Note: Descriptions are shown in the official language in which they were submitted.
WO 95/30409 2 1 8 8 5 6 6 PCT/CA95/00260
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TITLF, OF THF, INVENTION
TOPICAL POLYMERIC DRUG DELIVERY SYSTEM
This ar~ tirn is a c~ ;...,-in-part of crr~n~1in~
application Serial No. 08/238,409 filed May 5, 1994.
BACKGROUND OF THE INVENTION
The present invention is directed to a topical polymeric
delivery system for the ?~I...;";~I"";I~n of certain drugs over an extended
period of time via a non-propellant aerosol pump device.
Sustained release devices for controlled topical delivery of
drugs is a highly useful method of supplying m~ tinn when it is
beneficial to ~.1",;";~1~. m~.tlic~tic~n cnntiml~ ly. The idea of aerosol
delivery of a thin film for direct spraying on a woumd has been
5 described in an article by Fujita et aL, "Ph~rm9~-eutir~1 Research" 9,
(1992). However, the method described involves a CFC c~.lll;~;ll;
aerosol propellant.
Some of the advantages of this system over known
tr~ncd~rm~l delivery systems include:
1 ) Ease of application;
2) Ease of removal since the film is water soluble;
3) Freedom from adhesives;
4) Freedom from the use of a rate controlling Illc;l.ll,l~llle;
S) High patient s~rc-pf?~-ility as the film is practically invisible;
and
6) The use of a propellant-free aerosol which is
~ IVil...l,l....l~lly friendly.
SUMMARY OF THE INVENTION
According to the present invention it has been discovered
that certain drugs can be delivered via a propellant-free aerosol as a
~ulllluc~ lll of a polymeric system for prolonged adlllilli~ ion
compared to conventional formlll~ n~ In particular, the compound
inrlom.oth~lin and certain cyclou~y~llase II inhibitors such as 3-[3,4-
WO9~/30409 ~i 8856~ PCT/CA95/00260
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diri UUIUIU~ ly]]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone can be
topically applied usmg the delivery system of the invention resulting in
prolonged ~,l.";";~",~ir)n compared to conventional dosage forms.
FUILII~1I1IUI~ the system is capable of providing systemic delivery of
5 the ",r.l;. ~~1~ without causing the gastric irritation a~CoCiAf. d ~vith
indc,lll~,Llld~,ul, in particular, and NSAIDs, in general.
DESCRIPTION OF T}~F INVENTIQN
There has been discovered a novel polymeric drug delivery
system for prolonged topical delivery of a mf riir~mf nt via a propellant-
free aerosol pump. The system is adaptable to arly drug which is
soluble and stable in hydroalcoholic solutions and comprises a film
forming po]ymer, a pl~ctir.i7in~ agent, a crystAlli7Atil~n
hlllibilul/~ilizer, a ~nf tr~tjon enhancer, an alcoholic or
hydro~lcnhnlir solution and a suitable drug .
