Bioadhesive complexes of polycarbophil and azole antifungal or

16 Pages·2013·1.28 MB·English

US006423307B2
(12) United States Patent (10) Patent N0.: US 6,423,307 B2
Saettone et al. (45) Date of Patent: *Jul. 23, 2002
(54) BIOADHESIVE COMPLEXES OF (56) References Cited
POLYCARBOPHIL AND AZOLE
U.S. PATENT DOCUMENTS
ANTIFUNGAL OR ANTIPROTOZOAL
DRUGS
4,615,697 A * 10/1986 Robinson .................. .. 604/890
(75) Inventors: Marco Fabrizio Saettone; Luana 56,,615586,,935468 AA ** 128//21090907 SMaanrttoisn eett aa11.. ............. .. 424/426
Panichi; Boris Giannaccini; Enrico
FOREIGN PATENT DOCUMENTS
Boldrini; Pietro Bianchini, all of Pisa
(IT) 0501523 A1 2/1992
0497956 B1 1/1996
(73) Assignee: Farmigea S.p.A., Pisa (IT) 0770384 A1 2/1997
( * ) Notice: This patent issued on a continued pros OTHER PUBLICATIONS
ecution application ?led under 37 CFR
Mosby—1997 7"1 Edition 755—756, 1205—1206.*
1.53(d), and is subject to the tWenty year
DerWent WPIL on Questel, Week 9722, London: DerWent
patent term provisions of 35 U.S.C.
Publications Ltd., AN 97—237926 & EP,A1,0770384 (Mon
154(a)(2).
tefarmco spa), abstract.
Subject to any disclaimer, the term of this (List continued on next page.)
patent is extended or adjusted under 35
Primary Examiner—Thurman K. Page
U.S.C. 154(b) by 0 days.
Assistant Examiner—Blessing Fubara
(21) Appl. No.: 09/230,863 (74) Attorney, Agent, or Firm—Smith, Gambrell & Russell,
LLP
(22) PCT Filed: Jul. 25, 1997
(57) ABSTRACT
(86) PCT No.: PCT/IT97/00187
Mucoadhesive antimicrobial complexes of polycarbophil,
§ 371 (6X1),
i.e. a cross-linked polyacrylic acid With bioadhesive
(2), (4) Date: Feb. 2, 1999
properties, and an imidaZole or triaZole derivative With
(87) PCT Pub. No.: WO98/05303 antifungal or antiprotoZoal activity, in its basic form, for use
in the topical treatment of mucosal affections. The com
PCT Pub. Date: Feb. 12, 1998
plexes are obtainable by dissolving each of the tWo starting
(30) Foreign Application Priority Data products in a common solvent, then joining together the tWo
solutions in relative amounts such as to contain the same
Aug. 2, 1996 (IT) ..................................... .. RM96A0559 number of equivalents of the tWo starting products, evapo
rating the solvent and then drying and, if required, pulver
51 I nt. C].7 ........................ .. A61K 31/74 ; A61K 9/00 ; iZing and sieving the product so obtained. Particularly
A01N 25/00; A01N 25/24 preferred are formulations in gel in propylene glycol com
prising an econaZole-polycarbophil or omoconaZole
polycarbophil complex, With an excess of polycarbophil,
(52) US. Cl. .................. .. 424/78.18; 424/400; 424/405; together With pharmaceutically acceptable carrier and
424/407; 514/772.2 excipient substances, for use as sustained release antifungals
for vaginal administration.
(58) Field of Search ............................ .. 424/78.18, 426,
424/400, 407, 405; 514/724, 772.2; 609/890 25 Claims, 6 Drawing Sheets
TEMPERATURE (°C)
150 130 no 90 70 5o
\____|_|___l_l_|
6
OOo
a
5 m
X
0
a l
l
W 9
a econ azole ( base)
b econazole - polycarbophil
US 6,423,307 B2
Page 2
OTHER PUBLICATIONS Database WPIL on Questel, Week 9101, London: DerWent
Publications Ltd., AN 91—006976 & WO,A1,90/14832
Database WPIL on Questel, Week 9635, London: DerWent
(Curatek Pharrn. LP), abstract.
