Beruflich Dokumente
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IN THIS
ISSUE
INTERVIEW WITH
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PRESIDENT & CEO
Neurological
Diseases 22
Jennifer Brice
Products
That Pop 28
Josef Bossart, PhD
Pharma
Development 32
Joanna Bis, PhD
David Igo, PhD
Transdermal
Guidelines 36
Paul Lehman, MSc
Intranasal
Vaccines 54
Degenhard Marx, PhD
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“The recession is dead, long live the recovery! 36 Analysis of New FDA Transdermal Draft
Guidances: Insights on Study Design for
But not so fast. Just because your company Bioequivalence Assessment of Transdermal
made it through the recession, doesn’t Systems
Paul A. Lehman, MSc, says that since 2007, the US FDA has issued
necessarily mean it will make it through the 12 bioequivalence draft guidances for generic transdermal patch
Drug Development & Delivery April 2011 Vol 11 No 3
recovery. Yes, I’m dead serious. It is possible to designs, and while they provide insight into current regulatory
views on study designs for individual transdermal patch
screw this up. Your company has just been bioequivalence assessments, differences among the guidances make
through a savage economic battle. The pain of it challenging for product developers to glean essential principles
for study design.
it is seared in your memory. But -hurray!-
business is coming back. The risk now is that 42 Ultrasound & Microbubbles for In Vitro
we will let our caution reign us in too much.” Gene Delivery
J.M. Escoffre, PhD; A. Novell, MSc; A. Zeghimi, MSc; and A. Bouakaz,
PhD; focuses on the mechanisms of membrane permeabilization with
ultrasound and microbubbles and its use for in vitro gene delivery.
6 p.19
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A Promising
Alternative 48 2011 DDP Awards Indicate Traditional
Drug Delivery Model Isn’t Dead
In this post-show wrap-up of the Drug Delivery Partnerships
Conference, Marc Dresner highlights the companies recognized for
establishing successful relationships with their partners!
for the development of prophylactic and in place by mid-2013, and the intent of this discussion is to update
current analytical testing historically performed using USP<231>.
therapeutic vaccines for diseases that
until now have been out of reach, such 71 Cortex Pharmaceuticals: Developing Novel
Drug Development & Delivery April 2011 Vol 11 No 3
Dan Marino,
MSc
Executive Editorial
Director
Drug Delivery
Technology
Studies Show Triolex for Parkinson's Disease Crosses the BBB in Mice
arbor BioSciences, Inc., which is investigating the use the Harbor BioSciences believes Triolex may decrease chronic
H company's proprietary compound Triolex as a treatment for inflammation in the brain, thereby protecting neurons whose loss
Parkinson's disease (PD) with funding from The Michael J. Fox would otherwise lead to the damage associated with PD. This belief
Foundation (MJFF), recently announced positive results in initial is based on several factors: the company's previously reported data
preclinical studies. These studies in orally treated mice demonstrate regarding the anti-inflammatory effects of Triolex in human clinical
that Triolex crosses the blood-brain barrier in significant quantities. studies; attenuation of neuroinflammation in rodent models; and the
Harbor BioSciences designed these studies to determine if extensive literature describing the benefits of related natural
Triolex, an anti-inflammatory, small-molecule compound believed to compounds in both humans and animal PD models. To date, Triolex
reduce inflammation in the brain, was capable of crossing the blood- has been well tolerated when administered to more than 180 people
brain barrier. The results described here show that more than 50% of with type 2 diabetes and healthy volunteers.
levels of Triolex measured in plasma were found in mouse brains "It is a privilege to be collaborating with MJFF to assess the
after oral administration. These positive findings support rodent potential benefits of Triolex in patients suffering from PD,"
efficacy studies, which are expected to be completed before the end commented James M. Frincke, Harbor BioSciences' Chief Executive
The terms of the collaboration call for MJFF to fund up to inflammatory cytokines in PD patients similar to that observed in
approximately $150,000 toward preclinical development of Triolex in animal models and in type 2 diabetes patients, it should provide an
rodents. If these studies are successful, additional funding may be entirely new approach to the treatment of this debilitating disease.
awarded by MJFF to continue the clinical development of Triolex for We are also hopeful that if Triolex is able to reduce neuro-
the treatment of PD. inflammation and protect neurons in PD, it may also be useful in
Drug Development & Delivery April 2011 Vol 11 No 3
"Anti-inflammatory approaches to PD are of increasing interest other inflammation-driven neurodegenerative disorders, such as
to Parkinson's researchers, but even the most effective potential Alzheimer's disease and multiple sclerosis."
treatment must cross the blood-brain barrier in order to be translated Harbor BioSciences is a development-stage company with two
into practical treatments for PD patients," said Todd Sherer, PhD, product candidates that recently completed Phase I/IIa clinical trials:
Chief Program Officer, The Michael J. Fox Foundation. "We are Apoptone (HE3235) in patients with late-stage prostate cancer, and
encouraged by the initial data showing that Triolex may accomplish Triolex (HE3286) in obese type 2 diabetes mellitus patients.
both of these goals, and look forward to partnering with Harbor Apoptone and Triolex represent two of the lead candidates from
BioSciences to continue vetting this novel compound in the hope of Harbor BioSciences' small molecule platform based on metabolites
speeding its path to the clinic." or synthetic analogs of endogenous human steroids.
12
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120 employees upon closing, and plans to maintain operations at its ICIG is a privately owned industrial holding company focusing
primary location, a manufacturing facility in Liestal, Switzerland. The on mid-sized chemicals and pharmaceutical businesses. Since
acquired pharmaceutical intermediates business will be renamed inception in 2004, ICIG has acquired 15 businesses, all of which have
Corden Pharma Switzerland LLC and will operate as part of ICIG’s origins in major global chemical or pharmaceutical corporations and
pharmaceutical business within the Corden Pharma platform. The are independently managed. ICIG companies currently employ more
companies’ goal is to close the transaction during the first quarter of than 3,000 people and operate 15 manufacturing facilities in Europe
2011. Financial terms are not disclosed. and the United States. Corden Pharma group companies offer contract
As part of the agreement, ICIG will enter into a 5-year supply development and contract manufacturing for advanced pharmaceutical
contract to provide Genzyme with materials needed for the production intermediates, APIs, and drug product formulations with more than
of eliglustat tartrate, an investigational treatment for Gaucher disease 1,500 individuals supporting their customers with specialized
Type 1 that is currently in Phase III clinical trials. ICIG will also technologies in all international markets.
14
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development to clinical evaluation. screening, profiling, and lead optimization through full drug safety,
“The Fulcrum Pharma collaboration is an attractive and exciting metabolism, and efficacy development support, as well as clinical
proposition for Ricerca and our clients,” said Ian Lennox, CEO of supply and commercial API production capability. Fulcrum Pharma is
Ricerca. “Fulcrum Pharma brings deep experience in IND authorship a global leader in the provision of strategic and operational regulatory
and regulatory approval, which fits well with Ricerca’s preclinical support to assist clients in the authorship and approval of regulatory
services in discovery pharmacology, chemical development, and drug submissions. Aptiv Solutions is a global biopharmaceutical and
safety assessment. The relationship greatly expands our ability to medical device development services company focused on
serve our clients who are preparing for regulatory submission recognizing, understanding, and enabling clients to capitalize on rapid
anywhere in the world.” and fundamental changes facing companies developing products in the
“The collaboration offers our early stage clients a streamlined pharmaceutical, biotech, and medical device market.
15
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E lan, plc and PPD, Inc. recently announced they have formed a global
business collaboration focused on the advancement, progression, and
execution of Elan's development portfolio. The primary objective of this
commented David Grange, Chief Executive Officer of
PPD.
Elan Corporation, plc is a neuroscience-based
relationship is to deploy both companies’ skills and expertise in a flexible,
biotechnology company committed to making a
integrated manner to drive the execution of Elan's clinical programs in a
difference in the lives of patients and their families by
parallel and expedited basis and on a global scale.
dedicating itself to bringing innovations in science to fill
Under this business agreement, PPD will act as Elan's primary service
significant unmet medical needs that continue to exist
provider for all development functions and activities. Elan will retain
around the world. PPD is a leading global contract
ownership of its assets and accountability for decision-making with regard to
research organization providing drug discovery,
strategy and progression of the individual molecules as well as the overall
development, and life-cycle management services.
portfolio. This business construct will enable Elan to leverage the significant
16
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19
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T
he recession is dead, long live treatment. Investors too were angered, Genzyme CEO Henri Termeer made
the recovery! But not so fast. including Carl Icahn, who waged a the mistake of holding out in the
Just because your company proxy fight and prompted a board hopes of creating a bidding war. Mr.
made it through the recession, doesn’t probe into insider stock sales. Termeer was apparently a genius
necessarily mean it will make it As a manufacturer myself, for when it came to selling orphan drugs
through the recovery. Yes, I’m dead days I cringed to read the latest for awe-inspiring prices, but
serious. It is possible to screw this up. Genzyme news. I’ll confess I read of somewhat less adapt at selling a
Your company has just been the warning letters and consent company.
through a savage economic battle. The decrees with a measure of, “What But here’s the creative part: the
pain of it is seared in your memory. were they thinking?” tempered by a deal requires Sanofi-Aventis to cough
But -hurray!- business is coming dose of, “My God, could it ever up more money depending on various
back. The risk now is that we will let happen to my company?” It’s a factors, such as fixing manufacturing
our caution reign us in too much. blending of two emotions; problems and whether the Campath
After what we've been through, no schadenfruede - that secret, guilty leukemia med is approved for multiple
one is actually turning away business, delight we take in other’s misfortunes sclerosis (MS). These are called
are they? But here’s the rub: if we - and plain old night terrors. contingent value rights (CVRs), and
don't actively feed our companies as And yet, Genzyme lives on. Gone payouts could be as much as $4/share
they grow - with quality hires and are the days when a consent decree per CVR later. Or there could be no
measured facilities growth - we risk rules out the possibility of growth or a payouts. Or there could be payouts but
major quality issues. In our industry, merger. Genzyme soon found itself only years down the road.
quality issues are death. At least, they having to hold its nose and accept the CVRs are not new to deal-
should be. advances of a suitor offering a price making, only to deals like this. You
Quality issues were a near-death well below what it would’ve been might see them with a big
experience for Genzyme. How does worth without the quality issues. Even pharma/small start-up merger, but you
anyone get up in the morning with a with this low bid, the acquisition don't see them in the merger of two
whopping $175 million consent remained uncertain. The suitor large companies, like the Prizer-
decree for a host of manufacturing (Sanofi-Aventis) had to be sure it Wyeth deal or the Merck-SGP merger.
shortcomings? The company closed wasn't paying too much. How do you The implications of the structure
one plant and ended fill/finish fashion a merger with a company like of this deal go way beyond mere
operations in another for products Genzyme in which so many costs and financial ingenuity. It means that
sold in the US. Fill/finish activities for risks are unknown? regulatory actions - right up to the
Cerezyme (imiglucerase for
®
I will give the dealmakers their dreaded consent decree that was once
injection), Myozyme (alglucosidase
®
due. They crafted a deal of incredible considered a fatal blow to any
alfa), Fabrazyme (agalsidase beta),
®
creativity. Sanofi originally offered company’s growth or merger prospects
Drug Development & Delivery April 2011 Vol 11 No 3
and Thyrogen® (thyrotropin alfa for $69/share - an offer that sounds at - are now merely part of the cost of
injection) for the US market now take first blush very generous given the business in our industry. Consent
place at Genzyme’s Waterford, Ireland, fact that Genzyme was trading at decrees as a cost of doing business.
plant and at an external contract $56/share before the merger rumors This is stomach-turning. And it gets
manufacturer. started. But insiders know the worse.
On top of the corporate company was worth much more. “Pharma M&As have officially
humiliation resulting from these Some say that Genzyme could easily entered the high-risk world of
quality issues is the human suffering - have commanded a much higher price derivatives trading,” writes Jim
some patients were left with little or than the $74/share (a total of about Prutow, a partner in the healthcare
no supplies in the middle of their $20 billion) they came out with, but practice at the PRTM consulting firm.
20
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“CVRs are basically options in which could further destabilize the situation.
the investor is betting for or against I’m focussing on Genzyme here,
BIOGRAPHY
whether certain milestones will be but I could just as easily talk about the Derek G.
achieved, eg, FDA approval, etc. These embarrassment of Baxter Healthcare, Hennecke, MBA
President & CEO
types of trades are not regulated or where CEO Bob Parkinson recently
Xcelience
even posted on any type of public disclosed that he had received a Derek G.
exchange.” warning letter from the FDA Hennecke is a
founding
Welcome to our new industry. concerning problems at two plants in
member, CEO and
Quality issues are no longer a kiss of Puerto Rico. This comes just three President of
death, they’re just a higher risk level years after the company was front and Xcelience. He has a long history of growing
you can price into a deal. Will it be center in the contaminated Heparin strong businesses around the world.
Blending a scientific and business
worth it for Sanofi, acquiring a tainted scandal that led to deaths and a whole
background, he has nearly 2 decades of
company? In truth, quite possibly yes. lot of intense FDA scrutiny. international experience in the healthcare
For one thing, the structure of the deal Or I could have turned the lens to industry and a track record as a highly
makes it so that if the MS drug is the hundreds of millions of products successful international turn-around
manager in the global drug development
approved, it’s a win-win for both that have been recalled by the once
community. Xcelience is the first company
companies. More than that, Genzyme venerable Johnson & Johnson. There Mr. Hennecke has managed as an owner,
provides revenue streams and launches was Tylenol, Rolaids, Benadryl, having launched a management buy-out
from MDS Pharma Services in 2006. The
Sanofi into the rare disease business, contacts lenses, and hip replacement
newly formed company immediately
where competition should be less. And devices. We’ve seen government embarked on a robust pattern of strong
there are fewer and fewer biologically probes, a factory closing, layoffs, growth. This growth was recognized in May
focused biotechs out there, so it’s not bonus cuts, and then the story became 2008, when Mr. Hennecke was selected as
a finalist for the coveted 2008 Ernst &
like Sanofi had lots to choose from. about the company's bungled attempts
Young Florida Entrepreneur of the Year
Rare disease meds also command to manage the fallout from the their award, a nomination based on the
a lucrative pricing segment, though actual bungling. demonstration of extraordinary success in
that may not be a long-term reliable I’m not going to say that all these the areas of innovation, financial
performance, personal commitment to
assumption. As with any high-price industry catastrophes were the result of
community, and perpetual growth. Mr.
segment, other potential competitors trying to take on new business in the Hennecke was also recognized as a finalist
will be attracted and attempt to recovery without the necessary for the Ultimate CEO awards by the Tampa
Business Journal and Small Business of the
compete on price. There are other risks investment in people and facilities.
