Ali Wasti, A

Carresi, C

Coluccio, M

Di Fabrizio, E

Fini, M

Gliozzi, M

Maiuolo, J

Malara, N

Mollace, R

Mollace, V

Muscoli, C

Musolino, V

Rosano, G

Silvestrini, B

Vitale, C

Vincenzo Mollace

Giuseppe Rosano

Natalia Malara

Enzo Di Fabrizio

Cristiana Vitale

Marialaura Coluccio

Jessica Maiuolo

Ayesha Ali Wasti

Carolina Muscoli

Micaela Gliozzi

Rocco Mollace

Vincenzo Musolino

Cristina Carresi

Massimo Fini

Bruno Silvestrini

Crossref

European Heart Journal - Cardiovascular Pharmacotherapy

Aspirin wears smart

St George's Online Research Archive

.......................................Aspirin wears smartLow-dose aspirin is used worldwide for pre-venting thromboembolic disorders. Its use,however, is often associated with gastrointes-tinal bleeding, mostly due to direct irritation ofthe gastric mucosa. Here we provide evidencefor a novel sublingual formulation of aspirinmicronized and co-grinded with collagen pro-ven to be as effective as oral standard formula-tion in inhibiting platelet aggregation but withattenuated gastric irritation. This represents anew option for better aspirin treatment in theprevention of myocardial infarction and stroke.Orally given low-dose aspirin has been usedfor decades due to its anti-inflammatory andantithrombotic properties.1 Although standardoral formulation of aspirin allows rapid and com-plete absorption from the GI tract, new formu-lations have been developed and marketed, (e.g.dry granules, effervescent solution, and chew-able tablets)2,3 with the aim to achieve faster dis-solution and faster absorption4,5 as well asto reduce direct aspirin-induced gastric lesions.However, the occurrence of gastrointestinalbleeding still remains a significant problem ofchronic aspirin administration and, sometimes,limits the use of aspirin in primary prevention.6,7On the other hand, co-administration of protonpump inhibitors is currently used to counteractaspirin-induced gastric lesions,8,9 thereby repre-senting a pharmaco-economic issue in the areaof health care sustainability.Recently, we developed and patented (N.102015000079955) a new formulation of as-pirin which leads to faster absorption and activ-ity but devoid of direct gastrointestinallesioning effect. In addition, this formulationallows sublingual administration of the drugwhich, by passing the liver metabolism, leads toFigure 1 Micro-Raman spectra were excited by a 514 nm laser line through a 50X objective with a laser power of 10 mW at the sample level. Thesamples were deposited as powder on a calcium fluoride slide, and measurements were performed with an accumulation time of 30 s, in the rangefrom 500 up to 4000 cm-1. In (A) the image of the chemical compost aspirin in crystalline form. Raman spectra in (B) relative to the analysis of thecompost. The measures yield a spectrum with very sharp, intense Raman peaks. In (C) the optical image of the dried mixture composed of theamorphous material and the crystalline aspirin. The amorphous form is due to the presence of collagen. RAMAN measurements (D), collected in themarked points of the optical image, show broader less intense Raman peaks (indicated by the black square) in the presence of the amorphous speciesand sharp peaks (red squares) related to aspirin molecules...........................................................................VC The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permitsunrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.European Heart Journal - Cardiovascular Pharmacotherapy (2017) 3, 185–188 Correspondencedoi:10.1093/ehjcvp/pvx017Downloaded from https://academic.oup.com/ehjcvp/article-abstract/3/4/185/3827833 by St George's University of London user on 18 September 2019....................................faster serum peak concentration with moreprominent and rapid inhibition of cycloxyge-nase (COX), the major target of antiplateletand antinflammatory action of aspirin.MethodsCristalline aspirin was amorphized via micron-ization and co-grinding with collagen (seeSupplementary material online, Materials &Methods). Collagen was chosen due to itsgastro-protective action.10 The occurrence ofaspirin amorphization was demonstrated viameasurement of spectra collected with Ramanspectroscopy (Figure 1).Micronized collagen co-grinded aspirin formu-lations were developed for both oral and sublin-gual administration (see Supplementary materialonline, Materials & Methods) and used in healthyvolunteers, in a phase 1, randomized, doubleblind, placebo-controlled study (study EudraCTN. 