Publications Ltd., AN 96—353281, & US,A,5536743
Database WPIL on Questel, Week 8928,London: DerWent
(Curatek Pharrn. LP), abstract.
Publications Ltd., AN 89—206169 & US,A,4837378
Database WPIL on Questel, Week 9230, London: DerWent
(Curatek Pharrn. Inc.), abstract.
Publications Ltd., AN 92—249830 & WO, A1,92/10998
Database WPIL on Questel, Week 8423, London: DerWent
(Bornbart, F.), abstract.
Publications Ltd., AN 84—141201 & DE,A,3244027 (Bayer
Database WPIL on Questel, Week 9204, London: DerWent
AG), abstract.
Publications Ltd., AN 92—028853, & J P,A,3—275 619 (Nissui
Seiyaku KK), abstract. * cited by eXarniner
U.S. Patent Jul. 23, 2002 Sheet 1 0f 6 US 6,423,307 B2
TEMPERATURE (°C)
150 130 110 90 7O 50
l l I l l I
F.
§
8
3
E m
X
0
l
W E
a econazole ( base)
b econazole - polycarbophil
FIG. 1
U.S. Patent Jul. 23, 2002 Sheet 2 0f 6 US 6,423,307 B2
TEMPERATURE (°C)
0H1
I l I I
046L
MOOOWOl
<0—x—3-
3 JL, _
CLOUD)
clotrimazole ( base)
clotrimazoIe-polycarbophil
metronidazole ( base)
metronidazole-polycarbophii
FIG. 2
U.S. Patent Jul. 23, 2002 Sheet 3 0f 6 US 6,423,307 B2
FIG. 3
TEMPERATURE (°c)
c>o>oE?
IIII'I
mxO
a omoconazole (base)
omoconazoIe-polycarbophi|
b
U.S. Patent Jul. 23, 2002 Sheet 4 0f 6 US 6,423,307 B2
80 j
l.
2O -
G 1 i I l
O 5 1O 15 20
Tune, hours
E1 econazole-polycarbophil complex
0 physical mixture
FIG. 4
U.S. Patent Jul. 23, 2002 Sheet 5 0f 6 US 6,423,307 B2
4_
E
‘E 3- §
2
D‘)
E
8"
a 2
L3
8
g §
621
§ §
Q
o
O I I I l l I l
0 1 2 3 4 5 6 7
Time,hours
o FORMULATIONA (with the econazoIe-polycarbophil complex)
0 FORMULATION B (with econazole(base))
U.S. Patent Jul. 23, 2002 Sheet 6 6f 6 US 6,423,307 B2
FIG. 6
2
_
NE.b2Qm85EE61En
55251.
l2 I3 l4 l5 l6 l7
Time, hours
El FORMULATION A (with the omoconazoIe-polycarbophil complex)
<> FORMULATION B (with omoconazole (base) )
US 6,423,307 B2
1 2
BIOADHESIVE COMPLEXES OF dichlorophenyl)ethyl}-1H-imidaZole, is particularly Wide
POLYCARBOPHIL AND AZOLE spread and extensively tested. It has been synthesised by
ANTIFUNGAL OR ANTIPROTOZOAL Godefroi et al. in 1969 (J. Med. Chem., 12, 1969, 784, and
DRUGS US. Pat. No. 3,717,655). The antimicrobial activity of
econaZole, Which has been extensively shoWn in vitro, is
This application is a 371 of PCT/IT97/00187 ?led Jul. exerted against a Wide variety of fungi and against some
26, 1997. gram-positive bacteria, While no activity on gram-negative
The present invention concerns bioadhesive complexes
bacteria is present. The main site of the antimicrobial action
of polycarbophil and aZole antifungal or antiprotoZoal drugs.
is represented by the cellular membrane system, similarly to
More speci?cally, the invention relates to the formulation of
1O What happens for the other imidaZole antifungal agents. In
a complex of a cross-linked polyacrylic acid having remark
vitro tests With Tr ichophyton rubrum, Saccharomyces
able mucoadhesive properties, knoWn With the name of
cerevisiae, and Candida albicans have shoWn an increase in
polycarbophil, and an imidaZole or triaZole derivative hav
the permeability of the cell covering exposed to econaZole.
ing antifungal or antiprotoZoal activity, in the base form, for
Said increase occurs both in the groWing and in the groWn
use in the topical treatment of mucosal affections.