Year by the Greater Tampa Bay Chamber of
out there as well, such as the Only that in this environment, with Commerce, in 2008. Before founding
possibility that Sanofi won’t integrate sales coming back while everyone is Xcelience, Mr. Hennecke spent more than
Genzyme well, particularly on the still battered and shell-shocked and in 10 years abroad working for the Dutch-
based conglomerate DSM. In Montreal, he
rare drug side, where the a cost-cutting state of mind, the risk of
was GM of a 250-staff Biologics plant for
Drug Development & Delivery April 2011 Vol 11 No 3
physician/patient/drug company more quality failures is high. more than 2 years. In Cairo, Egypt, as GM,
dynamic can be quite different from We need to quit worrying. The he oversaw a radical turn-around in an
anti-infectives plant that had been slated
other more mundane pharmaceutical recession is over. Take measured risks
for closure. He spent 2 years in Holland
products. to expand to meet demand. We don’t developing new Pharma intermediates, and
Most any acquisition leads to a need anymore industry casualties. It two years in Mexico as Commercial Director
shakedown amongst staff - both those should be us doing the hiring, not the covering Central and South America. He
also worked for Roche, both in Canada and
who are laid off and those who choose FDA. We have a perfectly good
Germany. Mr. Hennecke has a BSc in
to get out rather than face the coming recovery brewing, let’s not blow it. u Microbiology from the University of Alberta
uncertainty. Loss of key staff taxed and an MBA from the Erasmus University in
with putting Genzyme back on track The Netherlands.
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B R I E F
MARKET
MARKET
B R I E F
INTRODUCTION
Some of the most difficult diseases to manage are those that involve malfunctioning nerve or brain structures, such as
dementias, seizures, vascular events, mental diseases, states of sleep and wakefulness, and pain. According to the World
Health Organization (WHO), neurological disorders are estimated to account for more than 10% of the world’s death and
disability. Efforts to improve the treatment of these disorders are increasing, and biopharmaceutical and drug delivery
companies are striving to improve treatments for these disorders.
A neurological disorder is a disorder of the body’s nervous system consisting of the central nervous system (CNS) and
the peripheral nervous system (PNS). The CNS consists of the brain and the spinal cord, while the PNS includes 31 pairs of
peripheral nerves and 12 pairs of cranial nerves.
CURRENT TREATMENT research has shown there is a decrease in by increasing the levels in the brain or by
METHODS FOR NEUROLOGIC the level of acetylcholine, a chemical strengthening the way nerve cells respond
DISEASES messenger that assists memory, thought, to the brain. This leads to an increase in
and judgment. Cholinesterase inhibitors communication between nerve cells that
In a recent survey, more than 100 improve the effectiveness of acetylcholine can temporarily improve or maintain
physicians who treat neurological disorders
were surveyed by Frost & Sullivan to
FIGURE 1
determine drug delivery usage patterns,
preferences, and opportunities in the US.1
For this survey, neurological disorders
were defined as depression, Alzheimer’s
Drug Development & Delivery April 2011 Vol 11 No 3
ALZHEIMER’S DISEASE
MARKET
B R I E F
antibody
Solanezumab/LY2062430 Eli Lilly
1 (IgG1) monoclonal
peptide immunoglobulin G-
Phase III 400 mg i.v. every 4 weeks
Humanized anti-A Beta
Immune Globulin
Corporation
Baxter Healthcare
Immune Globulin Phase III
2 weeks
200 or 400 mg/kg bodyweight every
day
Semagacestat/LY450139 Eli Lilly y-Secretase Inhibitor Phase III escalated to 140 mg orally once a
60 mg orally once a day gradually
antibody
Bapineuzumab Pfizer/J&J/Elan
Humanized monoclonal
Phase III 10 mg s.c. once per week
MARKET
B R I E F
SCHIZOPHRENIA
treating depression, with 16% of physicians • Perospirone (Lullan by Dainippon
preferring this method of treatment. SNRIs act Sumitomo Pharma)
Atypical (newer to the market than
upon two neurotransmitters in the brain,
typical) antipsychotics are the most commonly • Quepin (Specifar by Specifar ABEE in
serotonin and norepinephrine. These
prescribed drugs for treating schizophrenia, Greece)
neurotransmitters are known to be essential to
with 73% of physicians preferring this method • Quetiapine (Seroquel by AstraZeneca)
mood regulation. Similar to SSRIs, SNRIs
of treatment. Atypical antipsychotics are a
typically come in an oral administration. • Remoxipride (Roxiam by AstraZeneca)
group of antipsychotic tranquilizing drugs used
Examples of SNRIs include venlafaxine
to treat psychiatric conditions. Atypical and • Risperidone (Risperdal by Janssen-
(Effexor), nefazodone (Serzone), milnacipran
typical antipsychotics both tend to block Cilag)
(Dalcipran/Ixel), desipramine
receptors in the brain's dopamine pathways;
(Norpramine/Pertofraneis), and duloxetine • Sertindole (Serdolect by H.
however, atypicals are less likely to cause
(Cymbalta). Lundbeck/Abbott Labs) 25
22-27 DDD March 2011- Market Brief 2_Layout 1 3/24/11 1:00 PM Page 26
MARKET
B R I E F
antipsychotics, typical antipsychotics block • Perphenazine (Trilifon by various when patient cooperation and compliance is
receptors in the brain's dopamine pathways. generic manufacturers) required.
Typical antipsychotics are often classified by Assuming any form of delivery is
• Thiothixene (Navane by Pfizer)
potency. Examples include the following: available for atypical and typical
• Trifluoperazine (Stelazine by GSK) antipsychotics, oral administration is the
Low Potency preferred delivery method, with 67% of
• Chlorpromazine (Largactil, Thorazine physicians preferring this delivery type for
High Potency
by GlaxoSmithKline) schizophrenia patients. The second degree of
• Haloperidol (Haldol, Serenace by J&J)
• Thioridazine (Mellaril by Novartis, preference is injection at approximately 12% to
• Fluphenazine (Prolixin, by various
Discontinued in 2005) 14%.
generic manufacturers)
26
22-27 DDD March 2011- Market Brief 2_Layout 1 3/24/11 1:00 PM Page 27
MARKET
B R I E F
commonly prescribed drugs for treating ADHD, diseases, there seems to be increasing interest in View, where she devises strategies and
with 13% of physicians preferring this method transdermal delivery. In most cases, transdermal leverage resources to deliver projects in an
patch was selected as the second most preferred efficient manner from initial design to
of treatment. Atomexetine (Straterraby by Eli
delivery type if available for the disease. Key implementation. Ms. Brice has a strong ability
Lilly, an NRI) is the most well-known non-
to train, advise, and supervise analysts on
stimulant used to treat ADHD. considerations for transdermal patch include
project material and provide strategies for
Oral administration is the most common patient convenience, patient comfort, and low
collecting primary and secondary information,
delivery method for ADHD medication today. frequency of dosing (Figure 4).
as well as manages and executes quality
However, assuming any form of delivery is control activities to ensure client deliverables
available for stimulants and non-stimulants, oral For more information on the usage patterns,
meet top standards. Her industry expertise
administration would still be the preferred preferences, and opportunities in the US includes a strong network of key opinion
delivery method, with approximately 66% to among physicians treating neurological leaders and senior executives within the
74% of physicians preferring this delivery type disorders, please contact Jennifer Brice of pharmaceutical/biotech segments and an
for ADHD patients. The second degree of Frost & Sullivan at (650) 475-4560 or experience base covering a broad range of
preference is via transdermal patch at jennifer.brice@frost.com. sectors within the life sciences space,
Drug Development & Delivery April 2011 Vol 11 No 3
1. F&S 2008 U.S. Drug Delivery: Neurological roles in a consulting firm focused on the life
I
n the process of putting together the material for the Delivery The DDEPs included in the DDEP2011 Top 108 sales list
Report articles featured in this publication last year and more accounted for about 80% of all sales of DDEPs in that period, about
recently, our Drug Delivery Enabled/Enhanced Products report $250 billion in total sales. By extension, we can estimate that total
(DDEP2011), it was hard not to be impressed by a number of products sales for all DDEPs were more than $300 billion, or about $30 billion
that just seemed “different.” But different in a good way. These per year, in the US in the years 2000 to 2009.
products popped out and seemed to say “look at me, I’m special.” The
following discussion will take a look at these products and try to
understand what makes them different and special. WHAT POPS?
needs to be something else about a product that makes it pop out from and, dare we say, obvious. DDEPs that pop are different. How these
among its peers. DDEPs are different can point to new opportunities and new ways of
To be considered commercially successful for this article, a understanding the potential of DDEPs. From the DDEP2011 Top 108
DDEP (Drug Delivery Enabled/Enhanced Product1) needed to make it list, we identified a dozen products that popped (Table 1). We will look
on the DDEP2011 Top 108 sales list. This list ranks DDEPs according at six of these products a little closer to understand why they popped
to their US sales throughout the past decade, 2000 to 2009, primarily and what lessons they can teach us.
as presented in the SDI/Verispan Branded Drugs by Retail Dollars
sales report.2 The DDEP2011 Top 108 also includes some additional
DDEPs that aren’t captured in this sales audit. Why a Top 108? Well SUBOXONE – RECKITT BENCKISER
that’s the number of DDEPs that made the annual SDI/Verispan Top
200 list at some point between 2000 and 2009. To make the Suboxone has, perhaps surprisingly, captured more than $4
SDI/Verispan Top 200 list, a product, whether or not a DDEP, had to billion in sales worldwide since its launch. Suboxone, approved by the
have recorded more than $125 million in sales for a least 1 year in that FDA in 2002 as a treatment for opioid addiction, combines
period. buprenorphine, a partial agonist narcotic analgesic, and naloxone, a
28
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Vyvanse New River (Shire) ~$1 billion
Tricor Abbott >$6 billion
Suboxone Reckitt-Benckiser >$2 billion
Pulmicort Respules AstraZeneca >$4 billion
PegIntron Schering-Plough (Merck) >$2 billion
Pegasys Roche >$3 billion
OxyContin Purdue Pharma >$16 billion
Niaspan Kos (Abbott) >$3 billion
Maxalt MLT Merck >$1 billion
Concerta Alza (Johnson & Johnson) >$7 billion
Advair Diskus GlaxoSmithKline >$22 billion
Actiq Anesta (Cephalon) ~$2 billion
Product Sponsoring Company US Sales
sales. It was easy for patients, physicians, and NIASPAN - KOS REFERENCES
payers to rationalize treating HCV with
PegIntron and Pegasys; less doses and better An Oral SR formulation of niacin, a B 1. Bossart J. Decade in review - drug delivery
outcomes. Exact cumulative sales for both Vitamin, Niaspan provided a big pop to the product sales. Drug Delivery Technol.
products are hard to determine because they sales and prospects of Kos. By formulating 2010;10(7):28.
are packaged with ribavirin, but each has niacin into a once-daily oral dosage form, Kos 2. Website visited and accessed in March
cumulative sales approaching $10 billion leveraged the well-known ability of niacin to 2011.http://drugtopics.modernmedicine.co
worldwide since launch. lower LDL and triglycerides and provide m/Pharmacy+Facts+&+Figures
The second pop came with a reset of the clinicians with an enhanced therapeutic option
exclusivity clock for both company’s interferon synergistic with HMGCoA reductase
franchises. While the native molecules were inhibitors, such as Lipitor. Approved in 1997,
once on the verge of patent expiration Niaspan has racked up sales of more than $4
worldwide, these new PEGylated proteins, with billion through the end of 2010 despite, or BIOGRAPHY
new composition of matter patents, started a perhaps as a result of, a settlement and license
new clock. Who was going to use the agreement with Barr. The commercial success
unPEGylated proteins in the clinical setting of Niaspan led Abbott to acquire the company
given the more demanding dosing regimen and late in 2006 for $3.7 billion. A validated
the poorer outcomes? How much cheaper molecule, a relatively generic drug delivery
would an unPEGylated interferon alpha need to technology, and a large medical need all
be to make it a bargain? The FDA still doesn’t provided the means to develop a high-value
have a pathway for the approval of generic DDEP. US sales of Niaspan in 2010 popped
biotechnology products, such as interferon up again to a little bit less than $1 billion.
alpha. But even when it arrives, these billion- These are remarkable results for a
dollar products will still have a long and reformulated vitamin that once again reinforce
profitable future ahead of them. the value of vision and execution.
of years. Yes, there was additional cost to previously approved active, these products forecasting support for emerging and
Merck to license the Zydis technology used in have in many cases been able to extend their commercial-stage drug delivery
Maxalt MLT, but these costs have been more exclusivity to 10 years and beyond. companies. Dr. Bossart has more than 3
than paid for by the increased sales of the The epitaph for Jack King, a gambler
decades of experience in the
Maxalt brand. from Alfred Henry Lewis’ 1897 book
As the third triptan to the market, and biopharmaceutical sector, including
Wolfville, reads “life ain't in holding a good
first offering an ODT formulation, even hand, but in playing a pore hand well." That senior sales, marketing, business
without a nasal or injectable form, the Maxalt sentiment relates well to these DDEPs. While development, and management positions
brand has racked up total sales of more than these companies certainly weren’t dealt a poor with Enzon Pharmaceuticals,
$3 billion in the US and $5 billion worldwide. hand, they were able to create something of GeneMedicine, US Ethicals, and Rhône-
Of this total, Maxalt MLT has contributed to real durable value from molecules and Poulenc Rorer. Dr. Bossart earned his PhD
more than half of the sales, a nice pop for a technologies that others ignored. u in Medicinal Chemistry from The Ohio
late-to-market product that distinguished itself
State University, College of Pharmacy.
by improving convenience and the treatment
30 experience.
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D E V E L O P M E N T
PHARMACEUTICAL
PHARMACEUTICAL
D E V E L O P M E N T
Defining & Addressing Solid-State Risks
After the Proof-of-Concept Stage of
Pharmaceutical Development
By: Joanna Bis, PhD, David Igo, PhD
INTRODUCTION
Selection of an appropriate solid-state form (non-solvated or hydrated/solvated parent, salt, or cocrystal) is one of the
most important decisions in the development of a small-molecule API due to the inherent link between the physico-chemical
properties of the solid-state form and factors important to the success of its commercialization.1,2 Although the significance of
this decision is generally well appreciated across the pharmaceutical industry, strategies can vary widely between different
drug development programs as companies attempt to balance the tension between quality, speed, cost, and risks.3 In the
earlier phases of development, attrition rates can be as high as 90% due to the unknown safety profile of the drug candidate,
human exposure, and clinical efficacy.4 This failure rate has redirected development activities away from rigid workflows and
processes that focused on optimizing the solid form based on the intended commercial profile and toward defining
intermediate preclinical and clinical objectives and activities necessary to enable these objectives to be achieved.5 Examples of
these fit-for-purpose objectives targeted at early stages of development may include identifying a suitable solid form of the
API that 1) will exhibit adequate bioavailability and/or stability, 2) can be formulated to support evaluation of the toxicity of
the API in preclinical species, 3) enables isolation and purification of the API, and 4) is compatible with the simple dosage
form required for the first human trials (eg, powder-in-bottle or powder-filled capsule). Because the scope of early phase
studies is becoming more focused and constrained, APIs are more likely to enter the later phases of development with gaps in
knowledge and understanding. This means that when a molecule demonstrates its clinical efficacy, or proof-of-concept (PoC),
focus will need to quickly shift toward defining and understanding the solid-form space, surfacing and mitigating risks
associated with these forms, and ensuring that manufacturing operations are sufficiently robust in delivering the desired
materials. For more advanced drug programs, a comprehensive knowledge of solid forms and their attributes can also afford a
practical means of prolonging the life cycle of an asset after its commercialization and maximize the return on the discovery
and development investments.
