Issues and concerns in nanotech product development andits commercializationIndu Pal Kaur , Vandita Kakkar, Parneet Kaur Deol, Monika Yadav, Mandeep Singh, Ikksheta SharmaDepartment of Pharmaceutics, University Institute of Pharmaceutical Sciences, UGC Centre for Advanced Studies, Panjab University, Chandigarh 160014, Indiaabstract arti cle i nfoArticle history:Received 14 March 2014Accepted 6 June 2014Available online 14 June 2014Keywords:Nanoscale drug delivery systemsPharmaceutical industryUSFDAMarketed productsChallengesThe revolutionary and ubiquitous nature of nanotechnology has fetched it a considerable attention in the pastfew decades. Even though its enablement and application to various sectors including pharmaceutical drug de-velopment is increasing with the enormous government aided funding for nanotechnology-based products,however the parallel commercialization of these systems has not picked up a similar impetus. The technologyhowever does address the unmet needs of pharmaceutical industry, including the reformulation of drugs to im-prove their solubility, bioavailability or toxicity proles as observed fromthe wide array of high-quality researchpublications appearing in various scientic journals and magazines. Based on our decade-long experience in theeld of nanotech-based drug delivery systems and extensive literature survey, we perceive that the major hic-cups to the marketing of these nanotechnology products can be categorized as 1) inadequate regulatory frame-work; 2) lack of support and acceptance by the public, practicing physician, and industry; 3) developmentalconsiderations like scalability, reproducibility, characterization, quality control, and suitable translation; 4) toxi-cological issues andsafety proles; 5) lack of available multidisciplinary platforms; and, 6) poor intellectual prop-erty protection. The present review dwells on these issues elaborating the trends followed by the industry,regulatory role of the USFDA and their implication, and the challenges set forth for a successful translation ofthese products from the lab and different clinical phases to the market. 2014 Elsevier B.V. All rights reserved.1. Introduction to nanotechnologyThe ideas and concepts behind nanoscience and nanotechnologystarted with a talk by Dr. Richard Feynman, a physicist, way back in De-cember 29, 1959, delivered at an international forum in the meeting ofAmericanPhysicalSocietyatthe CaliforniaInstituteofTechnology(CalTech). He may not have conceived at that time, that his talk, onThere's Plenty of Room at the Bottom wherein he discussed the scopeof manipulation and control of individual atoms and molecules, willset the pace for the present era of nanotechnology [1].Nanotechnology is an amalgamation of science, engineering, andtechnology conducted at the nanoscale that is about 1100 nm. Howso-ever OECD refers to nanotechnology as a set of technologies that en-ables the manipulation, study or exploitation of very small (typicallyless than 100 nanometres) structures andsystems. It includes anall per-vasive denition for it, stating that nanotechnology contributes to novelmaterials, devices and products that have qualitatively different proper-ties. Advancement in the nanotechnology has the potential to affect vir-tually every area of economic activity and aspect of daily life [2].Drug delivery application in nanotechnology is proposed to be themost happening and an all-purpose technological engine for growth inthe 21st century. Although lofty public R&D investments have beenmade and are reected in the growing scientic database, howevernanotechnology is still in an uncertain phase of commercialization [3].Further to this, its responsible development on one hand is a concern,while on the other hand, it holds a key opportunity to develop a sciencethat is explicitly and self-consciously in step with and for the society.Current efforts in ethical analysis, public engagement, and new formsof governance and regulation of nanotech-based drug delivery systemsthough impressive are still in a nascent stage [4].The potential market size of nanotechnology is catching the eye ofinvestors, economic developers and public ofcials, and is being lookedupon as a futuristic rather than a contemporary industry with over 500manufacturers already identied [5]. Nanotechnology-based productsin general have already been catalogued and their global market, in2007, totaled $147 billion [6]. Lux (an independent researchand adviso-ryrm) and other industry analysts project that in the year 2015 themarket size for these nanotech-based products will grow to $3 trillion[7]. An analysis of the Total Addressable Market (TAM) in 2010, forthe key technologies in drug delivery, shows that among the majorplayers, drug nanocrystals may capture a market of US$596 million,followed by nanocarriers (US$434 million), targeted delivery (US$178million) and systems to improve solubility and bioavailability (US$139million). Drug nanocrystallization (nanosized drugs) is proposed to bethe key technology that will hold the leading TAM in 2021 of about USJournal of Controlled Release 193 (2014) 5162 Corresponding author. Tel.: +91 172 2534113; fax: +91 172 2541142.E-mail address: indupalkaur@yahoo.com (I.P. Kaur).http://dx.doi.org/10.1016/j.jconrel.2014.06.0050168-3659/ 2014 Elsevier B.V. All rights reserved.Contents lists available at ScienceDirectJournal of Controlled Releasej our nal homepage:www. el sevi er . com/ l ocat e/ j conr el$81,921 million. Among all the evaluated nanocarriers, it is assumedthat liposomes may lead TAM in 2021 by holding a US$15,313 millionmarket [8].The success of nanotechnology in the healthcare sector is primarilydriven by the possibility to simultaneously work at a nanoscale on sev-eral biological processes, cellular mechanisms, and organic molecules;for this reason, nanomedicine is being looked upon as ideal solutionfor the detection and treatment of many diseases [9]. From more than80,000 articles on nanoparticles that were available on PubMed in Janu-ary 2014 over half were published after 2010, revealing the interest andprogress that is being made in this area [10]. It is a technology that pos-itively promises to inuence several facets of lifeincluding severalareas under FDA oversight, be it the prescription drugs, the individual'smedical devices and therapeutics, the nutraceuticals, and the cosmetics[11]. Looking at the purported claims, government agencies are pumpingan extensively large amount of funds for research in this area. In the USbudget of 2014, the US government provided over $1.7 billion forthe National Nanotechnology Initiative (NNI), a sustained invest-ment in support of the President's priorities and innovation strategy,cumulatively totaling almost $20 billion since the inception of theNNI in 2001 (including the 2014 request) [1,12]. Such ample supportreects the expectations from nanotechnology especially in terms ofits potential to combat diseases and improve the health status ofgeneral public.2. Commercial breakdownThough commercialization of nanotechnology is still in its infancy,the rate of technology enablement is increasing, in no small measure,owing majorly to the substantial government-mandated funds directedtoward nanotechnology. Commercialization is the process of turningnewtechnologiesintosuccessfulcommercialventures, whichmayinvolve an array of professionals from technical, commercial, and eco-nomic background to successfully transforma newtechnology to usefulproducts or services [13]. The process includes a series of steps startingfrom the conception of idea, technology development, and its commer-cialization; fostering those ideas to development of technology; build-ing up a prototype to establish the validity of the idea; development ofthe new process or optimization of the existing processes,nally lead-ing to the supply of proposed deliverables to the market, its promotion,and creation of new infrastructures for facilitated supply and purchase[14]. Comprehensive studies by VDI Technologiezentrum in Germanyhave found that although, more than 1000 nanotechnology organiza-tions, several of which are concentrated in some active countries [15]exist, however, there is a lack of newrm creation in nanotechnology.This is accredited to the fact that the number of nanotechnology compa-nies that have achieved initial public offerings (IPOs) is very low; per-haps a handful in Europe in the last few years, and taking a cue fromthis observation, no new companies are being launched in this area.Due to a signicant concern and disapproval the nanotech-based phar-maceutical companies are left with limitednancial options, while theco-founders of start-up companies are committing their own moneyand expertise into it. Current state of the global economy is not nano-friendly, and the companies are facing great difculty in obtaining ini-tial fundings. Considering the risk of funding companies prematurely,the investors are reluctant to pour large amounts of capital into thesecompanies until they have dependable technologies; ready to commer-cialize products; defendable patents; growing target markets in sight;chance of high protability; and strong management teams [16]. Ac-cording to Lux Research, the heydays for