THE PORTAL TO OUR BLOOD SYSTEM I S

how nasal drug delivery experts v i e w the nose.

With the continuous development of more

potent and complex molecules and the imminent expira-

tion of many patents for major brands, novel delivery sys-

tems offer opportunities for developmental and

marketed compounds alike. Nasal delivery is ideal for

potent drugs that are to be delivered in small doses, as

low as tens of milligrams.

Although modified oral

delivery is the dominant deliv-

ery method for potent drugs—

comprising nearly half of drug

delivery projects in the major

pharmaceutical companies—

there are many cases when oral

delivery is not applicable. For

example, many compounds,

particularly macromolecules,

are not adequately bioavailable

when delivered orally or are

associated with adverse gas-

trointestinal effects. Nor is oral

medication appropriate if the

patient suffers from nausea or

vomiting or has difficulty swal-

lowing tablets or capsules, as is

often the case with children and

the elderly. Additionally, the

orally administered drug takes

longer to reach the bloodstream

than a nasally absorbed drug.

Traditionally, many drugs have been administered

intranasally for localized treatment of conditions such as

rhinitis and nasal congestion. Pharmacokinetic con-

cerns have caused formulators to overlook nasal deliv-

ery. These include true nasal absorption, acute or

long-term mucosal irritation and the need for prolonged

high blood levels. Nasal inflammation and mucosal

swelling due to infection, allergies and environmental

irritants and physiological changes may affect nasal

drug distribution. Studies are needed to clarify how such

conditions will influence nasal bioavailability.

However, the nasal cavity provides a large and easily

accessible area of highly permeable and vascularized tis-

sue through which drugs can be absorbed rapidly and

directly into systemic circula-

tion. By avoiding the gastroin-

testinal tract and the effects of

f i r s t-pass metabolism, the

nasal route offers the opportu-

nity to administer low-dose

m e d i c ations—from tens to

hundreds of milligrams of

powder or solution volumes

up to 150 mL per nostril. Nasal

route administration for cer-

tain medications may also

offer reduced side effects.

Nasal drug delivery can pre-

sent a convenient and patient-

friendly alternative for drugs

that otherwise would require

injectable administration. This

improves patient compliance,

may allow patients to self-med-

icate and avoids exposing

health workers to the risks of

needle-stick injuries and bio-

hazardous waste.

Nasal drug delivery offers a quick onset of action,

similar to injectables. Relief from chronic pain a n d

migraine headaches can come within minutes.

For these reasons, the exploration of the nasal route

for the delivery of drugs to systemic circulation is

growing. A number of small and macromolecules,

Nothing to Sneeze AtOften overlooked and long neglected, the nose has become one of the most viable drug

delivery p a t h w a ys for treating everything from the flu to erectile dysfunction.

Compiled by CINDY H. DUBIN

Excerpted from PFQ magazine, June/July 2002 issue

a d m i n i s t e r e d

systemically via

the nasal cavity, a r e

now on the market ( s e e

Table 1 on page 43).

POWDERS VS. SPRAYSL o n d o n-based Britannia Pharmaceuti-

cals is one company developing treat-

ments for nasal delivery, including

apomorphine for the treatment of Parkin-

son’s disease and erectile dysfunction.

Initial trials show Britannia’s proprietary

nasal powder formulation yields a bio-

availability equal to or greater than what is

delivered through injection or other

forms of drug delivery, as well as

i n c r e a s e d speed of onset and low poten-

tial for irritation.

Britannia claims the nasal powder is

a “rescue drug,” providing r e l i e f f o r

patients suffering an “off”2 , 5 period or

episode of immobility. The nasal powder

is marketed as a solution f o r u n c o m f o r t-

a b l e, subcutaneous injection/infusion.