Drug Development & Delivery APRIL 2011 Vol 11 No 3
CRYSTAL-FORM SPACE typically decrease with higher stability.8,9 also obtained through the use of binary and
Therefore, shortly after achieving PoC, ternary organic mixtures, which can extend
Because the crystalline form can extensive crystal-form screening studies are the range of solubility achievable using neat
impact attributes important to the employed in order to maximize the solvents while providing a chemically
performance of a medicine (eg, shelf-life opportunity for discovering important solid- diverse solvent system. Incorporating water
and bioavailability/efficacy), an state forms. These comprehensive studies is often of critical importance because
understanding of the solid-form space is typically involve 1000 to 2000 experiments hydration by vapor or liquid water can have
essential in defining the quality attributes and utilize an array of solvents that allows serious consequences on formulation
associated with the manufacturing and the effects of solvent polarity, hydrogen- methodology and ultimately on the stability
formulation processes.6,7 Undiscovered bonding, and geometric attributes on of the active ingredient and formulated
stable crystal forms pose a direct risk to crystal-form space to be thoroughly product. Such risks are assessed via the use
commercial supplies, particularly for exploited. This typically involves a large of water and aqueous solvent mixtures in
compounds exhibiting solubility-limited number of solvent classes (eg, alkanes, the solvent set to facilitate the discovery of
32
bioavailability, because both properties alcohols, ketones, aldehydes). Diversity is hydrates and, in the case of salts, probe
32-35-DD&D April 2011-Pharma Dev_Layout 1 3/24/11 1:02 PM Page 33
their disproportionation. achieved by in situ monitoring (eg, by Specifically, micronizing or compacting can
The diverse solvent arrays are used in a spectroscopy or reflectance) or by collecting induce formation of amorphous phase, which
variety of crystallization modes (eg, slurry grab-samples and analyzing them off-line (eg, under appropriate humidity conditions, may
ripening and evaporative, cooling, and by PXRD or vibrational spectroscopy). Solid- absorb moisture and disproportionate.
solvent/antisolvent crystallizations) to explore state forms can be stable when in contact with
the impact of temperature, degree of the crystallization mother liquor, yet
supersaturation, and solvent composition on physically unstable when isolated, resulting in SOLID-STATE FORM STUDIES TO
the ability to nucleate and grow important conversion to the desired, or sometimes, SUPPORT LIFE CYCLE
crystal forms. Solvent-less screening studies undesired crystal form. Therefore, the grab- MANAGEMENT
are also employed and may include exposure samples should be evaluated as a wet and
of the solid API to a variety of conditions: freshly isolated cake and throughout the The commercial opportunities of a
elevated humidity, solvent vapors, elevated drying process. pharmaceutical asset can be expanded via a
pressures, milling, melting/cooling, etc. The new indication, combination therapy, route of
products of the comprehensive screen are administration, or a formulation. These new
subjected to analyses to establish the nature of API FORMULATION & DRUG targets, or product line extensions (PLEs), are
the unique forms and assess their DELIVERY SUPPORT identified as clinical data from Phases IIa
thermodynamic stability and relationships to onward become available and highlight
each other. These analyses may include Secondary processing operations can specific physico-chemical properties of the
thermal analysis, solid-state stability studies, lead to the production of new crystal forms or molecule required to achieve a more desirable
solubility determinations, and competitive- result in a loss of crystallinity and or new clinical response. PLE can be enabled
ripening studies conducted at various corresponding increase in amorphous through the introduction of a new solid form
temperatures. content.11,12 Hence, the solid-state of the same API that exhibits the desired
characteristics of the API should be pharmaceutical performance. Alternative salts
monitored prior to and following each unit are frequently considered for PLE, and recent
CRYSTALLIZATION PROCESS process wherever possible. Laboratory-based research has indicated that pharmaceutical
SUPPORT experiments (eg, compression and milling) cocrystals may exhibit desirable attributes.13,14
can often be used to predict the likelihood of Discovery of new solid-state forms may
When an API exhibits polymorphism or processing-induced changes. However, while enable an extension of the original patent
can solvate with a process solvent and/or crystalline transformations are possible with term if the novelty, inventiveness, and utility
water, more detailed experiments are required these unit processes, some processes may also can be demonstrated.15 For example,
to understand the thermodynamic and kinetic induce disorder, in which case it is important undesired side-effects in the gastrointestinal
behavior of the system. In these cases, a to establish the fate of the disordered phase, track posed by an oral formulation of a
diagram of the thermodynamic stability of the the kinetics of change, and the influence that marketed API salt can prompt the search to
different phases with respect to temperature it has on drug product performance and identify, patent, and develop a topical
and solvent composition needs to be stability. formulation of another salt.16
generated to assist in understanding the risks If an API can exist as a hydrate, Extensive and thorough solid form
posed to the crystallization process. Once the aqueous-based manufacturing processes of screens are conducted in order to identify and
phase-diagram is known, the kinetics of the anhydrated form, such as wet granulation evaluate the potential solid form candidates
form inter-conversions (eg, relative rates of followed by tabletting are at risk. Properly for a variety of PLE strategies. These screens
crystallization, nucleation, and crystal- designed stability studies can be employed to may involve hundreds to thousands of
growth) can be evaluated to ensure the determine the critical water activity below experiments and utilize a broad range of Drug Development & Delivery APRIL 2011 Vol 11 No 3
avoidance of any undesired form in the which the anhydrate is thermodynamically counterions (CIs) and cocrystal formers
isolated product. stable. Such studies may enable the use of (CCFs) to maximize the probability of
As the scale of the manufacturing aqueous organic solvent system with producing new solid form with a desired
process increases, mixing and heating become appropriately low water content to destabilize property. The discovery of the novel
significantly more non-homogeneous the hydrate and to granulate the anhydrate multicomponent solid-state forms raises the
compared to small-scale laboratory studies. form. Similar studies should be considered need to consider compatibility of the CI
The resulting concentration and thermal for programs involving, for instance, aqueous and/or CCF attributes with those exhibited by
gradients can promote the appearance of new suspension formulations. the API and those that are desired in the final
crystalline forms and highlight the For salts, in particular those containing product. In addition to the toxicity and
importance of monitoring the product weak counterions, disproportionation risk physical property profiles of the coformers
throughout crystallization and/or salt- should be assessed in formulation medium (eg, hydrophilicity), which will likely affect
formation process.10 Monitoring can be and under mechanical processing conditions. the property of the product (eg, solubility), a
33
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comprehensive-screen design should also 5. Chen P, Igo D. Fit-for-purpose strategy toward solid form
address crystal engineering aspects.17,18 These screening & selection, Drug Dev & Delivery. 2011;11(1):38- BIOGRAPHIES
40.
aspects affect the likelihood of producing a Dr. David Igo earned
6. Yoshioka S, Stella VJ. Stability of Drugs and Dosage Forms.
stable crystalline material and may include: his PhD from the
New York, NY: Kluwer Academic Publishers, Plenum
propensity of components to interact via strong University of
Publishers; 2000.
ionic (eg, pKa considerations) and/or weaker Cincinnati, where he
7. York P. Solid-state properties of powders in the formulation
neutral supramolecular synthons, proton studied the structural
and processing of solid dosage forms. Int J Pharm. 1983;14:1-
donor/acceptor balance, geometrical fit (size behavior of inorganic/
28.
polymeric
and shape), conformational flexibility, 8. Liebenberg W, de Villiers M, Wurster DE, Swanepoel E,
electrochemical sensors
stereochemistry, etc. The successful application Dekker TG, Lotter AP. The effect of polymorphism on powder
using extended X-ray
of crystal engineering approaches to achieving compaction and dissolution properties of chemically equivalent
absorption fine-structure (EXAF) spectro-
enhanced dissolution characteristics has been oxytetracycline hydrochloride powders. Drug Dev Ind Pharm.
electrochemistry under the direction of William R.
demonstrated for new salts and cocrystals of 1999;25:1027-1033.
Heineman and Richard C. Elder. Dr. Igo began his
several marketed drugs, indicating its 9. Kobayashi Y, Ito S, Itai S, Yamamoto K. Physichochemical
industrial career with Glaxo Inc. in 1991 (now
properties and bioavailability of carbamazepine polymorphs
usefulness in supporting life-cycle management GlaxoSmithKline; GSK), where he supported various
and dehydrate. Int J Pharm. 2000; 193:137-146. aspects of drug development, including
strategies.19-21
10. Mangin D, Puel F, Veesler S. Polymorphism in processes of preformulation, product development, chemical
crystallization in solution: a practical review. Org Process Res development, materials characterization, and
Dev. 2009;13:1241-1253. technology development. In his nearly 2-decade
CONCLUDING REMARKS 11. Brittain HG, Fiese EF. Effect of pharmaceutical processing on tenure at GSK, he co-invented a variety of high-
drug polymorphs and solvates. In: Brittain, HG, ed. throughput technologies utilized in solid-state
Solid forms can impact the API and drug Polymorphism in Pharmaceutical Solids. New York, NY: screening along with a range of unique crystalline
product attributes that are important to shelf- Marcel Dekker, Inc;1999:331-362. salts and solid-state forms of GSK compounds. He is
life, robustness of the manufacturing 12. Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. Theoretical currently Director of OptiformTM Technologies at
operations, and reliability and efficacy of the approaches to physical transformations of active Catalent Pharma Solutions. Optiform Technologies
medicine. Once a compound achieves a pharmaceutical ingredients during manufacturing processes. combines novel automation tools and solid-state
successful PoC, efforts intensify in selecting the Adv Drug Delivery Rev. 2001;48:91-114. workflows to support the discovery and evaluation of
13. Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. crystalline forms, salts, and cocrystals.
proper solid-state form for development,
Pharmaceutical co-crystals. J Pharm Sci. 2006;95:499-516.
optimizing manufacturing operations, and
14. Schultheiss N, Newman A. Pharmaceutical cocrystals and Dr. Joanna Bis
identifying and mitigating risks that may be
their physicochemical properties. Cryst Growth Des. earned her MSc in
posed by other solid-state forms. The Analytical Chemistry
2009;9:2950-2967.
knowledge gained from these activities increase from Jagiellonian
15. Lucas J, Burgess P. When form equals substance: the value of
confidence in the ability to deliver the form screening in product life-cycle management. Pharma University, Kraków,
commercial product reliably and can play a key Voice. 2004:54-57. Poland, in 2002. In
role in successful life cycle management. In 16. Foraita HG. In: Stahl PH, Wermuth CG, eds. Handbook of 2006, she earned her
addition, discovering commercially viable Pharmaceutical Salts: Properties, Selection, and Use.
PhD from the University
of South Florida, where
crystalline forms and protecting these forms Weinheim, Germany: Wiley-VCH;2002;228-230.
under the supervision of Dr. Michael Zaworotko, she
with patents has become a common practice in 17. http://www.accessdata.fda.gov/
studied crystal engineering of organic compounds.
both innovator and generic pharmaceutical scripts/fcn/fcnNavigation.cfm?rpt=scogsListing.
While in the PhD program, she worked as a Research
sectors to develop and commercialize FDA- 18. Desiraju G. Supramolecular synthons in crystal engineering -
Assistant for TransForm Pharmaceuticals Inc. and
a new organic synthesis. Angew Chem Int Ed. 1995,34:2311-
approved APIs. applied the fundamental crystal engineering
2327.
Drug Development & Delivery APRIL 2011 Vol 11 No 3
TRANSDERMAL
G U I D E LI N E S
INTRODUCTION
Since 2007, the US FDA has issued 12 bioequivalence draft guidances for generic transdermal patch designs.
While these guidances provide insight into current regulatory views on study designs for individual transdermal
patch bioequivalence assessments, differences among the guidances make it challenging for product developers
to glean essential principles for study design. This review summarizes the recommendations to identify
commonalities and differences important to the design of successful studies.
OVERVIEW: FDA TRANSDERMAL as well as the new draft guidance on the evaluation of residual
GUIDANCES 2007-2010 drugs in transdermals, are beyond the scope of this article, and
product developers are advised to consult the FDA guidances
Designing studies for bioequivalence assessment of for details on those specific topics.2
transdermal patch systems had involved considerable
speculation until the FDA issued a series of draft guidances, Pharmacokinetic Bioequivalence Study
beginning with the transdermal patch for lidocaine. The FDA Requirements
website on individual product bioequivalence Although there are drug-specific requirements for PK
recommendations maintains the most current draft guidances. 1 study designs, the common elements across the draft
In this rapidly changing environment, it is recommended that guidances for PK bioequivalence studies include:
product developers review the FDA website frequently for new
and updated guidances. Table 1 provides the most current list • Design (single-dose, two-treatment, two-period cross-
of those guidances related to transdermal patch delivery over)
Drug Delivery Technology April 2011 Vol 11 No 3
systems.
• Number of subjects (36 to 48 subjects recommended)
TRANSDERMAL
G U I D E L I N E S
Selegiline 8/2009
Scopolamine 12/2009
Rivastigmine 11/2010 (Revised)
Oxybutynin 3/2009
Nitroglycerin 12/2009
Methylphenidate 7/2010
Lidocaine 5/2007
Fentanyl 2/2010 (Revised)
Ethinyl Estradiol: Norelgestromin 5/2009
Estradiol (3.5-day patch) 11/2010
Estradiol (7-day patch) 11/2010
Clonidine 11/2009
Active Ingredient Date Issued
duration, Oxybutynin is indicated to be worn test patch and the RLD. The frequency of
TA B L E 1
for a 96-hour dose duration, etc. Dose application, application duration, and dosage
Active Ingredient Date Issued
strength is the dose provided in the full-size strength vary depending on the patch design. Clonidine 11/2009
Estradiol (7-day patch) 11/2010
patch. In most cases, the highest strength is Before each next sequential patch Estradiol (3.5-day patch) 11/2010
Ethinyl Estradiol: Norelgestromin 5/2009
recommended. Lower strengths may be application, irritation is measured using two Fentanyl 2/2010 (Revised)
Lidocaine 5/2007
considered for a waiver under certain standardized scoring scales: one to score Methylphenidate 7/2010
Nitroglycerin 12/2009
circumstances. The appropriate frequency Dermal Response and one to score Other Oxybutynin 3/2009
Rivastigmine 11/2010 (Revised)
and timing of sample collection is a function Effects. Following the induction-irritation Scopolamine 12/2009
Selegiline 8/2009
of the patch design and is unique to each phase, there is a 14-day rest phase, during
Draft Guidances Available from the FDA as of
product, but if not already known, clinical which no patch is applied. After the rest
January 2011
research organizations (CROs) can often period, a challenge phase is conducted to
provide recommendations on these determine whether the subject has developed FDA has provided a standardized scoring
parameters. a sensitization response to the products. This system for dermal irritation assessment for
consists of a single 48-hour dose duration consistency across all of the guidances. The
Irritation & Sensitization (I/S) with monitoring for skin reactions during the system uses two scales: the Dermal
Study Requirements 72 hours following removal. Response scale for erythema and edema,
To evaluate skin irritation and Recommendations call for sensitization which assigns numeric values from zero (no
sensitization, the common elements across studies to be completed with 200 evaluable evidence of irritation) to 7 (strong reaction
the draft guidances for combined irritation subjects, which may require 240 to 300 spreading beyond the test application site),
and sensitization studies include: subjects for initial enrollment. Subject and the Other Effects scale, which measures
compliance and retention is affected by the physical changes to the skin (e.g., glazing,
• Induction-irritation phase (21 days of propensity of drug-related adverse events peeling, cracking, fissures). The Other
exposure) that may occur, study duration (6 weeks), Effects scale assigns letter grades with
frequency of return visits, time of year, numeric equivalents, from A (0) (slightly
• Challenge phase (a single, 48-hour
competency of the CRO, and other factors. glazed appearance) to H (3) (small petechial
dose duration)
The guidances indicate that irritation erosions and/or scabs). The Dermal
• Scoring scale (Standardized Visual and adhesive properties of transdermal patch Response score and Other Effects score are
Assessment) systems may be sensitive to climate, and combined to determine the final I/S scores.