nanotech products were theearlier part of 21st century i.e. before 2010, when overall investmentreached approximately $1.4 billion in the year 2008. In 2009, the sectorraised only $792 million, a 42% decline fromthe prior year. It is predict-ed that investments in this area will decrease or remain at in the nearfuture [17].3. Challenges to product development and commercializationThe present era is a no or low controversy era wherein aversion toor apprehension toward newtechnology is at an all time low. Hence thegeneral attitude rather welcomes the new technologies like nanotech-nology [18]. However, just achieving a technical knowhow or a newertechnological product does not necessarily mean successful sales. Thetechnology needs to be well taken by the industry i.e. the industryshould have faith in its performance only then will it harness all its en-ergies and efforts to get the public support. In this regard the nanotech-based products seem to face numerous challenges to their successfulcommercialization (Fig. 1) as discussed below. Formulating an efcientand a nontoxic product are the two primary prerequisites for a productto be successfullymarketed. Most of the nanotech-based products,however, at times fail to achieve either or both the requirements andthus fail to reach the market [4,19].3.1. SafetyThe guidance document of USFDA indicates that for a test productgenerating plasma levels that are substantially above those of the refer-ence product, as usually observed with nanobased systems, the regula-tory concern is not therapeutic failure, but the adequacy of the safety forthe test product [20]. Owing to the nano size of these products, they in-variably encounter issues of bioaccumulation, superaoptimal bioactivity[21], biocompatibility, metabolism, and elimination from the body [22]during their use. Further to this, there are some reports that questiontheir safety for human use. Recently, some Chinese researchers haveobservedthatduringanimaltesting, theabsorptionofnano-silvermay interfere with the replication of DNA molecules and can re-routemolecular networks that could create genetic mutations. Nanosilver,among myriad other uses, is incorporated into food packaging materialsto kill pathogenic bacteria and thereby extenda food's shelf life [23]. Re-ports like this have created a general negative perception regardingthese products.However, therst successful application of nanoproducts in theclinic was that of contrast agents. Numerous nanoproductshavebeen launched over the years by various leading companies (OmniscanbySalutar;MagnevistbyBayerScheringPharma;OptiMARKbyMallinckrodt; MultiHance by Bracco group and many more) [19,24]. These agents are biologically inert, optically transparent, waterdispersible in nature and do not suffer from the concern of bioaccumu-lation as they are not absorbed by the body and are efciently eliminat-ed from body [24]. Near infrared (NIR)uorescence-based contrastagent like ICG-doped calcium phosphate nanoparticles are cleared bya hepatobiliary mechanismfrombody [25]. Further to this, these agentsare generally for single use, this lessens the chances of their accumula-tion and hence toxicity associated with repetitive use.Another signicanteld which employs a large number of nano-technology-based components is that of cosmetics. Table 1 gives an in-sightintothewiderangeofnanotechnology-basedcosmeticssoldworldwide by global cosmetic giants. Nanosized ingredients are eitherused to provide better UV protection in sunscreens or to act as carriersystems for the actives to improve their skin penetration and hence ef-cacy. Use of nanosized titanium dioxide and zinc oxide has led to thedevelopment of transparent sunscreens with better sun protection.However, safety concerns have risen for such products because the ul-trane particles of these metal oxides may catalyze generation of freeradicals which could cause skin damage and even cancer [26]. Studieshave shown that 500 nm titanium dioxide particles have lesser abilityto cause DNA strand breakage while a 20 nm particle may cause com-plete destruction of super-coiled DNA, even at low doses and in the ab-sence of exposure to UV [27].From the mechanism point of view, potential nanoparticle cellularinteractions that may induce cytotoxicity and other cellular responsesinclude: (1) interaction with plasma membrane leading to instability52 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162associatedwithion transport, signal transduction, andcell death; (2) in-teraction with mitochondria so as to alter metabolism or interfere withanti-oxidant defenses; (3) binding to DNA and resulting in its damage,arrest of cell cycle division and protein synthesis; (4) interaction withcytoskeleton which may halt vesicular trafcking and cause mechanicalinstability and cell death; and (5) interaction with proteins, lipids, andother biomolecules. Nanoparticles can also cause cytotoxicity by adher-ence to the cell membrane, degradation of adhered nanoparticles andsubsequent release of cytotoxic degradation products, e.g. as observedwith cyanoacrylate nanoparticles [28].The long-term toxic effects of absorption of such nanoparticles haveyet to be conclusively studied. The lack of safety and toxicity data re-garding nanocosmetics has attracted the attention of social work groupsworldwide. They are nowraising their voice toward adoption of a strin-gent regulatory guideline for nanotechnology-based cosmetics, as well[29]. For the time being the guidelines for cosmetics were comparativelyless rigorous including the absence of any requirement for the post-market surveillance.A European consumer organization called Which? published a re-portin2008highlightingthelackofregulationandsafetydataofmarketed nanocosmetics. They conducted a survey with top companieslike Avon, The Body Shop and Unilever regarding the use of nano com-ponents in their products. Most companies conrmed the use of suchcomponents in sunscreens. However, some companies carried out ex-tensive safety studies on their products while others relied on safetydatasheets provided by their nanoparticle suppliers. Such a discrepancycan be harmful for the consumer who considers that all marketed prod-ucts comply with safety guidelines, according to another survey con-ducted by Which? [30,31].AustralianorganizationFriendsofEarth testedconcealersandfoundations fromtop 10 brands of cosmetics including Clinique, L'Oral,Revlon, Max Factor, Yves Saint Laurent and Christian Dior. Eight of thesecontained particles below100 nm in size while only one of these prod-ucts had a labeled claim for the presence of nanoparticles. Revelationslike these call for stringent safety guidelines and labeling instructionsso that the consumers are not kept in the dark about the true natureof the product being used by them[32,33]. It may be because of suchso-cial activist groups that the cosmetic products being launched presently(majorlyafter2008)bymost of thecompaniesdonot claimthenanonature of their products [30,32].Presence of large number of nanocosmetic products in the marketsworldwide can be attributed to the fact that FDA oversight for cosmeticsFig. 1. Challenges to development and commercialization of nano-based drug products.53 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162neither includes pre-market evaluation nor requires report on post-market surveillance, such that most adverse events may go unnoticedunless directly reported to the FDA [34]. While, a similar oversight can-not be granted to other nanoproducts, especially those catering to life-threatening diseases like cancers as these products would by defaultrequire more stringent guidelines.The intensity of these safety threats increases manifolds when nano-particles are applied to disease therapeutics in oral and parenteral dos-age forms rather than topical application usually followed for cosmeticproducts. Liposomes, solid lipid nanoparticles (SLNs) and polymericnanoparticles are the most widely employed drug delivery systems intherapeutics. A research pool of the last 510 years has however, pro-vided a large data bank justifying the wide applications and safety ofthese systems. Issues pertaining to use of organic solvents and non-biocompatible polymers for preparation of polymeric nanoparticles,have been addressed with the advent of newer preparatory techniquesinvolving safe solvents and biodegradable polymers [35]. Biologicalsafety of the lipids used for the preparationof SLNs is alsohighly indicat-ed. Ambisome (liposomal AmphotericinB) is found to be more safe thanAbelcet(AmphotericinB lipid complex) owing toits less infusion-related adverse effects and less nephrotoxicity [36].Silva et al. [37] studied the toxicity of risperidone-loaded SLNs (com-posed of glyceryl monostearate, 4055%) with Caco-2 cells by (4,5-dimthylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay.This test evaluates the mitochondrial function as a measurement ofcell viability, which allows the detection of dead cells before they losetheir integrity and shape. The results suggest that all the evaluatedformulations were biocompatible with Caco-2 cells and thus well toler-ated by the GIT. Similar results have been reported elsewhere [38,39].More extensive research in the area of