Accepted Manuscript Evolution of the scientific literature on drug delivery: A 1974–2015 bibliometric study C. Robert, C.S. Wilson, A. Venuta, M. Ferrari, C.-D. Arreto PII: DOI: Reference: S0168-3659(17)30661-2 doi: 10.1016/j.jconrel.2017.06.012 COREL 8835 To appear in: Journal of Controlled Release Received date: Revised date: Accepted date: 31 March 2017 13 June 2017 14 June 2017 Please cite this article as: C. Robert, C.S. Wilson, A. Venuta, M. Ferrari, C.-D. Arreto , Evolution of the scientific literature on drug delivery: A 1974–2015 bibliometric study. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Corel(2017), doi: 10.1016/j.jconrel.2017.06.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Evolution of the Scientific Literature on Drug Delivery: A 1974-2015 Bibliometric Study Robert C1* ; Wilson C.S2 ; Venuta A3,4 ; Ferrari M 3 ; Arreto C.-D.5 1* Université Paris Descartes, Paris, France; Gliaxone, France; 2 School of Information Systems, Technology and Management, University of New South Wales, UNSW Sydney, 2052 Australia; RI PT 3 Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030, USA; Department of Medicine, Weill Cornell Medical College, 1330 York Ave, New York, NY, 10065, USA.; 4 Department of Pharmacy, University of Naples Federico II, Naples 80131, Italy. SC 5 ROBERT Claude GLIAXONE 30 rue de la Fontaine 77 169 Saint Germain Sous Doue France Email : clauderobert99@yahoo.fr CE PT ED MA Corresponding author: AC * NU Université Paris Descartes, Faculté de Chirurgie Dentaire, Hôpital Bretonneau, HUPNVS, AP-HP, Paris, France ACCEPTED MANUSCRIPT Abstract This study charts the growth of the drug delivery literature published during 1974-2015 from journals indexed in the Science Citation Index Expanded database. The growth of publications on drug delivery paralleled the total scientific publications for three decades (1974- 2003); however, Industrialized RI PT from 2004 to 2015 it exploded fourfold, while the total increased only 1.75 fold. countries (USA, UK, Germany, Japan, Italy, France and Canada) were the most prolific during the first decades, but in 2014-2015 China, India and South Korea ranked 1 st , 3rd and 4th respectively SC among the productive countries. The number of participating countries increased fivefold (from 19 NU to 96). During the last 15 years, the journals targeted by drug delivery research increased nearly 2.4 fold (416 to 1,001) and three journals (Journal of Controlled Release, Advanced Drug Delivery MA Reviews, and International Journal of Pharmaceutics) published nearly one-fifth of the drug ED delivery research in 2014-2015. AC CE PT Keywords: Drug Delivery, Bibliometrics, Publication Trend, Journal Analysis, Country Productivity ACCEPTED MANUSCRIPT 1. Introduction Drug delivery (D.D.) concerns a large spectrum of approaches, formulations, technologies, and systems used to achieve and optimize the transport of pharmaceutical compounds in the human body by increasing their quantity and half-life in biological fluids while minimizing their adverse effects. One of the main benefits of D.D. systems is the opportunity to select the anatomical route RI PT through which drugs can be administered to the human body on the basis of the desired effect, the disease, and the type of molecule. The first D.D. devices were developed in the nineties and solely consisted of transdermal and oral delivery systems based on improving the drug release kinetics in SC order to obtain a constant rate over a certain period of time to enhance drug bioavailability, patient NU compliance, and decrease therapy costs [1]. Interestingly, since diseases such as cancer have been addressed as transport issues [2], there has been an increase in the exploitation of nanoparticles for MA medical applications. As a result, nanotechnology, whose conceptual foundations were laid down by Richard Feynman [3], has become one of the fastest growing research areas [4]. In