• Number of subjects (completion with recommend that studies be conducted at a One can refer to any of the draft transdermal
200 evaluable subjects) minimum of two sites with different climate guidances for the specific score definitions.
Drug Delivery Technology April 2011 Vol 11 No 3
conditions. However, it is not specified what The key to a successful I/S study is
• Study sites (multiple clinical sites
the different climate conditions should be ensuring the CRO has an intensive irritation-
with different climate conditions)
that are relevant to a North American score training program with validation of
• Control treatments (optional vehicle population. When placing these studies, it is scoring competency. Ideally, the same grader
patch and negative control) advisable to utilize a CRO that has clinic (scorer) should be used throughout the study.
sites at different locations within North Because this is not always possible,
• Acceptance criteria (non-inferiority of
America with average temperature particularly when two or more clinic sites are
the test product compared to the
differences of 10°F to 15°F, and with being used, it is important that all graders are
RLD)
average relative humidity differences of 10% cross-trained to achieve the same degree of
to 15% between sites. accuracy and reproducibility in their scoring
The initial induction-irritation phase Scoring systems for assessing dermal assessments.
38
consists of 21 days of exposure to both the irritation have evolved over the years. The
36-41 DDD April 2011- Transdermal Guidelines_Layout 1 3/24/11 1:03 PM Page 39
TRANSDERMAL
G U I D E L I N E S
Adhesion Performance Study adhesion studies, such as the number of adhesion, and ensure there are a sufficient
Requirements subjects needed for a particular product, the number of subjects to evaluate non-
The need for adhesion performance frequency of assessment, or the most inferiority for adhesion performance.
assessment arose in parallel with advances in appropriate statistical evaluation of the data.
patch adhesive matrix designs, in which The FDA has provided a standardized Adhesion Assessment: Issues
patch detachment from the skin may be a visual scoring scale for adhesion assessment. When Combined With I/S
concern. Adhesion performance is to be The system ranges from a score of zero (≥ Studies
assessed on both the test and reference 90% attachment to the skin) to 4 (completely When adhesion performance
transdermal patches. The common elements detached). One can refer to any of the draft assessment is combined with the I/S study,
for adhesion performance assessment in the transdermal guidances for the specific score adhesion is typically conducted on the first
draft guidances include: definitions. patch application only. Following that, tape
Assessment is based on the perceived re-enforcement of the patches may be used,
• Dose type (single full-size, full- percentage of detachment from the skin. if needed, to ensure full contact exposure for
strength patch application) This can be challenging, depending on the the remainder of the 21-day induction phase.
size of the patch and the type of detachment. In the protocol, it is important to
• Dose duration (matched to that of the
Detachment along the edges is easy to see differentiate the adhesion performance data
RLD)
and score. However, with larger patches, (for non-inferiority assessment) from
• Scoring scale (Standardized Visual detachment in the inner central areas may adhesion confirmation data (ensurance of
Assessment) also occur, which is more difficult to assess continuous exposure during the remaining
visually. Again, a comprehensive, period of the study), which is not used for
• Study sites (multiple clinical sites
competency-based training program is the non-inferiority comparison analysis.
with different climate conditions)
essential for study personnel assessing Only in those I/S studies in which a
• Acceptance criteria (non-inferiority of adhesion, and should be expected of the full-size patch is indicated can adhesion
the test product compared to the CRO conducting the study. performance be evaluated. When the I/S
RLD) study is indicated with a reduced sized patch
Adhesion Assessment: Issues (e.g., 1/2 cut patch), adhesion performance
Adhesion performance assessment is When Combined With PK cannot be evaluated.
conducted on a single dose application with Studies
a full-size patch for the dose duration Several of the draft guidances
dictated by the RLD. As with I/S studies, recommend combining the adhesion GUIDANCES BY GROUP:
adhesion studies are recommended to be performance assessment with the PK study. INSIGHT INTO DESIGN
Drug Delivery Technology April 2011 Vol 11 No 3
conducted in at least two sites with different However, the guidances do not offer clear APPROACHES
climate conditions. recommendations for situations when poor
An issue for adhesion studies is the adhesion is encountered. It is advisable that Patterns can be observed in the 12
uncertainty regarding the number of subjects the study protocol addresses conditional existing draft guidances that yield insight
required to sufficiently power the study for outcomes, to anticipate whether a subject into regulatory expectations for assessment
demonstration of non-inferiority. In addition, should be discontinued when significant of transdermal products that have not yet
the draft guidances do not offer clear detachment is observed, or how much been addressed by an FDA guidance. As
recommendations on frequency of adhesion detachment constitutes an inadequate dose product developers venture into transdermal
scoring during the patch application period. exposure. Enrollment in combined products where a guidance is not available,
An experienced CRO can often recommend PK/Adhesion studies should take into comparing the test product to the most
appropriate parameters for conducting consideration the potential for poor similar drug among existing guidances may 39
36-41 DDD April 2011- Transdermal Guidelines_Layout 1 3/24/11 1:03 PM Page 40
TRANSDERMAL
G U I D E L I N E S
help in developing study designs. Group 2: Adhesion Performance adverse events are likely to affect a small
There are four distinct groups of draft is Not Conducted With PK number of subjects. Adhesion performance
guidances for transdermals that distinguish The draft guidances recommend that is assessed on the first dose application only;
whether adhesion may be evaluated in adhesion performance is not conducted in tape reinforcement may be used thereafter if
parallel with a PK or I/S assessment: the PK study for the following four needed. Patch dose durations during the 21-
transdermal systems: day induction phase are a function of the
1. Adhesion performance is conducted indicated RLD patch application period.
with PK • Methylphenidate
2. Adhesion performance is not • Clonidine Group 4: Adhesion Performance
conducted with PK • Lidocaine is Not Conducted With I/S
• Selegiline Adhesion performance cannot be
3. Adhesion performance is conducted combined with the I/S study for the
with I/S following six transdermal systems:
There are specific distinctions within
4. Adhesion performance is not the recommendations for this drug group.
conducted with I/S First, fasting for PK is indicated for • Ethinyl Estradiol: Norelgestromin
methylphenidate and lidocaine, but not the • Lidocaine
others. Second, the use of an overlay is • Oxybutynin
Group 1: Adhesion Performance • Rivastigmine
indicated exclusively for clonidine. In
is Conducted With PK • Fentanyl
addition, one noteworthy observation is
The guidances recommend that PK
applicable to the lidocaine transdermal • Scopolamine
evaluation be combined with adhesion
system. A specific body site for patch
performance for the following seven
application is not indicated. Given the size of The reason adhesion performance
transdermal systems:
the lidocaine patch, the upper back is a cannot be combined with the I/S studies is
logical choice. due to the risk of drug-related adverse events
• Estradiol
from the double dose delivered if two full-
• Ethinyl Estradiol: Norelgestromin
• Fentanyl
Group 3: Adhesion Performance strength patches were to be used. To
• Nitroglycerin
is Conducted With I/S minimize drug-related adverse events, half-
Adhesion performance assessment is size or quarter-size patches are indicated. As
• Oxybutynin
indicated to be included with the I/S study adhesion performance must be evaluated on
• Rivastigmine
Drug Delivery Technology April 2011 Vol 11 No 3
for the following four transdermal systems: full-size patches, adhesion performance
• Scopolamine
cannot be included in these I/S studies. Tape
• Methylphenidate reinforcement can be used, and may even be
The common design is the single-dose
• Clonidine required to ensure continuous patch exposure
cross-over study with a full-size patch. Tape
• Nitroglycerin to the skin during the induction phase.
reinforcement is not allowed.
• Selegiline Unique to fentanyl and scopolamine,
This group presumes a low risk for the irritation and sensitivity tests actually
drug-related adverse events during the 21 evaluate only a vehicle patch - there is no
days of exposure in which full-size patches drug involved. Irritation comparison is made
are used. However, one should still anticipate to the positive control, which is nominally
that even at the lowest recommended dose, indicated as a 0.1% sodium laurel sulfate in
40
36-41 DDD April 2011- Transdermal Guidelines_Layout 1 3/24/11 1:03 PM Page 41
TRANSDERMAL
G U I D E L I N E S
water solution, dosed under an occlusive information; and the CRO conducting these
BIOGRAPHY
chamber or dressing. specialized studies should be experienced,
with processes and templates already in Paul Lehman is
place, proven, and validated, to ensure that the Director of
CONCLUDING OBSERVATIONS all the required data is appropriately the Clinical and
captured in a timely and efficient manner. Preclinical
Value of Pilot Studies Dermatology at
In the course of a transdermal product’s Cetero
Protocol Submission
development, particularly when different Research. He has
Because these guidances are still in
conducted
backing materials, adhesives or excipients, draft form, and are considered as
internationally
or manufacturing processes are used that recommendations, if there is any uncertainty recognized research in the field of topical
differ from the RLD, there may be regarding interpretation of the guidance, or if pharmacokinetics and topical bioequivalence
uncertainty in the PK, adhesion there is any planned study design variance to for 30 years and has been a Principal
performance, and irritation properties for the the guidance, it is recommended that the Investigator or Sub-Investigator on more than
patch. For patches in development, less- protocol be submitted to the FDA for review 500 clinical and preclinical dermatology
expensive pilot studies can provide early and comment prior to initiating a study.
studies for numerous pharmaceutical and skin
warning of unanticipated issues before care companies. He earned his BA in Biology
and Bachelor of Business Administration from
initiation of pivotal studies. Keys to Success Incarnate Word College in San Antonio, Texas.
One is encouraged to study the Mr. Lehman later earned his MS in
Lifestyle Guidelines in the guidances carefully to ensure proper study Pharmaceutics at the University of Washington
Protocol design, partner with an experienced CRO, in Seattle. His prior appointment was
It is important to include subject and monitor the FDA website for new or Executive Vice President of Clinical and
lifestyle guidelines in study protocols. In the revised guidances. Preclinical Dermatology at DermTech
course of a 21-day irritation study in which International in San Diego. Mr. Lehman has
the subjects are outpatients, activities, such also held faculty appointments at both the
as tanning, sunburn, hot tubs, sweat- REFERENCES University of Arkansas for Medical Sciences
and at the University of Washington. He has
producing sports, and exercise, can have a
also worked for 2 years at the National Center
major impact on patch adhesion, irritation, 1. Website visited:
for Toxicological Research (FDA) in Jefferson,
and compliance. Defining the lifestyle http://www.fda.gov/Drugs/GuidanceComplianceR
Arkansas, and is currently an Adjunct Professor
Drug Delivery Technology April 2011 Vol 11 No 3
guidelines in the protocol and informed egulatoryInformation/Guidances/ucm075207.htm at North Dakota State University in Fargo,
consent, and providing clear instructions to 2. Guidance for Industry, Residual Drug in North Dakota. Mr. Lehman has been an
the subjects, improves compliance, retention Transdermal and Related Drug Delivery Systems, integral partner with Dr. Thomas Franz in the
in the study, and data quality. Draft Guidance, CDER, August 2010 conduct of in vitro and in vivo topical
pharmacokinetics and the development and
validation of dermatopharmacokinetic
Volume of Data
bioequivalence methods for topical
Regulatory agencies are requesting
formulations. His credentials include several
significantly greater amounts of data, manuscript and book chapter publications, as
particularly from I/S and adhesion studies. well as numerous poster and lecture
Product developers should be prepared to presentations.
manage extensive data tables, listings, and
41
42-47-DD&D April 2011-Gene Delivery_Layout 1 3/24/11 1:03 PM Page 42
D E L I V E R Y
GENE
GENE
D E L I V E R Y
Ultrasound & Microbubbles for In Vitro Gene
Delivery
By: J.M. Escoffre, PhD; A. Novell, MSc; A. Zeghimi, MSc; A. Bouakaz, PhD
INTRODUCTION
Gene therapy is a potent strategy for the treatment of a wide variety of inherited and acquired diseases for which the
current treatments are inefficient or non-existent.1 Therapeutic genes can be transferred using viral or non-viral vectors. In
clinical trials, viral vectors are preferentially used due to their high gene delivery efficiency and their ability to induce high-
level and long-lasting gene expression in a wide range of tissues.2 Their effectiveness lies in the infectious properties of
viruses controlled by viral proteins. However, these proteins can induce specific immune responses that would limit the ability
to re-administer the viral vector and inhibit the efficiency of gene delivery.3 Moreover, some of the viral vectors can induce
insertional mutations during their integration into the host genome.4 In addition, previous investigations reported
recombination events that can lead to the formation of replication competent viruses.5
In contrast, plasmid DNA (pDNA) is straightforward covalent closed circles of naked double-stranded DNA. pDNA is simple
to mass produce, and easier to store compared to viral vectors.6 These molecules could stimulate the immune system due to
the recognition of immuno-stimulatory sequences associated with unmethylated Cytosine-phosphate-Guanine (CpG) motifs
present in bacterial-generated DNA. However, the use of mini-circle DNA, which does not harbor these sequences, does not
induce an immune response and can be re-administered.7 Low immunogenicity and lack of integration of pDNA make it a highly
attractive molecule for gene therapy provided that an efficient, safe, and targeted delivery method can be achieved.6
The use of ultrasound waves with gas microbubbles as a safe tool to deliver pDNA to tissues and organs has been rapidly
developing throughout the past decade. The method increased transiently the native permeability of cell membranes when
submitted to ultrasound waves in the presence of gas microbubbles. This process is commonly known as sonoporation or
microbubble-assisted ultrasound permeabilization. This review focuses on the mechanisms of membrane permeabilization with
ultrasound and microbubbles and its use for in vitro gene delivery.