nanotherapeutics especiallycovering the issues of safety and toxicity however needs to continue.Scientists do believe that issue of toxicity will soonnd a solution, andwhen that happens, investors will become even more receptive. How-ever, it is extremely important that therapeutic nanoparticle formula-tionsareputthroughstringentsafetyteststoevaluateboththeiracute and chronic safety proles. This crucial consideration cannot beleft unnoticed and requires immediate and efcient action fromregula-tory agencies.3.2. Developmental considerations3.2.1. Therapeutic efcacyOne of the mainrequisite for any product tobe successfully commer-cialized is establishing its superiority over existing options in terms ofefcacy [10]. Doxil and Abraxane are two successful examples ofnanotech-based products in clinics [19]. Doxil, a liposomal formula-tion of a toxic chemotherapeutic doxorubicin originally marketed bySequus, was approved by FDA in 1995 for Kaposi's sarcoma. Conven-tional chemotherapy involved injections of the free drug intravenously.The latter being highly cytotoxic would indiscriminately kill both thehealthy and the tumor cells. The clinical success of Doxil was drivenby its ability to concentrate preferentially in the tumors owing to thesmall size of the delivered nanosystem[42] and the phenomenon of en-hanced permeation and retention in the tumor cells [43]. Similarly,Table 1Nanotechnology-based cosmetic products on the market [29,40,41].S No Product Manufacturer Ingredients1 Plenitude Revitalift (1998) L'oreal Retinol2 Acnel Lotion N(2007) DERMAVIDUALS U.S.A Vitamin F (essential fatty acidsomega 3 and omega 6)3 Cutanova Cream Nano Repair Q10 (2005) Dr. Rimpler Q10, polypeptide, hibiscus extract, ginger extract, ketosugar4 Intensive Serum NanoRepair Q10 (2005) Isabelle Lancray Q10, polypeptide, mafane extract5 Cutanova Cream NanoVital Q10 (2006) Q 10, TiO2, polypeptide, oleanolic acid, sunower seed extract6 SURMER Crme Legre Nano-Protection (2006) Kukuinut oil, Monoi tiare tahiti, milk extract from coconut, wild indigo7 SURMER Crme' Contour Des Yeux Nano-Remodelante(2008)Kukuinut oil, Monoi tiare tahiti, pseudopeptide, hydrolized wheet protein8 NanoLipid Restore CLR (2006) Chemisches Laboratorium Black currant seed oil containing -3 and -6 unsaturated fatty acids9 Nanolipid Q10 CLR (2006) Dr. Kurt Richter, (CLR) Coenzyme Q10 and black currant seed oil10 IOPE SuperVital (2006) Amore Pacic Coenzyme Q10, -3 und -6 unsaturated fatty acids11 Regenerations crme' Intensiv (2007) Scholl Macadamia ternifolia seed oil, avocado oil, urea, black currant seed oil12 Swiss Cellular White Illuminating Eye Essence(2007)La prairie Glycoprotiens, Panax ginseng root extract, Equisetum arvense extract,Camellia sinensis leaf extract13 Skin Caviar ampoules Panax ginseng root extract, Caviar extract, Equisetum arvense extract among others14 Olivenl Anti Falten Pegekonzentrat (2008) Dr. Theiss Olea europaea oil, panthenol, acacia senegal, tocopheryl acetate15 Clearly It! Acne clearing lotion (2008) Kara Vita Retinol, lecithin, tocopheryl acetate, salicylic acid.16 Enlighten Me! (2008) Glycolic acid, kojic acid, hydroquinone17 Eye Tender (2008) Olive fruit oil, green tea extract, squalane, shea butter, tocopheryl acetate,hyaluronic acid18 Nano works shampoo and conditioner (2007) Pureology Green tea, sugar cane, citrus, apple and wine extracts19 Colourmax Chamomile, olive oil, soy milk20 Rewind time (2007) Jamie O skincare Vitamin C21 Ageless skin care miracle kit Freeze 24/7 Camellia sinensis leaf extract, Lupinus albus seed extract, tocopheryl acetate22 Ice Serum advanced brightening serum Licorice root extract and sodium hyaluronate23 Skin Blizzard instant hydrating serum Retinol and grapeseed oil24 Sunforgettable mineral sunscreens Colorescience Inc ZnO and TiO2 nanoparticles25 Olay complete UV protection moisture lotion Procter and Gamble Vitamin E and aloe26 Soltan Face Moisturising Suncare Cream Boots Octocrylene, cyclopentasiloxane, butyl methoxydibenzoylmethane,Bis-ethylhexyloxyphenol methoxyphenyl triazine, titanium dioxide27 Lineless cream Dr Brandt Hydroxyprolisilane, fullerenes, grapeseed extract, green tea28 Platineum restructuring cream Lancom Shea butter, hydroxyapatite, avocado oil, Panax ginseng extract29 Renergie Microlift Ammonium polyacryldimethyltauramide/ammonium polyacryloyldiemthyltaurate, adenosine, yeast extract, hydrolyzed soy protein30 ColorStay Revlon Titanium dioxide, dimethicone, cyclomethicone, retinyl palmitate31 Re-nutriv Este Lauder Shea butter, hibiscus extract, Silybum marianum extract, beta carotene32 Resilience Lift Melon fruit extract, Mimosa tenuiora bark extract, artemia extract, fatty acidsand oils Number in parenthesis denotes the year of launch, wherever available.54 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162Abraxane, approved in 2005 for the treatment of breast cancer andmarketedbyAbraxisBiosciences, wasanother successstoryof ananodrugdeliverysystemwheresystemictoxicityissignicantlylowered while the therapeutic efcacy is improved by simply develop-ing a nanocarrier system [44].3.2.2. ScalabilityThe development of a newpharmaceutical product is deemed com-plete only when it can be produced in industrially signicant quantitieson a large scale [45]. This step of product development is very relevantbecause the procedures employed in the laboratory cannot be mim-icked as such on an industrial scale. Scale-up requires the integrationof technology so that production can occur on a large scale while theproduct retains its unique characteristics. Like other products and deliv-ery systems, nanosized drug products also need to be scalable whileretaining their nano size and novel characteristics.It is very pertinent that the method of preparation of the nanotech-based product being used in the laboratory can be replicated, at leastpartially, in the industrial setup. A perfect example to shed light onthis requirement is in reference to the manufacture of liposomes; inthe laboratory they are mostly prepared using thin lmhydration tech-nique, but the same procedure cannot be employed for large-scale man-ufacture [46]. Regular manufacturing techniques used in the industryare usually not conducive to production of nanotech-based productsasexempliedforliposomalsystems. Moreover, industrypresentsother constraints like limited use of organic solvent due to high costand also due to environmental concerns in addition to the safety ofthe product containing signicant residual amounts of the organic sol-vent. Further to this, some preparations might require sterile prepara-tion and thus the manufacturing facility must be equipped with a welldesigned aseptic area [47] or the product should be rugged enough towithstand heat sterilization procedures. A recent patent (IPA/700/Del/2014) fromour owngroupdenes apath-breakingautoclavablenanovesicular system with capacity to encapsulate a variety of drugmolecules [48]. Shegokar et al. [49] reported a successful scale-up ofstavudine SLNs from lab scale (40 g) to medium scale (10 kg) andlarge scale (2060kg) usingAvestinC30(AvestinInc., Ottawa,Canada) while maintaining the desired particle size of 61.3 nm andPDI of 0.169. Similar reports on successful scale-up exist with Nevira-pine SLNs [50] and Sesamol SLNs [51].It is important that the method of manufacture is designed whilekeeping in mind the constraints faced during manufacture in the indus-try. Use of safe solvents [52] has been studied while performing thescale-up of curcumin-loaded PLGA nanoparticles. Researchers are nowshifting their focus from traditional preparatory techniques to thosewhich are industrially viable e.g. SLNs are widely produced in laborato-ries using the microemulsication technique, and though the techniquehas been scaled up to batches of 1 L [51], however, high-pressure ho-mogenization technique is more tuned to industrial production consid-eringthatthesehomogenizersmaybereadilyavailablewithbothsmall- and large-scale pharmaceutical industries involved in productionof emulsion and suspension-based products [53].Thus, for efcient commercialization of nanotech-based products,their production technique developed in the labs, must be scalableand industrially viable [54]. This would spark interest of manufacturinghouses in such laboratories.3.2.3. ReproducibiltyThe hallmark of a pharmaceutical product reaching the market isthat each and every batch produced would be same in terms of notjust physical appearance but also in characteristics important to thera-py. Nanotech-based products also need to qualify in this arena withlow inter-batch variations, because for a consumer it is important thatthe product does not just look similar but also performs equallywell with every batch. This reproducibility has to be built-in intothe nano drug delivery systemby virtue of the validated manufactur-ing procedure [55].Minute changes in operating conditions can have pronounced ef-fects on nanoparticles; many times even leading to an increase in sizeso that they fall out of the proposed or claimed nano range [56]. Alter-ationinsizeisoneofthemosteasilydetectablechangesthatcanoccur during manufacturing, while many others like altered crystallini-ty, change in drug entrapment and release characters and developmentof