{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:59:55Z","timestamp":1778029195954,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T00:00:00Z","timestamp":1646438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Epidermolysis bullosa is a genetically heterogenous skin fragility disorder with multiorgan involvement appearing already in newborn children. Severe progressive fibrosis follows skin blistering, mucosa lesions, and wound healing, favouring development of highly aggressive squamous cell carcinomas. Losartan potassium (LP) has been described to show positive effects; therefore, it was of clinical interest to develop 2 mm mini-tablets with LP for treatment of the affected children. Several challenges emerged during development: limited flowability and sticking to punches were observed in the first tableting experiments due to a high drug load, and a bitter taste of the LP was reported. Sticking to punches was reduced by using SMCC 50 and a combination of different lubricants; however, direct compression trials on a Korsch XM 12 rotary press were not successful due to compaction phenomena in the hopper. Thus, an intermediate dry granulation was successfully introduced. Two final formulations of the mini-tablets complied with the requirements of the European Pharmacopoeia regarding disintegration times (&lt;15 min) and friability (&lt;1.0%); mean tensile strengths amounted to about 1 MPa as a compromise between manufacturability and sufficient mechanical strength for further coating studies. The subsequent coating step succeeded delaying the initial drug release for more than 2 min. An acceptance value \u226415 was matched for the coated mini-tablets, and stability studies showed a promising shelf life.<\/jats:p>","DOI":"10.3390\/pharmaceutics14030570","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:40:02Z","timestamp":1646599202000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pharmaceutical Development of Film-Coated Mini-Tablets with Losartan Potassium for Epidermolysis Bullosa"],"prefix":"10.3390","volume":"14","author":[{"given":"Valentin\u00eb","family":"Elezaj","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ard","family":"Lura","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Canha","sequence":"additional","affiliation":[{"name":"Midas Pharma GmbH, 55218 Ingelheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3982-9823","authenticated-orcid":false,"given":"J\u00f6rg","family":"Breitkreutz","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, 40225 D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,5]]},"reference":[{"key":"ref_1","unstructured":"European Parliament and Council (2021, December 08). REGULATION (EC) No 1901\/2006 (12 December 2006) on Medicinal Products for Paediatric Use and Amending Regulation (EEC) No 1768\/92, Directive 2001\/20\/EC, Directive 2001\/83\/EC and Regulation (EC) No 726\/2004. Available online: https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/PDF\/?uri=CELEX:32006R1901&from=EN."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1016\/j.clinthera.2008.11.016","article-title":"European perspectives on pediatric formulations","volume":"30","author":"Breitkreutz","year":"2008","journal-title":"Clin. Ther."},{"key":"ref_3","unstructured":"WHO (2021, December 06). Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children. Available online: https:\/\/www.who.int\/selection_medicines\/committees\/expert\/17\/application\/paediatric\/Dosage_form_reportDEC2008.pdf?ua=1."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.xphs.2018.11.013","article-title":"Pediatric Oral Formulations: An Updated Review of Commercially Available Pediatric Oral Formulations Since 2007","volume":"108","author":"Strickley","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.4038\/cmj.v61i3.8340","article-title":"Time to change the paradigm of children\u2019s medicines from liquid formulations to flexible solid oral dosage forms","volume":"61","author":"Hoppu","year":"2016","journal-title":"Ceylon Med. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s13023-018-0944-x","article-title":"Mapping health care of rare diseases: The example of epidermolysis bullosa in Germany","volume":"13","author":"Reimer","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.matbio.2016.07.009","article-title":"Molecular pathology of the basement membrane zone in heritable blistering diseases: The paradigm of epidermolysis bullosa","volume":"57\u201358","author":"Uitto","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_8","first-page":"547","article-title":"Injury- and inflammation-driven skin fibrosis: The paradigm of epidermolysis bullosa","volume":"68\u201369","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s40291-020-00466-7","article-title":"Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020","volume":"24","author":"Has","year":"2020","journal-title":"Mol. Diagn. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.jid.2015.10.050","article-title":"Progress toward Treatment and Cure of Epidermolysis Bullosa: Summary of the DEBRA International Research Symposium EB2015","volume":"136","author":"Uitto","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.jid.2017.12.016","article-title":"EB2017-Progress in Epidermolysis Bullosa Research toward Treatment and Cure","volume":"138","author":"Uitto","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"244","DOI":"10.4103\/idoj.IDOJ_287_18","article-title":"Newer Treatment Modalities in Epidermolysis Bullosa","volume":"10","year":"2019","journal-title":"Indian Dermatol. Online J."},{"key":"ref_13","unstructured":"Kiritsi, D., Stiller, B., Nystroem, K.A., and Bruckner-Tuderman, L.K. (2021). Use of Losartan for the Treatment of Fibrotic Diseases, in Particular Epidermolysis Bullosa. (EP 3 842 099 A1), Patent."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.15252\/emmm.201505061","article-title":"Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms","volume":"7","author":"Thriene","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.12688\/f1000research.14974.1","article-title":"Recent advances in understanding and managing epidermolysis bullosa","volume":"7","author":"Kiritsi","year":"2018","journal-title":"F1000Research"},{"key":"ref_16","first-page":"100061","article-title":"Tableting of mini-tablets in comparison with conventionally sized tablets: A comparison of tableting properties and tablet dimensions","volume":"2","author":"Lura","year":"2020","journal-title":"Int. J. Pharm. X"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0378-5173(98)00206-3","article-title":"Minitabletting: Improving the compactability of paracetamol powder mixtures","volume":"173","author":"Lennartz","year":"1998","journal-title":"Int. J. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.jpeds.2013.07.014","article-title":"Favorable acceptance of mini-tablets compared with syrup: A randomized controlled trial in infants and preschool children","volume":"163","author":"Klingmann","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.jpeds.2015.07.010","article-title":"Acceptability of Uncoated Mini-Tablets in Neonates\u2013A Randomized Controlled Trial","volume":"167","author":"Klingmann","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jpeds.2018.05.031","article-title":"Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial","volume":"201","author":"Klingmann","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_21","unstructured":"Klingmann, V., Hinder, M., Langenickel, T., Chen, F., Khder, Y., Breitkreutz, J., and Bosse, H.M. (2021). Acceptability of multiple coated mini-tablet in comparison to syrup in infants and toddlers: A randomized controlled study. Pharmaceutics, submitted for publication."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119571","DOI":"10.1016\/j.ijpharm.2020.119571","article-title":"Development of low dose micro-tablets by high shear wet granulation process","volume":"587","author":"Gupta","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"118905","DOI":"10.1016\/j.ijpharm.2019.118905","article-title":"Decoding the small size challenges of mini-tablets for enhanced dose flexibility and micro-dosing","volume":"574","author":"Mitra","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3109\/10837450.2014.954728","article-title":"A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms","volume":"20","author":"Leane","year":"2015","journal-title":"Pharm. Dev. Technol."},{"key":"ref_25","unstructured":"EDQM (2020). 2.9.34 Bulk Density and Tapped Density of Powders. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_26","unstructured":"EDQM (2020). 2.9.36 Powder flow. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_27","unstructured":"EDQM (2020). 2.9.1 Disintegration of tablets and capsules. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_28","unstructured":"Kleinebudde, P. (1997). Pharmazeutische Pellets durch Extrudieren\/Sph\u00e4ronisieren: Herstellung, Eigenschaften, Modifizierung. [Ph.D. Thesis, University of Kiel]."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/jps.2600590523","article-title":"Determination of tablet strength by the diametral-compression test","volume":"59","author":"Fell","year":"1970","journal-title":"J. Pharm. Sci."},{"key":"ref_30","unstructured":"EDQM (2020). 2.9.7 Friability of uncoated tablets. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_31","unstructured":"EDQM (2020). 2.9.40 Uniformity of dosage units. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_32","unstructured":"EDQM (2020). Losartan potassium. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_33","unstructured":"EDQM (2020). 2.9.25 Dissolution test for medicated chewing gums. European Pharmacopeia, EDQM. [10th ed.]."},{"key":"ref_34","unstructured":"United States Pharmacopeial Convention (2016). Losartan Tablets. USP 39, The United States Pharmacopeial Convention."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1248\/cpb.58.1565","article-title":"Influence of compression pressure and velocity on tablet sticking","volume":"58","author":"Kakimi","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1248\/cpb.45.706","article-title":"Effect of Water Content on Sticking during Compression","volume":"45","author":"Danjo","year":"1997","journal-title":"Chem. Pharm. Bull."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1016\/j.xphs.2018.04.029","article-title":"Sticking and Picking in Pharmaceutical Tablet Compression: An IQ Consortium Review","volume":"107","author":"Chattoraj","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_38","unstructured":"Lloret Perez, S. (2007). Formulations Containing Losartan and\/or Its Salts. (WO 2007\/026261 A2), Patent."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1080\/03639040902774131","article-title":"Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: A case study","volume":"35","author":"Aljaberi","year":"2009","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_40","unstructured":"JRS Pharma (2021, December 06). PROSOLV SMCC\u2013High Functionality Excipient. Company\u2019s Brochure. Available online: https:\/\/www.jrspharma.com\/pharma-wAssets\/docs\/brochures\/prosolv-smcc_gb_1809.pdf."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ijpharm.2011.06.027","article-title":"Development of mini-tablets with 1 mm and 2 mm diameter","volume":"416","author":"Tissen","year":"2011","journal-title":"Int. J. Pharm"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1002\/jps.10403","article-title":"Tensile strength and disintegration of tableted silicified microcrystalline cellulose: Influences of interparticle bonding","volume":"92","author":"Kachrimanis","year":"2003","journal-title":"J. Pharm. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ejpb.2004.05.009","article-title":"Compaction mechanism and tablet strength of unlubricated and lubricated (silicified) microcrystalline cellulose","volume":"59","author":"Bolhuis","year":"2005","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_44","first-page":"76","article-title":"A review of co-processed directly compressible excipients","volume":"8","author":"Gohel","year":"2005","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/10837450500464255","article-title":"Excipients for direct compaction\u2014An update","volume":"11","author":"Bolhuis","year":"2006","journal-title":"Pharm. Dev. Technol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"W\u00fcnsch, I., Friesen, I., Puckhaber, D., Schlegel, T., and Finke, J.H. (2020). Scaling Tableting Processes from Compaction Simulator to Rotary Presses-Mind the Sub-Processes. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12040310"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1023\/A:1018973530443","article-title":"A spectroscopic investigation of losartan polymorphs","volume":"10","author":"Raghavan","year":"1993","journal-title":"Pharm. 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