BIOPHYSICAL MECHANISMS kHz. An acoustic pressure wave oscillates and hence its radius shrinks and
OF MEMBRANE alternatively compresses (compression expands following the respective effects of
PERMEABILIZATION
Drug Development & Delivery APRIL 2011 Vol 11 No 3
phase) and expands (rarefaction phase) the the high- and low-pressure phases of the
WITH SONOPORATION medium through which it travels. ultrasound wave. For higher acoustic
Therefore, when ultrasound waves pass pressures, the microbubble oscillates
To understand the principle of through a medium, the molecules that strongly, giving rise to nonlinear
microbubble-assisted ultrasound for gene comprise this medium can be physically components at multiples of the transmitted
delivery, it is important to describe the and locally moved. These molecules are frequency, the so-called harmonic
physics behind the interactions between compressed at high pressures and components. This acoustic regime is the
microbubbles and ultrasound. expanded at low pressures. 8
basis of modern ultrasound contrast
Microbubble response to an imaging methods. Such strong oscillations
Microbubble-Ultrasound ultrasound excitation depends on the induce intense liquid flows around the
Interactions applied acoustic pressure. For small microbubbles, termed acoustic
42 Ultrasound is a longitudinal pressure acoustic pressures, the microbubble microstreaming.9 At much higher
wave with a frequency higher than 20
42-47-DD&D April 2011-Gene Delivery_Layout 1 3/24/11 1:03 PM Page 43
consensus is available, three different from a few seconds to a maximum of a few kDa to 500 kDa).13 Fluorescence microscopy
scenarios are usually hypothesized: (1) hours, with different kinetics depending on showed homogeneous distribution of 4.4
membrane poration, (2) endocytosis, and (3) the molecular size. 12-16
Recent investigations kDa and 70 kDa dextrans through the
the formation of large cell membrane suggested that membrane resealing is an cytosol and localization of 155 kDa and 500
wounds. energy- and Ca2+-dependent process that kDa dextrans in distinct vesicles. The ATP
The generation of transient pores has involves the aggregation and fusion of lipid depletion reduced the uptake of 4.4 kDa
been ascribed to the increased uptake or vesicles trafficked to the pore site.17,18 dextrans but no uptake of 500 kDa dextrans.
release of marker compounds.12,13 Indeed, In addition to triggering transient pore Moreover, the independent inhibition of
Mehier-Humbert et al demonstrated that formation, recent electrophysiological clathrin and caveolae-mediated endocytosis
dextran molecules with a diameter between studies showed that microbubble-assisted and macropinocytosis significantly
11.6 nm and 37.0 nm were able to enter into ultrasound induces a cascade of events decreased the intracellular delivery of 4.4
the cell via pores, and no differences were characterized by the activation of BKCa kDa and 500 kDa dextrans. Thus, the
vesicles of 500 kDa dextrans colocalized Drug Development & Delivery APRIL 2011 Vol 11 No 3
12
found between molecule sizes. These data channels, a subsequent local
are in contrast with the recent study of hyperpolarization of the cell membrane with caveolin-1 and clathrin. This study
Meijering et al, who showed that the followed by an increase of the intracellular showed that the contribution of endocytosis
contribution of transient pores is less Ca2+ concentration.19 The local and micropinocytosis processes are
important for the delivery of hyperpolarization of the cell membrane dependent on macromolecule size.13
macromolecules with a molecular weight facilitates uptake of macromolecules through The last mechanism involves molecular
larger than 155 kDa.13 The formation of endocytosis and macropinocytosis. In the uptake through membrane wounds.20,21
transient pores has also been shown by recent investigation from Meijering et al, Schlicher et al showed that microbubble-
measuring changes in ionic conductivity.14 primary endothelial cells were subjected to assisted ultrasound facilitated the
Indeed, using voltage clamp techniques, microbubble-assisted ultrasound (1 MHz, intracellular incorporation of
Deng et al demonstrated that the application 0.22 MPa, 6.2% DC 30 sec, SonoVue ) in ® macromolecules up to 28 nm in radius
43
42-47-DD&D April 2011-Gene Delivery_Layout 1 3/24/11 1:03 PM Page 44
SF , sulfur-hexafluoride.
phosphoric acid; MPEG 5000-DPPE, polyethyleneglycol 5000-dipalmitoyl-phosphatidylethanolamine; C F , perfluorocarbon; C F , octafluoropropane;
HSA, human serum albumin; PA, palmitic acid; DSPC, distearoyl-phosphatidylcholine ; DPPC, dipalmitoyl-phosphatidylcholine; DPPA, dipalmitoyl-
Targeson
2.5 Surface-modified lipid Variable CF 55
SonoVue
2.5 DSPC/DPPG/PA Negative SF 52-54
Sonidel MB101
2.7 Stabilized lipid Neutral CF 52
PESDA
4.7 HSA/dextrose Negative CF 33,51
Optison
3-5 HSA Negative CF 27,38,51
Levovist
2-3 Galactose/ PA Negative Air 27,50
Definity
1.5 DPPE Negative CF 49
DPPC/DPPA/MPEG 5000-
BR14
2.6 Phospholipid Neutral CF 26
Albunex
4.5 HSA Negative Air 27,37
(µm)
Composition Charge
Microbubbles Diameter Gas References
Shell Surface
Mean
Optison
® Moreover, the type of microbubbles has been
3-5 HSA Negative C3 F8 27,38,51
demonstrated to be a major parameter for
PESDA
4.7 HSA/dextrose Negative C4F10 33,51
gene delivery. However, few investigations
®
Sonidel MB101 allow drawing up a comparative table of
2.7 Stabilized lipid Neutral C4F10 52
SonoVue
® microbubbles in terms of their transfection
2.5 DSPC/DPPG/PA Negative SF6 52-54
efficiency and safety. Li et al led a
®
Targeson
2.5 Surface-modified lipid Variable C4F10 55
comparative study of Albunex®, Levovist®,
HSA, human serum albumin; PA, palmitic acid; DSPC, distearoyl-phosphatidylcholine ; DPPC, dipalmitoyl-phosphatidylcholine; DPPA, dipalmitoyl-
phosphoric acid; MPEG 5000-DPPE, polyethyleneglycol 5000-dipalmitoyl-phosphatidylethanolamine; C4F10, perfluorocarbon; C3F8, octafluoropropane;
SF6, sulfur-hexafluoride. and Optison® microbubbles for gene delivery.
A survey of the different microbubble types used for in vitro gene delivery.
The authors showed that the use of Optison®
through repairable micro-scale wounds in the muscle cells that are known to be resistant to microbubbles induced a six-fold increase of
plasma membrane with lifetimes > 1 min. 21
conventional transfection methods. The transfection level compared to Albunex® and
Like the pore resealing, previous studies transfection level and efficiency are Levovist® microbubbles.27 These results can be
showed that cells resealed these membrane comparable to or even higher than the results explained by an enhanced acoustic activity
wounds by an active process involving obtained by lipofection and with Optison® microbubbles. The
trafficking of intracellular vesicles (eg, electroporation.22,23 concentration of microbubbles is a second
lysosomes) to the site of membrane injury. The efficiency of microbubble-assisted key parameter for optimal gene transfer.
Then, vesicle fusion resealed the membrane ultrasound lies in a narrow combination Indeed, a linear relation between the
on a timescale of minutes.20,21 between microbubbles (type, acoustic concentration of microbubbles and the
In conclusion, these data demonstrated properties, and concentration), acoustic percentage of transfected cells for Albunex®
that pore formation, endocytosis stimulation, parameters (excitation frequency, acoustic and Optison® microbubbles has been
and membrane wounds are likely to be key pressure, insonation time), and the reported.28,29 However, above a microbubble
mechanisms of molecular delivery by physiological state of the cells. concentration threshold, the transfection level
microbubble-assisted ultrasound. The is stabilized and thus does not exceed its
contribution of these mechanisms is The Microbubbles maximal rate. These results can be explained
dependent on molecular size. The microbubbles are echo-contrast by a strong attenuation of ultrasound waves
Drug Development & Delivery APRIL 2011 Vol 11 No 3
agents used in ultrasound imaging to improve due to the high concentration of the
IN VITRO GENE DELIVERY the scattering of ultrasound waves and to microbubbles. At higher concentrations of the
enhance the contrast.24 The microbubbles are microbubbles, the transfection level remained
Microbubble-assisted ultrasound as a gas-filled cores surrounded by a stabilizing constant, but the cell viability decreased.28,29
safe and efficient method to deliver plasmid shell. The shell prevents gas leakages and Recently, we performed a comparative study
DNA to target cells has rapidly evolved enhances the stability of the microbubbles using two types of microbubbles, ie,
throughout the past decade. Several cell lines, and their circulation time in blood. 24,25
SonoVue® and Vevo Micromarker®
including cancer and primary, have been Examples of currently available microbubbles microbubbles currently used in contrast
successfully transfected. This method is are shown in Table 1, and this list is indicative imaging. The results showed that the
efficient even in endothelial and smooth of the heterogeneity of these reagents in terms transfection level achieved with Vevo
44
42-47-DD&D April 2011-Gene Delivery_Layout 1 3/24/11 1:03 PM Page 45
BHK-21
EGFP 75000 80%
Luciferase
Optison 10% 1 MHz 2 W/cm 30 mins
44%
ND 0.19 80%
40
Cationic MB
EGFP Targestar-P
4.10 MB/mL 1 MHz 2 W/cm 3 mins 70% ND 70% 55
PESDA
HEK-293 beta-Gal
unloaded
PESDA
1600 1.3 MHz 1.6 MI 120 secs
10% ND 85%
40% ND 90%
33
loaded
HepG-2 EGFP
Microbubbles
Experimental
0.8 MHz 1 W/cm
5 min interval
2x30 secs with
45% ND 84% 43
VSMC Luciferase
PESDA 25% v/v 59%
Optison 25% v/v
1 MHz 0.41 MI 30 secs
ND 0.072
ND 0.040 61%
51
MATB-III EGFP
Microbubbles
Experimental
25-30 2.25 MHz 0.57 MPa 10 secs 20% ND 90% 22
BAEC Luciferase SonoVue 1.25% v/v 1 MHz 0.1 W/cm 30 secs ND 1300 ND 53
CHO Luciferase Albunex 10% 2.25 MHz 0.35 MPa 1 min ND 0.15 40% 39
® 2
successful in increasing pDNA delivery, it HUVEC EGFP SonoVue 2% 1.9 MHz 80 mW/cm 5 mins 20% ND 90% 54
® c
Levovist 0.2 mg/mL ND 0.25 15%
would be even more beneficial to bind the PC-3 Luciferase YM454 3 µL/mL 1 MHz 0.2 MPa 1 min ND 50
c
70% 50
c
MRX-815H 1 µL/mL ND 7.5 65%
microbubbles: (1) pDNA-carrying CHO, Chinese hamster ovarian cells; BAEC, bovine aorte endothelial cells; HUVEC, human umbilical vein endothelial cells; PC3, human
prostate carcinoma cells; MATB-III, rat mammary carcinoma cells, VSMC, vascular smooth muscle cells; HepG2, human hepatocellular
liver carcinoma cell; HEK-293, human embryonic kidney cells; BHK-21, Baby Hamster Kidney; MB, Microbubbles; EGFP, Enhanced green
microbubbles can locally release their a b 6 c 6 d e
fluorescent protein; -Gal, beta-Galactosidase; microbubbles/cell; ng/10 cellules; 10 RLU/mg protein; Luciferase activity (%); Arbitray
¶
unit; Continuous wave.
and a 60% decrease of the cell viability.40 approximately eighteen-fold and nineteen- primary cells, which are used in an
The total insonation time also plays a fold higher than the microbubble-assisted exponential way in repair medicine and in
major role in gene delivery using ultrasound ultrasound alone. These investigations
43
basic research. Microbubble-assisted
and microbubbles (Table 2). In the majority showed that the increase of membrane fluidity ultrasound is a promising strategy for gene
of published protocols, the insonation time might facilitate the permeabilization of cell delivery in order to treat (eg, gene therapy)
ranges from 1 sec to 30 mins, and the membrane. Moreover, the increase of and to prevent (eg, genetic vaccination)
extension of the insonation time induced an temperature may provide the necessary diseases in the human clinic. We believe that
increased transfection.41 Indeed, the increase conditions for the cell to reseal and survive its the clinical application of this approach will
of the insonation time from 10 mins to 30 membrane permeabilization. depend on the identification of optimal
mins (2 W/cm2, 1 MHz, Optison 10% v/v) led Thus, the cellular architecture is another disease targets to develop targeted
to a three-fold increase of transfection key factor for gene delivery. To date, most microbubbles, further refinements to
efficiency of BHK cells and 10% decrease of cell lines that have been successfully minimize the dose of microbubbles and
cell viability. However, the authors report that transfected were adherent cells, 34,44
whereas pDNA required while increasing efficiency,
30 secs was the optimal insonation time for only few attempts to transfect cells in and further optimization of ultrasound
gene delivery into BHK using the same suspension have been reported. 45-47
Thus, parameters. The combination of this approach
acoustic conditions. Hence, an insonation Kinoshita et al demonstrated using the same with ultrasound imaging would allow for
time of 40 mins caused respectively a three- acoustic conditions (1.7 MHz, 1.6 W/cm , 15 2
targeted, efficient, and safe delivery.
and seven-fold decrease of transfection secs, Optison® 2%), that the permeabilization
efficiency and decrease of cell viability level was similar in both cell suspension and ACKNOWLEDGEMENTS
compared to the 30 mins insonation time.41 adherent cells set-ups (around 20%).
These results can be explained by the fact that However, the viability of adherent cells was The authors would like to acknowledge Jackie
the intracellular trafficking of pDNA would two-fold higher than that of cell suspension Butterworth, PhD, for the proofreading of this
depend on the insonation time. As shown in (80% vs 30%).48 The development of more manuscript. This project is funded in part by the EU
the same study, the increase of insonation appropriate set-ups and the systematic Project SONODRUGS (NMP4-LA-2008-213706).
time from 10 mins to 30 mins induced a two- optimization of the applied acoustic
and-a-half- and ten-fold increase of BHK parameters would allow a high transfection
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Nosaki et al demonstrated that the lidocaine improve molecule delivery. We sincerely shock wave-induced cavitation. Biochim Biophys Acta. 2003,1624:131-138.
13. Meijering BDM, Juffermans LJM, van Wamel A, Henning RH, Zuhorn IS, selective populations of circulating blood cells. J Drug Target. 2009;17:392- BIOGRAPHIES
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Dr. Jean-Michel Escoffre
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14. Deng CX, Sieling F, Pan H, Cui J. Ultrasound-induced cell membrane ultrasound. Mol Pharm. 2010;7:217-226.
Biophysics from the University
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15. van Wamel A, Kooiman K, Harteveld M, Emmer M, ten Cate FJ, Versluis M, Mag. 1933;16:235-249. of Toulouse in 2010. Since April
de Jong N. Vibrating microbubbles poking individual cells: drug transfer 40. Bao S, Thrall BD, Miller DL. Transfection of a reporter plasmid into
2010, he is a post-doctoral
into cells via sonoporation. J Control Release. 2006;112:149-155. cultured cells by sonoporation in vitro. Ultrasound Med Biol. 1997;23:953-
16. Yudina A, Lepetit-Coiffé M, CTW Moonen. Evaluation of the temporal 959. fellow at the institute of Imagerie et Cerveau U930
window for drug delivery following ultrasound-mediated membrane 41. Duvshani-Eshet M, Baruch L, Kesselman E, Shimoni E, Machluf M.
of the INSERM in Tours, France. His main research
permeability enhancement. Mol Imaging Biol. (In Review). Therapeutic ultrasound-mediated DNA to cell and nucleus: bioeffects
17. Yang F, Gu N, Chen D, Xi X, Zhang D, Li Y, Wu J. Experimental study on revealed by confocal and atomic force microscopy. Gene Ther. 2006;13:163- interests lie in the fields of gene and drug delivery
cell self-sealing during sonoporation. J Control Release. 2008;131:205-210. 172. by ultrasound and microbubbles.