As it is knoWn, the diseases of a microbial origin 15 up cells, thus shoWing that the antimicrobial activity is due
affecting the mucous membranes, Which may be treated by to an action on the formed membranes, and not to the
exploiting the trans-mucosal administration route, are many formation of defective membranes in the groWth phase. The
and Widespread. In particular, among the diseases of this main action of the drug is the inhibition of 14-0.
kind Which affect the urogenital system, the mycotic infec demethylase, a cytochrome P45O-dependent microsomial
tions are very common, and among these, speci?cally, the enZyme system important for the synthesis of sterols. The
candidiases. said action has tWo effects: it causes a build-up of 14-0.
Candida albicans represents the species belonging to the methylsterols, and compromises the synthesis of ergosterol,
Candida genus Which is most commonly involved in human Which is necessary to the cytoplasm membrane. The built-up
candidiases, and is the only species pathogenic on laboratory methylsterols may desegregate the close packing of the
animals. The said species is held to be responsible of most 25 phospholipids acyl chains, thus compromising the functions
super?cial mycoses (muco-cutaneous mycoses) and of some of some enZyme systems connected to the membrane.
serious deep mycoses, and is commonly present on the EconaZole is used mainly for topical administration in
mucous membranes surfaces, such as those of the buccal the treatment of vaginal dermatomycoses and candidiases.
cavity and of the gastrointestinal tract in man, in equilibrium Several medicinal products containing econaZole as the
With the endemic ?ora of the said regions. In the healthy active ingredient are present on the market, specially for
population equilibrium conditions are normally established vaginal administration. In most of the said medicinal prod
betWeen the invasive potential of the fungus and the defence ucts econaZole is not present as the base, but in the form of
mechanisms of the host, Which are able to limit the tissue its nitrate salt.
invasion and, possibly, to eradicate the infection from the Another kind of microbial diseases Which have been
mucous membranes surface. The onset of a pathological 35 treated With therapies based on aZole active ingredients, to
process is the consequence of the breach of such be administered normally through the trans-mucosal route,
equilibrium, and this may be either due to the different are the infections caused by protoZoa of the genus Tnchomo
virulence of the infecting yeast or to the reduced resistance nas. These infections generally occur in Women, as
of the host. The importance of the host defence mechanisms, cervicites, vaginites and vulvovaginites, Which may also be
both natural and acquired, against candidiases is strongly associated With candidiases or With other bacterial infec
con?rmed by the incidence of fungal infections, and, tions. The active ingredient of choice for trichomoniases is
speci?cally, candidiases, in immunocompromised subjects. metronidaZole, Which also belongs to the group of imidaZole
The candidiases of the urogenital system, much more derivatives. For the topical treatment of infections caused by
Widespread in Women than in men, are characterised by itch Trichomonas, both in the man and in the Woman, metron
and discharge and, upon clinical examination, by erythema, 45 idaZole is advantageously combined With an imidaZole
edema and, sometimes, ulcerous or papular lesions. Epide derivative having mainly an antifungal action, i.e. clotrima
miologic statistics on the incidence of vaginal candidiases Zole.
