Solid, anhydrous, pharmaceutical compositions for vaginal use

Abstract: Anhydrous solid pharmaceutical composition for vaginal use, comprising at least one active ingredient in a mixture with conventional carriers and excipients, containing one or more muco-adhesive polymers dispersed in the carrier. These compositions allow for longer contact between the mucosa and the active ingredient and on-site residence, maintaining an effective therapeutic concentration for longer times.

Description: Filed of the Invention The present invention relates to pharmaceutical compositions for vaginal use. Background of the Invention Bioadhesive polymers have been and still are the subject of in-depth studies. Bioadhesive polymers are generally known for their ability of being bound to biological membranes. Numerous patents have come into being which have as their object the use of muco-adhesives in the form of tablets which contain a bioadhesive layer and a non-adhesive layer containing the medicament (U.S. Patent No. 4,292,299 to the Suzuki, et al.) or controlled release treatment compositions which, when in the presence of sufficient water to swell the bioadhesive, will adhere to skin or to a mucosal membrane (U.S. Patent No. 4,615,697 to J.R. Robinson). Other patents have been developed for muco-adhesive compositions which will bioadhesively attach to a mucosal membrane, but ca be removed by tap water if one wishes. Wang et al. (EP 93305950.3) disclosed the application of polyvinyl pyrrolidone-based muco-adhesive polymers and carboxy-functional polymers (characterized by the presence of carboxyl groups in the chains forming the polymer) dispersed in a pharmaceutically acceptable vehicle, preferably water, in an amount sufficient to form a liquid suspension, preferably a gel. Moreover, products containing a water-insoluble bioadhesive polymer and formulated as an oil-in-water emulsion for the treatment of vaginal dryness are commercially available (REPLENS- by Warner-Lambert Co.). Compositions containing bioadhesive polymers and therapeutic agents provide the desired contact between the mucosal membrane and the composition. The composition is left in contact with the mucosal membrane for a sufficient time for the treating agent to be released over a controlled period. It has now been found that an anhydrous solid pharmaceutical composition employing polycarbophil as the sole muco-adhesive polymer dispersed in a pharmaceutically acceptable vehicle improves residence at the application site and provides a long-lasting effetc. Pharmaceutical forms employing water-insoluble mucoadhesive agents containing water are already hydrated and immediately bond to a mucosal membrane upon application. Once applied, the composition is left in contact with the mucosal membrane for a sufficient time for the treating agent to be released over a controlled period, allowing for local or systemic activity. On the other hand, anhydrous pharmaceutical compositions containing mucoadhesive agents are hydrated only after contact with the mucosa. When the preparation is applied to the vaginal mucosa, the pharmaceutical form simultaneously disintegrates, forming an adhesive layer on the mucosa containing the active ingredient, allowing for local or systemic activity. Description of the Invention The present invention relates to anhydrous solid pharmaceutical compositions for vaginal use with at least one active ingredient comprising polycarbophil as the sole muco-adhesive polymer dispersed in a pharmaceutically acceptable vehicle. In addition, the composition may also contain pharmaceutically acceptable additives. These additives include stabilizers, preservatives, excipients, binders, coloring agents, odor controlling agents and the like. Polycarbophil is a muco-adhesive polymer well known to those skilled in the art. The content of polycarbophil in the composition of the invention ranges from 0.5% to 90% by weight of the composition. The pharmaceutically acceptable vehicle is the bulk substance through which the bioadhesive polymer and the active ingredients (s) are distributed to form a dispersion. This vehicle must also be capable of being used in or on humans or other mammals without causing any ill effects, such as toxicity or severe irritation to the mucosal tissue. Pharmaceutically acceptable vehicles suitable for use in the present invention include powders, solid and semi-solid