While administration of liquid i n t r a-

nasal apomorphine has been shown to be

effective in Parkinson’s disease (Dewey

et. al., van Laar et. al.)3 local side-effects—

in the form of nasal crusting, inflamma-

tion and infection—have been evident. In

addition, apomorphine is s u b j e c t to rapid

oxidation in solution, presenting pharma-

ceutical challenges in developing such a

product. The nasal-powder approach was

developed to overcome these problems.

Intranasal products currently avail-

able are generally formulated as a liquid,

delivered by a metered pump spray.

While liquid is effective for many com-

pounds, this formulation approach can be

limited by the solubility of the drug in the

vehicle, the limited capacity of the nasal

cavity to hold liquid without drainage to

the throat or from its anterior portion,

and stability of the formulation.

The delivery of drugs to the nasal cavity

as a powder has clinical and pharmaceuti-

cal advantages over liquid a d m i n i s t r a t i o n .

The administration of powder e n s u r e s

localized distribution of particles on the

surface of the mucosa, in contrast to a

widespread coating of the nasal cavity that

occurs with liquid administration. T h i s

provides two benefits: First, the surface

area exposed to the formulation is re-

duced, minimizing potential for irrita-

tion. Second, localized delivery presents

areas of high drug concentration, facilitat-

ing rapid absorption and reducing the res-

idence time in the nose. Therefore, based

on the assumption that a powder formu-

lation will be exposed to a lower surface

area for a reduced time, it is expected that

this formulation will be tolerated b e t t e r

than a liquid formulation. Rapid absorp-

tion may also increase bioavailability

resulting in the possibility of dosa g e

reduction. Ugwoke4 demonstrated this by

comparing the pharmacokinetics of apo-

morphine formulations administered

intranasally as b o t h powder and liquid,

and as a subcutaneous injection. This

study showed the powder formulation

had a more rapid absorption rate a n d

greater availability than the liquid.

Others, however, believe that one of

the major problems with traditional spray

pumps in use today is the localized depo-

sition in the anterior one-third of the

Britannia’s newsix-dose nasald e v i c e

Nasal Insulin D e l ivers MoreWhile sc i e n t i sts have spent yea rsresea rching alte r n a t i ves to insulini n j e c t i o n s, nasal delive ry is still in theearly sta g es of eva l u a t i o n s.Co m p a n i es are seeking to develop inhaledinsulin, which cu r rently ex h i b i ts low abso r p-tion and bioava i l a b i l i ty.

Sc i e n t i sts and re g u l a to rs are co n ce r n e dthat flooding the lungs with insulin part i c l eswill eve n tually ca u se life - t h rea tening side

effe c ts. Fu rther co m p l i cating the pro cess,some inhaled insulin never rea c h es the lungsb e ca u se it sett l es in the mouth or thro a t,making it diffi cult to ensure that the patientis getting the co r rect drug dosa g e.

The historic challenge of delive r i n ginsulin has been to find a way to enhancehormone abso r ption without irritating then a sal passa g es. Other obsta c l es include lowp ayload delive ry and va r i a b i l i ty.

Be n t l ey Pharmace u t i ca l s, Inc. of Nort hH a m pton, NH claims to have ove rco m e

t h ese iss u es with high bioava i l a b i l-i ty, lack of irritation and low va r i a-tion. Animal tests of its CEP-215 (a

sy n t h etic ve rsion of a natu rally occu r r i n gcompound that enhances abso r ption of medi-cine through the skin, nasal passa g es andeyes) enhanced intra n a sal insulin indica tethat 30% of the hormone rea c h es the blood-st ream without signifi cant irritation, triplethe ra te of inhaled insulin.

Be n t l ey plans to fo r m u l a te CPE-215 intoan insulin that diabet i cs would spray into

their noses. This yea r, the co m p a ny plans tobegin human trials of nasal insulin. If thetechnology proves viable, nasal insulin wo u l dtap a US insulin market cu r rently wo rth about$ 1 .3 billion.

Pfi zer Inc. has part n e red with Be n t l eya fter independently studying CPE-2 1 5. Th ea g reement calls for Be n t l ey to fo r m u l a tePfi zer compounds using CPE-215 and Pfi ze rwould develop the drugs.