Suitable drugs for use in therdpy with the device of the
invention include without limit~ti~n
1. Protein drugs such as insulin;
2. Anti-infectives, such as antibiotics, including penicillin,
t~,.la~ycliule, chlorotetracycline bacitracin, nystatin,
~LIUI ~OIIIY~;UI~ neomycin, polymyxin, gramicidin,
oxytetracycline, chlul- "l)i.- ,;rol, and ~ LIll~llly-;iul;
sulfnn~mi~ifg, including slllfArft~midP, glllrAlll~ ;ll;~n
Sulr~ull~,lll~iulC~ glllf?~fi~7inf, Svlr~ .f~ and
s~lfi~oS- 1~, cefoxitin; anti-virals includir~g irfnsllri~iin
and other arlti-infectives including ~ lurul~C~ and
sodium propionate;
3. Steroidal anti-;~ri- ~ ly agents such as hydrocortisone,
cortisone, l~ydluculLi~ullc acetdte, dex~llcLlldsûl~,
dex~ll.,Lll~sull~, 21-~ , fluocinolone, triamcinolone,
medrysone, prednisolone, prednisolone 21-phosphate and
prednisolone acetate;
4. Estrogens such as estrone, 17 ~-estrddiol, ethinyl estradiol
and diethyl stilbesterol;
21 ~8~66
WO 9S/30409 PC11CA95100260
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5. P.u~ AI agents such as pro~,~,at~,lvllc, megestrûl,
mf lf n~f. strûl, chlnrmq~linonf, clllialelulle, nul~illy.lodl~
19-nor-~,1u~,_at-,lulle, norethindrone, medroAy~lu~,.,si~lu-le
and 17 ,~-hydroxy-pro~ a~-,lulle;
5 6. Humoral agents such as the prosta~lqn~in~) for example,
PGE1, PGE2 and PFG2;
7. Allli~,.y.~,lics anolgf~irS such as aspirin, sodium salicylate,
salicylamide and ~lifllmi~al;
8. Al.~ ,.. ,n-lins such as atropine, .. ~ inf, papaverine
and ~ c.,~,olamine bromide;
9. A..l;l.i~ ...i..f-~, such as lil h~,lllly~ f, dllll~llllydlil~t~,
II;~-~f-1~,""A"~;"f.~ F...~ f' and chlolu~ ;llf;
10. Non steroidal anti-i.,llA~ u,y agents such as
i".~ llal ... and sulindac; and
1 1. Cyclooxygenase Il inhibitors such as those disclosed in U.S.
Patent No. 5,409,944 issued April 25, 1995 and those
disclosed in copending applications 08/147,804 filed
November 4, 1993; 08/179,467 filed January 10, 1994;
08/330,172 filed October 27, 1994; 08/361,268 filed
December 21, 1994 and 08/371,179 filed January 11, 1995.
Other drugs having the same or different physiological
activity as those recited above can be employed in drug-delivery devices
within the scope of the present invention.
This system is particularly useful with drugs such as
2s in~nmftllarin which can cause severe upper gAs~ l irritation
and nausea when ,a"llllilli~lrlud by conventional means.
The system involves the use of film forming polymers
which are soluble and rapidly form a thin film upon application via a
Ilydlu-,~bùll propellant-free system. The film fonned allows vapor
30 penetration and can be considered l,lti_lllal~lc. The choice of a chloro-
fluoro-carbon (CFC) free preparation was essential due to the
potentially cllvi ulllll~ lly damagimg ~ t~,lialh,s of CFC
propellants. With the use of a llydlu~,~bull propellant-free system, it
was also essential that the solvent employed be volatile enough to allow
2 1 ~ g 5 6 6 ` ` :
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rapid film formation on A.l,..;..;~, Al;on Alcohols or hydroalcoholic
solutiorls using lower alkanol solvents such as ethanol and isv,u~v~ol have
been found useful with ethanol being the preferred solvent. Other potential
solvent systems may include ethyl acetate.
The film forlning polymer selected was ~ ~ " ,;. ,~ in view of the
solvent employed. It is necessary that the polymer be soluble in the solvent
chosen. Polymers which have been foumd to be useful in the invention
include J~ yla~s, celluloses, siloxanes amd copoly2ners of
methac~ylates, celluloses and silox~mes. PrefeIred polymers are meth-
0 acrylates with poly(2-hydroxy ethyl ~~ iLa.,~ylaL~) (PHEMA) the most
prefeIred choice. PED~A was the most preferred because of the quality of
the film formed in the system.
Plasticizing agerlts are also necessary for the delivery system.