are dif?cult to establish, although it may be considered that The conventional administration forms used for the topi
the said incidence has greatly increased in the last feW years, cal antimicrobials of the kinds referred to above are most
also due to a Wider use of hormone contraceptives and of commonly creams, suppositories for vaginal administration
antibiotic antimicrobials. Candidiases, and in general all of (pessaries, inserts, ovules) and tablets. In the case of
the fungal affections of the urogenital system, may be econaZole, for instance, there are commercially available
therapeutically treated With antimicrobial drugs for topical pessaries and creams based on econaZole nitrate, Which
use, speci?cally imidaZole derivatives such as econaZole, represent the preparations of choice, as Well as douches
tioconaZole, miconaZole and the like, or triaZole derivatives 55 (lavages) and foams for external use, both in the nitrate and
such as terconaZole, or also With drugs for oral in the base form, Which are generally used as adjuvants in
administration, in particular of the triaZole type, such as the therapy. Pessaries (containing from 50 to 150 mg of
?uconaZole. It is usually recommended to initially use the active ingredient) and creams (With 1% by Weight of active
topical aZole therapy, to be replaced by a systemic therapy ingredient, to be applied in 5 g doses) are administered once
in non responsive patients or in patients Who do not With a day, preferably just before going to bed in order to improve
stand the topical therapy. This is due to the slight toxicity of retention. The said forms do not alloW, in general, to obtain
the agents for systemic administration in comparison With an optimal bioavailability of the drug. Actually, for the
agents Which perform their activity in situ, as Well as to the therapy to perform at best its action it is necessary that the
need to limit the use of these drugs in order to avoid the folloWing conditions are realised: a) a good adhesion of the
occurrence of resistant strains. 65 medicament on the infected site, and b) the complete release
Among the antifungal drugs mentioned above, of the active ingredient. Very often the above does not occur
econaZole, i.e. 1-{2-[(4-chlorophenyl)methoxy]-2-(2,4 With the medicinal products noW in use: in the case of the
US 6,423,307 B2
3 4
suppositories for vaginal administration, in particular, the Among the latter, a particularly advantageous product in
problem of retention arises, since as soon as the fusion has vieW of its bioadhesive properties is polycarbophil
occurred the preparation may be rapidly discharged from the (produced by B.F. Goodrich Company of Cleveland, Ohio,
site of administration. under the trade name Noveon® AA-1). Polycarbophil is an
A suitable spreading of the formulation on the infected acrylic acid polymer loosely cross-linked With divinyl
site, if possible folloWed by an interaction With the mucous glycol, in particular With a quantity comprised betWeen 0.5
layer of the said site, could result in a remarkable increase and 1% by Weight of 3,4-dihydroxy-1,5-hexadiene, corre
of the bioavailability of the drug. The said result may be sponding to CAS No. 9003-01-04. The particles making out
achieved by increasing the duration and the closeness of the polycarbophil are sWellable, but not soluble, in Water, and
contact betWeen medicament and mucous membrane: on 10 they sWell to different extents also in organic solvents, in
these grounds the concept of bioadhesion, and in particular strong mineral acids and in bases, While remaining
mucoadhesion, has recently gained a remarkable importance insoluble. The Water sWelling features depend both on pH
in the formulation of systems for the controlled release of and on the ionic strength of the solution: the sWelling degree
drugs for trans-mucosal administration, including, but not increases With increasing pH. The amount of Water that the
exclusively, the systems for vaginal topical administration. 15 polymer may absorb ranges from 15—35 ml per gram, at loW
By the term bioadhesion it is meant the creation of an pH values (1—3), to 100 ml per gram, in neutral or basic
intimate contact, for a prolonged period of time, betWeen a medium. Polycarbophil is described, together With other
pharmaceutical material and a biological substrate, due to polymers of a similar chemical nature, in the Us. Pat. No.
the formation of chemical bonds, to interfacial forces and/or 3,202,577 (R. L. Markus, 1965), Where it is proposed for use
to simple physical interactions betWeen the tWo surfaces. 20 in the treatment of diarrhoea, in vieW of its outstanding
When the bioadhesive interaction is established betWeen the ability of sWelling and absorbing liquids.
pharmaceutical material and the mucus Which covers most Later, it has been found that polycarbophil shoWs excel
of the tissues, the phenomenon is referred to as mucoadhe lent mucoadhesive properties, Which have been extensively
sion. The advantages obtainable by administering an active described in the literature (see, e.g., H. Park and R.
ingredient through a bioadhesive pharmaceutical form are 25 Robinson, J. Controlled Release, 2, 1985, 47—57; K. V. R.