Ea st Norriton, PA- b a sed Auxilium Pharma-ce u t i cals Inc. is resea rching a nasal fo r m u l a-tion of an ex i sting opiate pain drug usingC P E-2 1 5. The ex p e c tation is that the nasal paindrug would begin working more quickly thanpills while avoiding injections. Human test i n ghas yet to begin, suggesting that the drug isat lea st three yea rs from reaching market.

Bentley Pharmaceuticals, Inc.N o rth Hampton, NH6 03 - 96 4- 8 0 0 6w w w. b e n t l ey p h a r m .co m

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nose. Considerable efforts are underway

to achieve a more widespread distribution.

The anterior segment is predominantly

lined by squamous epithelium, and not by

mucose. Thus, for both topical and sys-

temic substances, the goal is to reduce the

deposition to this anterior area. Sub-

stances delivered to the mucosal site will

be cleared along the lower parts of the

nasal airway.

LEADING WITH THE NOSEThe nose has a number of roles, one of

which is to act as a protective organ, filter-

ing particles from inhaled air prior to

entry into the lungs. Most inspired parti-

cles will be retained in the nasal cavity,

although very small particles (<5-10µm )

have the potential to pass through the

nasal cavity and enter the pulmonary

region. Particles retained in the nasal cav-

ity have a very short residence time as the

process of mucociliary clearance will send

particles to the throat within 5-15 minutes

of deposition. The r e f o r e, the physico-

chemical properties of a nasal powder are

key to i t s safety and efficacy.

A limitation of liquid nasal adminis-

tration can be its solubility. Each nostril

has the capacity to hold a maximum vol-

ume of 100-150µL before the

formulation drains to the b a c k

of the throat. Therefore, the

drug delivered must be thera-

peutically active in an amount

soluble in 200-300µL of liq-

u i d . There is also a limit to the

amount of powder that can be

safely and comfortably deliv-

ered into the nose so all

intranasal administration m u s t

be limited to relatively potent

c o m p o u n d s . However, the po-

tential exists to deliver larger

powder doses of compounds

that have limited solubility.

In addition, many com-

pounds are not sufficiently stable as a liq-

uid. In these cases, powder formulation

may offer an a l t e r n a t i v e approach that

confers a greater degree of stability on the

c o m p o u n d .

West Pharmaceutical Services of

Lionville, PA has developed a nasal drug

delivery technology that can be used either

i n liquid or powder form, depending on

the drug’ s solution stability. The patented

ChiSys nasal delivery system u s e s a natu-

rally occurring substance, chitosan,

derived from crustacean sh e l l s. Chitosan

is a bioadhesive that allows a nasally

administered compound to reside in the

nose longer by bonding with mucus,

resulting in increased bioavailability.

ChiSys-morphine has been approved

for clinical trials to treat pain in cancer

patients and other analgesia indications,

and ChiSys-leuprolide has been approved

for clinical trials for the treatment of

endometriosis and other gynecological

conditions. West and Brussels-based

Solvay Pharmaceuticals are developing

Influvac, an influenza vaccine.

Intranasal Drugs Administeredfor Systemic Effect

COMPOUND COMPANY

Nicotine Pharmacia

Dihydroergotamine Novartis

Sumitriptan GSK

Oestradiol Servier

Calcitonin Novartis

Desmopressin Ferring, Norgine

Buserelin Shire

Narafrelin Pharmacia

SOURCE:Britannia PharmaceuticalsTable 1

The Results Are InA non-inva s i ve alte r n a t i ve to injecta b l eI n te r fe ron beta may be on the horizo nfor multiple sc l e rosis suffe re rs.N a stech Pharmace u t i cal Co. Inc. of Haup-p a g e, N, has re ce i ved the res u l ts of itsP h a se I pharmaco k i n et i c, pharmaco d y n a m i c,sa fety and to l e ra n ce study demonst ra t i n gthe nasal delive ry of Inte r fe ron beta -1 a .The single-dose, open-label stu d y, invo l v i n gh ea l t hy male vo l u n te e rs, re q u i red each tore ce i ve either a 60-mcg dose of Inte r fe ro nb eta -1a as an intra m u scular injection or a30–60 mcg nasally administe red Inte r fe ro nb eta -1a spray of either Naste c h’s fo r m u l a-tion or a sta n d a rd formulation withouta bso r ption enhance rs. The subjects we reeva l u a ted at various time inte rvals afte rd os i n g .

