Biological Evaluation of Medical Devices in the Form of Suppositories for Rectal and Vaginal Use
Keywords:medical devices, rectal suppositories, vaginal suppositories, antibacterial suppositories, cytotoxicity, sensitizing effects, irritating effects
Background. Programs of preclinical safety studies of the health care products depend on the regulatory status of the investigated products. The classification of such products, in particular suppositories for rectal and vaginal use, is a critical step of developing tactics for their biological evaluation. Adaptation of biological evaluation methods for the medical devices based on the combination of biologically active substances, as well as evaluation of the results of such studies is urgent task of biomedicine.
Objective. To substantiate the regulatory status and to carry out a biological evaluation of medical devices in the form of vaginal suppositories based on octenidine dihydrochloride ("Prodexyn") and in the form of rectal suppositories based on Saw palmetto, Levisticum officinale and Calendula officinalis extracts ("Pravenor").
Methods. Biological evaluation was conducted according to the requirements of ISO 10993 standards using in vitro and in vivo biological test systems (cytotoxicity in cell culture and the MTT test, sensitizing and irritating effect in guinea pigs).
Results. The cytotoxicity (СС50) of the medical device "Prodexyn" extract in Vero cell culture was 8.35 μg/ml calculated as octenidine dihydrochloride and 416.65 μg/ml calculated as dexpanthenol. "Pravenor" medical device was found to be non-toxic in Vero cell culture. According to the results of MMT assay CC50 for octenidine dihydrochloride was 1.67 μg/ml, and 83.33 μg/ml – for dexpanthenol. CC50 indicators calculated for the different active ingredients of the medical device "Pravenor" were the following: 50 mg/ml for the dwarf palm berries extract (Saw palmetto), 16.67 mg/ml for the lovage roots extract (Levisticum officinale), and 16.67 mg/ml for the calendula flowers extract (Calendula officinalis). No sensitizing or skin irritating effects were observed in guinea pigs.
Conclusions. Biological evaluation of medical devices in the form of rectal suppositories "Pravenor" and vaginal suppositories "Prodexyn" performed using in vitro and in vivo biological systems. It was demonstrated an acceptable level of safety of the products. The MTT test was 5 times more sensitive than the Vero cell culture method in determination of cytotoxicity.
Tretiakova A.M. The role and place of medical technologies in modern healthcare systems. Med Technol Assess Choice. 2011;4:48-52.
Peter L, Hajek L, Maresova P, Augustynek M, Penhaker M. Medical devices: regulation, risk classification, and open innovation. J Open Innov Technol Market Complex. 2020;6(2):42. DOI: 10.3390/joitmc6020042
Green J. Medical device legislation for custom-made devices after the UK has left the EU: answers to ten important ques-tions. Br Dent J. 2021 Oct;231(8):513-521. DOI: 10.1038/s41415-021-3530-x
Onkar B, Krishan P, Singh G. Regulatory requirements for medical devices: an insight. Appl Clin Res Clin Trials Regul Affairs. 2017;4(1). DOI: 10.2174/2213476X03666160804153513
Parvizi N, Woods K. Regulation of medicines and medical devices: contrasts and similarities. Clin Med (Lond). 2014 Feb;14(1):6-12. DOI: 10.7861/clinmedicine.14-1-6
Godlee F. Why aren't medical devices regulated like drugs? BMJ. 2018;363:k5032. DOI: 10.1136/bmj.k5032
Kramer DB, Tan YT, Sato C, Kesselheim AS. Ensuring medical device effectiveness and safety: a cross-national comparison of approaches to regulation. Food Drug Law J. 2014;69(1):1-i.