particular, ED nanotherapeutics (i) improve the properties of drugs without affecting the carried molecules, (ii) provide the drugs with the ability to overcome several biological barriers that normally reduce the PT accumulation of therapeutics in the target area (iii) can consist in nanovectors loaded with various CE compounds such as two different drugs or a drug with an imaging agent in order to track the particles, (iv) increase the therapeutic impact by interacting with specific tissues and cells through AC surface functionalization and, (v) permit potential clinical application. Several types of nanovectors such as liposomes [5-7], polymeric nanoparticles [8], micelles [9, 10], and iron based nanoparticles [11] have been exploited. Unfortunately, nanotechnology did not achieve the expected results, in fact a recent work showed that only a small portion of the injected dose accumulated at the target site [12] due to the presence of multiple biological barriers in the body that represent the main obstacles of D.D. [13]. New technologies arise from a multidisciplinary approach that involves biology, chemistry, physics, and engineering based on the micro scale. Multistage discoidal vectors are an example of the next generation D.D. systems, and can be loaded with nanotherapeutics ACCEPTED MANUSCRIPT thereby overcoming biological barriers in a sequential manner to promote the accumulation at the site of interest [14, 15]. In addition to injectable D.D. systems, other devices must be mentioned. Examples include the transdermal drug D.D., which is an effective alternative to the oral administration of various compounds [16], osmotic D.D. systems, that are suitable for implantation as well as for oral delivery by exploiting the movement of water through a selectively permeable RI PT membrane driven by a difference in osmotic pressure [17], and mucoadhesive D.D. systems which are tablets, polymer gels, and films that remain in close contact with the tissue such as the oral cavity, the eye, and the nasal cavity resulting in high drug accumulation at the site of release [18]. SC In addition, implantable D.D. systems are based on microfluidics and can exploit both micro- and nano-scale technologies. Such systems display some disadvantages such as higher cost and the NU necessity to be implanted with surgery, but at the same time they provide therapeutic drug MA concentrations over the whole treatment, even if it requires continuous or repeated administration [19-21]. ED External Medical devices play an important role in several therapies such as the therapies for pulmonary diseases. On the market there are several devices working with passive and active PT mechanisms such as dry powder inhalers (DPI) that make up a large part of the market [22]. It is important to stress that all this approaches, formulations, technologies, and systems arise from basic CE science or bench research and can potentially be translated into clinical applications. AC During the last decades, qualitative evaluations of the progress in D.D. are available through the publication of numerous reviews [23,24]. Although such literature reviews provide readers updated and synthesized subject information, to our knowledge there is an absence of quantitative data describing the scientific publishing pattern of D.D. over time thus preventing scientists, physicians, decision-makers, politicians, and others a global view of scholarly communication in this field. The aim of this study is to use bibliometric techniques to provide a 40+ year longitudinal view (1974 to 2015) of the evolution of the scientific literature on D.D. without focusing on a ACCEPTED MANUSCRIPT specific area. Two indicators were chosen to follow this evolution: the publishing outputs of D.D. AC CE PT ED MA NU SC RI PT research by countries, and the journals used to publish research on D.D.. ACCEPTED MANUSCRIPT 2. Method The data were collected between 20 