Ad m i n i st ration of the sta n d a rd nasa lformulation did not result in dete c ta b l ee l evations in biologic marke rs for Inte r fe ro nb eta -1a, howeve r, subjects re ce i v i n gN a ste c h’s formulation showed elevations in

biologic marke rs similar to those pro d u ce dby the intra m u scular pro d u c t, suggesting ap h a r m a cologic effe c t. In addition, theN a stech formulation was well to l e ra ted withfewer re p o rted side effe c ts than for thei n j e c ted pro d u c t. No nasal irritation wa so bse rved during the stu d y.

“ H aving previously demonst ra ted thes u ccessful nasal delive ry of Inte r fe ro nalpha, we consider these res u l ts a furt h e rvalidation of our co re te c h n o l o g y,”says Steven C.Q u ay, MD, PhD,c h a i r m a n ,p res i d e n tand CEO ofN a ste c h .“ N a sally administe re dI n te r fe ron beta mayp otentially provide MS patientswith a more co nvenient alte r n a t i ve toI n te r fe ro n - b eta injections.”

I n te r fe ron beta is a drug used tore d u ce the fre q u e n cy and seve r i ty of

re l a pses afflicting MS patients. The marketfor Inte r fe ron beta is more than $1.4 billion.

N a stech has also re cently re ce i ved a$2 million development milestone pay m e n tf rom Pharmacia Co r p. under their co l l a b o ra-tion and licensing agreement fo ri n t ra n a sally administe red apomorphine fo rsexual dysf u n c t i o n .

West expects

to receive F D A

approvals to begin

clinical trials for addit i o n a l

therapeutic products using

ChiSys within the coming year.

Pharmacokinetic studies of Br i t a n-

nia’s apomorphine powder show the for-

mulation is absorbed at least as quickly

as the injected product and equally avail-

able. Acute- and short-term chronic use

Phase II studies have shown the product

is effective with no evidence of the local

side-effects associated with the liquid for-

mulation. Long-term safety and efficacy

studies are on-going. In addition, Phase I

studies are underway in developing a sec-

ond apomorphine product for the treat-

ment of male erectile dysfunction

(MED). Known to be an effective treat-

ment of MED, the drug is marketed by

other companies for this indication as a

sublingual tablet. However, the nasal-

powder formulation is expected to be

superior to the sublingual product, pro-

viding a more rapid effect at a reduced

dose with fewer associated side-effects.

Liquid and powder formulations are

of particular interest to Oslo, Norway-

based OptiNose, which is developing

devices for nasal delivery of vaccines and

drugs with topical or systemic action.

Through manipulation of the particle

size profile and nasal aerodynamics, the

patented OptiNose concept allows opti-

mized delivery of liquids and powders to

the nasal mucosa (widespread and tar-

geted), while at the same time eliminat-

ing the risk of inhalation of small

particles to the lungs.

The work of these companies, and

others like them, demonstrates that the

nasal cavity is a promising administra-

tion route that has long been neglected.

It is a viable and relatively safe method

for drug delivery; the products coming to

market reflect this sentiment. – P FQ

AUTHORS

Per G Djupesland, MD, PhD, is founder andh ead of R&D at Opt i N ose. He can bereached at pgd@optinose.no.

Khurshid Iqbal, PhD, vice president, globaldrug delive ry, West Pharmace u t i cal Se r-v i ces, Inc. Co ntact him at khurs h i d _Iqbal@westpharma.com.