surface charge; may cause catastrophic changes in the formulationanditsperformance, if undetected. Also, manynanoformulationscontain biologically active agents like proteins and nucleic acids; andthese products require special attention during manufacture due totheir high susceptibility to degradation.The challenge brought to light here is the need to control batch-to-batch variations during nanotech-based product manufacture at the in-dustrial scale. The use of a robust preparation technique that allows forthe broad operational qualications, and does not change the formula-tion drastically, in case the operating conditionsuctuate within a setlimit due to manual or equipment errors, is highly desirable. Also, im-portant is the need for strict in-process testing to ensure the integrity,bioactivity and uniformity of formulations from one batch to the other[57].3.2.4. Characterization and quality controlAs a corollary to the previous issue, it is important to shed light onthe characterization techniques used for nanotech-based products andthe industry's outlook toward them. Like any other pharmaceuticalmanufacturing procedure, it is essential that manufacturing of theseproducts should include strict quality control checks at each and everystep. These analytical check points help to maintain the quality andreproducibility of the batches which is an essential feature for anymarketed pharmaceutical product [47].Industries are usually equipped with standard analytical equipmentlike hardness testers, dissolution equipment, spectrophotometers andpHmeters. However, nanoparticle characterizationinvolves use of high-ly advanced and sophisticated techniques like microscopy (atomic forcemicroscopy, transmission electron microscopy (TEM), and scanning elec-tron microscopy); measurement of particle size and size distributionwithlight scattering (static and dynamic); analytical ultracentrifugation, capil-lary electrophoresis; analysis of surface charge or zeta potential; examina-tion of surface chemistry by X-ray photoelectron spectroscopy or Fouriertransform infrared spectroscopy; differential scanning calorimetry andX-ray diffraction, among others [58]. These analytical equipment andperformance of these checks are not just expensive but also requiretrained personnel to carry out the analysis and interpret the results.Thus, foranindustrytobeconducivetonanotech-basedproductmanufacturing, it should not just be equipped with specialized analyti-cal techniques but should also have a team of experts to handle theseequipment [47]. This wouldsubstantially add to the cost of manufactureand would denitely deter a company from investing in the develop-ment of such a product. Even if the industry plans to outsource theseanalyses to otherrms, it would still be expensive as each and everybatch would have to be run through several tests and transportationto the premises of investigating institute/company will be required.Ananswer to this situationwouldbe the setting upof analytical clus-ters in vicinity of thriving industrial areas so as to support these indus-tries withsophisticated analytical and characterizationtechniques.Establishment of such a symbiotic industrial framework by the govern-ments would surely help the nano-based drug industry bloom.3.2.5. Translation into suitable dosage formsSolid oral dosage forms are the most extensively prescribed and ac-cepted dosage forms worldwide. Most industries have well-establishedinfrastructure to handle the manufacturing of tablets and capsules.However, most nanotech-based products are often produced in theform of aqueous dispersions. However, conversion of these systems55 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162Table 2Approved nanotechnology-based therapeutic products [6163].Type of nanosystem Product/brandnameCompany/alliance Active ingredient Dosage form FDA approval Indication and remarksPolymeric systems Adagen Enzon Pharmaceuticals Adenosine deaminase Parenteral 1990 Adenosine deaminase enzyme deciencyOncaspar Enzon Pharmaceuticals L-asparaginase Parenteral 1994 Patients with acute lymphoblastic leukemia (ALL) hypersensitiveto native forms of L-asparaginase2006 1st line treatment of patients with ALL; as a component of amulti-agent chemotherapy regimenCopaxone Teva Pharmaceuticals Glatiramir acetate Parenteral 1996 20 mg daily dose; remitting relapsing multiple sclerosis2014 40 mg thrice a week; remitting relapsing multiple sclerosisRenagel Genzyme Pharmaceuticals Sevelamer hydrochloride Oral solid (tablet) 2000 Hyperphosphataemia in dialysis patientsPeg-intron Schering-Plough Peginterferon -2b Parenteral 2001 Hepatitis CPegasys Roche Peginterferon -2a Parenteral 2002 Hepatitis CNeulasta Amgen Peglgrastim Parenteral 2002 NeutropeniaSomavert Pharmacia and Upjohn Pegvisomant Parenteral 2003 AcromegalyMacugen Pzer & Eyetech Pharmaceuticals Pegaptanib Parenteral 2004 Wet age-related macular regenerationMircera Roche Methoxy PEG-epoetin beta Parenteral 2007 Anemia associated with chronic kidney diseaseRenvela Genzyme Pharmaceuticals Sevelamer carbonate Oral solid (tablet) 2007 Hyperphosphataemia in dialysis patientsCimzia UCB Inc. Certolizumab pegol Parenteral 2008 Rheumatoid arthritis2013 Active Ankylosing Spondylitis in adultsSylatron Schering Corp. Peginterferon -2b Parenteral 2011 Melanoma with nodal involvement after surgical resection.Liposomal systems Survanta Abbott Laboratories Beractant (bovine lung homogenate) Suspension (intra-tracheal) 1991 Pediatric respiratory distress syndromeDoxil/Caelyx Ortho Biotech, Schering-Plough Doxorubicin Parenteral 1995 HIV-related Kaposi's sarcoma, metastatic breast cancer andovarian cancerDaunoxome Nexstar Inc. Daunorubicin Parenteral 1996 HIV-related Kaposi's sarcomaAmBisome Gilead Sciences Amphotericin B Parenteral 1997 Fungal and protozoal infections2000 Cryptococcal meningitis in HIV-infected patientsCurosurf Dey laboratories Poractant alfa (porcine lung homogenate) Suspension (intra-tracheal) 1998 Pediatric Respiratory Distress SyndromeVisudyne QLT Inc. Vertepron Parenteral 2000 Wet age-related macular degenerationMyocet Teva Pharma Doxorubicin Parenteral - Breats neoplasms;Approved by EMEA in 2000Estrasorb Novavax Estradiol Topical emulsion 2003 Menopausal hotashesDepoDur SkyePharma PLC and EndoPharmaceuticalsMorphine sulphate Parenteral 2004 PainDepocyt SkyePharma & Enzon Liposomal cytarabine Parenteral 2007 Accelerated approval in 1999; Lymphomatous meningitisInexal V Crucell Virosomal adjuvanted vaccine Parenteral 2008 Marketed in other countries since 1997; Inuenza vaccineSurfaxin Discovery Laboratories synthetic peptide surfactant Suspension (intra-tracheal) 2012 Pediatric respiratory distress syndromeMarqibo Talon Therapeutics Liposomal vincristine sulphate Parenteral 2012 Philadelphia chromosome-negative acute lymphoblastic leukemiaNanocrystal-basedsystemsZanaex Elan Pharmaceuticals Tizanidine HCl Oral solid (capsule) 1996 Muscle spasticityRapamune Wyeth Sirolimus Oral solid (tablet) 2000 Prevention of organ rejectionTricor Abbott Laboratories Fenobrate Oral solid (tablet) 2001 HypercholestrolemiaAvinza Elan Pharmaceuticals Morphine sulphate Oral solid (capsule) 2002 PainRitalin LA Novartis Methylpheni-date HCl Oral solid (tablet) 2002 ADHDEmend Merck Aprepitant Oral solid (capsule) 2003 Chemotherapy induced vomiting2008 Emend injection approved in US; sold as Ivemend in other countriesTriglide SkyePharma Fenobrate Oral solid (tablet) 2005 Lipid disordersFocalin XR Novartis dexmethylphenidate HCl Oral solid (tablet) 2005 ADHDMegace ES Par Pharmaceuticals megestrol acetate Oral liquid (suspensioin) 2005 Appetite stimulantMiscellaneous Eligard Atrix Laboratories Leuprolide acetate Parenteral 2002 Advanced prostate cancerAlimta Eli Lilly Pemetrexed Parenteral 2004 Non-small cell lung cancerAbraxane Abraxis BioScienceAstraZenecaPaclitaxel (taxol) bound albuminnanoparticlesParenteral 2005 Metastatic breast cancer patients who have failed combination therapyElestrin BioSante Calcium phosphatebased nanoparticlesof estradiolTopical gel 2006 Vasomotor symptoms (hotashes) in menopausal women56I.P.Kauretal./JournalofControlledRelease193(2014)5162into solid orals is a formidable task. The process will require large-scalelyophilization of nanoparticle batches to produce a solid or a semisolidpowder. Subsequent to lyophilization, the powder form may belledinto capsules or compressed into a tablet, albeit with other excipients.However, not only is lyophilization an expensive procedure, especiallyif it has to be performed at a large industrial scale but the nanoparticlesmay undergo aggregation and a subsequent increase in size may occurwhichmay not be completely reversible onreconstitution[59]. During ly-ophilization, certain cryo-protectants are also added which may alter thedrug release characteristics of the formulation [60]. It may not be possibleto directly lyophilize the nanoparticulate systemanda step-likedialteration or centrifugation may need to be performed. These stepsagain add to the complexity of the process and make large-scale produc-tion less viable. More so, the integrity of the nal product in terms of thenanonature, stability and biological performance will also need to be re-established. Hence, conversion of aqueous