th October and 10th November 2016 from the Science Citation Index Expanded (SCI-E), a multidisciplinary index to the journal literature of science and technology, through the ISI Web of Knowledge (http://www.isiwebofknowledge.com/) – a part of RI PT the Web of Science (WoS) database. The search strategy consisted of:  all documents published in journals with at least one of the following keyphrases in the title: SC drug deliver*, drug release*, drug carr*, sustained release*, controlled release*, intranasal administra*, sustained deliver*, intelligent delivery system, pulsatile releas*, transdermal NU deliver*, drug nanocarr*, nasal deliver*, rectal deliver*, oral deliver*, buccal deliver*, MA drug nanopart*, nanopart* deliv*, nanopart* releas*, nanoparticule drug, with asterisks replacing characters following the word-stems; all documents published in the following journals: Journal of Controlled Release, Advanced ED  Drug Delivery Reviews, Expert Opinion on Drug Delivery, Drug Delivery, Journal of Drug PT Delivery Science and Technology, Current Drug Delivery, Critical Reviews in Therapeutic Drug Carrier Systems, Drug Delivery and Translational Research, Journal of Aerosol CE Medicine and Pulmonary Drug Delivery, Polymeric Drug Delivery I Particulate Drug, AC Cancer Drug Delivery, Polymeric Drug Delivery II Polymeric Matrix, Polysaccharides for Drug Delivery and Pharmaceutical Applications, Advances in Controlled Drug Delivery Science Technology and Products, Filled Elastomers Drug Delivery Systems. Only journal article and journal review-type publications (as defined in the SCI-E database) published during 1974-2015 were considered. The 2015 impact factors (IF) were collected using the Thomson Scientific Journal Citation Reports. Downloaded documents were then analyzed by countries, and for each two-year period from 1974 to 2015 the following parameters were considered: ACCEPTED MANUSCRIPT  the total number of publications authored or co-authored by researchers in each country – publications issued from more than one country were assigned equally to each contributing country – and,  the top-10 most prolific journals publishing drug delivery research. Publications originating from England, Wales, Scotland and Northern Ireland were assigned RI PT to the United Kingdom (UK), and the European Union (EU) was defined as the official member States registered on the 1st of January for each of the two year-periods considered. The set of AC CE PT ED MA NU SC BRICS countries includes Brazil, Russia, India, China and South Africa. ACCEPTED MANUSCRIPT 3. Results and Discussion 3.1. Evolution of the drug delivery research During the past 40+ years the scientific literature on D.D. emerged and has grown rapidly (Fig. 1). The global evolution of D.D. literature can be split into 2 parts. From 1974 to the start of RI PT the 2000s, the D.D. scientific literature grew slowly (from 63 publucations published in 1974-1975 to 1,750 publications in 2000-2001) paralleling the growth of the total WoS literature. However, from 2002 to 2015, the growth exploded: there was a fourfold increase of the D.D. literature (1,848 SC D.D. publications published in 2002-2003 vs. 7,823 in 2014-2015), while the total for the WoS NU literature only increased 1.75 fold. MA D.D. publications 9000 8000 6000 5000 PT 1500000 1000000 D.D. publ i ca ti ons 500000 0 1974-75 1976-77 1978-79 1980-81 1982-83 1984-85 1986-87 1988-89 1990-91 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 2012-13 2014-15 AC 0 2000000 CE 3000 1000 2500000 Tota l WoS publ i ca ti ons 4000 2000 3000000 ED 7000 Total WoS publications Figure 1. Number of Drug Delivery and total WoS research articles and review p ublications: 1974-2015 ACCEPTED MANUSCRIPT 3.2. Evolution of countries publishing drug delivery research As shown in Table 1, from 1974 to 2015 the number of countries involved in D.D. research increased fivefold: 19 countries in the 