AKVANO®: A Novel Lipid Formulation System for Topical Drug Delivery-In Vitro Studies

Jan Holmbäck, Vibhu Rinwa, Tobias Halthur, Puneet Rinwa, Anders Carlsson, Bengt Herslöf, Jan Holmbäck, Vibhu Rinwa, Tobias Halthur, Puneet Rinwa, Anders Carlsson, Bengt Herslöf

Abstract

A novel formulation technology called AKVANO® has been developed with the aim to provide a tuneable and versatile drug delivery system for topical administration. The vehicle is based on a water-free lipid formulation where selected lipids, mainly phospholipids rich in phosphatidylcholine, are dissolved in a volatile solvent, such as ethanol. With the aim of describing the basic properties of the system, the following physicochemical methods were used: viscometry, dynamic light scattering, NMR diffusometry, and atomic force microscopy. AKVANO formulations are non-viscous, with virtually no or very minute aggregates formed, and when applied to the skin, e.g., by spraying, a thin film consisting of lipid bilayer structures is formed. Standardized in vitro microbiological and irritation tests show that AKVANO formulations meet criteria for antibacterial, antifungal, and antiviral activities and, at the same time, are being investigated as a non-irritant to the skin and eye. The ethanol content in AKVANO facilitates incorporation of many active pharmaceutical ingredients (>80 successfully tested) and the phospholipids seem to act as a solubilizer in the formulation. In vitro skin permeation experiments using Strat-M® membranes have shown that AKVANO formulations can be designed to alter the penetration of active ingredients by changing the lipid composition.

Keywords: antibacterial; antifungal; antiviral; atomic force microscopy; in vitro eye irritation; in vitro skin irritation; in vitro skin permeation; phospholipids; physicochemical methods; topical drug delivery.

Conflict of interest statement

J.H., A.C. and B.H. were co-founders of Lipidor AB. J.H., V.R. and P.R. are presently employed by Lipidor AB. T.H. reports no conflict of interest. The sponsor designed, executed and interpreted the in vitro permeation experiments but had no role in the design, execution and interpretation of the other parts of the study.

Figures

Figure 1
Figure 1
Average (triplicates) size distribution of AKVANO formulations based on DMPC (red) and DOPE (green) lipids, without (a) and with (b) additions of water, as measured by DLS measurements.
Figure 2
Figure 2
AFM image of AKV006 (DOPC) scanned at a location with a thin deposited lipid film, where (a) shows the topography data, (b) the amplitude signal, (c) the phase signal, and (d) the topography profile for the two lines drawn in the topography image.
Figure 3
Figure 3
AFM image of AKV006 (DOPC) scanned at a location with “thicker” deposited lipid film, where (a) shows the topography data and (b) the amplitude signal (c) the phase signal, and (d) the topography profile for the two lines drawn in the topography image.
Figure 4
Figure 4
AFM image of AKV007 (DOPE) scanned at a location with a thin deposited lipid film, where (a) shows the topography data and (b) the amplitude signal.
Figure 5
Figure 5
AFM image of AKV007 (DOPE) scanned at a location with “thicker” deposited lipid film, where (a) shows the topography data and (b) the amplitude signal.
Figure 6
Figure 6
Log reduction ± SEM (standard error of mean) of AKVANO skin disinfectant sprays AKV012 and AKV013 compared to reference solution 2-propanol 60% (v/v).
Figure 7
Figure 7
Log reduction of three virus strains by AKVANO skin disinfectant formulations AKV012 and AKV013. Calculations are based on the proportion of ten replicates showing cytopathic effects at a certain dilution level.
Figure 8
Figure 8
Viability of test item AKV011 in comparison with positive and negative controls after in vitro eye irritation test (percentage of negative control ± SEM).
Figure 9
Figure 9
Cumulative permeation of ketoprofen through Strat-M membranes.
Figure 10
Figure 10
Cumulative permeation of diclofenac diethylamine through Strat-M membranes.
Figure 11
Figure 11
Cumulative permeation of diclofenac sodium through Strat-M membranes.

