Nanotherapeutics in the EU: an overview on current state and future directions

Figures & data

Figure 1 Rationale for the nanotherapeutic approach.

Abbreviation: R&D, research and development.

Table 1 Examples of commercially available nanotherapeutic products for oral administration in the EU

Nanotechnology-based approach	Drug	Major indication	Dosage form	Brand name (Manufacturer* info source)	Marketing authorization in Europe**
Nanocrystals	Sirolimus	Graft rejection, Kidney transplantation	Tablet	Rapamune® (Pfizer Ireland Pharmaceuticals, Dublin, IE)	CP: -MAH: Pfizer Ltd, Tadworth, UK
	Fenofibrate	Hypercholesterolemia	Tablet	Tricor®/Lipanthyl®/Lipidil® (Recipharm, Fontaine, FR)	MRP: -RMS: DE -CMS: AT, BE, CZ, FI, FR, EL, ES, HU, IE, IT, LU, PL, SK -MAH in RMS: Abbott Arzneimittel GmbH, Wiesbaden, DE NP: HR
	Aprepitant	Postoperative nausea and vomiting, Vomiting, Cancer	Capsule	Emend® (Merck Sharp and Dohme BV, Haarlem, NL)	CP: -MAH: Merck Sharp and Dohme, Hoddesdon, UK
Nanoemulsions	Cyclosporine	Prophylaxis of organ rejection following organ transplant	Soft capsules	Neoral® (Novartis AG, Basel, CH)	NP: FR, HR, IE, NL, UK -MAH: Novartis AG, CH
	Ritonavir	HIV infections	Soft capsules	Norvir® (Aesica Queenborough Ltd, Queenborough, UK)	CP: -MAH: Abbvie Ltd, Maidenhead, UK
Polymeric drugs	Sevelamer	Hyperphosphatemia, Renal dialysis	Tablet	Renagel® (Genzyme Ltd, Oxford, UK)/Renvela® (Genzyme Ireland Ltd, Co, Waterford City, IE)	CP: -MAH: Genzyme Europe BV, Naarden, NL

Notes:

* Manufacturer responsible for batch release as stated in package leaflet approved in the EU

** EMA, HMA, national regulatory authorities’ information source.

Abbreviations: AT, Austria; BE, Belgium; BG, Bulgaria; CH, Switzerland; -CMS, concerned member state; CP, centralized procedure; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; EMA, European Medicines Agency; ES, Spain; FI, Finland; FR, France; HMA, Heads of Medicines Agencies; HR, Croatia; HU, Hungary; IE, Ireland; IS, Iceland; IT, Italy; LT, Lithuania; LU, Luxembourg; LV, Latvia; -MAH, marketing authorization holder; MRP, mutual recognition procedure; MT, Malta; NL, Netherlands; NO, Norway; NP, national procedure; PL, Poland; PT, Portugal; -RMS, reference member state; RO, Romania; SE, Sweden; SI, Slovenia; SK, Slovakia; UK, United Kingdom.

Table 2 Examples for commercially available nanotherapeutic products for parenteral administration in the EU

