Fda Experience With Nanotechnology Product Applications

Historically, the FDA has encountered and approved many products with particulate materials characteristic of a nanomedicine or nanoproduct (e.g., small size, mechanism of delivery, increased

TABLE 8.1

Nanomedicines: Drugs/Devices FDA Approved and in Development

Name

Structure

Company

Size (nm)

Phase

Indication

Referencea,b

Magnevist®c

PIO

Shering AG

<1

APP

MRI tumor imaging

3-5

Feridex®c

SPIO

Adv.Magnetics

120-180

APP

MRI tumor imaging

5-9

Rapamune®c

Nanocrystal drug

Wyeth

100-1,000

APP

Immunosuppressant agent

10-12

Emend®c

Nanocrystal drug

Merck

100-1,000

APP

Nausea

13,14

Doxil®c

Liposome-drug encapsulation

Ortho Biotech

z100

APP

Metastatic ovarian cancer

15-17

Abraxane®c

Nanoparticulate albumin

American Pharmaceutical

z 130

APP

Non-small-cell lung cancer, breast cancer,

18-20

Partners

others

SilvaGard®

Silver nanoparticles

AcryMed

z 10

APP

Antimicrobial surface treatment (medical

21-23

devices)

AmBisome®c

Liposome-drug encapsulation

Gilead Science

45-80

APP

Fungal infections

24-26

Leunesse®

Solid lipid nanoparticles

Aano-therapeutics

N/A

On market

Cosmetics

N/A

NB-001d

Nanoemulsion

NanoBio Corp

z 150

Phase II

Topical microbicide for herpes labialis

27-30

VivaGel®

Dendrimer

Starpharma Holdings Ltd.

N/A

Phase I

Vaginal microbicide (STI and HIV

31-34

prevention)

INGN-401c

Drug-liposome complex

Introgen Therapeutics

N/A

Phase I

Metastatic lung cancer

35-38

Combidex®c

USPIO

Advanced Magnetics

20-50

NDA filed

MRI tumor imaging

39-42

IT-101c

Drug-polymer complex

Insert Therapeutics

N/A

IND filed

Metastatic solid tumors

43,44

Dendrimersc

Polymeric spheres, multifunctional

Dendritech Nanotech.,

>1 to <500

IDV

Diagnostic, contrast agents, microbicide,

45-54

Starpharma

drug delivery, B neutron capture

Nanoshellsc

Metal shell, SiO2 core

Nanospectra

100-200

IDV

Photo-thermal ablation therapy /imaging

55-58

tumors

Fullerenesc

Carbon sphere, C60, multifunctional

C Sixty

1

IDV

MRI contrast agent, antiviral, antioxidant

59-67

Quantum dotsc

CdSea nanocrystal

Evident Technologies

2-10

IDV

Optical imaging, tumor imaging,

68-74

photosensitizer

APP, approved; IDV, in development; PIO, paramagnetic iron oxide; SPIO, superparamagnetic iron

oxide; USPIO, ultrasmall superparamagnetic iron oxide; STI, sexually transmitted

infection; HIV, human immunodeficiency virus; N/A, not available.

n oo

a Most typical semiconductor metal used, however can also be composed of nearly any other semiconductor metal (e.g., CdS, CdTe, ZnS, PbS, etc.). b References do not necessarily refer to the product described, and may reflect general properties about the product. c Drugs with proposed or proven diagnostic or therapeutic benefit to cancer patients.

d Unable to locate peer-reviewed publications. References listed are press releases found during internet search.

surface area, specialized function related to size and increased surface area, etc.). Although the field of nanomedicine may be new, the submission of applications for products containing novel dosage forms or drug delivery systems, including nanomaterials, nanoparticlized drugs and medical devices, is not particularly new to this agency. Products are reviewed on a product-by-product basis, and as such, various concepts of risk management (i.e., risk identification, risk analysis, risk control, etc.) are often implemented to support the drug review process.