dispersions of nanoparticlesinto solid oral formulations is a capital intensive technical step. Samecould be the reason for the existence of fairly large number of nano-tech-based cosmetic preparations (Table 1) in the market. The latter isagain attributed to the fact that these aqueous dispersions can be easilyincorporated into topical preparations viz. gels and creams still maintain-ing the nanonature of these systems.Thus, to fully utilize the potential of nanotech-based products, tech-niques need to be devised to use them as solid dosage forms or try andimprove their acceptance as liquid orals. However, use of such dispersesystemsasparenteralsespeciallyascarriersforchemotherapeuticagents (Table 2), is highly viable, provided their sterile production ornal sterilization, per se, is not an issue.A glance of the approved therapeutic products in the last two de-cades (Table 2) indicates the existence of a large number of parenteralproducts but relatively fewer oral dosage forms. Thus, to fully utilizethe potential of nanotech-based products, techniques need to be de-vised to develop them as solid dosage forms or improve their accep-tance as liquid orals.3.2.6. Lack of multidisciplinary platformNanotech-based products belong to an interdisciplinary area, wherelife sciences interacts closely with nanoscience, nanoengineering, andnanotechnology [19]. Thus transdiscipilinary approach is required notonly for the conception of the idea, but also for its development, scale-up, evaluation, and nally its successful commercialization [64]. No sin-gle professional has all the necessary skills to bring a nanotech productto the market on its own. Furthermore, those in the scientic eld gen-erally lack the understanding or the business acumen required to con-vert technology into a commercialized product.On the other handinvestors want to get involved with the next big thing but generallylack the patience and technical expertise required in the developmentand evaluation of these nanotech-based products [9,19].Moreover, the unidisciplinary treatment given to these productsmakes them rather complex when a single person tries to answer ormeet the questions and special requirements outside of their limited ex-pertise and prociency. While, better answers may be obtained to ques-tions raised during product development, if a multidisciplinary team ofscientists and researchers involving formulation scientist, economist,statistician, engineer, and a chemist come together to hold intense de-liberationsandconsolidatetheoriesinreferencetotheseproducts[65]. It is for this reason that the National Institute of Health (NIH)roadmaptothefuturefornanomedicine isfundingcenterstobring different disciplines together to adequately address various is-sues pertaining to nanotech-based products [66]3.3. Inadequate regulationInternationally, regulatory guidance for nanotechnology is generallylacking. A major problem that regulators, policymakers, researchers,and lawyers are presently facing in reference to nanotechnology isassigning an all encompassing denition to it. Although widely used,no single internationally acceptable denition of nanotechnology isyet in order [67,68]. FDA has not yet adopted a formal denition ofnanotechnology, nanoscale, or related terms, howsoever some FDA-regulated products do contain nanomaterials or involve the applicationof nanotechnology. However, in its draft guidelines (Guidance for In-dustry Safety of Nanomaterials in Cosmetic Products, 2012), it is indicat-ed that engineered material/products that have at least one dimensioninthe nanoscale range (approximately 1100 nm); or exhibit propertiesor phenomena, including physical or chemical properties or biologicaleffects, that are attributable to its dimension(s), even if these dimen-sions fall outside the nanoscale range, up to 1 m may be consideredto fall under the category of nanoscale/nanotech products [69]. Howev-er, there are challenges in deciding howto address aggregates, agglom-erates and some other complex structures and there is also a need toconsider an account on novel engineering properties of nanoproductsforregulatorypurposes[10]. Sincenanoparticlesarecomposedofdifferent materials, with unique surface properties and enhanced reac-tivity[22], hencetheyarenotbioequivalent(ratherseveral timesmore active) to the parent version in general. Therefore, AbbreviatedNew Drug Application (ANDA) under section 505(b) (j) of the FederalFood, Drug, and Cosmetic Act cannot be applied to them [70,71].The FDAis a critically important regulatory agency of the US govern-ment. The breadth of products that it regulates represents about 20% ofUS consumer products worth billions of dollars. Employing various lawsand regulatory mechanisms and depending on the particular productclass, the FDA conducts specic pre-market and/or post-market over-sight [72] and fruitful efforts are then made for developing harmonizedregulatory guidelines for nanotechnology and nanotech products.Regulating nanoproducts, whether they are a drug, device, biological,food and color additive or a combination thereof, is creating challengesfor FDA regulators as they struggle to accumulate data. Formulating test-ing criteria with better predictive and risk assessment capacity on theseproducts, their physiochemical characterization, biological evaluation,and a need for new expertise to ensure the development of safe and ef-cacious nanoproducts is presently the main concern of FDA [11,73].To facilitate the regulationof nanoproducts, the FDAformeda Nanotech-nology Task Force, which came out with a report in 2007. Experts [72] inthe eldfeel that this report inadvertently indicates that the existing reg-ulations may for the time being sufce for evaluation and safetyofnanoproducts. This was attributed to the comprehensive nature of theexisting guidelines, and FDA felt that since these products would under-go a pre-market testing and approval either as newdrugs under the NewDrug Application(NDA) process or under the Class III Premarket Approv-al (PMA) process, so they will be subjected to suitable evaluation param-eters [34,74]. Further, it was presumed that the regulatory requirementspresently in place, would detect any and all toxicity via clinical studies,even if nanoproducts presented, size-related unique nano properties.However, these assumptions are debatable. This is especially so, becausemost of the nanoproducts approved by the FDA are partly or whollybased on the studies of non-nanoversions or bulk counterparts. Onemajor contradiction to this pretension is that since nanoproducts areusually more effective so they require administration at a lower doseand hence a chance of observing drug-related toxicity is diminished.Howsoever, it has now been pointed out that the techniques used fortoxicity evaluation has been developed to detect only the drug-relatedadverse events while their capacity to evaluate nanomaterials or drugencapsulated in the nanocarrier is limited or unconrmed. All the samereport does indicate that the FDA can ask for more data or tests to ensuresafety and efcacy of a nanoproduct, depending on its nature and relatedcharacteristics [34]. Another aspect of concern is that FDA regulatesnanoproducts and not the nanotechnology involved therein [75].In 2011, the FDA reopened dialog on nanotech regulation by pub-lishing a draft guideline on how the agency will identify whether FDAregulated products contain nanomaterials or involve the application ofnanotechnology. Alsoin2011, theFDAcommissioner, Dr. Margaret57 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162Hamburg, emphasized on a science-based nanoregulation [76], in whichit was claimed by the FDA that their goal is to regulate these productsusing the best possible science. It was indicated by the FDA that under-standing nanotechnology remains a top priority within the agency's reg-ulatory science initiative and, in doing so, it is prepared to usher science,public health, and FDA into a new and a more innovative era.Furthermore in 2012, the FDA commissioner summarized a broadlyinclusive initial approach with respect to nanogovernance in a two-page policy paper published in Science [76]. To set at rest the general ap-prehensions of both the public and the prescribing physicians, FDA cat-egoricallyindicated inthe paper that it willnot judge all productscontaining nonmaterial or otherwise involving the application of nano-technology, as intrinsically benign or harmful. This statement was prob-ably issued with reference to the fact that, advances in both basic andapplied nanotechnology science may be unpredictable, rapid, and un-evenly distributed across product applications and risk managementtools such that each product or technology will need to be consideredin isolation from case to case. The guidelines may not apply generallyto all products but may need to be limited to or framed for special prod-uct types. It may thus be appreciated here that FDA is careful but notwary of nanotech-based products.Recently, FDA published its 2013 Nanotechnology Regulatory Sci-ence Research Plan whose goal was to provide a coordinated leadershipof FDA's regulatory science research, to address key scientic gaps inknowledge, methods, or tools (Fig. 2) needed to make