Pete Lambert is Technical Manager at Bri-tannia Pharmace u t i ca l s. Co ntact him atpete.lambert@forumgroup.co.uk.

R E F E R E N C E S

1. Adding Value to Products’ Life-Cycle Man-

agement: Product Enhancement Through

Drug Delivery Systems, A. Baichwal and D.

A. Neville, Drug Delivery Technology; Vol.. 1,

No. 1, Oct. 2001.

2. Intranasal Apomorphine Rescue Therapy

for Parkinsonian “Off” Periods, Dewey R.,

Maraganore D. M., Ahlskog E., Matsumoto

J. Y., Clinical Neuropharmacology: 1996;

19(3): 193-201.

3. Intranasal Apomorphine in Parkinsonian

On-Off Fluctuations, T. van Laar, E. N. H.

Jansen, A. W. G. Essink, C. Neef, Arch.

Neurol. 1992; 49: 482-484.

4. Nasal Administration of Apomorphine:

The Powder Advantage, M. I. Ugwoke, E.

Sam, G. Van Der Mooter, P. Augustijns, N.

Verbeke and R. Kinget, Proc. 2nd World Meet -

ing APGI/ APV, Paris, 15-28 May 1998.

5. A Double-Blind, Placebo-Controlled Study

of Intranasal Apomorphine Spray as a Rescue

Agent for Off-States in Parkinson’s Disease,

Dewey R., Maraganore D. M., Ahlskog E.,

Matsumoto J. Y., Movement Disorders: 1998;

13 (5): 782-787.

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Flu Spray Returns to DCG a i t h e rs b u rg, MD-based MedImmuneInc. hopes to win FDA approval just intime for the 20 02-20 03 flu sea son withFluMist, an experimental vaccine, thefirst to be delivered as a nasal spray.The 14-year-old biotech company ispinning its hopes on the promise thatFluMist pushes the company into the elite

group of biotech firmsthat have

developedblock-

buster drugs, bringing in $1 billion inannual sales.

While patient trials have found then e e d l e -a l te r n a t i ve va ccine to be highlyeffe c t i ve, an FDA a d v i so ry panel re co m-mended against FluMist’s approval lastJ u l y, raising questions about its sa fety.In January, the co m p a ny res u b m i tted itsF DA a p p l i cation with additional data toa d d ress FDA’s co n ce r n s. PFQ tried ca l l i n gMedImmune seve ral times to learn whythe biotech co m p a ny ex p e c ts approva lthis time around, but the co m p a ny did notreturn the ca l l s. Wall St re et analystsb e l i eve FluMist will win approval this time

for seve ral rea so n s, one of which isthat the co m p a ny hired a former FDAofficial to help rev i ew the va cc i n e.

I n t ra n a sal va ccination offe rs loca lm u cosal immune protection for manyva cc i n es. Some health ex p e rts sup-

p o rt FluMist beca u se it offe rs docto rs

a n other tool to fight infl u e n za and makesup for re cent shorta g es of the flu va cc i n e.

O t h e rs believe, howeve r, that thereis not a pressing need for a nasally deliv-e red flu va cc i n e. Even if FluMist winsa p p roval, indust ry insiders question howm a ny people would be willing to pay asmuch as $20 or more for a nasa l - s p rayva ccine when the cu r rent needle va cc i n ewo r ks just fi n e. In addition, they say Flu-M i st will be less accessible to the publicb e ca u se the va ccine must be sto red atcool te m p e ra tu res.“MedImmune has a solution to a pro b l e mthat does n’t ex i st,” said David Hines,p resident of Avalon Resea rch Group Inc.,of Bo ca Ra ton, FL, in a March 18, 20 02Wa s h i n g ton Post art i c l e. “It’s too ex p e n-s i ve and inco nve n i e n t. If it’s important tova cc i n a te children for flu, give them a$10 shot. It’s sa fe and effe c t i ve, triedand true.”

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