lipid masses, and anhydrous liquids, normally used in pharmaceutical and cosmetic preparations. The active ingredients suitable for use in the present invention are of different types (natural, semisynthetic and synthetic) and include antimycotic agents, antiprotozoal agents, disinfectants, hormones, antibiotics, chemotherapeutic agents and others) and are generally present in the composition ranging from 0,002% to 90% by weight of the composition. Examples of active ingredients used in the present invention are imidazole antimycotics such as miconazole, econazole, ketonazole, local antiseptics and hormones. The composition of the present invention may take the form of vaginal tablets, soft gelatin capsules, semi-synthetic glyceride-based suppositories, which may or may not contain surfactant substances and polyethylene glycol-based suppositories. The dosage forms of the invention may be prepared by experts of the art according to well known techniques (see Remington's Pharmaceutical Sciences Handbook, XVII ed., Mack Pub., N.Y., U.S.A.). A study was carried out on a total of 20 healthy female volunteers in order to compare the release rates of econazole nitrate from a conventional drug without a bioadhesive and from three formulations, each containing a different concentration of polycarbophil as mucoadhesive agent (25, 50, and 100 mg/suppository). Vaginal fluid samples were taken at 0 and at 2, 6, 12 and 24 h from administration and drug concentrations measured by HPLC. Results showed slower release rates of econazole nitrate plus the muco-adhesive as compared to the commercially available drug. High vaginal fluid drug concentrations were measured up to 24 h following the administration of the vaginal suppositories containing polycarbophil while no drug was detected 12 h following the administration of the commercially available product. Econazole levels (mg/ml) in vaginal fluid Product Time (hours) 0 2 6 12 24 Commercial Product 0 48.6 0.85 0 0 Formulation 1 0 56.4 44.7 36.9 0.12 Formulation 2 0 88.7 54.3 28.9 12.6 Formulation 3 0 96.8 68.3 46.3 18.9 The sustained release of the drug is regulated by the presence of the muco-adhesive polymer. The use of polycarbophil in the manufacture of anhydrous solid vaginal pharmaceutical compositions with controlled release fall within the scope of the present invention. The following examples further illustrate the invention. Example No. 1: Vaginal suppositories containing an antimycotic Econazole Nitrate (active ingredient) Component Unitary Formula Econazole Nitrate 100 mg Policarbophyl (Noveon® AA1) 100 mg Semi-synthetic Triglicerides (m.p. 37°C) q.s. to 3 g Example 2: Vaginal suppositories containing an antimycotic Miconazole Nitrate (active ingredient) Component Unitary Formula Miconazole Nitrate 100 mg Policarbophyl (Noveon® AA1) 200 mg Polyethylene-glycol mixture q.s. to 3 g Example 3: Vaginal suppositories containing Povidone-Iodine (active ingredient) Component Unitary Formula Povidone-Iodine (Iodine 10%) 200 mg Policarbophyl (Noveon® AA1) 200 mg Polyethylene-glycol mixture q.s. to 3 g Example N. 4: Soft-gelatine capsules containing Estriol (active ingredient) Component Unitary Formula Estriol 0.5 mg Policarbophyl (Noveon® AA1) 50 mg Labrafil® q.s. to 500 mg Gelatin shell q.s.

Claims: An anhydrous solid pharmaceutical composition for vaginal use with at least one active ingredient comprising polycarbophil as the sole mucoadhesive polymer dispersed in a pharmaceutically acceptable vehicle. A composition according to claim 1, wherein the amount of polycarbophil is from 0.5% to 90% by weight of the composition. A composition according to claims 1-2, wherein the active ingredient(s) are selected from the group consisting of antimycotic agents, antiprotozoal agents, disinfectants, hormones, antibiotics, chemotherapeutic agents. A composition according to claims 1-3, in form of vaginal tablets, soft gelatin capsules, semi-synthetic glyceride-based suppositories, optionally containing surfactant substances and polyethylene glycol-based suppositories. Use of polycarbophil in the manufacture of controlled release, anhydrous, solid pharmaceutical compositions.

Inventors: BERLATI FABIO, RONCHI CELESTINO, SCAGLIONE FRANCESCO, BERLATI, FABIO, RONCHI, CELESTINO, SCAGLIONE, FRANCESCO
Applicants: MONTERES S R L, MONTERESEARCH S.R.L.
Application year: 1996
Main classification: A61K9
IPC codes: A61K9, A61K47