assessment ofnano products [77]. This plan identies eight priority topics for theagency to focus on, in the upcoming years which fall within the fourareas dened by FDA in its program (Fig. 2). The research plan clearlyindicates the readiness of FDAto evaluate innovative emerging technol-ogies of which nanotechnology is a strategic part.Under this plan, the major thrust was to develop suitable toxicolog-ical techniques onpriority (topic 1), and dene clinical evaluation(topic2) models and parameters, in addition to promoting a multidisciplinaryand coordinated effort to identify ways to improve product manufac-ture and quality (topic 3), accumulate sufcient information (topic 5)to improve health outcomes, and interface between social and behavioral(topic 8) science to help public to evaluate the innovative emerging tech-nology without any preconceived notions and to arrive at more informeddecisions. Other topics of concern were prevention-focused food safetysystems (topic 6) and development of medical countermeasures for glob-al health and security (topic 7) in order to indicate FDA's readiness toevaluate innovative emerging technologies (topic 4).Intent of the framework is to ensure transparency and public aware-ness of FDA's activities and its investment strategy in nanotechnologyregulatory science to formulate consistent andpredictable pathway. An-other aim of the research plan is to enhance or facilitate developmentand availability of safe and effective FDA-regulated products that con-tain or apply the science of nanotechnology.Inspite of these toddler steps by the FDA regarding nanoregulation,most experts continue to criticize its rather lax and uncoordinated effortas no clear framework has yet been designed by it to produce the realworld regulatory guidelines that can be depended upon by industryand consumers alike. However, going through various publications inthis regardandlistening tovarious researchers including someFig. 2. A consolidated FDA Nanotechnology Regulatory Science Research plan framework covering the four areas (IIV) dened by it. In the same programUSFDA identied eight prioritytopics which have been linked here with the key areas. For a better comprehension, numbers in brackets, indicate the dened priority topics.58 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162regulatory persons at various conferences we strongly feel that it seemsthe absence of guidelines should not deter the researcher/investor fromsubmitting their application for approval, of the nano-particulate prod-uct, to FDA. Once an academician or a potential researcher,le submis-sionstoFDAwithsufcient data, proclaimingthebenetsof theproduct, the onus would automatically shift to the regulatory hands toeither make a favorable decision or ask for more data if not satised.The latter will in itself overcome the limitation of absent regulatoryframework. The process may become a little lengthy, whichrequires ad-dressing of the queries as and when they are raised by the regulators.FDAhas indicated that the rst stage will be the assessment that wheth-er any special test is required for the proposed nanoproduct, which willsubsequently be followed by dening and assessing the individual testmethodappliedfortestingandtheneedformodicationofthesetests, if required. But one must understand that it is only the regulatorysatisfaction which plays an immense role for receiving approvals ofnanotech products rather than compliance to any framework, which ispresently nonexistent.In the present scenario the choice thus lies with the investor or theinventor to keep their data or product in abeyance and keep contendingthe need for dening guidelines, or, take the leap and do theling. Inthis regard FDA also encourages industry to consult early with the agen-cy to address any questions related to the safety, effectiveness, or otherattributes of products that contain nanomaterials, or about the regulato-ry status of such products.3.4. Lack of support3.4.1. IndustryMajorly it is the small- and medium-sized enterprise (SME) which ispresently involved in nanotech-based product research [22]. Evidencehas however shown that these SMEs are seldom successful in commer-cializing any new product without support of multinational companies[78]. Therefore collaboration with larger pharmaceutical companies iscrucial and important for the success of nanotech-based products [79].However, for large pharmaceutical companies, the protability of theirtraditional blockbuster drugs is so high, that, they do not wish to takea risk by investing in nanotherapeutics: the latter has high uncertaintyassociated with their safety and efcacy [9,19] (Fig. 3) making thesecompanies highly apprehensive. There are conventional areas wherereturns on investment may be 35 years away whereas in the area ofnanotech-based product, uncertainty is high, risk of delay or even lowreturnsduringtheinitialphaseismore, andattimesmayrequirelarge investments (Fig. 3).It has to be noted that investor's risk aversion attitude for mostnanotech-based products unfortunately is based on unfamiliarity ratherthan on facts [80]. Majority of the market makers are still sitting on side-lines waiting and watching for the market to mature so as to accept thepromise offered by such products.However, good returns can be ensured by a more accurate risk assess-ment by the investors. An elaborate and exhaustive pharmacoeconomicFig. 3. Investors concerns: Selection between conventional blockbuster products and nanotech-based products.59 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162analysiswouldallowtheefcientallocationofmonetaryresources,allowing maximization of highest returns at low incurred costs [19]. Ap-proaches like cost-effective analysis (CEA) canhelptoconvince private in-vestors or third-party payers in the viability of these products [22]. Thereturns on these products are not limited to money, but also need to beconsidered in terms of improved patient health thus reducing the totalduration and cost of therapy which will also manifest in terms of lowhealth insurance costs and government investments [81]. CEA is helpfulin demonstrating whether the cost per additional health effect is worthpaying for. It will also play an important role in identifying the failure/risk associated with new nanotech-based products in advance, therebyavoiding wastage of resources. The most common approach used to esti-mate cost effectiveness is to calculate quality adjusted life years (QALY)[22]. Since health burden on the society is borne by the governmentand the taxpayer's money, therefore a more intelligent and farsighted ap-proach for the government, the health organizations and the researcherswould be to smartly and intelligently invest resources (time, manpower,andmoney) to developtechnologies whichcancater toimproving qualityand span of life. Nowadays, organizations like NIH have started seekingQALY as an important criterion for calculation of cost-effectiveness of anew medicine [81].Two FDA-approved formulations of amphotericin B, AmBisome (li-posomal system) sold by Gilead Sciences and Fujisawa Healthcare andAbelcet (lipid complex) marketed by Elan Corporation, for treatmentof fungal infection were subjected to pharmacoeconomic studies. Re-sults of the analysis indicated AmBisome to be more cost effective andbetter accepted in the market in comparison to Abelcet [19],Further to this, initiatives have to be taken to bridge the gapbetweenthe laboratory-based research and the industrial applications of nano-tech-based products so as to facilitate their commercialization ratherthan producing publications (a few of which are indeed high quality)or the randomling of patents. In this regard European Commissionhas started aninitiative called NanoCom in November 2012 with a sim-ilar mandate [82].3.4.2. PublicSuccessful commercialization of nanotech-based product is primari-ly dependent on their reputation with the general public. Unfortunatelydespite its huge potential health benets, the general public is relativelyignorant of these products. Even among informed citizens, perceptionsvary widely, leading to a plethora of reservations and opinions on theassociateddebatesregardingtoxicity, environmental damageandlong-term effects of these nanotech-based products [22]. Lack of infor-mation and inadequate communication gives rise to doubts, distrustand even fear. This may lead not only to the dismissal of a specicnanomedical project, but may also endanger the future of nanotechnol-ogy as a whole. However, the picture is not so dismal. ArmcalledNovaCentrix in Texas USA has raised 25 million dollars in past 9 years as aresult of a joint venture of public, government and industry to reinforcethe intent to develop these nanotech-based products for the generalbenet of the society [7].3.4.3. PhysiciansPhysicians' need for newer therapeutic options is the major drivingforce for development of novel products and their faith in the products'performance governs the success of such products. However, in case ofnanotech-based products, physicians have signicant concern regard-ing their safety and efcacy. Failure of a nanoproduct developed byMagForce Nanotechnologies, Germany, a major player in theeld ofnanotechnologies, fortumorcurewithminimalsideeffectsisonesuch example where a product failed due to the lack of acceptability/faith shown by the physicians for it [22]. Although MagForce investedheavilyincampaigningtheir promisingnewtechnologythroughjournals and on television, the technology failed to gain a widespreadacceptance due to their unsuccessful effort to make the medical com-munity aware of and receptive toward their technology [83].Furthermore it is generally difcult to get approvals for conductingclinical trials with these agents thus limiting the prior exposure of clini-cians to such products to gain condence in their performance [22].3.5. Poor intellectual property protectionMost patents risk expiry within a short span of their commerciallaunch due to the long period of development required for nanotech-based products [22]. Consequently, the number of years available for re-covery of developmental costs and to earna reasonable prot to encour-age further innovation in this particular area is simply too short. Thisdiscouraging scenario of extremely low, expected returns, andFig. 