Miclăuş T, Valla V, Koukoura A, Nielsen AA, Dahlerup B, Tsianos GI, et al. Impact of design on medical device safety. Ther Innov Regul Sci. 2020 Jul;54(4):839-49. DOI: 10.1007/s43441-019-00022-4
Palojoki S, Saranto K, Lehtonen L. Reporting medical device safety incidents to regulatory authorities: An analysis and classification of technology-induced errors. Health Informatics J. 2017 Sep;25(3):731-40. DOI: 10.1177/1460458217720400
Geavlete P, Multescu R, Geavlete B. Serenoa repens extract in the treatment of benign prostatic hyperplasia. Ther Adv Urol. 2011;3(4):193-8. DOI: 10.1177/1756287211418725
Spréa RM, Fernandes Â, Finimundy TC, Pereira C, Alves MJ, Calhelha RC, et al. Lovage (Levisticum officinale W.D.J. Koch) roots: a source of bioactive compounds towards a circular economy. Resources. 2020;9(7):81. DOI: 10.3390/resources9070081
Ashwlayan VD, Kumar A, Verma M, Garg VK, Gupta SK. Therapeutic potential of Calendula officinalis. Pharm Pharmacol Int J. 2018;6(2):149-55. DOI: 10.15406/ppij.2018.06.00171
Stahl J, Braun M, Siebert J, Kietzmann M. The effect of a combination of 0.1% octenidine dihydrochloride and 2% 2-phenoxyethanol (octenisept) on wound healing in pigs in vivo and its in vitro percutaneous permeation through intact and barrier disrupted porcine skin. Int Wound J. 2010 Feb;7(1):62-9. DOI: 10.1111/j.1742-481X.2009.00648.x
Stahl J, Braun M, Siebert J, Kietzmann M. The percutaneous permeation of a combination of 0.1% octenidine dihydro-chloride and 2% 2-phenoxyethanol (octenisept®) through skin of different species in vitro. BMC Vet Res. 2011 Aug 11;7(1):44. DOI: 10.1186/1746-6148-7-44
Proksch E, de Bony R, Trapp S, Boudon S. Topical use of dexpanthenol: a 70th anniversary article. J Dermatolog Treat. 2017 Dec;28(8):766-773. DOI: 10.1080/09546634.2017.1325310
Gorski J, Proksch E, Baron JM, Schmid D, Zhang L. Dexpanthenol in wound healing after medical and cosmetic interventions (postprocedure wound healing). Pharmaceuticals (Basel). 2020 Jun 29;13(7):138. DOI: 10.3390/ph13070138
Stern AD. Innovation under regulatory uncertainty: evidence from medical technology. J Public Econ. 2017 Jan;145:181-200. DOI: 10.1016/j.jpubeco.2016.11.010
Kramer DB, Xu S, Kesselheim AS. How does medical device regulation perform in the united states and the european union? A systematic review. PLoS Med. 2012;9(7):e1001276. DOI: 10.1371/journal.pmed.1001276
Van Norman GA. Drugs and devices: comparison of European and U.S. Approval processes. JACC Basic Transl Sci. 2016 Aug 29;1(5):399-412. DOI: 10.1016/j.jacbts.2016.06.003
Van Norman GA. Drugs, devices, and the FDA: Part 1: An overview of approval processes for drugs. JACC Basic Transl Sci. 2016 Apr 25;1(3):170-9. DOI: 10.1016/j.jacbts.2016.03.002
Van Norman GA. Drugs, devices, and the FDA: Part 2: An overview of approval processes: FDA approval of medical devices. JACC Basic Transl Sci. 2016 Jun 27;1(4):277-87. DOI: 10.1016/j.jacbts.2016.03.009
Tian J, Song X, Wang Y, Cheng M, Lu S, Xu W, et al. Regulatory perspectives of combination products. Bioact Mater. 2022 Sep 7;10:492-503. DOI: 10.1016/j.bioactmat.2021.09.002
Contardi M. Changes in the medical device's regulatory framework and its impact on the medical device's industry: from the medical device directives to the medical device regulations. Erasmus Law Rev. 2019;12(2):166-77. DOI: 10.5553/ELR.000139
Di Pierro F, Di Paola G, Risso P. Role of a medical device for intra-vaginal use in improving the quality of the colposcopic examination and the anatomical/pathological reading of the cytological test and biopsy. Acta Biomed. 2014 Aug 20;85(2):121-6.
Plummer EL, Bradshaw CS, Doyle M, Fairley CK, Murray GL, Bateson D, et al. Lactic acid-containing products for bacterial vaginosis and their impact on the vaginal microbiota: A systematic review. PLoS One. 2021 Feb 11;16(2):e0246953. DOI: 10.1371/journal.pone.0246953
Papa R, Troncone M, Altruda F, Rullo V, Saponati G. Clinical evaluation of the efficacy and safety of a medical vaginal device containing rigenase® for the treatment of vaginosis: a randomized study. J Clin Gynecol Obstetr. 2017;6(1):6-11. DOI: 10.14740/jcgo424w
Montanino Oliva M, Poverini R, Lisi R, Carra MC, Lisi F. Treating woman with myo-inositol vaginal suppositories improves partner's sperm motility and fertility. Int J Endocrinol. 2016;2016:7621942. DOI: 10.1155/2016/7621942
Ham AS, Buckheit RW Jr. Designing and developing suppository formulations for anti-HIV drug delivery. Ther Deliv. 2017;8(9):805-17. DOI: 10.4155/tde-2017-0056
Sibona M, Destefanis P, Agnello M, Lillaz B, Giuliano M, Cai T, et al. The association of Boswellia resin extract and propolis derived polyphenols can improve quality of life in patients affected by prostatitis-like symptoms. Arch Ital Urol Androl. 2020 Jan 14;91(4):251-5. DOI: 10.4081/aiua.2019.4.251
Montrone S, Gonnelli A, Cantarella M, Sainato A. Use of Proktis-M suppositories in patients undergoing neoadjuvant radiochemotherapy for adenocarcinoma of the rectum. Minerva Gastroenterol Dietol. 2015;61(4):293-7.