The rlAchr.i7~rc are used to impart the desired IIIF. IIAII;I .A1 proper~ies to the
fi]m such as fiexibility. Suitable r1A~ agents include Tween 20
(TradeMarkforpolyoxyethylene(20)sorbitan~.. r.1A ~AIr)andTween
(Trade Mark) products of higher molecular weight, low molecular weight
po~yethylene glycola, glycerine or Labrasol (Trade Mark for PEG-8-
capryiic-capritriglyceride). Preferred rlAch~i7~rc are the Tween (Trade
2 o Mark) products with Tween 20 the most prefelred. The rlA chr;7in~ agent
is generally present in an amount from about 10%-50% as a IJ~ of
the total solid contents of the film
An additional ~ for the delively system is a
cr~st^Alli7Ah~-n ir~hibitor/stabilizer andlor a penetration erlhancer. These are2 5 used to modulate drug delivery. Suitable c~lmr~ ' include, 1 ~
~y~ 1.~1. . 11 .1.~ such as ~dlu~.yl~uyyl beta-cyclodextrm (HPBCD),
Ly~Lu~.,lLyl beta-~iy~,lod~"~L...~ diethyl beta-~y-,lod.,~L~ and hy~Lu~,Lilyl
and Ly~Lu~y~lu~yl ga~ma cyclodextrin and transcutol, urea and
;s..t 1~ ~ ~ The choice of cyclodextrm iâ governed by the si_e of the drug
3 o . molecule used in the particular ff~rmlll~hr~n Hydroxypropyl beta-
cyclodextnn (HPBCD) was the preferred cry~-c~lli7Ahon m~ubitor.
The following example illustrates the invention but is not
construed to be limiting.
AMENDE~ SHEE`T
`21 ~856~
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E~AMPLE 1
Fihn Formation
PHEMA was dissolved in a Tween (Trade Mark)/ethanol
solution w_ich hadbeen warmed to 50C. TnrTr)m.-fhArin free acid was
5 added to the solution and when fully dissolved the resultant solution was
poured imto a glass petri dish. The petri dish was covered with an inverted
funnel and the solution was left to evaporate to dryness at room
C~ . The films were placed in a vacuum oven for 16 hours at 37C
to ensure that the moisture level in all fihns was cnmr~r-hl~ Moisture
0 levels were d~ .. ;"~.d to be less than 3/O, in all fihns, by theremogravi-
metric analysis As a p~ of the total solid contents of the fihn,
;".1,).,.. ~ was present in quantities ranging from 9 to 14%, and Tween
20 (Trade Mark) from 14 to 45%. In films containing HPBCD, ~uanthies
were used which gave molar ratios of 1:1, 1:2 and 1 3, inrlrlm~t~A-
5 cin:HPBCD.
EXAMPL~ II .
In Yitr~ Dissolution Testin~ of Fihns ~ th T...TI~..,, :1. . .;..
Films were cut to the ~ U~Iial~ size to fit an Enhancer (Trade
2 o Mark) cell (Varlkel Industries, USA) and were weighted before testing. The
film was covered with a Durapore (Trade Mark) .. I~ filter
(Millipore, USA) to provide additional -.f.~ I support. Dissolution
testing, using the USP paddle method (100 r.p.m ), waS carried out irl
phosphate buffer (pH 7.2) at 37C. Sarnples were taken over an eighthour
2 5 period and inrTr m~.th~rin c~" ,~...., l, A; ~r~n was qTl~n1;tAtPd by HPLC.
HPLC Conditions
A Beclc~nan Ultrasphere 511 C-18 (Trade Mark) (4.6 x 250 mm)
colurnn was used at 40C with a mobile phase of 35% aqueous (3% acetic
3 o acid in distilled water) and 65% organic (15% aAetr ni~ and 85%
methanol) phases. F1QW rate was 1 ml/min When arl~lyzing T.,~ .;"
AMENDED SHET
2 1 ~ 8 5 6~ . . ` `
samples and standards, 4-androsten-17,~-ol-3-one (t~,DLUb~lUllC) was used
as _n int~m_l standard. Detechon was by W Dy~.LI..D~,u~y measuring at
260 nm. An inflf~rnf th~^in standard curve was cl .,.~I. . . t~ ~ by prepa7ing
st~7ndards in met7aanol which ramged from 0.5 to 10 ~/ml each with 10
5 ~g/ml ot ~eD~uDt~ u l . c. The limit of detection for inflf mf th -f in ~
by 1 IPL'~ with W detection at 260 nm was d~ .. rd as 0.05 ~lg/ml.