4. Proposed journey of a nanotech product from conception to a successful commercial venture.60 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162uncertainty and risk associated with these projects has deterred compa-nies to invest in nanotech-based products. According to the informationobtained from the US Patent and Trademark ofce (PTO), as of Decem-ber 2012 over 8000 US nanopatents have been issued by various PTOtechnology centers [10,84]. Because of excessive patent proliferationand continued issuance of surprisingly broad patents by the patentand trademark ofce (PTO) in this eld, issues like overlapping patentslead to signicant disputes [70]. A classsic example is the issue of multi-ple US patents (approx. 200) on carbon nanotubes with highly overlap-ping or legally identical patent claims [10].In this regard, it is suggested that the industry and academia shouldcome together to strike an interface so that the long and expensive in-puts made by the scientic community and its insight in the benetsof nanotechnology can be translated directly to the market. This will re-duce the time invested initially in the development of a product and itspatent ling which may already have been initiated by the involved re-search organization or the individual scientist.4. ConclusionsDespite all the issues including safety, lack of multidisciplinary plat-form, poor intellectual property protection, uncertainty of expectedreturns, scalability and reproducibility concerns, and meticulous andlengthy FDA regulatory processes, investments in the market of nano-tech-based products are predicted to increase (Fig. 4). However, wefeel that some proactive changes in the conventional approach to prod-uct development, technology transfer, and regulations need to be madebefore sucha promising technology canreachthe market. Some of thesepoints are consolidated and listed below for the benet of the readers,researchers and investors involved in the area: Regulatory agencies need to be more creative in developing newmodels of technological governance through better coordination andharmonization of existing regulatory procedures (smart regulations)[22]. A suggestion to the scientic community in this regard is thatthey do not need to wait for FDA to draw regulations. The advice isthat if you believe in your science, just go ahead andle approvals. We need to include approaches like cost-effective analysis (CEA)which can help in convincing private investors or third-party payersin the viability of these products. This will help in abandoning devel-opment of unsuccessful drugs in initial stages and will save resourcesfor more promising compounds. Public awareness regarding benet over risk of new therapeutics is amust for acceptance of these products followed by their successfulcommercialization. One way of informing the public is through orga-nizing public debates, conferences and other educational events. The patent and trademark ofce (PTO) needs to be more vigilant in is-suing wide patents inorder to avoid overlapof patents. Incase overlapis suspected, the PTO needs to determine which inventor conceivedthe invention rst or it may opt for cross licensing of patents. The lat-ter strategy can help to settle disputes which may arise from suchoverlap. Nanotechnology is a team sport which requires multidisciplinaryplatform. All the persons involved need to appreciate that it is a ne-cessity and not an option to involve a multipronged team and atti-tude. Being comparatively new in market, we feel this technology needstime to generate sufcient data proving its safety, only then people(public, physicians, industry) will develop condence andnally ac-cept it. So all those involved need to be kind enough to grant a suf-cient lag time to nanotechnology before touting it as redundant. Joint initiatives like Nanocom have to be taken to bridge the gap be-tween the laboratory-based and the industrial applications of nano-tech-based products.Nobel Laureate Horst Stormer has probably said it the best: Nano-technology has given us the toolsto play with the ultimate box ofnatureatoms and molecules. Everything is made of it.. The possibil-ities to create new things appear to be limitless [85]. We concludeour discussion with a message to understand that there is only ONESCIENCE. Nano is just a part of it, even if it is considered to be a par-adigm shift from the conventional science.DeclarationDr. Vandita Kakkar helped in conception of the review. Parneet KaurDeol was involved in conception, compiling of information, consolida-tion and framing the manuscript in the present form. All other co-authors contributed equally.References[1] http://www.nano.gov/nanotech-101/what/denition(Accessed on 1 March 2014).[2] OECD Working Party on Nanotechnology (WPN): Vision Statement 2010, http://www.oecd.org/sti/nano/oecdworkingpartyonnanotechnologywpnvisionstatement.htm 2010 (Accessed on 28 February 2014).[3] C. Palmberg, The transfer and commercialisation of nanotechnology: a comparativeanalysisof universityandcompanyresearches, J. Technol. Transf. 33(2008)631652.[4] L. Mazzola, Commercializing nanotechnology, Nat. Biotechnol. 21 (2003) 11371143.[5] http://www.nanotechproject.org/inventories/ (Accessed on 2 March 2014).[6] www.luxresearchinc.com(Accessed on 27 February 2014).[7] How can a big state like Texas become a leader in development of small products?Introductionsmall is becomingbigbusiness, https://www.google.co.in/#q=NovaCentrix:+Growing+an+Ultratiny+Company (Accessed on 2 March 2014).[8] Market Opportunities in Nanotechnology Drug Delivery, Cientica Ltd, 2012. 119.[9] T. Flynn, C. Wei, The pathway to commercialization for nanomedicine, Nanomedicine:NBM 1 (2005) 4751.[10] R.A. Stein, Nanotechnology: is the magic bullet becoming reality? Insight and Intel-ligence, 2014.[11] M. Taylor, Regulating the Products of Nanotechnology: Does FDA Have the Tools ItNeeds? Wilson Center and The Pew Charitable Trusts, Washington, 2006.[12] The National Nanotechnology Initiative supplements to the president's 2014 budget(2013) 188.[13] A. Reamer, L. Icerman, J. Youtie, Technology Transfer and Commercialization: TheirRole in Economic Development, U.S. Department of Commerce, 2003.[14] Technology Commercialization, The Handbook of Technology Transfer, Pacic Cen-ter for Technology Transfer, Asia, 2005.[15] T. Spinverse, Commercialisation of NanotechnologyKey Challenges WorkshopOrganised by Nanoforum in Helsinki, Finland, 2007. 127.[16] R. Allen, Venture capital investment in nanotechnology, http://www.jonesday.com/practiceperspectives/nanotechnology/venture_capital.html (Accessed on 2 March2014).[17] J. Bradley, Nanotech venture capital: healthcare and life sciences provide life sup-port, https://portal.luxresearchinc.com/research/document_excerpt/5891 2009(Accessed on 4 March 2014).[18] T. Sattereld, M. Kandlikar, C. Beaudrie, J. Conti, B. Harthorn, Anticipating the per-ceived risk of nanotechnologies, Nat. Nanotechnol. 4 (2009) 752758.[19] V. Morigi, A. Tocchio, C. Pellegrini, J. Sakamoto, M. Arnone, E. Tasciotti, Nanotechnol-ogy in medicine: from inception to market domination, J. Drug Deliv. (2012) 17.[20] USFDA, www.fda.gov/safety 2003 (Accessed on 20 March 2014).[21] K. Vega-Villa, J. Takemoto, J. Yanez, C. Remsberg, M. Forrest, N. Davies, Clinical tox-icities of nanocarrier systems, Adv. Drug Deliv. Rev. 60 (2008) 929938.[22] R. Bosetti, L. Vereeck, Future of nanomedicine obstacles and remedies, Nanomedicine 6(2011) 747755.[23] S. Suppan, Racing Ahead U.S. Agri-Nanotechnology in the Absence of Regulation, In-stitute for Agriculture and Trade Policy, 2011. 320.[24] A.M. Hahn, A.K. Singh, P. Sharma, C.B. Scott, M.M. Brij, Nanoparticles as contrastagents for in-vivo bioimaging: current status and future perspectives, Anal. Bioanal.Chem. 399 (2011) 327.[25] E. Altnolu, T.J. Russin, J.M. Kaiser, B.M. Barth, P.C. Eklund, M. Kester, J.H. Adair,Near-infrared emittinguorophore-doped calcium phosphate nanoparticles forinvivo imaging of human breast cancer, ACS Nano 2 (2008) 20752084.[26] W. Soutter, Nanotechnology in Cosmetics, vol. 20142012.