Nanotechnology-based approach	Drug	Major indication	Dosage form	Brand name (manufacturer* info source)	Marketing authorisation in Europe**
Nanocrystals	Olanzapine	Schizophrenia	Powder and slovent for prolongeed release suspension for injection	Zypadhera® (Lilly Pharma Fertigung und Distribution GmbH and Co, KG, Gießen, DE)	CP: -MAH: Eli Lilly Nederland BV, Houten, NL
	Paliperidone	Schizophrenia	Prolonged release suspension for injection (im)	Xeplion® (Janssen Pharmaceutica NV, Beerse, BE)	CP: -MAH: Janssen-Cilag International NV, Beerse, BE
Polymer-protein conjugates	Pegaspargase (mPEG-asparaginase)	Acute lymphoblastic leukemia	Solution (iv/im)	Oncaspar® (Sigma-tau Arzneimittel GmbH, Düsseldorf, DE)	NP:DE -MAH in DE: Sigma-tau Rare Diseases SA, Funchal, PT
	Pegvisomant (PEG-HGH antagonist)a	Acromegaly	Powder and solvent for solution for injection (sc)	Somavert® (Pfizer Manufacturing Belgium NV, Antwerpen, BE)	CP: -MAH: Pfizer Ltd, UK
	Peginterferon alpha-2b (mPEG-interferon alpha-2b)b	Hepatitis C, chronic	Powder and solvent for solution for injection (sc)	Peglntron® (Schering-Plough Labo NV, Heist-Op-Den-Berg, BE)	CP: -MAH: Merck Sharp and Dohme Ltd, UK
	Peginterferon alpha-2a (mPEG-interferon alpha-2a)b	Hepatitis B, chronic, Hepatitis C, chronic	Solution (sc)	Pegasys® (Roche Pharma AG, Grenzach-Wyhlen, DE)	CP: -MAH: Roche Registration Ltd, Welwyn Garden City, UK
	Pegfilgrastim (PEG-rhGCSF)c	Chemotherapy-induced (febrile) neutropenia	Solution (sc)	Neulasta® (Amgen Technology Ireland [ADL], Dublin, IE)	CP: -MAH: Amgen Europe BV, Breda, NL
	Certolizumab pegol (PEG-anti-TNF Fab)	Rheumatoid arthritis	Solution (sc)	Cimzia™ (UCB Pharma SA, Brussels, BE)	CP: -MAH: UCB Pharma SA, BE
	Methoxy polyethylene glycol-epoetin beta	Anemia, kidney failure, chronic	Solution (iv/sc)	Mircera® (Roche Pharma)	CP: -MAH: Roche Registration Ltd, UK
Liposomes	Amphotericin B	Fungal infections	Suspension (iv)	AmBisome® (Gilead Sciences Ltd, Co, Cork, IE)	NP: AT, BE, DE, DK, ES, FI, FR, HU, IE, IS, NL, NO, PT, SE, SI, UK -MAH in UK: Gilead Sciences International Ltd, Uxbridge, UK
	Cytarabine	Meningeal neoplasms	Suspension (intrathecal)	DepoCyt® (Almac Pharma Services Ltd, Craigavon, UK)	CP: -MAH: Pacira Ltd, High Wycombe, UK
	Doxorubicin	Breast neoplasms, Multiple myeloma, ovarian neoplasms, Kaposi’s sarcoma	Suspension (iv)	Caelyx® (Janssen Pharmaceutica NV)	CP: -MAH: Janssen-Cilag International NV
	Doxorubicin	Breast neoplasms	Suspension (iv)	Myocet® (GP-Pharm, Barcelona, Spain/Teva Operations Poland Sp. z o.o., Krakow PL)	CP: -MAH: Teva Pharma BV, Utrecht, NL
	Daunorubicin	Cancer advanced HIV-associated Kaposi’s sarcoma	Suspension (iv)	DaunoXome® (Gilead Sciences Ltd)	MRP: -RMS: DE -CMS: AT, DK, EL, IE, IT, NL, PT -MAH in RMS: Gilead Sciences GmbH, Planegg, DE NP: FI, FR, NO, UK
	Morphine	Pain relief	Suspension (epidural)	DepoDur® (Almac Pharma Services Ltd)	NP:UK -MAH in UK: Flynn Pharma Ltd, Dublin, IE
	Mifamurtide	Osteosarcoma	Suspension (iv)	Mepact® (Takeda Ireland Ltd, Wicklow, IE/Takeda Italia Farmaceutici SpA Cerano, IT)	CP: -MAH: IDM Pharma SAS, Puteaux, FR
	Propofol	Anaesthetic	Emulsion (iv)	Diprivan® (AstraZeneca UK Ltd, London, UK/Corden Pharma SpA, Caponago, IT)	NP: BE, BG, DK, ES, FR, HR, HU, IE, IS, NL, NO, PT, SE, SI, UK
				Propofol-Lipuro® (B Braun Melsungen AG, Melsungen, DE)	MRP: -RMS: DE -CMS: AT, CY, CZ, DK, EE, EL, ES, Fl, FR, HU, IE, IT, LT, LU, LV, MT, NL, NO, PL, PT, SE, SI, SK, UK -MAH in RMS: B Braun Melsungen AG NP:HR
				Propofol® (Fresenius Kabi Austria GmbH, Graz, AT)	MRP: -RMS: DE -CMS: AT, BE, CY, CZ, DK, EE, EL, ES, FI, FR, HU, IE, IS, IT, LT, LU, LV, NL, NO, PL, PT, SE, SI, SK, UK -MAH in RMS: Fresenius Kabi Deutschland GmbH, Friedberg, DE NP:HR
	Verteporfin	Macular degeneration, myopia, degenerative	Suspension (iv)	Visudyne® (Novartis Pharma GmbH, Nürnberg, DE)	CP: -MAH: Novartis Europharm Ltd, Horsham, UK
Nanoparticles	Paclitaxel	Breast neoplasma	Powder for suspension for infusion	Abraxane® (Celgene Europe Ltd, Uxbridge, UK)	CP: -MAH: Celgene Europe Ltd
	^90Y-ibritumomab tiuxetan	Lymphoma, follicular	Solution (iv)	Zevalin® (Bayer PharmaAG, Leverkusen, DE/CIS bio international, Gif-sur-Yvette, FR)	CP: -MAH: Spectrum Pharmaceuticals BV, Amsterdam, NL
Virosomes	Inactivated hepatitis A virus	Vaccine against hepatitis A	Suspension (iv)	Epaxal® (Crucell Spain SA Madrid, ES)	MRP: -RMS: SE -CMS: AT, BE, DE, DK, EL, ES, Fl, IE, IT, LU, NL, NO, PT, UK -MAH in RMS: Crucell Italy Srl, Baranzate, IT NP:FR
	Adjuvanted influenza vaccine	Vaccine against influenza	Suspension (iv)	Inflexal® V (Crucell Spain SA)	MRP: -RMS: IT -CMS: AT, BE, DE, DK, ES, Fl, IE, LU, NL, NO, PT, SE, UK -MAH in RMS: Crucell Italy Sri, IT NP:HU
Polymeric drugs	Glatiramer (Glu, Ala, Tyr, Lys copolymer)	Multiple sclerosis	Solution (sc)	Copaxone® (Teva Pharmaceuticals Europe BV, Utrecht, NL)	MRP: -RMS: UK -CMS: AT, BE, CY, CZ, DE, DK, EE, EL, ES, FI, HU, IE, IS, IT, LT, LU, LV, MT, NL, NO, PL, PT, SE, SK -MAH in RMS: Teva Pharmaceuticals Ltd, Castleford, UK NP: FR, HR
Nanocomplex	Sodium ferric gluconate	Iron deficiency anemia	Solution (iv)	Ferrlecit® (Avertis Pharma Dagenham, UK/Sanofi-Aventis SpA IT)	NP: CZ, DE, HU -MAH: Sanofi-Aventis SpA
	Ferumoxytol	Anemia, kidney failure, chronic	Solution (iv)	Rienso® (Takeda Italia Farmaceutici SpA)	CP: -MAH: Takeda Global Research and Development Centre (Europe) Ltd, London, UK
	Iron sucrose (iron (III)-hydroxide sucrose complex)	Iron deficiency	Solution (iv)	Venofer® (Vifor France SA Neuilly-sur-Seine, FR)	MRP: -RMS: UK -CMS: AT, BE, DK, EL, ES, Fl, IE, IT, LU, SE -MAH in RMS: Vifor France SA FR NP: CZ, EE, FR, HR, HU, IS, NL, NO, PT, SI, SK
	Ferric carboxymaltose	Iron deficiency	Solution (iv)	Ferinject® (Vifor France SA)	MRP: -RMS: UK -CMS: AT, BE, BG, CY, CZ, DE, DK, EE, EL, ES, Fl, FR, HU, IE, IS, IT, LT, LU, LV, MT, NL, NO, PL, PT, RO, SE, SI, SK -MAH in RMS: Vifor France SA FR NP:HR
	Iron (III) isomaltoside	Iron deficiency	Solution (iv)	Monofer® (Pharmacosmos A/S, Holbaek, DK)	MRP: -RMS: SE -CMS: AT, BE, BG, CY, DK, EE, Fl, DE, EL, HU, IS, IE, LV, LT, LU, NL, NO, PL, PT, RO, ES, UK -MAH in RMS: Pharmacosmos A/S, DK
	Iron (III)-hydroxide dextran complex	Iron deficiency	Solution (iv)	Ferrisat® (Pharmacosmos A/S)	NP:FR
	Iron (III)-hydroxide dextran complex	Iron deficiency	Solution (iv)	Cosmofer® (Pharmacosmos A/S)	MRP: -RMS: DK -CMS: AT, BE, CY, EE, DE, EL, IE, LV, LT, LU, NL, NO, PT, ES, SE, UK -MAH in RMS: Pharmacosmos A/S, DK NP:FI