2013-002980-24) to verify their pharmacoki-netic profile compared to standard crystallineformulations of aspirin (see Supplementary ma-terial online, Clinical Study Protocol and healthyvolunteer demographics). Measurement ofserum thromboxane B2 (TXB2), and its urinarymetabolite 11-dehydro-TXB2 after both oral andsublingual standard as well as micronized aspirinwere carried out to assess the inhibitory activityat the COX level.ResultsOral administration of 100 mg of standard crys-talline aspirin (n= 10 healthy volunteers) for 7consecutive days produced a rapid rise of ace-tylsalicylic acid serum concentration whichpeaked at 2–4 h after the administration andFigure 2 Plasma concentration vs. time profile of acetylsalicylic acid after oral and sublingual administration of aspirin either standard crystallineand micronized and co-grinded with collagen (MCþ coll) (detected via LC-MS and expressed as ng/mL-1) of healthy subjects (n= 10 for each treat-ment) after dosing with 50 and 100 mg/daily of both formulations (Graphs A–D). Curves display changes of levels of acetylsalicylic acid after adminis-tration of the first and seventh dose of aspirin of both formulations. Graphs E and F show the area under the curve (AUC calculated as ng/dL/h) andCmax (expressed as ng/dL), respectively, of acetylsalicylic acid serum concentrations after oral or sublingual administration of both aspirin formulations(standard or MCþ coll) given in healthy volunteers (n= 10 for each treatment). In G are shown the changes of TXB2 serum levels detected via ELISAimmunoassay in subjects treated with oral standard aspirin vs. sublingual administration of MCþ coll formulation. Data show that the decrease ofserum TXB2 occurs earlier in subjects treated sublingually with aspirin MCþ coll compared to the standard oral administration of 50 and 100 mg, re-spectively. Similar effect was seen in urinary 11-dehydro-TXB2, the metabolite of TXB2, thus reflecting a better effect of sublingual aspirin MCþ collformulation on platelet COX enzyme.......................................................................186 CorrespondenceDownloaded from https://academic.oup.com/ehjcvp/article-abstract/3/4/185/3827833 by St George's University of London user on 18 September 2019....................................................................declined 8–12 h later (Figure 2–F). This effectwas accompanied by a decrease of TXB2 serumconcentration at 6 h which declined 16–20 hafter the administration. (Figure 2G). A similarresponse was seen in healthy volunteers(n= 10) receiving 50 mg of standard aspirin or-ally, with lower effect compared to 100 mg,(Figure 2A–F). No significant differences wereseen when 50 and 100 mg of micronized andcollagen co-grinded aspirin were given orally tohealthy volunteers (n= 10 for each dose; Figure2A–F)In contrast, sublingual administration of 50and 100 mg (n= 10 for each dose) of aspirinmicronized and co-grinded with collagen, pro-duced a dose-related peak of serum concentra-tion of acetylsalicylic acid which occurred earliercompared to both sublingual and oral adminis-tration of aspirin (1 h) with a decline of serumconcentration occurring 4–5 h after the adminis-tration (n= 10 for each dose; Figure 2A–F).This effect was accompanied by early inhibitionof TXB2 levels which was observed after 2 hand lasted 10 h after aspirin administration.Furthermore, the effect of aspirin formulation inTXB2 was confirmed by detection of its urinarymetabolite11-dehydro-TXB2 after Day 7 of thestudy (Figure 2H), thus suggesting that sublingualadministration of micronized co-grinded aspirindisplays a non-inferiority response on COX en-zyme compared to crystalline standard formula-tion. Determination of serum TXB2 serumlevels and of urinary 11-dehydro-TXB2 showedno changes before and after treatment inhealthy volunteers receiving placebo (notshown).Neither changes on routine blood analyticalbiomarkers nor side effects or adverse drug re-actions were noted in any of the groups afteradministration of oral or sublingual aspirin. Pillcount adherence was 100% and no enrolledsubject was excluded from the study (seeSupplementary material online).Finally, to verify the attenuated impact ongastric mucosa of micronized collagen co-grinded aspirin compared to standard oral for-mulation, experiments have been carried out inrats receiving doses of aspirin proven toproduce gastric lesions (see Supplementary ma-terial online, Materials & Methods). In particu-lar, acute oral administration of aspirin (400 mg/Kg) both crystalline or micronized and co-grinded with collagen produced gastric lesionwith an elevated ulcer score index.11 In particu-lar 83% of the stomachs in the group of ratstreated with standard aspirin contained one ormore lesions and mean lesion score was23.7 ± 3–5. The severity of ulceration was how-ever reduced by 73 ± 6% in the gastric tissueswhen aspirin was given micronized and co-grinded with collagen. This was confirmed byevaluating microphotographs of gastric mucosastained. In particular, we have found that stand-ard aspirin formulation leads to production ofsevere erosions marked by the presence of het-erogeneous mixture of tissues retracting fromthe mucosal surface. A variety of surface epithe-lial changes in shape, size, and orientation,accompanied by marked loss of surface mucusepithelial cell were found. Marked disorganiza-tion and atrophy of glands were invariablynoted. This seems to be prevented whenFigure 2 Continued.......................................................................................................................................Correspondence 