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A novel controlled-release technologycould revolutionize the delivery of pro-tein drugs for use in cancer and manyother diseases. InfiMed Therapeutics(Cambridge, MA, USA) has recentlybeen awarded a US patent1 that protectsits Improved Formulation Entity (IFE™)technology platform for incorporatingproteins and peptides into fishnet-likehydrogel polymers, which can be ad-ministered via several routes. Until now,developing a system that could deliverlarge, labile protein-drugs in a sustained,controlled manner was thought to be animpossible task.

Many protein drugs (such as insulin)are degraded rapidly by the stomachand have to be administered via fre-quent injections. Existing methods ofprotein delivery often cause a ‘burst’ ofdrug release and associated unpleasantside-effects, which reduces patient com-pliance and treatment efficacy, andwastes expensive protein drugs. InfiMedhas focused on the delivery of major protein-drug candidates such as inter-feron, human growth hormone (hGH)and erythropoietin. The company will be embarking on Phase I clinical trials of asustained-release hGH product in thenear future and hopes to be in Phase IIItesting by the end of 2001.

The technologyThe IFE technology uses water-soluble,non-toxic hydrogel prepolymers consist-ing of a polyethylene glycol (PEG) back-bone with biodegradable linking groups,such as α-hydroxy acid, and acrylate termini at each end. An aqueous solutionconsisting of these prepolymers and abioactive material, such as a protein

drug, is photopolymerized to form aunique fishnet-like hydrogel structurewith the protein drug uniformly encap-tured within the 3D microparticle (Fig. 1)2.

Once inside the body, these small mi-croparticles (approximately the diameterof a human hair) degrade by hydrolysisof the α-hydroxy-acid linkers and releasethe protein drug. The microparticlesthen further degrade into water-solubleproducts that are excreted by the kidneys; ‘The whole chemistry is very safe’, says Stephen Rowe, President andCEO of InfiMed. Indeed, the safety and efficacy of the hydrogel technology has

already been proven in studies carriedout by Focal (Lexington, MA, USA; co-founded by Rowe and his colleagueJeffrey Hubbell) that demonstrated itsapplication in wound healing, by boththe formation of a sealant-barrier on theskin and the localized release of urokinaseand tissue plasminogen-activator3.

Rowe explains that: ‘In general, noone has really come up with somethingthat has found any significant market ac-ceptance in terms of a sustained-releaseprotein formulation. That is not the casewith peptide drugs: polylactic acid (PLA)formulations can work effectively for

Holy Grail of drug delivery caught usingnovel fishnet technologyJoanna Owens, Joanna.Owens@current-trends.com

Figure 1. InfiMed’s Improved Formulation Entity (IFE™) hydrogel technology: non-toxichydrogel prepolymers consisting of a polyethylene glycol (PEG) backbone withbiodegradable linking groups are mixed with the protein drug and photopolymerized toform a unique fishnet-like hydrogel structure with the protein drug uniformly encapturedwithin the 3D hydrogel microparticle.

Prepolymer

+Initiator

+Light

+

Protein drug

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3–4 months. In essence, I think we havesomething that is effective for proteindrugs for up to a month, or perhapsmore, and for peptide drugs we canachieve efficacy for ~3–6 months be-cause peptides are inherently more sta-ble at body temperature.’ He continues:‘What is nice about the system is that we can ‘‘dial in’’ to the release profile by changing the percentage of the poly-mer we have within the microsphere, orthe number of degradable groups, togive us exquisite control over the releaseprofile.’

Rowe anticipates that this technologycan be used to eliminate the burst oftencreated by administration of proteindrugs such as hGH and interferon (Fig. 2).This is possible because of the uniquenature of the fishnet-like structure,which means that the protein drug is not released until the hydrogel starts to degrade. By contrast, PLA-microspheredrug delivery systems tend to be porousso that on administration to a tissue, themicrospheres act like a sponge and theircontents enter the body rapidly and cre-ate a burst. Usually, administering largequantities of protein exaggerates theproblem of burst, but because hydrogelmicrospheres are not as porous as otherdelivery vehicles, relatively high protein-loading can potentially be achieved.Moreover, this technology does not in-volve binding of the protein to a deliveryvehicle, therefore, retaining the integrityof the protein.

Claudio Mapelli (Principal Scientist,Bristol-Myers Squibb, Princeton, NJ, USA),believes that: ‘The sustained, controlleddrug release that seems possible with IFEcould certainly represent a major ad-vancement in the delivery of peptideand protein biologics. Effectively, thiscould position IFE very competitivelyrelative to other drug depot formulationapproaches such as subcutaneous implants.’

The sustained release of several pro-teins using the IFE technology has beenproven by research in animal models.