18. Zhou Y, Shi J, Cui J, Deng CX. Effects of extracellular calcium on cell 42. Zarnitsyn VG, Prausnitz MR. Physical parameters influencing optimization
membrane resealing in sonoporation. J Control Release. 2008;126:34-43. of ultrasound-mediated DNA transfection. Ultrasound Med Biol.
19. Juffermans LJM, Kamp O, Dijmans PA, Visser CA, Musters RJP. Low- 2004;30:527-538. Anthony Novell earned his
intensity ultrasound-exposed microbubbles provoke local hyperpolarization 43. Nozaki T, Ogawa R, Feril LB Jr, Kagiya G, Fuse H, Kondo T. Enhancement
MSc in Medical Imaging
of the cell membrane via activation of BKCa channels. Ultrasound Med of ultrasound-mediated gene transfection by membrane modification. J Gene
2008;95:4124-4138. density lipoprotein receptor gene expression in HepG2 cells. Biochem in 2007. He is currently pursuing
21. Schlicher RK, Radhakrishna H, Tolentino TP, Apkarian RP, Zarnitsyn V, Biophys Res Comm. 2006;343:470-474.
his PhD at the French Institute for Health and
Prausnitz MR. Mechanism of intracellular delivery by acoustic cavitation. 45. Suzuki, R Takizawa T, Negisti Y, Hagisawa K, Tanaka K, Sawamura K,
Ultrasound Med Biol. 2006;32(6):915-924. Utoguchi N, Nischioka T, Maruyama K. Gene delivery by combination of
Medical Research (INSERM) in Tours, France. His
22. Mehier-Humbert S, Bettinger T, Yan F, Guy RH. Ultrasound-mediated gene novel liposomal bubbles with perfluoropropane and ultrasound. J Control research focuses on contrast agent imaging and
deliver: kinetics of plasmid internalization and gene expression. J Control Release. 2007;117:130-136.
acoustic properties of contrast agents.
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23. Escoffre JM, Kaddur K, Rols MP, Bouakaz A. In vitro gene transfer by in suspension by ultrasound cavitation. J Control Release. 2010;142:251-
applications. Bubble Sci Eng Technol. 2009;1:3-17. ultrasons et microbulles: Application au transfert de gènes. Reproductive and Developmental
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Biology from the University
Agents: nature and types of ultrasound contrast agents. Ultrasound Med vitro settings: the importance of standing wave in sonoporation. Biochem
Biol. 2007;33:187-196. Biophys Res Comm. 2007;359:860-865. Denis Diderot, Paris, France, in
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2010. She is currently pursuing
therapy for hepatocellular carcinoma using sonoporation enhanced by gene delivery with ultrasound and microbubbles. J Exp Nanosci. 2008;3:17-
28. Greenleaf WJ, Bolander ME, Sarkar G, Goldring MB, Greenleaf JF. S, Fuse H, Kondo T. Effects of microbubbles on ultrasound-mediated gene ultrasound and microbubbles.
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transfection. Ultrasound Med Biol. 1998;24:587-595. YM454 and MRX-815H. Cancer Lett. 2008;265:107-112.
29. Miller DL, Dou C, Song J. DNA transfer and cell killing in epidermoid cells 52. Pislaru SV, Pislaru C, Kiniick RR, Singh R, Gulati R, Greenleaf JF, Simari Dr. Ayache Bouakaz
by diagnostic ultrasound activation of contrast agent gas bodies in vitro. RD. Optimization of ultrasound-mediated gene transfer: comparison of
graduated from the University of
Ultrasound Med Biol. 2003;29:601-607. contrast agents and ultrasound modalities. Eur Heart J. 2003;24:1690-1698
30. Piron J, Escoffre JM, Kaddur K, Novell A, Bouakaz A. (2010) Enhanced 53. Li YS, Davidson E, Reid CN, McHale AP. Optimising ultrasound-mediated Sétif, Algeria and earned his PhD
gene transfection using ultrasound and Vevo Micromarker microbubbles. gene transfer (sonoporation) in vitro and prolonged expression of a
in 1996 from the Department of
Drug Development & Delivery APRIL 2011 Vol 11 No 3
IEEE Ultrasonics Symposium, San Diego USA (In Review). transgene in vivo: potential applications for gene therapy of cancer. Cancer
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Electrical Engineering at the
for ultrasound triggered delivery. Soft Matter. 2009;5:2161-2170. 54. Meijering BDM, Henning RH, Van Gilst WH, Gavrilovic I, Van Wamel A, Institut National des Sciences Appliquées de Lyon
32. Christiansen JP, French BA, Klibanov Al, Kaul S, Lindner JR. Targeted Deelman LE. Optimization of ultrasound and microbubbles targeted gene
(INSA Lyon), France. Since January 2005, he has
tissue transfection with ultrasound destruction of plasmid-bearing cationic delivery to cultured primary endothelial cells. J Drug Targeting.
microbubbles. Ultrasound Med Biol. 2003;29:1759-1767. 2007;15:664-671. held a permanent position as a Director of Research
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at the French Institute for Health and Medical
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the ultrasound laboratory. His research focuses on
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Deliv. 2008;5:1121-1138. 47
48-53- DDD April 2011-DDP Awards Feature_Layout 1 3/24/11 1:04 PM Page 48
o much has changed in the drug delivery sector since the Clearly, the line demarcating the traditional pharmaceutical and drug
technologists to specialty pharmaceuticals manufacturers who are in categories: Industry Achievement, Technology/Company Innovation,
fact developing their own medicines in tandem with the delivery On-The-Rise Company, and Pipeline Value Creation. The winners and
technologies required to optimize them and who are building the
FIGURE 1
highly focused, lean marketing infrastructure required to move their
products.
In addition, many Big Pharmas - while not altogether abandoning
the concept and/or option of partnering with delivery technologists -
have bolstered their internal capabilities because they recognize that
delivery innovation will be part and parcel of R&D in a world where
biotechnology will play a critical role in health science progress.
48
48-53- DDD April 2011-DDP Awards Feature_Layout 1 3/24/11 1:04 PM Page 49
48-53- DDD April 2011-DDP Awards Feature_Layout 1 3/24/11 1:04 PM Page 50
INDUSTRY ACHIEVEMENT
the skin without a needle. It was developed to delivery of drugs. All other transdermal tech- currently requiring administration by
address the major reasons for the under- nologies combined can only deliver about 12 injection. Technosphere technology offers
to 15 drugs (eg, nicotine, testosterone, estro- several competitive advantages over other
utilization of current injectable therapies: fear
gen, fentanyl, etc, which have a rare molecular
of needles, lack of confidence to use a needle pulmonary drug delivery systems. Most
structure). Only VALE technology has
injector, and concerns with storage and safe
disposal. The achievement embodied by the FIGURE 3
introduction of SUMAVEL DosePro breaks
the barrier to self-administered subcutaneous
Drug Delivery Technology April 2011 Vol 11 No 3
50
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• Based on feedback from clinical trial WINNER: GLAXOSMITHKLINE - ADDING NEW disorders.
to prevent glass-to-glass friction; 3) packaging also the possibility to develop drug candidates by designing from the outside in. The device
operations in Grade A/Class 100 environment; that are currently too poorly soluble. Pierre is able to handle extremely viscous drugs and
4) packaging units subjected to a validated Fabre’s coating process is not a “one more” volumes of 0.1 ml to 3.0 ml, which is
ETO sterilization process (3-log endotoxin coating process; it provides high-performance reportedly not possible for other autoinjectors
reduction). Pharmaceutical companies can taste-masking even for very small and currently on the market, many of which have a
outsource the first part of the manufacturing sensitive particles, without organic solvent history of unreliability and market recalls.
process, thereby reducing their costs and use, at room temperature with a high Oval’s design is robust; it’s made of cyclic
concentrating their resources on their own productivity (30 Kg/h) not ever proposed by olefin plastic instead of glass (Figure 5). This
aseptic fills. The EZ-fill for vials and preformulators. has enabled its autoinjector to be produced at
cartridges can be easily integrated into half the size of any other autoinjector on the
existing pharmaceutical manufacturing market, making it the preferred choice of
capabilities, both automatically and semi-
ON-THE-RISE COMPANY users - and much easier to use. Not only does
automatically. An extended range of available it offer advantages to the patient and the drug,
WINNER: MEDINCELL BIOPOLYMER -
containers for direct filling operations will but it offers significant potential commercial
REDUCING LIFE-CYCLE MANAGEMENT RISK
result in more flexibility in pharma R&D advantage to pharmaceutical companies; it’s
MedinCellTM (Figure 4) offers game-
activities for new formulations. Very specific highly cost effective compared with other
changing technology for delivery of peptides,
production, like clinical trials or orphan autoinjectors, and in the long- term, Oval
small molecules, and biologics. The
products, will be possible without investing claims its autoinjector will increase a
company’s biodegradable depot chemistry
huge capital for the washing and sterilization pharmaceutical client’s market share.
requires no API modification, and can target
of these containers, resulting in a consistent
subcutaneous durations from 4 days through 6 FINALIST: NEOS THERAPEUTICS - A PROFILE IN
time-to-market reduction.
months. Product feasibility studies can be CUSTOMIZED CONTROLLED RELEASE &
completed within 6 months to 1 year, making FLEXIBILITY
FINALIST: PIERRE FABRE MEDICAMENT -
TASTFUL, HIGH-PERFORMANCE, GREEN this an economical, low-risk strategy for life Neos Therapeutics has developed
COATING INNOVATION cycle management. proprietary drug delivery technologies that
Pierre Fabre Medicament has extensive
expertise in SuperCritical fluids and has FINALIST: OVAL MEDICAL - INJECTING FIGURE 5
developed completely new and very INNOVATION INTO A STAID MARKET
processes are high performance: the results autoinjector market. Since its February 2009
are better than those obtained by conventional launch, Oval has achieved tremendous
processes and, moreover, these processes are commercial traction - securing two
Drug Delivery Technology April 2011 Vol 11 No 3
totally environmentally safe. The processes pharmaceutical company deals with another
dispersion), and FORMULCOAT (taste- manufacturing partners - all within in its first
masking) performed with supercritical CO2 full year of operation. Oval’s technology
are mild and green processes that can be differs from category competitors because its
applied even to OTC drugs. The results are so devices focus both on patient ease of use and
efficient that they permit not only increased the pharmaceutical industry’s need to contain
solubility and bioavailability of an API, but fragile drugs. Oval has taken a fresh approach
52
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FIGURE 6
enable the creation of stable controlled release coupled with the know-how and expertise to Since 2001, 12 products using EDT’s
(CR) products; CR liquids and CR oral bring such products successfully through technologies have been launched for their
disintegrating tablets (ODTs), with suitable development. Presently, Elan has 14 clients, making them the most successful drug
flavors and mouth feel. Neos’ technology can compounds in clinical development for clients. delivery company in the past decade in terms
provide a customized release profile and Examples of value-creating products of product launches.
accommodate the need for a variety of release developed by EDT include:
FINALIST: HALOZYME - SUBCUTANEOUS MADE
profiles, including the combination of IR and
POWERFUL & PAINLESS
CR profiles for a single active ingredient or a • The Cardizem® SR and CD products in
EnhanzeTM technology (Figure 7), a
combination of active compounds. The Neos the late 80s, which resulted in the
proprietary drug delivery platform using
technology platform leverages a drug/resin successful building of one of the first
Halozyme’s first approved enzyme, rHuPH20,
complex to create controlled release Rx or blockbuster franchises in the US.
is a broad technology opportunity that can
OTC products in convenient oral liquid and
• TriCor® 145, launched with Abbott in potentially lead to additional partnerships with
ODT dosage forms to better serve patients
2005, which has consistently achieved other pharmaceutical companies. When
who experience difficulty swallowing oral
over $1billion in sales in the past 5 formulated with other injectable drugs,
solid forms, benefit from titration flexibility, or
years. Enhanze technology can facilitate the
prefer the portability of ODTs.
subcutaneous dispersion and absorption of
• NCEs such as Acorda’s AMPYRA®,
these drugs. Generally, MAbs require a higher
which was approved last year and has
PIPELINE VALUE CREATION demonstrated strong performance in the
dosage (100 to 1000 mg/dose) than typical
protein therapeutics; however, it is commonly
initial stages of its launch with gross
WINNER: ELAN DRUG TECHNOLOGIES - accepted that subcutaneous (SC) injections over
sales by the end of Q3 of approx. $85
EPITOMIZING DELIVERY PORTFOLIO 1 mL cause skin distortion and pain. As a
million, and Emend® with Merck
PERFECTION result, most biotech companies spend much
(consistent annual sales of more than
In the past decade alone, Elan Drug effort concentrating MAbs to 100 mg/mL or
$300 million).
Technologies’ (EDT) solutions have been more and then try to stabilize these
• Other successes include the formulations to avoid aggregates and
applied to more than $17 billion of client in-
Drug Delivery Technology April 2011 Vol 11 No 3
INTRANASAL
VA C C I N E S
Do We Need New Devices for Intranasal
Vaccination?
By: Degenhard Marx, PhD, Matthias Leitz, Christophe Fagot
INTRODUCTION
After years of getting very little attention, vaccines are back in the spotlight of big pharma. According to the WHO, the
vaccine industry is experiencing a new, more dynamic period. The global vaccine market reached over $22.1 billion in revenue
in 2009, making vaccines one of the fastest growing sectors of the pharmaceutical industry with a predicted 9.7% CAGR for
the next 5 years. In the past, the highest share came from routine vaccination programs for children, proposed by WHO and
adopted by local authorities and health insurance systems. An increasingly important market is preparation for pandemic
outbreaks of highly infectious, fast-spreading diseases, such as H1N1 or swine flu, bird flu, and severe acute respiratory
syndrome (SARS), which may have a severe global social and economic impact. When they can afford to, countries invest in
new vaccine technologies or create stockpiles for vaccination campaigns to maintain essential services during pandemics.
Following the 9/11 terrorist attacks and the mailing of anthrax-contaminated envelopes, the fear of biological warfare was
revived, and substantial support for the development of vaccines for anthrax and smallpox was made available. Although less
recognized, prevention of travel-related diseases, such as hepatitis A and diarrhea, is another attractive market. One result of
globalization is the enormous increase in people traveling for pleasure or business to areas where there is high risk of
infection. Preventive measures, such as vaccination and anti-malaria medication, are normally paid for by travelers out of their
own pockets.