[27] K. Donaldson, P.H. Beswick, P.S. Gilmour, Free radical activity associated with thesurface of particles: a unifying factor in determining biological activity? Toxicol.Lett. 88 (13) (1996) 293298.[28] C. Lherm, R.H. Mller, F. Puisieux, P. Couvreur, Alkylcyanoacrylate drug carriers. II.Cytotoxicity of In vitro uptake of polystyrene latex cyanoacrylate nanoparticleswith different alkyl chain length, Int. J. Pharm. 84 (1992) 1322.[29] S. Raj, S. Jose, U.S. Sumod, M. Sabitha, Nanotechnology in cosmetics: opportunitiesand challenges, J. Pharm. Bioallied Sci. 4 (3) (2012) 186193.[30] Small Wonder? Nanotechnology and Cosmetics, vol. 20142008.[31] Safety Fears Over Nanocosmetics, vol. 2014BBC News, 2008.[32] Nanoparticles Found in 10 Top Brand Cosmetics, vol. 2014Friends of the EarthAustralia, 2009.[33] Nanotech Widespread in Cosmetics, Report Finds, vol. 2014The Sydney MorningHerald, 2009.61 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162[34] US FDA, Nanotechnology: a report of the U.S. Food and Drug Administration Nano-technology Task Force, 23 July 2007, available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108954.htm(Accessed on 24 February2014).[35] A. Kumari, S.K. Yadav, S.C. Yadav, Biodegradable polymeric nanoparticles based drugdelivery systems, Colloids Surf. B 75 (2010) 118.[36] J. Mehta, J. Blake, C. Craddock, Comparative efcacy of amphotericin B lipid complexand liposomal amphotericin B for the treatment of invasive fungal infections inHSCT recipients and other immunocompromised patient populations with hemato-logic malignancies: a critical review, Open Transplant. J. 5 (2011) 2329.[37] A.C. Silva, M.L. Garcia, M.A. Egea, J. Fonseca, R. Silva, Preparation, characterizationand biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN):high pressure homogenization versus ultrasound, Colloids Surf. B: Biointerfaces 86(2011) 158165.[38] R.H. Muller, S. Runge, K. Schulze-Forster, W. Mehnert, Cytotoxicity of solid lipidnanoparticles as a function of the lipid matrix and the surfactant, Pharm. Res. 4(1997) 458462.[39] M. Nassimi, H.D. Lauenstein, R. Hussein, H.G. Hoymann, W. Koch, A toxicologicalevaluation of inhaled solid lipid nanoparticles used as a potential drug delivery sys-tem for the lung, Eur. J. Pharm. Biopharm. 75 (2010) 107116.[40] Consumer products inventory, The Project on Emerging Nanotechnologies, 2014.(http://www.nanotechproject.org/cpi/ . Accessed on 1 March 2014).[41] J. Pardeike, A. Hommoss, R.H. Muller, Lipid nanoparticles (SLN, NLC) in cosmetic andpharmaceutical dermal products, Int. J. Pharm. 366 (2009) 170184.[42] M. Ferrari, Nanogeometry: beyond drug delivery, Nat. Nanotechnol. 3 (2008) 131132.[43] Y. Barenholz, Doxil - The rst FDA approved nanodrug: lessons learned, J. Control.Release 160 (2012) 117134.[44] J.H. Sakamoto, A.L. van de Ven, B. Godin, E. Blanco, R.E. Serda, A. Grattoni, A. Ziemys,A. Bouamrani, T. Hu, S.I. Ranganathan, E. De Rosa, J.O. Martinez, C.A. Smid, R.M.Buchanan, S.Y. Lee, S. Srinivasan, M. Landry, A. Meyn, E. Tasciotti, X. Liu, P.Decuzzi, M. Ferrari, Enablingindividualizedtherapythroughnanotechnology,Pharmacol. Res. 62 (2010) 5789.[45] F.L. Muller, J.M. Latimer, Anticipation of scale up issues in pharmaceutical develop-ment, Comput. Chem. Eng. 33 (2009) 10511055.[46] A. Laouini, C. Jaafar-Maalej, I. Limayem-Blouza, S. Sfar, C. Charcosset, H. Fessi, Prep-aration, characterization and applications of liposomes: state of the art, J. Colloid Sci.Biotechnol. 1 (2012) 147168.[47] N. Desai, Challenges in development of nanoparticle-based therapeutics, AAPS J. 14(2012) 282295.[48] I. Kaur, S. Kakkar, M. Yadav, K. Jindal, I. Sharma, Autoclavable nanovesicular compo-sition, IPA/700/Del/2014, 2014. (Filed on 11 March 2014).[49] R. Shegokar, K.K. Singh, R.H. Mller, Production & stability of stavudine solid lipidnanoparticlesFrom lab to industrial scale, Int. J. Pharm. 416 (2011) 461470.[50] R. Shegokar, K.K. Singh, R.H. Mueller, Nevirapine nanosuspension: comparative in-vestigation of production methods, Nanotechnol. Dev. 1 (2011) e4.[51] V. Kakkar, I.P. Kaur, Preparation, characterization and scale-up of sesamol loadedsolid lipid nanoparticles, Nanotechnol. Dev. 2 (2012) 4045.[52] A.P. Ranjan, A. Mukerjee, L. Helson, J.K. Vishwanatha, Scale up, optimization and sta-bility analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy, J.Nanobiotechnol. 10 (2012) 38.[53] R.H. Muller, K. Mader, S. Gohla, Solid lipid nanoparticles (SLN) for controlled drugdelivery - A review of the state of the art, Eur. J. Pharm. Biopharm. 50 (2000)161177.[54] S.A. Galindo-Rodriguez, F. Puel, S. Briancon, E. Allemann, E. Doelker, H. Fessi, Com-parative scale-up of three methods for producing ibuprofen-loaded nanoparticles,Eur. J. Pharm. Sci. 25 (2005) 357367.[55] M.M. Mojahedian, S. Daneshamouz, S.M. Samani, A. Zargaran, A novel method toproduce solid lipid nanoparticles using n-butanol as an additional co-surfactant ac-cording to the o/w microemulsion quenching technique, Chem. Phys. Lipids 174(2013) 3238.[56] M. Gaumet, A. Vargas, R. Gurny, F. Delie, Nanoparticles for drug delivery: the needfor precision in reporting particle size parameters, Eur. J. Pharm. Biopharm. 69(2008) 19.[57] K. Langer, M.G. Anhorn, I. Steinhauser, S. Dreis, D. Celebi, N. Schrickel, S. Faust, V.Vogel, Human serum albumin (HSA) nanoparticles: reproducibility of preparationprocess and kinetics of enzymatic degradation, Int. J. Pharm. 347 (12) (2008)109117.[58] W. Mehnert, K. Mader, Solid lipid nanoparticles: production, characterization andapplications, Adv. Drug Deliv. Rev. 47 (2001) 165196.[59] A. Saez, M. Guzman, J. Molpeceres, M.R. Aberturas, Freeze-drying of polycaprolactoneand poly(D, L-lactic-glycolic) nanoparticles induce minor particle size changes affectingtheoralpharmacokineticsofloadeddrugs, Eur. J. Pharm. Biopharm. 50(2000)379387.[60] P. Fonte, S. Soares, A. Costa, J.C. Andrade, V. Seabra, S. Reis, B. Sarmento, Effect ofcryoprotectants on the porosity and stability of insulin-loaded PLGA nanoparticlesafter freeze-drying, Biomatter 2 (2013) 329339.[61] C.L. Ventola, The nanomedicine revolution Part 3. Regulatory and safety challenges,Pharm. Ther. 37 (2012) 632639.[62] L. Zhang, F.X. Gu, J.M. Chan, A.Z. Wang, R.S. Langer, O.C. Farokhzad, Nanoparticles inmedicine: therapeutic applications and developments, Clin. Pharmacol. Ther. 83 (5)(2008) 761769.[63] R. Duncan, R. Gaspar, Nanomedicine(s) under the microscope, Mol. Pharm. 8 (6)(2011) 21012141.[64] G. Heimeriks, Interdisciplinarity in biotechnology, genomics and nanotechnology,Sci. Public Policy 40 (2013) 97112.[65] D. Mowery, Nanotechnology and the US national innovation system: continuity andchange, J. Technol. Transf. 36 (2011) 697711.[66] L. Kantor, NIH roadmap for medical research, Alcohol Res. Health 31 (2008) 1213.[67] R. Bawa, Special report: patentsandnanomedicine, Nanomedicine2(2007)351374.[68] R. Bawa, Patenting inventions in bionanotechnology A primer for scientists andlawyers, in: D.E. Reisner (Ed.), Bionanotechnology: Global Prospects, CRC Press,Boca Raton FL, 2009, pp. 309337.[69] FDA, Guidance for Industry Safety of Nanomaterials in Cosmetic Products, 2012.124.[70] R. Bawa, Nanopharmaceuticals, eujnm, 32010. 3439.[71] H.M. Mansour, C.W. Park, R. Bawa, Design and development of approvednanopharmaceutical products, in: R. Bawa, G. Audette, I. Rubinstein (Eds.), Hand-bookof clinical nanomedicine-frombenchtobeadsideremedies, vol. 1, PanStanford publishing/CRC press, Singapore, 2014.[72] R. Bawa, FDA and nanotech: baby steps lead to regulatory uncertainty, in: D. Bagchi(Ed.), Bionanotechnology: A Revolution in Biomedical Sciences and Human Health,Wiley Blackwell, UK, 2013, pp. 720732.[73] R. Bawa, Regulating nanomedicinecan the FDA handle it? Curr. Drug Deliv. 8(2011) 227234.[74] C. Rados, Nanotechnology: the size of things to come, FDA consumer Nov-Dec, 2005.4042.[75] G. Mendel, Nanotechnology governance, Albany Law Rev. 59 (2008) 13231329.[76] M. Hamburg, FDA's approach to regulation of products of nanotechnology, Science336 (2012) 299300.[77] US FDA, Nanotechnology Regulatory Science Research Plan, http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm273325.htm 2013 (Accessedon 1 March 2014).[78] V. Wagner, A. Dullaart, A. Bock, A. Zweck, The emerging nanomedicine landscape,Nat. Biotechnol. 24 (2006) 12111217.[79] R. Bawa, S. Melethil, W. Simmons, D. Harris, Nanopharmaceuticalspatenting issuesand FDA regulatory challenges, Am. Bar Assoc. Sci. Technol. Lawyer 5 (2008) 1015.[80] D. Kahan, D. Braman, P. Slovic, J. Gastil, G. Cohen, Cultural cognition of the risks andbenets of nanotechnology, Nat. Nanotechnol. 4 (2009) 8791.[81] http://www.nice.org.uk/newsroom/features/measuringeffectivenessandcosteffectivenesstheqaly.jsp (Accessedon2march2014).[82] NANOCOM, http://www.nanocom-eu.org/NanoCom/Homepage.html 2012 (Accessedon 18 February 2014).[83] NanoMed Round Table Communication Working Group, www.nanomedroundtable.org/system/les/private/WP6%20Communication_Annex1.pdf (Accessed on 20February 2014).[84] J. Paradise, Claiming nanotechnology: improving USPTO efforts at classication ofemerging nano-enabled pharmaceutical technologies, Northwest. J. Technol. Intel-lect. Prop. 10 (2012) 171189.[85] H. Stormer, Capital Report on Nanotechnology, Lux Research, New York, 2002.62 I.P. Kaur et al. / Journal of Controlled Release 193 (2014) 5162