187Downloaded from https://academic.oup.com/ehjcvp/article-abstract/3/4/185/3827833 by St George's University of London user on 18 September 2019...............................................................................................aspirin is micronized and co-grinded with colla-gen, which maintains the adherent mucus liningresisting the erosion of glandular cells. No sig-nificant gastric mucosal lesion was observed incontrol group of rats.ConclusionOur data show that sublingual formulation ofaspirin micronized and co-grinded with collagendisplays a better pharmakinetic profile com-pared with standard crystalline aspirin. This ef-fect was accompanied by attenuated directgastric ulcerogenic effect of the new formula-tion and by non-inferiority profile on TXB2serum and urinary levels after a 7-day treatmentcompared to the standard formulation of as-pirin. The potential remaining warning ongastrointestinal bleeding due to inhibition onprostaglandin-related production of protectivegastric mucus of the new formulation is to bebetter clarified. This represents a new optionfor better aspirin treatment in the preventionof thromboembolic disorders.Supplementary materialSupplementary material is available at EuropeanHeart Journal—Cardiovascular Pharmacotherapyonline.Conflict of interest: none declared.References1. Piepoli MF, Hoes AW, Agewall S, Albus C, BrotonsC, Catapano AL, Cooney MT, Corra U, Cosyns B,Deaton C, Graham I, Hall MS, Hobbs FD, LøchenML, Lo¨llgen H, Marques-Vidal P, Perk J, Prescott E,Redon J, Richter DJ, Sattar N, Smulders Y, TiberiM, van der Worp HB, van Dis I, Verschuren WM.2016 European Guidelines on cardiovascular dis-ease prevention in clinical practice: The Sixth JointTask Force of the European Society of Cardiologyand Other Societies on Cardiovascular DiseasePrevention in Clinical Practice (constituted by rep-resentatives of 10 societies and by invitedexperts)Developed with the special contributionof the European Association for CardiovascularPrevention & Rehabilitation (EACPR). Eur Heart J2016;37:2315–2381.2. Voelker M, Hammer M. Dissolution and pharmaco-kinetics of a novel micronized aspirin formulation.Inflammopharmacology 2011;20:225–231.3. Doyle G, Jayawardena S, Ashraf E, Cooper SA.Efficacy and tolerability of nonprescription ibupro-fen versus celecoxib for dental pain. J ClinPharmacol 2002;42:912–919.4. Hersh EV, Moore PA, Ross GL. Over-the-counteranalgesics and antipyretics: a critical assessment.Clin Ther 2000;22:500–548.5. Neeti R, Murugesan SK, Nanjaian M. Solubility: par-ticle size reduction is a promising approach to im-prove the bioavailability of lipophilic drugs. Int JRecent Adv Pharm Res 2011;1:8–18.6. Fletcher RH. Aspirin for CVD primary preventionincreases gastrointestinal bleeding and hemorrhagicstroke. Ann Intern Med 2016;165:178.7. Saito Y, Okada S, Ogawa H, Soejima H, Sakuma M,Nakayama M, Doi N, Jinnouchi H, Waki M, MasudaI, Morimoto T. Low-dose aspirin for primary pre-vention of cardiovascular events in patients withType 2 diabetes mellitus: 10-year follow-up of arandomized controlled trial. Circulation 2017;14:135–142.8. Vaduganathan M, Bhatt DL. Aspirin and proton-pump inhibitors: interpreting the interplay. EurHeart J Cardiovasc Pharmacother 2016;2:20–22.9. Fortuna LA, Pawloski PA, Parker ED, Trower NK,Kottke TE. Proton pump inhibitor use by aspirin-treated coronary artery disease patients is notassociated with increased risk of cardiovascularevents. Eur Heart J Cardiovasc Pharmacother2016;2:13–19.10. Castro GA, Sgarbieri VC, Carvalho JE, Tinti SV,Possenti A. Protective effect of collagen derivateson the ulcerative lesions caused by oral administra-tion of ethanol. J Med Food 2007;10:154–158.11. Robert A. Cytoprotection by prostaglandins.Gastroenterology 1979;77:761–767.Vincenzo Mollace1*,Giuseppe Rosano2, Natalia Malara1,3,Enzo Di Fabrizio3,4, Cristiana Vitale2,Marialaura Coluccio3,4,Jessica Maiuolo1, Ayesha Ali Wasti1,Carolina Muscoli1,2, Micaela Gliozzi1,Rocco Mollace1, Vincenzo Musolino1,Cristina Carresi1, Massimo Fini2, andBruno Silvestrini1,51Department of Health Sciences, Institute ofResearch for Food Safety & Health, NutramedScarl, University of Catanzaro “Magna Graecia”,Catanzaro, Italy; 2San Raffaele IRCCS Pisana,Rome, Italy; 3Department of Experimental andClinical Medicine, University of Magna Graecia,Catanzaro, 88100, Italy; 4King AbdullahUniversity of Science and Technology, Thuwal,23955-6900, Saudi Arabia; and 5SBM srl, Italy*Corresponding author. Tel:13274758007,Fax:109613695732, Email: mollace@libero.it............................................................................................................................................................................................188 CorrespondenceDownloaded from https://academic.oup.com/ehjcvp/article-abstract/3/4/185/3827833 by St George's University of London user on 18 September 2019

Aspirin wears smart.

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Aspirin wears smart.

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