In hypophysectomized rats, adminis-tration of hGH by controlled releasefrom a hydrogel implant was shown tobe as effective as daily subcutaneous injections at inducing growth of the ani-mals, confirming previous data obtainedwith bovine somatotropin1. Furthermore,studies in diabetic rats using a subcuta-neous hydrogel implant to deliver insulinsignificantly lowered blood glucose lev-els, thus demonstrating that insulin wasreleased in an active form1. As Mapellipoints out, ‘One of the biggest problemsin the clinical management of diabetes is that current intravenous insulin injec-tions cause bursts of drug release andunwanted fluctuations in glucose levels.The controlled release of insulin pro-duced by the IFE approach leads tosteadier, as well as lower, blood glucoselevels. Now, the critical question iswhether these results can be reproducedin humans.’

Delivering the goodsProtein delivery using IFE technology

can potentially be achieved via severalroutes. If injected subcutaneously, theprotein will be released in a controlledmanner at the site of injection and willsubsequently enter the systemic circu-lation. Intravenous administration couldprove particularly effective for cancertreatment; the blood flow within tu-mours is often slow as a result of leakyvasculature and, therefore, it is hypothe-sized that the microparticles could be-come lodged and provide a means ofadministering the drug directly withinthe tumour. Microparticles could also beshaped to fit a particular body cavity,providing a depot from which the con-trolled release of a drug can be achieved.There is also the potential to deliverdrugs orally, intranasally and via inha-lation, using either freeze-dried micro-particles or microparticles in solution.

Figure 2. Release kinetics showing the efficacy of InfiMed’s Improved Formulation Entity(IFE™) hydrogel technology. In vitro release of growth hormone was measured by size-exclusion HPLC from hydrogel microspheres composed of either polylactic acid links,caprolactone links or a blend of the two polymers. The chart shows that by altering thepolymer composition of the microspheres, a different release curve can be achieved, andthat there is a delay in release of the drug, rather than the burst that is often seen withother delivery systems.

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1.2

1.0

0.8

0.6

0.4

0.2

00 5 10 15

Days

20 25 30

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ulat

ive

rele

ase

(mg)

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ean

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Polylactic acidPolylactic acid and caprolactoneCaprolactone

Mapelli comments: ‘A major advan-tage of IFE – although more data will beneeded to demonstrate it – is the scopeand versatility of the routes of adminis-tration it can utilize’, he continues: ‘Ithink that the IFE platform could have aneven bigger impact on how drug biolog-ics are developed and delivered if it couldallow, at least in a few therapeuticallysignificant cases, oral dosing of proteinor peptide drugs.’

Future strategiesInfiMed now plans to launch a daily liquid formulation of hGH, Infitropin-AQ™, on the US market in collaboration with Grandis Biotech GmbH (Novartis,Freiburg, Germany), and is developing its

own sustained release version, Infitropin-CR™, for marketing in North America,which should enter clinical trials in thenear future. InfiMed has an agreementwith Grandis, under which Grandis will market Infitropin-CR in Europe.Furthermore, InfiMed is hoping to enterinto corporate partnerships for the development of sustained-release formsof therapeutically and commercially suc-cessful protein drugs, such as erythro-poietin, α- and β-interferon, and granu-locyte-colony stimulating factor (G-CSF),in addition to generating products for itsown development pipeline.

In the long term, future applications ofIFE technology might include the tissue-specific targeting of proteins and improved

delivery of novel drug candidates thatarise from the recent advances with theHuman Genome Project.

AcknowledgementsI would like to thank Stephen Rowe, Guy

Gelardi and Claudio Mapelli for their help

with this article.

References1 Hubbell, J.A. et al. (2000) Biodegradable

macromers for the controlled release ofbiologically active substances. US6,153,211

2 West, J.L. and Hubbell, J.A. (1995)Photopolymerized hydrogel materials fordrug delivery applications. React. Polym. 25,139–147

3 Hubbell, J.A. (1996) Hydrogel systems forbarriers and local drug delivery in the controlof wound healing. J. Control. Release 39,305–313

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The first lead compound to come from aseries of synthetic pheromones has shownpromise in a pilot study for acute anxietyin women and is hoped to provide a newmethod of avoiding the problems associ-ated with delivery across the blood–brainbarrier. Pherin Pharmaceuticals (MountainView, California, USA) have producedPH94B from a series of over 1000patented ‘vomeropherins’, synthetic vari-ants of naturally occurring pheromonesthat stimulate the vomeronasal organ(VNO).

The VNOThe VNO is located in the nasal passagesof most mammals and some reptiles and was first described in mammals in the early nineteenth century, when it was suspected to be a sensory organ1. Inlower mamals, it is known to mediate

sexual and reproductive behaviour in response to pheromone binding.

As recently as 1998, the human VNOhas been described by some investigators

as ‘vestigial’1. However, there is substan-tial evidence to show that it can act as anadditional sensory system – a ‘sixth sense’2.The human VNO is a bilateral, tubular

Sixth sense could avoid the blood–brainbarrierClare Sansom, Freelance writer

Figure 1. Thevomeronasal organ(VNO)–hypothalamuspathway.

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Vomeronasal-terminalis nerveplexus

VNO

Hypothalamus

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