Maresova P, Rezny L, Peter L, Hajek L and Lefley F. Do regulatory changes seriously affect the medical devices industry? Evidence from the Czech Republic. Front Public Health. 2021 Apr;9:666453. DOI: 10.3389/fpubh.2021.666453
Jenull S, Hojdar K, Laggner H, Velimirov B, Zemann N, Huettinger M. Cell growth and migration under octenidine-antiseptic treatment. J Wound Care. 2015;24(6):280-8. DOI: 10.12968/jowc.2015.24.6.280
Schmidt J, Zyba V, Jung K, Rinke S, Haak R, Mausberg RF, et al. Cytotoxic effects of octenidine mouth rinse on human fibroblasts and epithelial cells - an in vitro study. Drug Chem Toxicol. 2016;39(3):322-30. DOI: 10.3109/01480545.2015.1121274
Proksch E, Berardesca E, Misery L, Engblom J, Bouwstra J. Dry skin management: practical approach in light of latest research on skin structure and function. J Dermatolog Treat. 2020 Nov;31(7):716-22. DOI: 10.1080/09546634.2019.1607024
Klöcker N, Rudolph P, Verse T. Evaluation of protective and therapeutic effects of dexpanthenol on nasal decongestants and preservatives: results of cytotoxic studies in vitro. Am J Rhinol. 2004;18(5):315-20.
Klöcker N, Verse T, Rudolph P. The protective effect of dexpanthenol in nasal sprays. First results of cytotoxic and ciliary-toxic studies in vitro. Laryngorhinootologie. 2003;82(3):177-82. DOI: 10.1055/s-2003-38406
Iguchi K, Okumura N, Usui S, Sajiki H, Hirota K, Hirano K. Myristoleic acid, a cytotoxic component in the extract from Serenoa repens, induces apoptosis and necrosis in human prostatic LNCaP cells. Prostate. 2001;47(1):59-65. DOI: 10.1002/pros.1047
Shimada H, Tyler VE, McLaughlin JL. Biologically active acylglycerides from the berries of saw-palmetto (Serenoa repens). J Nat Prod. 1997;60(4):417-8. DOI: 10.1021/np960552o
Sertel S, Eichhorn T, Plinkert PK, Efferth T. Chemical composition and antiproliferative activity of essential oil from the leaves of a medicinal herb, Levisticum officinale, against UMSCC1 head and neck squamous carcinoma cells. Anticancer Res. 2011;31(1):185-91.
Sargazi S, Saravani R, Galavi H, Mollashahee-Kohkan F. Effect of Levisticum officinale hydroalcoholic extract on DU-145 and PC-3 prostate cancer cell lines, gene cell tissue. 2017; 4(4):e66094. DOI: 10.5812/gct.66094
Cruceriu D, Diaconeasa Z, Socaci S, Socaciu C, Rakosy-Tican E, Balacescu O. Biochemical profile, selective cytotoxicity and molecular effects of Calendula officinalis extracts on breast cancer cell lines. Notulae Botanicae Horti Agrobotanici Cluj-Napoca. 2020;48(1):24-39. DOI: 10.15835/nbha48111778
Jiménez-Medina E, Garcia-Lora A, Paco L, Algarra I, Collado A, Garrido F. A new extract of the plant calendula officinalis produces a dual in vitroeffect: cytotoxic anti-tumor activity and lymphocyte activation. BMC Cancer. 2006 May 5;6(1):119. DOI: 10.1186/1471-2407-6-119
How to Cite
Copyright (c) 2021 The autror(s)
This work is licensed under a Creative Commons Attribution 4.0 International License.
The ownership of copyright remains with the Authors.
Authors may use their own material in other publications provided that the Journal is acknowledged as the original place of publication and National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute” as the Publisher.
Authors are reminded that it is their responsibility to comply with copyright laws. It is essential to ensure that no part of the text or illustrations have appeared or are due to appear in other publications, without prior permission from the copyright holder.IBB articles are published under Creative Commons licence:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under CC BY 4.0 that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.