The FDA is aware of several FDA regulated products that employ nanotechnology. However, to date, few manufacturers of regulated products have claimed the use of nanotechnology in the manufacture of their products or made any nanotechnology claims for the finished product. The FDA is aware that a few cosmetic products and sunscreens claim to contain nanoparticles to increase the product stability, modify release of ingredients, or change the opacity of the product by using nanoparticles of titanium dioxide and zinc oxide. Similarly, several drugs w 3_5 w such as Gd-DTPA (Magnevist , tumor contrast agent), ferumoxides (Feridex , tumor contrast agent),5_9 liposomal doxorubicin (Doxilw, chemotherapeutic),15_17 and albumin-bound paclitaxel (Abraxanew, chemotherapeutic),18_20 to name a few, have all been approved for human clinical use in the diagnosis and treatment of a variety of patient tumors and metastatic cancers. For public information regarding FDA approval letters, label information, and review packages for each of these drugs and others listed in Table 8.1, please visit the following website: http://www. accessdata.fda.gov/scripts/cder/drugsatfda/.

Of the many drugs listed in Table 8.1, tumor contrast agents comprise some of the earliest nanosized products to receive FDA approval for human clinical use. Critical to therapeutic outcome, diagnostic imaging of nanosized contrast agents using non-invasive magnetic resonance imaging (MRI) and positron emission tomography (PET), have shown advanced utility for early detection of small tumors, metastatic lymph nodes, and altered tumor microenvironments.90 The leading MR contrast agent, Magnevistw, a paramagnetic, gadolinium-based contrast medium, and Feridexw, a superparamagnetic iron oxide contrast agent, received primary FDA approval for clinical use in 1988 and 1996, respectively. Each contrast agent has a different mean particle size (< 1 nm and 120_180 nm, respectively), is approved for different clinical indications, and demonstrates product-specific adverse sensitivity and pharmacology/toxicology profiles in patients.3_9

Another early nanomedicine, liposomal encapsulated doxorubicin (Doxilw), is regulated by the FDA and has been available in the clinic for treatment of various cancers since 1995. Drug incorporation inside the hydrophilic core or within the hydrophobic phospholipid bilayer coat of liposomes, has been shown to improve drug solubility, enhance drug transfer into cells and tissues, facilitate organ avoidance, and modify drug release profiles, minimizing toxicity.91 The liposomal formulation of the popular anthracyline, doxorubicin, which is commonly used to treat metastatic breast and ovarian cancer, is reported to have diminished cardiotoxicity and enhanced therapeutic efficacy compared to the free form of the drug.15_17 This increased efficacy is most likely due to the passive targeting of solid tumors through the enhanced permeability and retention effect inherent to tumor vasculature and aberrant tumor morphology.17 The approximate diameter of the doxoru-bicin_liposomal product is reported to be 100 nm, near the size limits described in the FDA definition of a nanomedicine.

Nanoparticlized, albumin-bound paclitaxel, Abraxanew, is one of the first FDA-approved (January, 2005) cancer drugs that was submitted to the FDA with specific claims regarding nano-related characteristics that improved this particular formulation over previous sub-missions.18_20 Initially identified as (ABI-007), this chemotherapeutic agent that is approved for the treatment of metastatic breast cancer eliminates the excipient Cremophorw by overcoming intrinsic insolubility with nanoparticlization of the active paclitaxel ingredient. Although widely used in many drug formulations, Cremophor has been associated with an adverse hypersensitivity reaction that limited the amount of paclitaxel that could be safely administered.20 Unlike the previous three agents, the approximate diameter of Abraxane is 130 nm, slightly larger than the requirements described in the National Nanotechnology Initiative (NNI) definition of nanotechnology (<100nm), and thus originally was determined not to fit the size requirement of a nanomedicine. However, the fact that the exact particle size exceeds 100 nm may not necessarily preclude Abraxane and other similarly-sized or larger products from being considered nanotechnology.

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