1974-1975 period, 36 in 1984-1985, 52 in 1994-1995, 72 in RI PT 2004-2005, and 96 countries in 2014-2015. Table 1 1974-1975 #publications % World EU 63 18 100.0 28.5 NU Countries/Territories 22 12 4 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 CE PT ED MA USA UK Canada Norway Fed Rep Germany Germany Dem Rep Sweden United Arab Rep Belgium Bulgaria Denmark Finland India Ireland Israel Netherlands New Zealand Switzerland Trinidad & Tobago AC SC The number of Drug Delivery research articles and review publications by countries, the EU countries, BRICS countries, and the World: 1974-1975, 1984-1985, 1994-1995, 2004-2005 and 2014-2015 34.9 19.0 6.3 4.7 3.1 3.1 3.1 3.1 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 Rank 1 2 3 4 5 5 5 5 9 9 9 9 9 9 9 9 9 9 9 ACCEPTED MANUSCRIPT Table 1 (continued) 1984-1985 # publications 527 169 % 100.0 32.0 Rank USA UK Japan Fed Rep Germany France Netherlands Canada Israel Denmark Austria India Italy Belgium Australia Switzerland Egypt Finland Sweden Turkey Czechoslovakia New Zealand P oland South Africa Taiwan Germany Dem Rep Ireland Jordan Norway Thailand Argentina Bahamas Hungary Kenya Nigeria P eoples R China P hilippines 230 80 33 26 21 18 16 13 11 10 10 10 8 6 6 5 4 4 4 3 3 3 3 3 2 2 2 2 2 1 1 1 1 1 1 1 43.6 15.1 6.2 4.9 3.9 3.4 3.0 2.4 2.0 1.8 1.8 1.8 1.5 1.1 1.1 0.9 0.7 0.7 0.7 0.5 0.5 0.5 0.5 0.5 0.3 0.3 0.3 0.3 0.3 0.1 0.1 0.1 0.1 0.1 0.1 0.1 1 2 3 4 5 6 7 8 9 10 10 10 13 14 14 16 17 17 17 20 20 20 20 20 25 25 25 25 25 30 30 30 30 30 30 30 SC NU MA ED PT CE AC RI PT Countries/Territories World EU ACCEPTED MANUSCRIPT Table 1 (continued) 1994-1995 # publications 1329 67 411 % 100.0 5.0 30.9 Rank USA Japan UK France Germany Italy Canada Netherlands Israel India Belgium Sweden Switzerland Spain Denmark Finland P eoples R China Turkey Australia Egypt Taiwan South Africa New Zealand Austria Czech Rep Norway Russia South Korea Saudi Arabia Greece Hungary Iceland Argentina Bulgaria Chile Croatia Hong Kong Malaysia Mexico Nigeria P ortugal Singapore Thailand Bangladesh Estonia Ireland Jordan P hilippines P oland Romania Slovenia Ukraine 533 173 150 62 60 57 52 42 41 36 31 23 17 17 17 15 15 15 14 12 12 10 9 8 7 6 6 6 5 4 4 4 3 3 3 3 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 40.1 13.0 11.2 4.6 4.5 4.2 3.9 3.1 3.0 2.7 2.3 1.7 1.2 1.2 1.2 1.1 1.1 1.0 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 1 2 3 4 5 6 7 8 9 10 11 12 13 13 13 16 16 18 19 20 20 22 23 24 25 26 26 26 29 30 30 30 33 33 33 33 37 37 37 37 37 37 37 44 44 44 44 44 44 44 44 44 SC NU MA ED PT CE AC RI PT Countries/Territories World BRICS EU ACCEPTED MANUSCRIPT Table 1 (continued) 2004-2005 #publications 2485 373 833 % 100.0 15.0 33.5 Rank USA Japan UK P eoples R China Germany India South Korea Italy France Canada Spain Switzerland Netherlands Australia Belgium Singapore Taiwan Israel Turkey Austria Sweden Brazil Finland Iran Ireland Denmark Egypt New Zealand Russia P ortugal Thailand Czech Rep South Africa Norway Romania Argentina Greece Mexico Malaysia Croatia Kuwait Slovenia Iceland P hilippines P oland Cuba Hungary Jordan Nigeria P akistan Saudi Arabia Yugoslavia Bulgaria Estonia Indonesia U Arab Emirates Bahrain Chile Kazakhstan Latvia Lebanon Lithuania Malta Myanmar Nepal Rep Of Georgia Serbia Montenegro Slovakia Tanzania Tunisia Ukraine Uruguay 746 262 222 169 153 146 137 126 126 98 57 56 55 47 46 45 44 38 36 33 33 31 23 23 21 17 17 17 17 16 15 13 12 11 11 8 8 8 7 6 6 6 4 4 4 4 3 3 3 3 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 30.0 10.5 8.9 6.8 6.1 5.8 5.5 5.0 5.0 3.9 2.2 2.2 2.2 1.8 1.8 1.8 1.7 1.5 1.4 1.3 1.3 1.2 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 20 22 23 23 25 26 26 26 26 30 31 32 33 34 34 36 36 36 39 40 40 40 43 43 43 43 47 47 47 47 47 47 53 53 53 53 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 SC NU MA ED PT CE AC RI PT Countries/Territories World BRICS EU ACCEPTED MANUSCRIPT Table 1 (continued) 2014-2015 # publications 7824 3153 1924 % 100.0 40.2 20.5 Rank Peoples R China USA India South Korea UK Germany Japan Italy France Iran Spain Australia Canada Brazil Taiwan Saudi Arabia Egy pt Netherlands Portugal Singapore Switzerland Belgium Malay sia Israel Denmark Turkey Thailand Pakistan Poland Sweden Russia Romania South Africa Finland Austria Greece Argentina Ireland Czech Rep Hungary Norway New Zealand Serbia Slovenia Mexico Nigeria Jordan Chile Vietnam U Arab Emirates Estonia Bulgaria Croatia Indonesia Bangladesh Colombia Iceland Slovakia Algeria Cuba Sy ria Iraq Mauritius Tunisia Cy prus Lebano Luxembourg Morocco Philippines Qatar Rep of Georgia By elarus Ghana Montenegro Oman Tanzania Yemen Azerbaijan Benin Brunei Burkina Faso Cameroon Costa Rica Ecuador Ethiopia Keny a Kuwait Liby a Macedonia My anmar Nepal Sudan Uganda Ukraine Venezuela Zimbabwe 2042 1675 872 408 383 341 290 252 236 229 219 208 190 146 144 140 139 123 121 119 113 95 94 83 71 69 65 62 61 61 60 59 54 52 48 48 42 42 34 34 34 29 23 23 22 22 18 17 16 11 10 8 8 8 6 6 6 6 5 5 5 4 4 4 3 3 3 3 3 3 3 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 26.0 21.4 11.1 5.2 4.8 4.3 3.7 3.2 3.0 2.9 2.7 2.6 2.4 1.8 1.8 1.7 1.7 1.5 1.5 1.5 1.4 1.2 1.2 1.0 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 29 31 32 33 34 35 35 37 37 39 39 41 42 43 43 45 45 47 48 49 50 51 52 52 52 55 55 55 55 59 59 59 62 62 62 65 65 65 65 65 65 65 72 72 72 72 72 72 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 SC NU MA ED PT CE AC RI PT Countries/Territories World BRICS EU ACCEPTED MANUSCRIPT In the first four of the five two-year periods analyzed the USA was by far the most productive country with a lead of 43.6% of the total share in 1984-1985; however, it ranked second in 2014-2015 with only 21.4% of the total publications. Some industrialized countries (UK, Japan, Germany, France, Netherlands and Canada) that were present among the leading countries in 19841985 slowly lost their high ranking positions, but remained among the leading countries in 2014- RI PT 2015. These observations are in line with the domination (in terms of the number of publications) of these countries in various fields of Biology [25], Medicine [26, 27], and in research fields more closely allied to D.D. research such as Nanotechnologies [28] and Liposomes [29]. Contrariwise, SC two Asian newcomers, China and South Korea, along with the continuous presence of India among the productive countries have progressively joined the industrialized countries in their D.D. research NU efforts: China from ranked 17th in 1994-1995, 4th in 2004-2005, to 1st in 2014-2015; and South MA Korea from ranked 28th in 1994-1995, 7th in 2004-2005, to 4th in 2014-2015. The increasingly leading position of China is also supported by the fact that five of the ten ED most productive institutions in D.D. research are located in China (data not shown). The recent increase of Chinese D.D. publication (see Fig. 2) can be correlated to the explosion of publications PT authored by Chinese scientists in Pharmacology and Pharmacy journals [30]. More globally, it can CE be seen as a consequence of the recent increase of China’s total expenditure on Research and Development – on average 23% per annum over the last decade [31]. Additionally, the recent AC ascendancy of China over the USA was predicted in a report of the Royal Society [32]. # publications ACCEPTED MANUSCRIPT 3500 3000 2500 2000 EU BRICS China USA South Korea UK Germany India 1500 RI PT 1000 500 NU SC 0 Figure 2. ED MA Number of Drug Delivery research articles and review publications for top-producing countries, the EU countries and BRICS countries: 1974-2015 PT While the share of D.D. publications among the EU countries remained stable from 1994 to 2005 (30.9% in 1994-1995, and 33.5% in 2004-2005) but decreased to 20.5% in 2014-2015; the CE share of the BRICS countries increased continuously (mainly due to the D.D. research output of AC China and India): 5.0% in 1994-1995, 15.0% in 2004-2005 and 40.2% in 2014-2015. As noted earlier, three members of BRICS (China, India and South Korea) were present in the top-ranking countries in 2004-2005 and in 2014-2015. 