Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
1999-02-02
2002-07-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S400000, C424S405000, C424S407000, C514S772200
Reexamination Certificate
active
06423307
ABSTRACT:
This application is a 371 of PCT/IT97/00187 filed Jul. 26, 1997.
The present invention concerns bioadhesive complexes of polycarbophil and azole antifungal or antiprotozoal drugs. More specifically, the invention relates to the formulation of a complex of a cross-linked polyacrylic acid having remarkable mucoadhesive properties, known with the name of polycarbophil, and an imidazole or triazole derivative having antifungal or antiprotozoal activity, in the base form, for use in the topical treatment of mucosal affections.
As it is known, the diseases of a microbial origin affecting the mucous membranes, which may be treated by exploiting the trans-mucosal administration route, are many and widespread. In particular, among the diseases of this kind which affect the urogenital system, the mycotic infections are very common, and among these, specifically, the candidiases.
Candida albicans
represents the species belonging to the Candida genus which is most commonly involved in human candidiases, and is the only species pathogenic on laboratory animals. The said species is held to be responsible of most superficial mycoses (muco-cutaneous mycoses) and of some serious deep mycoses, and is commonly present on the mucous membranes surfaces, such as those of the buccal cavity and of the gastrointestinal tract in man, in equilibrium with the endemic flora of the said regions. In the healthy population equilibrium conditions are normally established between the invasive potential of the fungus and the defence mechanisms of the host, which are able to limit the tissue invasion and, possibly, to eradicate the infection from the mucous membranes surface. The onset of a pathological process is the consequence of the breach of such equilibrium, and this may be either due to the different virulence of the infecting yeast or to the reduced resistance of the host. The importance of the host defence mechanisms, both natural and acquired, against candidiases is strongly confirmed by the incidence of fungal infections, and, specifically, candidiases, in immunocompromised subjects.
The candidiases of the urogenital system, much more widespread in women than in men, are characterised by itch and discharge and, upon clinical examination, by erythema, edema and, sometimes, ulcerous or papular lesions. Epidemiologic statistics on the incidence of vaginal candidiases are difficult to establish, although it may be considered that the said incidence has greatly increased in the last few years, also due to a wider use of hormone contraceptives and of antibiotic antimicrobials. Candidiases, and in general all of the fungal affections of the urogenital system, may be therapeutically treated with antimicrobial drugs for topical use, specifically imidazole derivatives such as econazole, tioconazole, miconazole and the like, or triazole derivatives such as terconazole, or also with drugs for oral administration, in particular of the triazole type, such as fluconazole. It is usually recommended to initially use the topical azole therapy, to be replaced by a systemic therapy in non responsive patients or in patients who do not withstand the topical therapy. This is due to the slight toxicity of the agents for systemic administration in comparison with agents which perform their activity in situ, as well as to the need to limit the use of these drugs in order to avoid the occurrence of resistant strains.
Among the antifungal drugs mentioned above, econazole, i.e. 1-{2-[(4-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole, is particularly widespread and extensively tested. It has been synthesised by Godefroi et al. in 1969 (J. Med. Chem., 12, 1969, 784, and U.S. Pat. No. 3,717,655). The antimicrobial activity of econazole, which has been extensively shown in vitro, is exerted against a wide variety of fungi and against some gram-positive bacteria, while no activity on gram-negative bacteria is present. The main site of the antimicrobial action is represented by the cellular membrane system, similarly to what happens for the other imidazole antifungal agents. In vitro tests with
Trichophyton rubrum, Saccharomyces cerevisiae,
and
Candida albicans
have shown an increase in the permeability of the cell covering exposed to econazole. Said increase occurs both in the growing and in the grown-up cells, thus showing that the antimicrobial activity is due to an action on the formed membranes, and not to the formation of defective membranes in the growth phase. The main action of the drug is the inhibition of 14-&agr;-demethylase, a cytochrome P
450
-dependent microsomial enzyme system important for the synthesis of sterols. The said action has two effects: it causes a build-up of 14-&agr;-methylsterols, and compromises the synthesis of ergosterol, which is necessary to the cytoplasm membrane. The built-up methylsterols may desegregate the close packing of the phospholipids acyl chains, thus compromising the functions of some enzyme systems connected to the membrane.
Econazole is used mainly for topical administration in the treatment of vaginal dermatomycoses and candidiases. Several medicinal products containing econazole as the active ingredient are present on the market, specially for vaginal administration. In most of the said medicinal products econazole is not present as the base, but in the form of its nitrate salt.
Another kind of microbial diseases which have been treated with therapies based on azole active ingredients, to be administered normally through the trans-mucosal route, are the infections caused by protozoa of the genus Tnchomonas. These infections generally occur in women, as cervicites, vaginites and vulvovaginites, which may also be associated with candidiases or with other bacterial infections. The active ingredient of choice for trichomoniases is metronidazole, which also belongs to the group of imidazole derivatives. For the topical treatment of infections caused by Trichomonas, both in the man and in the woman, metronidazole is advantageously combined with an imidazole derivative having mainly an antifungal action, i.e. clotrimazole.
The conventional administration forms used for the topical antimicrobials of the kinds referred to above are most commonly creams, suppositories for vaginal administration (pessaries, inserts, ovules) and tablets. In the case of econazole, for instance, there are commercially available pessaries and creams based on econazole nitrate, which represent the preparations of choice, as well as douches (lavages) and foams for external use, both in the nitrate and in the base form, which are generally used as adjuvants in the therapy. Pessaries (containing from 50 to 150 mg of active ingredient) and creams (with 1% by weight of active ingredient, to be applied in 5 g doses) are administered once a day, preferably just before going to bed in order to improve retention. The said forms do not allow, in general, to obtain an optimal bioavailability of the drug. Actually, for the therapy to perform at best its action it is necessary that the following conditions are realised: a) a good adhesion of the medicament on the infected site, and b) the complete release of the active ingredient. Very often the above does not occur with the medicinal products now in use: in the case of the suppositories for vaginal administration, in particular, the problem of retention arises, since as soon as the fusion has occurred the preparation may be rapidly discharged from the site of administration.
A suitable spreading of the formulation on the infected site, if possible followed by an interaction with the mucous layer of the said site, could result in a remarkable increase of the bioavailability of the drug. The said result may be achieved by increasing the duration and the closeness of the contact between medicament and mucous membrane: on these grounds the concept of bioadhesion, and in particular mucoadhesion, has recently gained a remarkable importance in the formulation of systems for the controlled release of drugs for trans-mucosal administration, inc
Bianchini Pietro
Boldrini Enrico
Giannaccini Boris
Panichi Luana
Saettone Marco Fabrizio
Farmigea S.p.A.
Fubara Blessing
Page Thurman K.
Smith , Gambrell & Russell, LLP
LandOfFree
Bioadhesive complexes of polycarbophil and azole antifungal... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bioadhesive complexes of polycarbophil and azole antifungal..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bioadhesive complexes of polycarbophil and azole antifungal... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2865264