In the past, intramuscular and oral administration of prophylactic vaccines were considered to be the ultimate vaccination
methods. Fine hypodermic needles and prefilled syringes make vaccine administration safe and less painful, but injections are
still linked with pain and fear of an anaphylactic response. Moreover, because of the appearance of HIV, needlestick injuries,
and disease transmission have become important threats, these obvious disadvantages of injections led to the search for more
gentle alternative administration routes. Intranasal vaccination provides a promising non-invasive alternative. Used
successfully in veterinary medicine for years, this route should transfer across to use in humans and may gain a reasonable
share of the market in the near future.
Drug Development & Delivery APRIL 2011 Vol 11 No 3
WHY CHOOSE THE vaccine-strain-specific circulating administration route may enable the
INTRANASAL DELIVERY antibodies. Intranasal vaccination development of therapeutic vaccines
ROUTE? elicits broader protection. It induces for chronic, hard-to-treat diseases, such
mucosal (protection at the site of as hepatitis B.1 Although there are
Using a Natural Immune- infection) and systemic immunity, many publications supporting this view,
Competent Site which includes antibody formation as this route may not work for all antigens
For most microbes, the nasal well as activation of circulating or vaccines.
mucosa is the first barrier that must be immune cells. It has also been reported
conquered. It is then no surprise that that the nasal route induces cross- Patient Comfort
this mucosa is extremely immune- protection against variant strains, an One unquestionable advantage of
competent. Intramuscular vaccination observation that may contribute to the intranasal vaccination is the nasal
primarily induces systemic immune development of so-called “universal cavity is easily accessible to liquids and
54
response, mainly via formation of vaccines.” There is also evidence this even dry powders. Intranasal spray
54-59-DD&D April 2011-Intranasal Vaccines_Layout 1 3/24/11 1:05 PM Page 55
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SELECTING AN APPROPRIATE
pandemic. Depending on the antigen, Waste Disposal DEVICE FOR INTRANASAL
intranasal vaccines may outperform here. VACCINATION
Following successful administration
For example, the influenza virus is still of the vaccine, the used device and the
widely grown on eggs and as a rule of Existing Market References
secondary packaging must be safely
thumb, the antigen yield from one egg is Although there are some intranasal
disposed of in an environmentally friendly
used for one injection. The same amount vaccines on the market for pets and farm
manner. The amount of potentially
would be sufficient for up to four animals, only three intranasal influenza
harmful medical waste is steadily
adjuvanted intramuscular doses vaccines are on the market for human use.
increasing and is also a cost factor, which
(inactivated) or for 20 to 100 intranasal All are intended for the prevention of
devices without needles and blood
shots of live- attenuated viruses. seasonal or pandemic influenza and use
contamination make it much easier to deal
live-attenuated viruses. Although the
with. The use of material that can be
Cost of Safe Administration seasonal influenza market is quite large at
incinerated completely at low
Another factor affecting cost is the an estimated $3 billion for 350 million
temperatures without producing toxic
level of skill necessary for safe doses per year, intranasal products are still
fumes will be highly appreciated in
administration of the vaccine. Egg protein not widely used. The first on the market
developing countries.
remaining in the vaccine can cause an was Microgen’s Ultravac® seasonal
Drug Development & Delivery APRIL 2011 Vol 11 No 3
anaphylactic response in susceptible vaccine, which is available for about $3 in
Dry Powder Vaccines to Avoid
people, and the presence of a physician to Russia only (Figure 1). The live-
Need for Cold-Chain Storage
administer first aid can save lives. Even in attenuated virus form of this particular
Most vaccines are temperature
people with allergies, intranasal vaccine is under development by
sensitive, and a cold chain is therefore
administration of antigens causes a much BioDiem/Nobilon for developed
mandatory. Transportation and storage
milder, non-life-threatening response, so it countries, and for developing countries,
under cold-chain conditions can cause
can be performed by nurses or the project is supported by WHO. Very
substantial costs (estimated at 20% of
pharmacists. Intranasal vaccines may also recently, it became available as Nasovac®
vaccination costs) and require an
be suitable for self-administration, an in India to prevent pandemic flu. For both
appropriate infrastructure. With the
option for travel-related diseases or vaccines, the administration device is very
introduction of new vaccines and the
pandemic situations. cheap and simple but inconvenient: a
inclusion of additional target groups for
single use syringe with an attached 57
54-59-DD&D April 2011-Intranasal Vaccines_Layout 1 3/24/11 1:05 PM Page 58
sprayer (Figures 1 and 2). The third reduce the amount of antigen needed to vials need to be nested to fit into existing
device on the market and probably the elicit reliable protection. In this case, the washing and filling lines. The filling
best known is MedImmune’s Flumist , ®
cost of the saved antigen should balance volume for nasal administration is also
which uses a prefilled syringe fitted with out the likely higher price for the device. much smaller than the 0.5 to 1.0 ml for
a sprayer and a removable clip to Another aspect to consider is whether the prefilled syringes. To avoid investment in
separate the two actuations (one per vaccine should be administered in one or new expensive filling equipment, device
nostril). The moderate commercial both nostrils. The latter option seems to manufacturers are working intensively on
success of these intranasal vaccines is not give patients more confidence and will a solution to adapt the existing filling
due to low effectiveness but linked to increase acceptance for the intranasal technology for Ready-to-fill syringes to
inconvenient handling and storage route. the technology for nasal sprays. The
conditions and the risk of flu-like future will see alternative approaches to
symptoms after immunization. Prefilled Nasal Delivery keep costs down and speed up filling. It
Devices may include the use of primary
User-Friendly Nasal Vaccine Prefilled syringes are increasingly packaging molded from new plastic
Sprayers replacing multi-dose bottles for vaccines materials developed for prefilled
There is certainly no device that can because they are easy to handle. So it is syringes, such as Cyclic Olefin
accommodate all intranasal vaccines in safe to predict a bright future for Copolymer (COC) or Daikyo’s Crystal
development, but there are some prefilled intranasal devices. The Zenith® to replace glass vials, or pouches
common considerations. For nasal packaging of the vaccine (dry powder or made from laminated foils.
administration, the applied volume is liquid) must avoid loss of antigen during
comparably low. For liquids, 100 storage and transportation (e.g., Dry Powder Devices
microliters per nostril is optimum in adhesion). Although well established, In the near future, the development
adults, but should be reduced for children glass vials in combination with rubber of intranasal vaccines will probably focus
to avoid nasal dripping, which produces stoppers are not as cheap as one might on dry powder vaccines to take
discomfort and reduces effectiveness. believe. For effective filling and optional advantage of improved storage
When using live-attenuated viruses, a Water for Injection (WFI) washing, the conditions. It may be a challenging task
simple dropper should be sufficient
because the virus will behave like a wild- FIGURE 4
type infection, which normally does not
need a sophisticated device to infect
people. The simple blow-fill-seal
container approach for vaccines is used
by the Swedish company Eurocine. The
disadvantage here is that to administer
Drug Development & Delivery APRIL 2011 Vol 11 No 3
by the nasal air flow (Figure 3). congestion, and providing fast pain relief. During this time in the pharmaceutical industry, he
collected ample experiences in the drug development
This means that easy-to-use and price-
of anti-inflammatory and cardiovascular drugs. Since
Multi-Dose Spray Pumps for competitive devices for intranasal 2008, he is Business Development Manager at Ing.
Mass Vaccinations administration are already available. The E. Pfeiffer, Pharma Division, which became Aptar
Pharma in 2010. Now he is Director Scientific Affairs
Multi-dose spray pumps are a very near future will see the development of
within the Consumer Healthcare division.
cost-effective option for liquid vaccines. cheap sophisticated devices, optimized for
The major challenge is to prevent fast filling and safe disposal. Matthias Leitz, following
training as a paramedic, he
microbial contamination of the bottle Intranasal vaccination is set to
successfully graduated in
content when a single device is used by become an attractive segment of the Business Engineering at the
many people. The principle of how this vaccine market in the near future. Non- University of Cooperative
Education Stuttgart - Horb. In
could work is shown in Figure 4. Some of invasive administration and the potential
2004, Mr. Leitz joined the
the so-called preservative-free pump to use dry powder formulations may Aptar Group, initially working on ophthalmic drug
systems, and in particular, systems with further assist its wider use. The intranasal delivery technologies. After gaining first experiences
in this field, he started focusing on single-dose
the means to prevent drain-back of liquid route is also likely to gain support from
devices administered via the nasal and oral route,
into the nasal actuator (also called a tip- patients who fear injections. which target vaccination, pain management and the
seal), can fulfill this requirement. central nervous system. He currently works as
Transmission of diseases from patient to REFERENCES Product Manager in Aptar Pharma’s Prescription
Division.
patient (eg, common cold or rhinoviruses)
can be effectively prevented using 1. Aguilar A, et al. Phase I clinical trial in Christophe Fagot is
disposable sleeves or protection caps. This healthy adults of a nasal vaccine Associate Director, Business
Development Manager for Pain
is a very cost-effective approach not only candidate containing recombinant
& Vaccines at Aptar Pharma,
for mass vaccinations in developing hepatitis B surface and core antigens. where he worked for 13 years.
countries but also for the stockpiling of Int J Infect Dis. 2007;11:394-401. He graduated in Mechanical
Engineering from Supmeca
vaccines for pandemics or to fight 2. Hamilton JG. Needle phobia: a
(Paris) in 1994 and is currently part of the Executive
neglected diagnosis. J Fam Pract.
Drug Development & Delivery APRIL 2011 Vol 11 No 3
bioterrorism. In this case, one would be Part-Time MBA programme of the Ecole Supérieure de
well prepared without spending too much 1995;41(2): 169-175. Gestion (Paris). From 1998 to 2009, he worked in
different technical positions in the Engineering
money on vaccines and devices, which 3. Kissmann J, et al. Stabilization of
Department and then in the R&D Department as a
hopefully would never have to be used. measles virus for vaccine formulation. Design Engineer, Project Manager, and Director of
Hum Vaccin. 2008;4(5):350-359. DPI development. In 2010, he decided to join the
Covaris Flow Division headquartered in Woburn, MA, and was built upon its team's in-depth knowledge in fields ranging
General Manager from acoustic physics and mechanical engineering to biophysics and molecular biology. The
Covaris technological foundation is based on it’s proprietary and patented AFA technology. AFA
Covaris, Inc
enables a vast array of non-contact, isothermal processes to be developed for use in a broad range
of applications in formulation, drug delivery systems, genomics, proteomics, cell biology, and drug
discovery research. In many cases, the ability to impart precision, kinetic control of application
“The scientist is able to processes could not be obtained prior to the development of the isothermal, non-contact AFA
use the same process
technology. These important characteristics provide Covaris with a truly sustainable competitive
technology from 0.1 ml
advantage. With over 1500 systems installed world-wide for processing of bench top volumes,
through pilot-scale
volumes. This is
Covaris was constantly receiving requests to process larger sample volumes. In 2010, the Covaris
significant because it Flow DivisionTM was launched to deliver upon the pent-up demand for processing of higher
enables methods and volume, continual processes. With all the same attributes as the core technology and the ability to
processes to carry scale to higher volumes, it is now possible to address new and exciting applications with Covaris
through the entire AFA. Indeed, AFA enables performance previously unobtainable with currently available
discovery/development
technologies. Drug Development and Delivery recently sat down with Carl Beckett, Covaris Flow
cycle, eliminating the
Division General Manager, to discuss how AFA is enabling new drug delivery systems.
need to re-engineer and
Vol 11 No 3
re-design formulations The sonic energy often does not reach the target in an
Q: Can you please tell our readers
when a higher volume of
what makes your technology unique? effective dose because the energy is scattered,
material is needed for
absorbed, and/or not properly aligned with the target.
Drug Development & Delivery April 2011
process of mechanical disruption, typically involving control. In addition, this approach is prone to cross-
the direct immersion of an unfocused sonic source contamination and finally, sonication processes
into a fluid suspension of the material being treated. cannot effectively scale from small (< 1 ml) through
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Pilot Scale volumes (> 100 L) as the clinical dosing. This results in a from 2 days to less than 3 minutes. At the
energy is unfocused (ie, due to the significant reduction of the overall same time, we were able to reduce material
fundamental long wavelength of the development timeline for a new molecule. degradation by 1500%. This means more
sonicators, typically 10 to 15 cm). While The use of high mechanical energy at the than 2.5 times more of the API was
there are also specific clinical examples molecular level, such as the controlled delivered. Furthermore, using a repeatable,
acoustic dosing available with Covaris, automated system allows standard
of the utilization of therapeutic and
often enables a process or reaction with procedures for formulation to transfer
diagnostic ultrasound (eg, fetal imaging),
fewer catalysts or solvents. By reducing across organizational boundaries. The
until AFA, ultrasonics have not been
or eliminating certain solvents/surfactants, formulation scientist can develop a method
controlled to provide an automated, broad
the results of a particular study are less that directly translates to the PK group, or
range, precise materials processing or
error prone by eliminating possible false even the CRO performing a study.
reaction control mechanism for both
negatives that could be due to the solvent Problems and issues with a study are not
bioanalytical and bioprocess sciences. and not the active ingredient itself. uncommon, and when they occur, there is
Covaris systems are uniquely capable Complete temperature control during the always an investigation into why. Common
of providing controlled delivery of process eliminates the molecular questions include: were the doses
acoustic energy to closed vessels. Using degradation that is common for many of homogenous, was the formulation properly
AFA with sample sets can improve both today’s methods. Less degradation means prepared, were procedures properly
the quality and efficiency of the drug more of the active ingredient is followed, what were the subjective grading
development process, with unparalleled maintained intact and available for elements, and were these calibrated to
reproducibility, precision, and recovery biological uptake. It also creates those specified? AFA has proven to be
for a variety of sample types with a broad flexibility in the dosing, formulation extremely helpful in that it reduces the
choices, and ultimately end efficacy of source for many of these types of errors by
range of sample output sizes.
the drug. More choice and design providing a precise, repeatable, automated
freedom during the discovery/ process. Obviously, this results in a better
Q: How does AFA accelerate
development cycle results in more drugs animal study, saving time and money, but
the drug development
entering the market more quickly. most importantly, improves the quality of
process?