3.3. Evolution of journals publishing drug delivery research During the 40+ years studied, the number of journals targeted by D.D. researchers increased in two trajectories (Fig. 3). From 1974 to the beginning of the 2000s, the increase of D.D. journals more or less paralleled that of the SCI-E database; however, from 2002 to 2015, the number of D.D. journals increased 2.4 fold (416 journals in 2002-2003 and 1,001 for 2014-2015) while the total ACCEPTED MANUSCRIPT number of journals indexed in the SCI-E increased only 1.2 fold (7,822 journals for 2002-2003 and 9,550 for 2014-2015). D.D. journals Total WoS journals 1200 10000 1000 RI PT 12000 8000 Tota l WoS journals 6000 SC 4000 D.D. journa l s NU 2000 600 400 200 0 MA 1974-75 1976-77 1978-79 1980-81 1982-83 1984-85 1986-87 1988-89 1990-91 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 2012-13 2014-15 0 800 Figure 3. PT ED Number of journals publishing Drug Delivery research articles and review p ublications: 19742015 CE The top-10 most productive journals on D.D. research in each of the last four time periods are presented in Table 2. During the last three periods analyzed (1994-1995, 2004-2005 and 2014- AC 2015) three journals (Journal of Controlled Release, Advanced Drug Delivery Reviews, and International Journal of Pharmaceutics) were ranked among the top-4 most productive journals; two other journals (Drug Delivery and Journal of Drug Delivery Science and Technology) were present among the top-10 most productive journals in the two most recent rankings (2004-2005 and 2014-2015). For the last time period studied, eight of the top-10 ranked journals had an IF >3.00 with a maximum IF of 15.60 for the journal Advanced Drug Delivery Reviews. ACCEPTED MANUSCRIPT Table 2. The top-10 journals publishing Drug Delivery research articles and review publications: 1984-1985, 1994-1995, 2004-2005 and 2014-2015 (including 2015 IFs) 1984-1985 % of 527 10.0 5.5 3.4 3.2 2.8 2.0 2.0 2.0 1.5 1.3 1.3 1.3 1994-1995 AC CE PT Source Titles Journal of Controlled Release Advanced Drug Delivery Reviews Journal of Drug Delivery Science and Technology International Journal of Pharmaceutics Drug Delivery Biomaterials Drug Development and Industrial Pharmacy European Journal of Pharmaceutics and Biopharmaceutics Pharmaceutical Research Journal of Applied Polymer Science Source Titles Journal of Controlled Release Advanced Drug Delivery Reviews Iinternational Journal of Pharmaceutics Expert Opinion on Drug Delivery RSC Advances Journal of Drug Delivery Science and Technology Journal of Materials ChemistryB Drug Delivery Colloids and Surfaces B Biointerfaces Current Drug Delivery WoS category Chemistry, Multidisciplinary Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Chemistral, Medicinal;Pharmacology & Pharmacy Chemistry, Multidisciplinary; Chemistry, Medicinal; Pharmacology & Pharmacy Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry, Multidisciplinary; Chemistry, Medicinal; Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy n.a. NU % of 1329 24.4 8.0 7.2 4.8 3.5 3.3 1.4 1.2 1.2 1.0 1.0 1.0 MA # publications 325 107 96 65 47 45 19 17 16 15 15 15 ED Source Titles Journal of Controlled Release Advanced Drug Delivery Reviews International Journal of Pharmaceutics Drug Development and Industrial Pharmacy Journal of Pharmaceutical Sciences Pharmaceutical Research Chemical Pharmaceutical Bulletin STP Pharma Sciences Journal of Pharmacy and Pharmacology Journal of Drug Targeting Journal of Clinical Pharmacology Critical Reviews in Therapeutics Drug Carrier System WoS category n.a. Pharmacology & Pharmacy Chemistral, Medicinal;Pharmacology & Pharmacy