan, carbopol/hydroxypropyl methylcellulose/alginate [17], carboxymethyl chitosan/starch [18], deacetylated gellan gum/hydroxy propyl methylcellulose [19] and methylcellulose [20]. It is worthwhile noting that other strategies to enhance drug permeability across the nasal mucosa, such as the use of cyclodextrins [21] and nano structured carriers [14,15] have been reported.…”

“…Such systems abolish the need for frequent glucose monitoring and dose adjustment by patients. Yu et al [14] developed a glucose-responsive microneedle (GR-MN) patch with the use of phenylboronic acid as the glucose sensitizing element. This patch was evaluated in vivo using an Streptozotocin (STZ)-induced diabetic mouse model and an Streptozotocin-induced diabetic model.…”

High-Payload Nanosuspension of Centella asiatica Extract for Improved Skin Delivery with No Irritation

“…To provide sink condition with adequate solubility for AS, AA, and MA, 1% (w/v) of sodium lauryl sulfate (SLS) was added to 10 mM phosphate buffer. The dissolution media (1 mL) was withdrawn by syringe and replaced with equal volume of pre-warmed dissolution media at predetermined times (15,30,45,60,120, and 240 min). Withdrawn samples were centrifuged at 13,000 rpm for 5 min, removing undissolved materials including the drug nanocrystals.…”

“…26,27 Moreover, the increased dissolution rate and saturation solubility intensifies the concentration gradient between the biological membranes including stratum corneum and topical preparation, subsequently allowing higher penetration into skin layers. [28][29][30] Moreover, an increase in the particle curvature with a crystal size below 500 nm facilitates the penetration of intact drug particles into the skin through the hair follicles and its subsequent absorption by the surrounding follicular epithelium. 31 Particularly, nanosuspension system allows high drug-loading in topical preparation by dispersing the insoluble compound in solid state with minimal use of suspending agent, rather than in dissolved state in continuous phase.…”