Overcoming even a small design hurdle the study itself by eliminating unknowns.
can make a difference that saves weeks or
A: AFA can be used for a variety of
months of effort. Q: Are there other
Vol 11 No 3
produce liposomes of the quality, and nm, we can do so in just a few minutes, of material is needed. In summary, the time
with the ease and convenience, of the while controlling heat and contamination, as and effort invested in a discovery phase can
Covaris system. Also, the AFA process well as scaling this same process from 1 ml be carried through to larger studies, such as
is completely self-contained, meaning through 1000 ml. As an example, a 200-ml cell culture, animal, and even clinical trials.
all the wetted surfaces are disposable batch of material is reduced to ~60 nm
and any risk of contamination is mean particle size in 30 minutes. The Q: There are a growing
eliminated. This is a significant benefit distribution was very monodisperse with a number of applications using
over some of the current processes that PDI ~0.2, resulting in a stable formulation biological materials. Can
heat or contaminate the material. Again, validated 1 month later. Looking ahead, we AFA be applied for these?
volumes from as low as 0.1 ml up envision producing even larger volumes of
through pilot scale are possible. material (multiple liter scale), as the AFA A: Covaris was founded on the basis that
Delivery of sensitive biologicals, such as process is completely computer controlled, the initial preparation of biological samples
RNA/DNA-based active components, is repeatable, and a hands-off operation. will become an increasingly critical step for
enabled as long as the strand is below a analytical sciences. This is evident in
certain size range. We have multiple Q: Where does AFA end and applications in which best-in-class
research projects under way validating formulation begin? processing of biological materials is
the benefits of the process, including required for advanced instrumentation
one with Dr. Jean-Bosco Tagne of the A: The two are deeply interrelated, and systems (eg, next-generation DNA
Boston University School of Medicine, each molecule and application is a unique sequencing). Lysis, separation, disruption, or
to evaluate the potential as a delivery design challenge. Although we have extraction of a target molecule is at the core
system for miRNA molecules in formulation expertise in-house, oftentimes a of our expertise and capability. With the
respiratory disease research. customer is working with a highly ability to scale these processes, we believe
confidential compound that must remain there is a significant opportunity in the area
Q: What about drugs with secret. We understand these needs, and our of biological production that includes
extremely low solubility best results are achieved when the customer vaccine development. Transfection,
levels? formulation scientists work closely with our sonophoresis, and extraction/lysis are also
formulation and acoustical process scientists key capabilities having tremendous
A: The formation of nanosuspensions is to optimize a result. The type of potential. Because we are able to precisely
another exciting area for Covaris and AFA. formulation does impact the optimum control the energy level, we are able to
Vol 11 No 3
More and more of today’s molecules are processing conditions; therefore, by working achieve a very high process efficiency rate,
problematic in terms of solubility, which together, the results are almost always better without damaging the target molecule.
creates a problem in effective formulation. (and certainly more efficient) than when a Often, a currently required detergent or
Drug Development & Delivery April 2011
We see an increase in applications needing customer purchases our equipment without intermediary step can be significantly
to micronize to a particle size below 200 understanding the underlying unique reduced or even eliminated entirely by using
nm, after which the material can be passed molecular interactions of the AFA AFA, resulting in higher overall yields. For
through a sterile filter before dosing. The technology. example, a small increase in the yield of a
current methods almost always contaminate One of the salient features of this vaccine production of 10% could have a
or degrade the material, or result in technology is when the optimization is considerable commercial impact. u
significant material loss. Not only are we complete; the process is highly repeatable,
able to produce nanoparticles as small as 13 and can then be scaled to whatever volume
62
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development
timeframe and
BD Medical - Pharmaceutical Systems provides high-quality,
achieve Faster Time to
customized, clinically proven drug delivery systems and self-injection
First in Man. A fully automatic cGMP-compliant machine, it fills and
technologies to help pharmaceutical and biotechnology customers’
seals up to 1,200 capsules per hour with liquid or semi-solid
injectable drugs reach their full potential. BD has over 100 years of
formulations without banding. It is designed for ease-of-use and high
experience in manufacturing and processing technology for parenteral
reliability, with the ability to quickly clean and change capsule sizes
drug delivery systems and has developed an in-depth understanding of
with available change parts. Product integrity is ensured with gentle
the pharmaceutical industry’s requirements. BD has leveraged this
handling of capsules before sealing and during the drying cycle.
experience when developing advanced drug delivery systems that span
Other features include a robust filling pump with highly a ccurate
from small-scale clinical through large-scale commercial programs.
temperature control, improved capsule manipulation before sealing
With a broad range of innovative systems and services, BD Medical -
and during drying using new “Cap-edge” handling system, and
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information, contact BD at (800) 225-3310 or visit
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63
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Analytical
Testing
Heavy Metals Testing (USP<231>) Revisions:
New Limits & Procedures for Elemental
Impurities in Pharmaceuticals & Dietary
Supplements
By: Jeff Grindstaff and Colleen Schroeder, Columbia Analytical Services, Inc.
Introduction
Changes to heavy metals test procedures for the analysis of
pharmaceuticals and dietary supplements are under review with new
standards set to be in place by mid-2013.1 The intention of this
review is to update current analytical testing historically performed
using United States Pharmacopeia (USP) <231>. The revisions
(USP<232>, USP<233>, and USP<2232>) are designed to set safer
limits for public exposure and to reduce the environmental impact of
dated methods. Many in the pharmaceutical industry have concerns
about the new instrumentation, more stringent requirements, and the
Vol 11 No 3
associated costs. Nonetheless, the revisions should have a beneficial
impact on the industry by significantly improving specificity and
analyte recoveries, as well as by yielding overall time-savings,
resulting in safer, higher quality products. APRIL 2011
10 to 300 mg/Kg.
heart disruptions, brain damage, and death. Acute oral LD values range from
arsenic can cause infertility, skin disturbances, declined resistance to infections,
Arsenic (As) decreased white and red blood cell production. Very high exposure to inorganic
stomach and intestine irritation and skin disturbances, lung irritation and
arsenic is readily absorbed by the human digestive system. Symptoms include
Inorganic forms of arsenic are particularly toxic and water-soluble inorganic
68
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Vol 11 No 3
agreement on interpretation of the revisions.
The following are brief descriptions of the procedures. As with any analytical technique, have to be more complicated to offset
methodologies being proposed. interferences (chemical and/or physical) exist relatively high DL for the instrumentation.
with each technique. Intelligent decisions Alternatively, GFAA or ICP/MS would be
Sample Preparation - Sample relative to the elements of interest and the preferable choices.
APRIL 2011
preparations range from relatively simple sample matrix will indicate the appropriate The instruments listed in Table 3 are
acidification and direct injection to more analytical approach. capable of performing analysis of some or all
complex total oxidations/dissolutions Although the majority of applications of the elements listed in USP<232>. This
performed under elevated temperature and can be satisfied by the use of ICP/MS and/or table compares the instruments and
pressure in appropriate acid(s) to ensure ICP/OES, expert trace metals chemists equipment most commonly required to meet
SPECIALTY PHARMA
dissolution of target elements. Sample recognize that alternative procedures are the USP requirements. Approximate values
preparations are intended to yield an aqueous required at times to satisfy unusual analytical representing initial purchase and ongoing
digestate suitable for instrumental analysis challenges. Careful examination of each operating costs as well as abbreviated
via one or more instrumental techniques.1,7 application must be done from a quality summaries of strengths and weakness are also
See Figure 1 for a decision tree on sample assurance perspective. There are situations listed.
preparation and analysis.5 when multi-element techniques that utilize
the plasma as an ion source or light emission
source are capable of producing values that
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(annual)
Equipment 2. Operating Costs
Instrument/
Best Use Advantages Disadvantages
1. Purchase Price
1. Purchase Price
Instrument/ Jeffery Grindstaff
Best Use Advantages Disadvantages
Equipment 2. Operating Costs
(annual)
limit of quantitation, range, and linearity. 2. Raghu ram P. IPC-USP 75th Annual Scientific Meeting 2008. USPOrg.
2008. Hetero.
expertise is in metals analysis and
http://www.usp.org/pdf/EN/meetings/asMeetingIndia/2008Session4track2.p
Both types of validations will need to be df. Last accessed Januray 20 2011. instrumentation.
3. Lewen M, Schenkenberger R. A rapid ICP-MS screen for heavy metals in
verified experimentally. In addition, sample pharmaceutical compounds. J Phar Biomed Anal. 2004;35:739-752.
4. Sergio L, Brush P, Senak L, Wu C, Malawer E. The use of inductively
preparation not specified in the monograph coupled plasma-optical emission spectroscopy in the determination of
heavy metals in crospovidone and povidone as a replacement for the
will also require verification. The concomitant visual comparison test. Pharmacopeial Forum 2008;34(6).
5. Elemental Impurities. Pharmacopeial Forum. 2010;36(1).
compendial procedures encompass both 6. Lenntech, Home Page, http://www.lenntech.com/periodic/periodic-
chart.htm, January 19, 2011.
ICP/OES and ICP/MS technologies, and 7. Standard methods for the examination of water and wastewater. 20th ed.
American Public Health Association. Washington, DC. Horwitz W, ed.
the general instrumental and suitability 2000.
8. Stellmack M, Rhodes K. Metal contamination in biopharmaceutical drugs:
requirements for each procedure are solving a puzzle without all the pieces. The McCrone Group. October 1,
2010. McCrone Associates Inc.
http://www.mccrone.com/media/2010/10/14. Last accessed January 19,
specified for users. Laboratories will be 2011.
9. Howard TE. Inductively coupled plasma-mass spectrometry, practices and
able to choose the appropriate technology techniques. San Diego: Academic Press;2001.
10. Ole P. Pharmaceutical chemical analysis: methods for identification and
that best fits their needs. limit tests. Boca Raton: CRC;2006.
11. Wilbur S. A comparison of the relative cost and productivity of traditional
metals analysis techniques versus ICP-MS in high throughput commercial
laboratories. Agilent. 2005. Agilent Technologies.
Executive
Summary Mark Varney, PhD
President & CEO
Cortex Pharmaceuticals
Q: Before discussing their specific potential compounds facilitate the response to glutamate, essentially
amplifying the normal level of signaling between neurons.
applications, can you tell our readers what Vol 11 No 3
Research by Cortex and its collaborators, including Professors
AMPAKINES are and what effects they
Gary Lynch and Christine Gall from the University of California,
have on the human brain?
Irvine, have demonstrated that AMPAKINE molecules also
APRIL 2011
Q: What is the status of Cortex’s efforts in the mGluR5 antagonists have shown promising results in Fragile
X patients, and in animal studies, the combination of these
Parkinson’s disease arena?
agents with our AMPAKINE compounds has been seen to
provide additional benefit via a synergistic mechanism. If
A: We have been awarded a grant by The Michael J. Fox
these effects hold up in clinical studies, the combination
Foundation for Parkinson’s Research to test selected
could be an important treatment option.
compounds from our AMPAKINE platform for their ability to
restore brain function in animal models for PD. We aim to test
our high-impact AMPAKINE drug candidates in the mouse
model of Parkinson’s, a well-validated model that exhibits Q: Can AMPAKINES also prove useful for
many of the hallmarks of human PD and has been used those with the symptoms of ADHD?
extensively for drug development in PD. If successful, the
work could lead to a neuroprotective treatment for the disease A: Yes. Again, the key attribute here is the ability of
with the potential to slow or stop the course of the disease - AMPAKINES to increase levels of neurotransmitters in parts
something no currently available therapy has been proven to of the brain that help people focus and control impulses, and
do. Current treatments for PD alleviate the symptoms but do to activate brain regions that are sluggish so that they regulate
not attack the underlying disease, or alter its course. Positive cognitive activity at a more normal level. Currently, there are
results will support moving selected compounds toward a host of drugs already on the market, including Ritalin,
human clinical trials. Adderall, Concerta, and Vyvanse, which operate on these
principles. However, these medications belong to the class of
drugs known as stimulants and have an increased risk for
addiction, and in some patients, lead to unacceptable
Q: Moving to Fragile X syndrome, how are
increases in heart rate and blood pressure. In contrast,
you attempting to address this condition,
AMPAKINE compounds have the potential to be unique
which is the most common genetically
agents in treating ADHD because they lack the side-effect
proven cause of autism, with liabilities of existing treatments. Cortex is hoping to initiate
AMPAKINES? clinical trials of its AMPAKINES for treatment of ADHD in
late 2010.
A: We have been granted an exclusive license by the
Vol 11 No 3
fidgeting and impulsive actions to epilepsy, OCD, and autism sleep apnea. Could you discuss this
or autistic-like behavior. The first of these two substances are endeavor?
AMPAKINES, which, as I noted earlier, serve to increase the
SPECIALTY PHARMA
strength of signals at connections between brain cells and A: People with obstructive sleep apnea experience multiple
increases levels of BNDF. The second class of substance interruptions of breathing that last 10 seconds or more while they
bears the name “metabotropic glutamate receptor type 5 sleep. The interruptions usually occur when the relaxation of
antagonists,” better known as mGluR5 antagonists. These upper airway muscles decreases airflow to the lungs, lowering
appear to amplify the positive effects of the AMPAKINES in the oxygen level in the blood and waking sufferers as they
alleviating Fragile X symptoms. Early clinical studies with struggle to breathe before falling back asleep. This can happen
72
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many hundreds of times every night. One of the most effective Q: What would you say to our readers who
treatments is a machine called a Continuous Positive Airway
experience the symptoms of Parkinson’s,
Pressure (CPAP). This involves sleeping with a large facemask
Fragile X, ADHD, or obstructive sleep
connected to a machine that pumps in air under pressure. Because
apnea, or know someone who does? And
of the uncomfortable nature of this treatment, patient compliance
is low. This demonstrates the great need for a better solution. what message do you have for potential
The efficacy of AMPAKINES to treat obstructive sleep apnea investors in Cortex?
was discovered after their use in treating psychiatric and
neurological diseases was recognized. It turns out that in addition A: Those who currently have one of these conditions or who
to the other effects on the brain I have mentioned thus far, have friends or family with them should be aware of cutting-
AMPAKINES can also lead to the stimulation of a unique brain edge research developments, such as the ones we have been
stem structure believed to play a major role in the modulation and discussing. Although currently there is no firm timeframe for
generation of the respiratory drive. Put in a more simple way, bringing Cortex’s AMPAKINE compounds to market, we are
AMPAKINES work by telling the brain to keep on breathing, and all looking forward to a day in the not-too-distant future when
also by amplifying the signals from the brain to the upper airway these compounds may offer a very substantial alternative or
muscles to maintain muscle tone. supplement to existing strategies. An important message
CPAP devices represent a significant business, with sales of at should also be sent to healthcare providers, who stand to reap
least $1 billion dollars annually. We certainly hope that as our potentially big savings if AMPAKINE technology becomes
molecules undergo further clinical testing on the road to market, standard. We believe our AMPAKINE compounds will tempt
that they will one day gain the prominence among healthcare physicians to take a fresh look at the treatment options
providers and obstructive sleep apnea patients as CPAPs currently available to them. Keep in mind the total cost of these
enjoy. ailments involves more than just the immediate price of
existing treatments themselves. Dealing with the
complications that sometimes result from these conditions can
Q: Who do you see as your chief competitors, be more expensive than anyone expects. When hospitals see
the potential savings involved in switching to our
and what is the current status of the
AMPAKINE compounds as a standard treatment, we believe
clinical testing involving Cortex’s
they will be enthusiastic.
AMPAKINES? As for potential investors, I would stress the fact that
Cortex Pharmaceuticals’ goals are broader than merely Vol 11 No 3
A: At this time, we at Cortex do not see any genuine improving the lives of those with any one specific condition.
competition in our quest to develop molecules that can be We are a neuroscience company focused on the discovery,
APRIL 2011
used as widely and as effectively as our AMPAKINE development, and commercialization of novel drug therapies
compounds. As for clinical testing, we currently have one for the treatment of a variety of neurological and psychiatric
compound in clinical development: CX1739, which is
SPECIALTY PHARMA
BASF 15 www.soluplus.com
BIO 35 www.convention.bio.org
BD 9 800-225-3310 www.bd.com/pharmaceuticals
Catalent 76 www.catalent.com
CMO/CRO 11 www.CMOCRO.com