Chemistry, Multidisciplinary; Chemistry, Medicinal; Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Chemistry, Multidisciplinary; Chemistry, Medicinal; Pharmacology & Pharmacy Medicine, General & Internal n.a. Pharmacology & Pharmacy n.a. RI PT # publications 53 29 18 17 15 11 11 11 8 7 7 7 SC Source Titles Cancer Drug Delivery International Journal of Pharmaceutics Drug Development and Industrial Pharmacy Journal of Pharmaceutical Sciences British Journal of Clinical Pharmacology Journal of Pharmacy and Pharmacology International Journal of Clinical Pharmacology and Therapeutics Chemical Pharmaceutical Bulletin American Journal of Medicine Pharmacy International Biopharmaceutics Drug Disposition Annals of the New York Academy of Sciences 2004-2005 # publications 678 217 134 127 85 46 41 40 31 31 % of 2485 27.2 8.7 5.3 6.1 3.4 1.8 1.6 1.6 1.2 1.2 WoS category Chemistry, Multidisciplinary Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Engineering, Biomedical; Materials Science, Biomaterials Chemistral, Medicinal;Pharmacology & Pharmacy Pharmacology & Pharmacy Chemistry, Multidisciplinary Pharmacology & Pharmacy Polymer Science 2014-2015 # publications 962 280 277 251 228 217 186 179 141 128 % of 7823 12.2 3.5 3.5 3.2 2.9 2.7 2.3 2.2 1.8 1.6 IF (2015) WoS Category 7.44 15.60 3.99 5.43 3.28 0.62 4.87 4.84 3.90 1.44 Chemistry, Multidisciplinary Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Pharmacology & Pharmacy Chemistry, Multidisciplinary Pharmacology & Pharmacy Materials Science, Biomaterials Pharmacology & Pharmacy Biophysics; Chemistry, Physical; Materials Science, Biomaterials Pharmacology & Pharmacy ACCEPTED MANUSCRIPT Furthermore, during the same three time periods the distributions of publications in journals were markedly skewed:  in 1994-1995, 1% (3 journals) of D.D journals concentrated 39.7% of the 1,329 D.D. publications, while 9l.3% (276 journals) of D.D. journals had ≤5  RI PT publications; in 2004-2005, 1% (5 journals) of D.D. journals concentrated 50% of the 2,485 D.D. publications, while 9l.5% (457 journals) of D.D. journals had ≤5 in 2014-2015, 1% (10 journals) of the journals concentrated 36.4% of the 7,823 D.D. publications, while 8l.9% (820 journals) of D.D. journals had ≤5 NU  SC publications; and finally MA publications. With the rapid growth of the scientific literature, review publications are essential ED updating tools for researchers [33]. During the last fifteen years, the number of D.D. review publications increased 3.5 fold (347 reviews in 2000-2001 vs. 1,220 in 2014-2015) while the PT total number of reviews in the SCI-E database only increased 2.6 fold (60,394 in 2000-2001 CE vs. 155,926 in 2014-2015). As in numerous scientific disciplines, a review journal, Advanced Drug Delivery Reviews, specifically dedicated to the field of D.D., was launched in 1987. AC This journal publishes approximately 150 publications per year, has a 2015 JCR impact factor of 15.60, and ranked 3rd (of 255) among the leading journals in the Pharmacology & Pharmacy WoS category. Although this journal published most of the D.D. review publications, other review publications were scattered among a broad range of journals: prestigious journals such as The Lancet [34], Nature [35], Nature Reviews Drug Discovery [36] and more specialized journals [37, 38]. Additionally, the increasing ratio of review publications / review+non-review publications from 1974 to 2000 and the stabilization since ACCEPTED MANUSCRIPT 2001 to 2015 from between 15% to 20% are indications of the evolving and maturing of the D.D. field. Although two emblematic journals targeted by D.D. researchers began in the mid1980s (The Journal of Controlled Release in 1984 and Advanced Drug Delivery Reviews in RI PT 1987), the recent explosion of the D.D. literature was accompanied by the launching of six more journals dedicated to D.D. in the 2000s: The Journal of Drug Delivery Science Technology (launched in 2004), Expert Opinion on Drug Delivery (2004), Current Drug SC