D~ , was linear over the range O. l to 100 ~/rnl. The ~ irul ~ y
of detection was ~ . ".;,.. 3 by injecting the same st~mdard ten times and
~,7~tf.nnjnin~ the relative standard deviation for the peak areaD obtained. The
relative standard deviation was less than two.
EXAMPLE m
Fil7n Fomlation
PH~MA was dissolved in a Tween (Trade Mark)/HPBCD/-
eth~nol solution which had been warmed to 50C. 3-[3,4-Difluorophenyl]-
4-E4-(methylsulforlyl)phenyl]-2(5H)-furanone was added to the solution
and stir~ed umtil fully dissolved. The resulting solution was filled into a
Valois (Trade Mark) airless pump and made up to volume with ethanol.
The pump was sealed with a metered valve (200ml, VP36, 20m7n CS gasket
2 o 3/~æ, spring 1674). As a ~ L.~ of the total solid content of the f~m
3-r3,4-difluoro-phenyl}-4-[4-~ LhylDulru,.yl)phenyl]-2(5H)-furanone was
present in quantities ranging from 1.15% to 4.45/0, HPBCD at 10% amd
Tween 20 (Trade Mark) from 14 to 4~%.
2~ Rat Paw Edenna Assav-Protocol
Five Fuzzy rats (250-300g) (Harlan Sprague Dawley,
In~ f lic ~. USA) were used. The dorsal mid-lumbar area was spayed
topica7.1y with the r.. ~ .T~ .. covering an area of about 4 x 4 cm.
This 5l.1.. ~l.rl.. was given once a day for tbree days. On the
3 o th7rd day, one hour at^ter the topica7. ~.l, .., ., . ~l ". l ;f n a line was d7 awn
using a p~.. . ,~L marker at the level above the a7~1e 7n one hind paw
.
AMENDED SHEEr
WO 95/30409 2 1 8 8 5 6 6 PCT/CA95/00260
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to define the area of the paw to be monitored. The paw volume was
measured using a pL,ll~ llu~ ,t~,l (Ugo-Basile, Italy) based on ~e
principle of water ~ "~ , l The animals were then injected
Z~"~ ly with 50 ~11 of a 1% call~g~ll~l solution in saline (FMC
5 Corp., Maine) into the paw using an insulin syringe with a 25-gauge
needle (i.e., S00 llg C~ lldll per paw). Three hours later, the paw
volume was measured and the increases in the paw volume were
r~ ,d A five hour plasma sample was also taken to correlate the
plasma levels with % paw edema inhi1~i*nn The animals were
;,f d by C02 d~ iàli-J.I. Paw edema data were compared with
the vehicle control group and percent inhibition r~ taking the
values in the control group as 100%. The topical fnrrmlls'fi~n was given
at different doses to the animals and was also compared to an orally
,d dose of j"~ ;., and a ~ ... f l~ lly available topical
gel fnrrnllls~if~)n of illf~l.lllr~ ;ll Re~ ive results are shown in
Table 1.
21 8856~
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F~rm~ tio3ls Dose (m~ ) % Inhibition Plasma Conc
(3hr) (U~lml~
(5hr)
5 Tnt-lm~th~in
spray 1 31 + l 3.6 i 1,2
3 54:~2 7,6~2.1
', 10 70 i: 2 8.5 i l.2
0 Amuno~) Gel 5 41 i 2 4,5 i 1.5
Oral Tntl~m~th~.in
(0,5 % Methocel
- Trade Mark) 3 55 i 3 7,2 i 3.1
3-[3,4-Diiluoro-
phenyl]4-[4-(methyl-
sulfonyl)phenyl 1]-2-
(5H)-f~ranone spray 7 56 i 5 1.2 ~ 0 2