Notes:

* Manufacturer responsible for batch release as stated in package leaflet approved in the EU

** EMA, HMA, national regulatory authorities’ information source

a pegvisomant is a pegylated recombinant analogue of the human GH, which has been genetically engineered to function as a GH receptor antagonist

b peginterferon alfa-2b is a covalent conjugate of recombinant alfa interferon with mPEG

c pegfilgrastim is a covalent conjugate of rhGCSF (filgrastim) with a single 20 kDa PEG. rhGCSF, is used for stimulation of granulopoiesis and stem cell mobilization in healthy donors for allogeneic stem cell transplantation; in oncology and hematology with certain cancer patients it is used to accelerate recovery from neutropenia after chemotherapy, allowing higher-intensity treatment regimens.

Abbreviations: Ala, alanine; AT, Austria; BE, Belgium; BG, Bulgaria; -CMS, concerned member state; CP, centralized procedure; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; EMA, European Medicines Agency; ES, Spain; Fab, fragment antigen binding; Fl, Finland; FR, France; Glu, glutamic acid; HIV, human immunodeficiency virus; HGH, human growth hormone; HMA, Heads of Medicines Agencies; HR, Croatia; HU, Hungary; IE, Ireland; im, intramuscular; IS, Iceland; IT, Italy; iv, intravenous; LT, Lithuania; LU, Luxembourg; LV, Latvia; -MAH, marketing authorization holder; mPEG, monomethoxypoly(ethylene glycol); MRP, mutual recognition procedure; MT, Malta; NL, Netherlands; NO, Norway; NP, national procedure; PEG, polyethylene glycol; PL, Poland; PT, Portugal; rhGCSF, recombinant human granulocyte colony-stimulating factor; -RMS, reference member state; RO, Romania; sc, subcutaneous; SE, Sweden; SI, Slovenia; SK, Slovakia; TNF, tumor necrosis factor; Tyr, tyrosine; UK, United Kingdom.

Figure 2 Nanotherapeutics with the greatest pharmaceutical and commercial potential.

Abbreviation: PEG, polyethylene glycol.