manifold, and may be synthesised in the folloWing points: Rao and P. Buri, Int. J. Pharm., 52, 1989, 265—270). The
localisation of the drug in a speci?c region: this is advan polymer interaction With mucin is made easier by the fact
tageous in a topical therapy, since the increase in the that the polymer chains undergo sWelling in Water, and this
duration and in the closeness of the contact betWeen alloWs a good degree of interpenetration With the glycopro
pharmaceutical form and tissue improves the bioavail 30 tein chains of mucus present on the tissues surface.
ability of the drug; The mucoadhesive properties mentioned above are actu
increase of the in situ residence time: the pharmaceutical ally the core of the European patent publications No. 0 163
form has a prolonged activity, and this alloWs to reduce 696 and No. 0 501 523, in the name of Columbia Labora
the number of daily administrations, thus improving the tories Inc., concerning the use of a class of polymer
patient’s compliance; 35 products, including polycarbophil as the preferred example,
optimal contact With the absorption surface: this results in a as bioadhesives for the production of sustained release
better drug permeation through the tissues, inhibits the pharmaceutical products. In the said documents (the second
degradative enZyme activity on the active ingredient and one of Which is a divisional application of the ?rst one) the
reduces the mucus secretion; bioadhesive polymeric product is proposed for use in admix
maintenance of a high concentration gradient betWeen the 40 ture With pharmaceutical or cosmetic active ingredients, but
pharmaceutical form and the absorption site: this alloWs it has also been proposed, by the same research group, to use
an optimal release of the drug, in accordance With the polycarbophil alone, for the treatment of various
knoWn laWs describing the passive diffusion. ophthalmic, vaginal and buccal affections, Which are char
In the last years a great interest has been shoWn for the acterised by a feeling of excessive dryness of the mucous
inclusion of bioadhesive polymers in conventional pharma 45 membranes. In this connection, a product for vaginal rehy
ceutical forms. The so obtained bioadhesive forms mainly dration containing polycarbophil has recently been placed
consist of polymer materials Which are capable of interact on the market, under the trade name Replens® Said product
ing With mucus or With mucins. The features that a bioad is said to be able to adhere to the mucosa, While gradually
hesive polymer should shoW in order to be pharmaceutically releasing, for about 72 hours, its Water content (S. H. Leung
acceptable may be summarised as folloWs: 50 and J. R. Robinson, Polym. NeWs, 15, 1990, 333—342).
absence of toxicity; The European patent No. 0 497 956 discloses sustained
ability to form a strong non-covalent bond With the epithelial release formulations similar to the foregoing ones, but based
cells of the mucous surfaces, and to quickly adhere to the on the calcium salt of polycarbophil, Wherein the active
moist surfaces; ingredient to be delivered is incorporated in the polymeric
ability to incorporate the drug readily and in a repeatable 55 matrix formed by calcium polycarbophil through dissolution
Way, Without exerting any adverse effect on the release or dispersion of the active ingredient in the matrix. As an
thereof. alternative, a hydrogel matrix of calcium polycarbophil may
A number of bioadhesive polymers may be employed, in be formed, by adding Water to the formulation. The inter
particular, in vaginal preparations: among the natural hydro action of the polymeric matrix With the active ingredient
gels one may cite starch, collagen, gelatin, some dextrans 60 results in an intimate mixture, through Which the active
and also cellulose derivatives, including ingredient sloWly diffuses and from Which it is said to be
hydroxypropylmethylcellulose, hydroxypropylcellulose and released in a controlled Way.
sodium carboxymethylcellulose. Among the synthetic poly On the basis of the above knoWn art, it appears that the
mers capable of forming hydrogels only tWo classes appear features of polycarbophil could be advantageously exploited
to be employed in preparations for vaginal administration: 65 for the production of mucoadhesive mixtures With aZole
polyethylene oxides (high molecular Weight ethylene antifungal and/or antiprotoZoal drugs for transmucosal
glycols) and polyacrylic acids. administration, in particular for vaginal topical use. With the