Wound-healing effect of topical nanoemulsion-loaded cream and gel formulations of Hippophae rhamnoides L. (sea buckthorn) fruit oil and their acute dermal toxicity study on female SD rats.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of topical nanoemulsion (NE)-loaded cream and gel formulations of Hippophae rhamnoides L. (sea buckthorn [SBT]) fruit oil for wound healing. MATERIALS AND METHODS: The NE-loaded cream and gel formulations of H. rhamnoides L. (SBT) fruit oil (IPHRFH) were prepared and evaluated for their wound-healing activity on female Sprague-Dawley (SD) rats. They were further divided into groups (seven) and the wound-healing activity was determined by measuring the area of the wound on the wounding day and on the 0th, 4th, 8th, and 10th days. The acute dermal toxicity of the formulations was assessed by observing the erythema, edema, and body weight (BW) of the rats. RESULTS: The topical NE cream and gel formulations of H. rhamnoides L. (SBT) fruit oil showed significant wound-healing activity in female SD rats. The cream formulation of IPHRFH showed 78.96%, the gel showed 72.59% wound contraction on the 8th day, whereas the positive control soframycin (1% w/w framycetin) had 62.29% wound contraction on the 8th day. The formulations also showed a good acute dermal toxicity profile with no changes significantly affecting BW and dermal alterations. CONCLUSIONS: The results of this study indicate that topical NE-loaded cream and gel formulation of H. rhamnoides L. (SBT) fruit oil are safe and effective for wound healing. The formulations showed no signs of acute dermal toxicity in female SD rats.

Nanocrystal-based gel of apremilast ameliorates imiquimod-induced psoriasis by suppressing inflammatory responses.

Apremilast is 'difficult-to-deliver' in stratum corneum and viable layers (viable epidermis, dermis) owing to its modest lipophilicity and poor aqueous solubility, respectively. The objective of the present research was to develop apremilast nanocrystal-based gel for enhanced anti-psoriatic efficacy for the treatment of psoriasis. Nanosuspension was generated by wet media milling with a mean particle size of 200 nm. In-vivoefficacy of nanocrystal-based gels was evaluated in the imiquimod-induced psoriatic plaque model. Nanocrystal-based gel (1% and 3% w/w) improved phenotypic, histopathological features of psoriatic skin and attenuated splenic hypertrophy, psoriasis area severity scoring. Enzyme-linked immunosorbent assay was performed to evaluate levels of psoriatic biochemical markers indicating a significant decrease in the concentration of cytokines such as IL-23, IL-17A, IL-6 and TNF-α by nanocrystal-based gels (1% and 3% w/w) over disease induced group. Skin irritation study revealed that nanocrystal-based gel was significantly less irritating than the positive control. These results suggest that nanocrystal-based gel of apremilast can be an effective strategy for the management of psoriasis.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Preparation and Characterization of Co-Processed Mannitol and Sorbitol Using NanoCrySP Technology.

Particle engineering of excipients, at sub-particulate level using co-processing, can provide high functionality excipients. NanoCrySP technology has been recently explored as a novel approach for the generation of nanocrystalline solid dispersion of poorly soluble drugs, using spray drying process. The purpose of the present study was to generate co-processed mannitol and sorbitol (SD-CSM) using NanoCrySP technology having similar composition to commercial co-processed excipient (Compressol® SM, CP). The characterization of excipients was performed to evaluate their various physicomechanical properties. The sub-micron crystallite size of sorbitol in the matrix of mannitol was determined using the Williamson-Hall equation and Halder-Wagner equation. The reduction in crystallite size of sorbitol and mannitol, lower melting point, and lower heat of fusion of SD-CSM could be responsible for excellent compactibility, better tabletability, and comparable compressibility with respect to CP. This was confirmed by the compressibility-tabletability-compactibility (CTC) profile and Heckel plot analysis. Overall, SD-CSM generated using NanoCrySP technology improved functionalities of excipients over CP and would be useful for direct compression application.

Pharmaceutical nanocrystals: A promising approach for improved topical drug delivery.

The barrier function of skin and the non-optimal physicochemical properties of drugs present challenges to the skin penetration of many drugs, thus motivating the development of novel drug delivery systems. Recently, nanocrystal-based formulations have been investigated for topical drug delivery and have demonstrated improved skin penetration. This review highlights barriers in skin penetration, current techniques to improve topical delivery and application of nanocrystals in conquering obstacles for topical delivery. Nanocrystals can improve delivery through the skin by mechanisms including the creation of a higher concentration gradient across skin resulting in increased passive diffusion, hair follicle targeting, formation of diffusional corona, and adhesion to skin. The recent research would be of interest for formulation scientists seeking to develop products involving molecules that are 'difficult-to-deliver' topically.

Co-processing of small molecule excipients with polymers to improve functionality.

INTRODUCTION: Polymers have various applications such as binder, film coating agent, stabilizer, drug release modification, and as primary packaging materials. Recently, they have been explored in co-processing technique to improve the functionality of small molecule excipients (SMEs). Co-processing is a concept wherein two or more excipients interact at sub-particle level to provide synergy in functionality and minimize drawbacks of individual excipients. AREA COVERED: The present review highlights the application of co-processing to improve the functionality of SMEs using polymers; physicochemical and mechanical properties of polymers for co-processing; advantages of co-processed excipients for different applications; functionality enhancement of co-processed excipients; novel concepts/methods for co-processing; mechanistic insights on co-processing and commercial products available in the market. EXPERT OPINION: Most of the SMEs do not possess optimal multifunctional properties like flow, compressibility, compactibility, and disintegration ability, required to compensate for poorly compactable drugs. Some of these drawbacks can be overcome by co-processing of SMEs with polymers. For example, co-processing of a brittle SME and plastic material (polymer) can provide a synergistic effect and result in the generation of single entity multi-functional excipient. Besides, novel co-processed excipients generated using combinations of SMEs and polymers can also generate intellectual property rights.

Novel nanocrystal-based formulations of apremilast for improved topical delivery.

Nanocrystals can enhance skin penetration of drug by increased saturation solubility, dissolution rate and adhesion on the skin. Apremilast is 'difficult-to-deliver' in viable layers (epidermis, dermis) and stratum corneum (SC) owing to its poor aqueous solubility and modest lipophilicity, respectively. Apremilast is currently available as oral tablet formulation for the indication of psoriasis but its effectiveness is limited by systemic side effects. Therefore, the present study aimed to develop novel nanocrystal-based formulations of apremilast for improved topical delivery. Nanosuspension was prepared using wet media milling and exhibited a mean particle size of 200 nm. The saturation solubility of nanocrystals was improved by 2-fold than micronized apremilast and showed significant advantage during dissolution study. Nanosuspension and micronized apremilast was incorporated into gel and cream and characterized for rheological properties. Skin permeation and ex vivo dermatokinetic study of topical formulations were performed on pig ear skin at a dose of 1% w/w using Franz diffusion cells. Skin permeation studies indicated that non-detectable amount of apremilast permeated through pig ear skin during exposure of formulations. Nanosuspension showed 2.6- and 3.2-fold drug penetration in SC and viable layers, respectively, over microsuspension. Nanogel showed 2.7- and 2.4-fold drug penetration in SC and viable layers, respectively, over microgel. Nanocream showed 1.2- and 2.8-fold drug penetration in SC and viable layers, respectively, over microcream. Thus, nanocrystal-based formulations of apremilast aid in selective delivery into viable layers by crossing the SC barrier. This is of paramount importance in enhancing therapeutic effectiveness utilizing localized delivery and provides an alternative delivery approach for the treatment of psoriasis. Graphical abstract.