Delivery (2004), Drug Delivery (2007), Journal of Aerosol Medicine and Pulmonary Drug NU Delivery (2008) and Drug Delivery and Translational Research (2011). From 1974 to 2015 the scientific literature on D.D. spread among a broad range of MA scientific fields (WoS subject categories): 24 in 1974-1975; 70 in 1984-1985, 100 in 19941995; 124 in 2004-2005; and 144 in 2014-2015. During this period, the WoS subject category ED Pharmacology & Pharmacy was the most targeted field; some of the top-leading WoS fields (Ophthalmology and Dermatology) disappeared while other fields gained in importance: PT Biochemistry Molecular Biology in 1984-1985, Materials Science Biomaterials, Polymer CE Science, or Engineering Biomedical in 1994-1995, and Nanoscience Nanotechnology and AC Chemistry Physical in 2004-2005. ACCEPTED MANUSCRIPT 4. Conclusion This brief bibliometric investigation on the evolution of the scientific literature on D.D. during 40+ years reveals three major trends: an explosion of D.D.-related publications (63 publications for 1974-1975 vs. 7,824 for 2014-2015); the spread and distribution of RI PT publications among publishing countries (19 countries in 1974-1975 vs. 96 in 2014-2015); and an increase of the number of journals involved in D.D. publications (42 journals in 1974- SC 1975 vs. 1,001 in 2014-2015). Despite an overall increase in publications that seem to result in a rapid advancement of the field after an initial success achieved by the first D.D. systems, NU production of approved D.D. systems for clinical use slowed down in the following years. This happens because overcoming the physiochemical and biological barriers is still a MA challenge [39]. The development of new delivery systems that are able to address current challenges in medicine was often driven by discoveries in basic science. Specifically, biology ED gave a huge boost to the development of nanotechnologies with discoveries such as the enhanced permeability and retention (EPR) effect [40]. Likewise, chemistry and material PT sciences have had a tremendous impact on the development of all D.D. systems, while physics CE and mathematics have added to the understanding of transport through the organism. Therefore, it is easy to understand how the collaboration among different disciplines is AC fundamental and that it is critical to maintain a detached view from the major scientific trend to keep up with new scientific discoveries [41]. Overcoming such limits will have a great impact also on the healthcare economy by introducing new technologies. As an example, the commercialization of Doxil [42], the first approved nanoformulated drug, decreased the cost of treatment and hospitalization [43]. Furthermore, the economic investments play a critical role in the translation of basic research into the clinic. In particular, the funding management varies among countries. For example, there is a substantial difference in the funding ACCEPTED MANUSCRIPT approaches between the U.S. and China, which are the two leading countries in D.D. research. U.S. governmental agencies that provide research funding, such as the National Institutes of Health (NIH), promote the development of projects in which the translational aspect is a major component, thereby making the U.S. the leader in translational research. On the other hand, in the last few decades China has been investing most of its funds in basic sciences, RI PT which has led to a massive production of scientific publications less focused on translational science. of D.D. systems thereby resulting in increased research activities NU commercialization SC In the years to come there will be an increase in the development and the worldwide and consequentially in an increased production of related scientific publications, MA probably with a similar trend observed in the last two decades among the countries ED considered. 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