References

    1. Laughlin R.G. The Aqueous Phase Behavior of Surfactants. Academic Press; London, UK: 1994. pp. 42–44.
    1. Carlsson A. Physical Properties of Phospholipids. In: Gunstone F.D., editor. Phospholipid Technology and Applications. Volume 22. The Oily Press; Bridgewater, England: 2008. pp. 95–139.
    1. Evans D.F., Wennerström H. The Colloidal Domain: Where Physics, Chemistry, Biology, and Technology Meet. 2nd ed. Wiley-VCH; New York, NY, USA: 1999. pp. 401–441.
    1. Iwai I., Han H., den Hollander L., Svensson S., Ofverstedt L.-G., Anwar J., Brewer J., Bloksgaard M., Laloeuf A., Nosek D., et al. The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. J. Investig. Dermatol. 2012;132:2215–2225. doi: 10.1038/jid.2012.43.
    1. Stilbs P. Fourier transform pulsed-gradient spin-echo studies of molecular diffusion. Prog. Nucl. Magn. Reason. Spectrosc. 1987;19:1–45. doi: 10.1016/0079-6565(87)80007-9.
    1. Swedish Standard. Chemical Disinfectants and Antiseptics—Hygienic Handrub—Test Method and Requirements (Phase 2/Step 2) BSI; London, UK: 2013.
    1. European Standard. Chemical Disinfectants and Antiseptics—Quantitative Suspension Test for the Ddetermination of Bactericidal Activity in the Medical Field—Test Method and Requirements (Phase 2/Step 1) BSI; London, UK: 2014.
    1. The British Standards. Chemical Disinfectants and Antiseptics—Quantitative Suspension Test for the Evaluation of Fungicidal or Yeasticidal Activity in the Medical Area—Test Method and Requirements (Phase 2, Step 1) BSI; London, UK: 2013.
    1. European Standard. Chemical Disinfectants and Antiseptics—Quantitative Suspension Test for Evaluation of Virucidal Activity—Test Method and Requirements (Phase 2/Step 1) BSI; London, UK: 2015.
    1. Organisation for Economic Co-Operation and Development . Test Guideline No. 439: In Vitro Skin Irritation (Reconstructed Human Epidermis Test Method), Section 4. Organisation for Economic Cooperation and Development; Paris, France: 2015. [(accessed on 2 March 2022)]. Available online: .
    1. MatTek Corporation . In Vitro EpiDerm™ Skin Irritation Test (EPI-200-SIT), for Use with MatTek Corporation’s Reconstrucked Human Epidermal Model EpiDerm™. MatTek Corporation; Ashland, MA, USA: 2014. [(accessed on 2 March 2022)]. pp. 1–35. No. EPI-200-SI. Available online: .
    1. Organisation for Economic Co-Operation and Development . Test Guideline No. 492: Reconstructed Human Cornea-like Epithelium (RhCE) Test Method for Identifying Chemicals Not Requiring Classification and Labelling for Eye Irritation or Serious Eye Damage. OECD; Paris, France: 2015. [(accessed on 2 March 2022)]. Guidelines for the Testing of Chemicals. Available online: .
    1. MatTek Corporation . EpiOcular™ Eye Irritation Test (OCL-200-EIT) for the Prediction of Acute Ocular Irritation of Chemicals for Use with Reconstructed Human EpiOcular Model. MatTek Corporation; Ashland, MA, USA: 2014. [(accessed on 2 March 2022)]. pp. 1–40. No. MK-24-007-0055. Available online: .
    1. Uchida T., Kadhum W.R., Kanai S., Todo H., Oshizaka T., Sugibayashi K. Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-M™. Eur. J. Pharm. Sci. 2015;67:113–118. doi: 10.1016/j.ejps.2014.11.002.
    1. Iadaresta F., Manniello M.D., Östman C., Crescenzi C., Holmbäck J., Russo P. Chemicals from textiles to skin: An in vitro permeation study of benzothiazole. Environ. Sci. Pollut. Res. Int. 2018;25:24629–24638. doi: 10.1007/s11356-018-2448-6.
    1. Lodén M., Åkerström U., Lindahl K., Berne B. Bioequivalence determination of topical ketoprofen using a dermatopharmacokinetic approach and excised skin penetration. Int. J. Pharm. 2004;284:23–30. doi: 10.1016/j.ijpharm.2004.07.018.
    1. Fernández-García R., Lalatsa A., Statts L., Bolás-Fernández F., Ballesteros M.P., Serrano D.R. Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to industrial scale. Int. J. Pharm. 2020;573:118817. doi: 10.1016/j.ijpharm.2019.118817.
    1. Kumar P., Sharma D.K., Ashawat M.S. Development of phospholipids vesicular nanocarrier for topical delivery of tea tree oil in management of atopic dermatitis using BALB/c mice model. Eur. J. Lipid Sci. Technol. 2021;123:1–12. doi: 10.1002/ejlt.202100002.
    1. Kampf G. Efficacy of ethanol against viruses in hand disinfection. J. Hosp. Infect. 2018;98:331–338. doi: 10.1016/j.jhin.2017.08.025.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner