WO2021154188A1

WO2021154188A1 - Pharmaceutical composition suitable for vaginal delivery

Info

Publication number: WO2021154188A1
Application number: PCT/TR2021/050086
Authority: WO
Inventors: Gulay YELKEN DEMIREL
Original assignee: Exeltis Ilac Sanayii Ve Ticaret Anonim Sirketi
Priority date: 2020-01-31
Filing date: 2021-01-29
Publication date: 2021-08-05
Also published as: ECSP22067445A; MX2022009303A; EP4096655A1; EP4096655A4; BR112022015112A2

Abstract

Use of a combination comprising fenticonazole and an antibacterial agent in a therapeutic method in women having conditions of the vulvovaginal system wherein such a combination of active agents is indicated. Pharmaceutical compositions suitable for vaginal delivery of a combination of fenticonazole with an antibacterial agent, optionally one or more analgesics or local anesthetics and pharmaceutically acceptable excipients or carriers.

Description

PHARMACEUTICAL COMPOSITION SUITABLE FOR VAGINAL DELIVERY

Field of the invention

The present invention is related to a pharmaceutical composition suitable for vaginal delivery, as well as to the pharmaceutical composition for use in the treatment of infectious diseases in the female reproductive system. More particularly, the invention relates to a pharmaceutical composition comprising fenticonazole with an antibacterial agent, optionally one or more analgesics or local anesthetics agents and a pharmaceutically acceptable excipient and/or auxiliary agent.

Background of the invention

Inflammation of the vagina, or vaginitis, is caused by various external and internal factors that alter the vaginal microbiota. The most common causes of infectious vaginitis are bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) and trichomonal vaginitis (TV), representing about 90% of cases in women of reproductive age in first level clinics. A significant percentage of infectious vaginitis occurs in women of all ages, both sexually active and inactive, so many women have had a vaginal infection at least once in their life. The healthy vaginal tract of reproductive-aged women is colonized by normal microbiota formed of lactobacilli, which protects against pathogenic bacterial species when present in sufficient numbers. Internal factors such as the alteration of the vaginal microenvironment and pH, and external factors such unprotected sexual activity, tobacco use, douching, immune system deficiencies, diabetes and radiation therapy, among others, are the most common causes of infectious vaginitis. These factors generate an imbalance in the vaginal ecosystem and produce rapid growth of pathogenic microorganisms, which can lead to a decrease in the ability of the normal vaginal microbiota to inhibit the growth of aerobic and anaerobic bacteria that cause increased vaginal discharge, bad smell, inflammation and irritation, all common symptoms of bacterial vaginosis.

Vulvovaginal candidiasis is caused by the overgrowth of yeasts, mainly Candida albicans, which are essentially part of the vaginal flora. Symptoms of vulvovaginal candidiasis include vaginal discharge, itching, pain, and swelling. Although Candida albicans is the most common cause of vulvovaginal candidiasis, non albicans species of Candida, such as Candida glabrata. Candida parapsiiosis, Candida krusei, Candida cerevisiae, Candida tropicalis, Candida iusitaniae, and Trichosporon sp. have increasingly been identified as cause of vulvovaginal candidiasis. Bacterial and Candida infections can coexist. Mixed bacterial and Candida infection occurs in up to about one-fifth of vaginitis cases.

Trichomonas vaginalis is a flagellate protozoan parasite that causes trichomoniasis, characterized by profuse, yellow-green discharge and vaginal or vulvar irritation.

In the art, it is well-known that vaginal infection treatments include fungicidal and/or antibiotic treatment with azole derivatives. Reference and consolidated therapies (either local or systemic) for the treatment of the above conditions are well stablished.

For example, recommended regimens for bacterial vaginosis include:

Metronidazole 400-500 mg orally twice daily for 5-7 days or 2 g orally in a single dose, or Intravaginal metronidazole gel (0.75%) once daily for five days, or

Intravaginal clindamycin cream (2%) once daily for seven days or 300 mg orally twice daily for seven days, or

Tinidazole 2 g orally in a single dose or 1 g orally for five days. Recommended regimens for vaginal candidiasis include:

Fluconazole orally 150 mg as a single dose, or Itraconazole orally 200 mg twice daily for one day, or

Clotrimazole vaginal tablet 500 mg as single dose or 200 mg once daily for three days, or Miconazole vaginal ovule 1200 mg as a single dose or 400 mg once daily for three days, or - Econazole vaginal pessary 150 mg as a single dose.

First line recommended regimens for the treatment of Trichomonas vaginalis include:

Metronidazole 400-500 mg orally twice daily for 5-7 days, or Metronidazole 2 g orally in a single dose, or Tinidazole 2 g orally in a single dose. Additionally, the increasing incidence of mixed vaginal infections, poses a therapeutic challenge because such infections require treatment with multiple drugs.

European application EP 1712229 A1 discloses oral compositions containing fluconazole, tinidazole or secnidazole for treating vaginal infections of the type Gardnerella vaginalis, Actinomyces, Candida and Trichomonas vaginalis microorganisms present in vaginitis and bacterial vaginosis. International application WO 2010026469 A1 discloses a pharmaceutical composition comprising the combination of fluconazole, tinidazole and clindamycin and/or pharmaceutically acceptable salts thereof for treating sexually transmitted infections.

Application EP 910377 A1 discloses pharmaceutical compositions for topical administration in the treatment of vaginitis comprising a combination of metronidazole and miconazole and one or more local anesthetics such as lidocaine or benzocaine.

Application WO 2005087270 A1 discloses a pharmaceutical composition for topical administration comprising terconazole and tinidazole and/or tioconazole

Plowever, oral antifungal therapies favor that drug-resistant non-albicans species thrive and spread in the vagina, since a significant amount of drug remains in the gastrointestinal tract, reducing C. albicans and allowing less susceptible non-albicans species to grow. Moreover, such above therapies can be complicated by the emergence of drug-resistant yeasts with variable and even full resistance to conventional prescribed antifungal drugs such as fluconazole, tioconazole, clotrimazole and miconazole.

Thus, a need exists in the art for alternative pharmaceutical compositions suitable for vaginal delivery as well as methods of treatment that conveniently and effectively treat vaginal infections with the pharmaceutical compositions. Brief Description of the Invention

The present invention was made in view of the prior art described above, and the object of the present invention is, in a first aspect, to provide a new pharmaceutical composition suitable for vaginal delivery comprising fenticonazole or a pharmaceutically acceptable salt thereof with an antibacterial agent or a pharmaceutically acceptable salt thereof, optionally one or more analgesics or local anesthetics agents, and a pharmaceutically acceptable excipient and/or auxiliary agent.

In an embodiment, the pharmaceutical composition comprises a pharmaceutically effective amount of fenticonazole in combination with a pharmaceutically effective amount of an antibacterial agent and a pharmaceutically acceptable excipient and/or auxiliary agent. In another embodiment, the pharmaceutical composition comprises a pharmaceutically effective amount of fenticonazole in combination with a pharmaceutically effective amount of an antibacterial agent, a pharmaceutically effective amount of an analgesic or a local anesthetic and a pharmaceutically acceptable excipient and/or auxiliary agent.

In a preferred embodiment, fenticonazole is present as fenticonazole nitrate. In a preferred embodiment, the antibacterial agent is tinidazole.

In a preferred embodiment, the analgesic or local anesthetic is lidocaine or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is to provide a process for preparing a dosage form suitable for vaginal administration comprising the steps of mixing fenticonazole or a pharmaceutically salt thereof in combination with an antibacterial agent and, optionally an analgesic or local anesthetic and a pharmaceutically acceptable excipient and/or auxiliary agent, then, processing the mixture to produce the dosage form.

Another aspect of the invention is a pharmaceutical composition comprising the combination of the first aspect for use as a medicament for the treatment of infectious diseases or conditions in female reproductive system, such as vulvovaginal infections.

Detailed Description of the Invention

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are set forth below and are intended to apply uniformly through-out the specification and claims unless otherwise expressly set out definition provides a broader definition.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.

Furthermore, the word "comprise" encompasses the case of "consisting of". Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. The present invention is related to an association or combination of fenticonazole and an antibacterial agent, and optionally with an analgesic or local anesthetic, for use in the treatment of infectious diseases conditions in female reproductive system.

Fenticonazole is an imidazole derivative exhibiting wide spectrum antimycotic activity. It also exerts antibacterial activity, with a spectrum that includes Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermis, Streptococcus spp.) and antiparasitic action against Triconomonas vaginalis and some bacterial species such as Gardnerella vaginalis.

Fenticonazole is well absorbed through the vaginal wall and it is retained in the outermost layer of the epidermis (stratum corneum) for a long time. This allows its accumulation in the mucosal tissue up to 72 hours, thus maintaining its activity during a long period and delaying consecutive administration. Furthermore, fenticonazole is poorly absorbed at a systemic level.

According to one aspect, the present invention provides, a pharmaceutical composition suitable for vaginal delivery comprising fenticonazole or a pharmaceutically acceptable salt thereof as antifungal agent in combination with antibacterial agent and a pharmaceutically acceptable excipient and/or auxiliary agent. Ina preferred embodiment, fenticonazole is present as fenticonazole nitrate.

Illustratively, fenticonazole or a pharmaceutically acceptable thereof can be included in the composition of the invention in an amount of about 0.5% to about 70%, for example about 5% to about 60%, or about 10% to about 55%, or about 15% to 50% by weight. In a preferred embodiment, fenticonazole is present in the composition of the invention in an amount of about 20 to 50% by weight, more preferably of about 25% to 48% by weight.

In a preferred embodiment, the amount of fenticonazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is preferably from about 50 mg to about 2000 mg, more preferably from about 100 mg to about 1500 mg, and even more preferably from about 200 mg to about 1000 mg. In a more preferred embodiment, the amount of fenticonazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is 600 mg.

The antibacterial agent can comprise any antibacterial known in the art to be useful in treatment of bacterial infections of the vulvovaginal system. Illustrative examples of antibacterials that can be useful include without limitation acriflavine, ampicillin, ceftriaxone, chloramphenicol, chlorquinaldol, ketoconazole, clindamycin, iodoquinol, metronidazole, nimorazole, ornidazole, pivampicillin, secnidazole, spiramycin, tetracycline, tinidazole, dequalinium chloride and pharmaceutically acceptable salts and esters thereof, combinations thereof and the like.

In a preferred embodiment, the antibacterial agent is selected from clindamycin, metronidazole, ketoconazole and tinidazole. In a most preferred embodiment, the antibacterial agent is tinidazole.

Typically, the antibacterial agent can be included in the composition of the invention in an amount of about 0.5% to about 70%, for example about 5% to about 60%, or about 10% to about 55%, or about 15% to 50% by weight. In a preferred embodiment, fenticonazole is present in the composition of the invention in an amount of about 20 to 50% by weight, more preferably of about 25% to 48% by weight.

It will be understood that the amount of the antibacterial agent or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention will depend of the activity of the specific antibacterial agent employed and the type of dosage form of the vaginal composition usedTypically, the amount of antibacterial agent in the pharmaceutical compositions of the invention is preferably from about 10 mg to about 10000 mg, more preferably from about 100 mg to about 5000 mg, still more preferably from about 500 mg to about 3000 mg, and even still more preferably from about 1000 mg to about 2000 mg.

In an embodiment of the invention, the antibacterial agent used in the pharmaceutical compositions of the invention is tinidazole or a pharmaceutically acceptable salt thereof. Typically, the amount of tinidazole or a salt thereof in the pharmaceutical compositions of the invention is from about 200 mg to 5000 mg, more preferably from 500 mg to 3000 mg. In a more preferred embodiment, the amount of tinidazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is from about 1000 mg to about 2000 mg.

In another embodiment of the invention, the antibacterial agent used in the pharmaceutical compositions of the invention is metronidazole or a pharmaceutically acceptable salt thereof. Typically, the amount of metronidazole or a salt thereof in the pharmaceutical compositions of the invention is from about 10 mg to 800 mg, more preferably from 200 mg to 600 mg. In a more preferred embodiment, the amount of metronidazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is from about 300 mg to about 600 mg, preferably of about 500 mg. In another embodiment of the invention, the antibacterial agent used in the pharmaceutical compositions of the invention is ketoconazole or a pharmaceutically acceptable salt thereof. Typically, the amount of ketoconazole or a salt thereof in the pharmaceutical compositions of the invention is from about 200 mg to 2000 mg, more preferably from 500 mg to 1000 mg. In a more preferred embodiment, the amount of ketoconazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is from about 600 mg to about 900 mg, preferably of about 800 mg. In still another embodiment of the invention, the antibacterial agent used in the pharmaceutical compositions of the invention is clindamycin or a pharmaceutically acceptable salt thereof. Typically, the amount of clindamycin or a salt thereof in the pharmaceutical compositions of the invention is from about 50 mg to 200 mg, more preferably from 750 mg to 150 mg. In a more preferred embodiment, the amount of clindamycin or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is from about 90 mg to about 120 mg, preferably of about 100 mg.

In a preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising from 200 mg to about 1000 mg fenticonazole or a pharmaceutically acceptable salt thereof as antifungal agent in combination with 500 mg to 3000 mg tinidazole or a pharmaceutically acceptable salt thereof as antibacterial agent and a pharmaceutically acceptable excipient and/or auxiliary agent. In a more preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising 600 mg fenticonazole or a pharmaceutically acceptable salt thereof as antifungal agent in combination with 1000 mg to about 2000 mg tinidazole or a pharmaceutically acceptable salt thereof as antibacterial agent and a pharmaceutically acceptable excipient and/or auxiliary agent.

In one embodiment, the relative amount of fenticonazole or a pharmaceutically acceptable salt thereof to antibacterial agent is in the range of from about 10:1 to about 1 :10 on a weight basis. In another embodiment, the relative amounts of fenticonazole or a pharmaceutically acceptable salt thereof to antibacterial agent in the range of from about 7:1 to about 1 :7, preferably from 4:1 to 1 :4. In a further aspect of the invention, the pharmaceutical composition according to the invention can further comprise one or more analgesics or local anesthetics agents. Non-limiting examples analgesics include butorphanol, codeine, dihydrocodeine, fentanyl, hydrocodone, levorphanol, meperidine, methadone, morphine, naloxone, oxycodone, oxymorphone, pentazocines propoxyphene, pharmaceutically acceptable salts and esters thereof, and combinations thereof.

Non-limiting examples of local anesthetics include benzocaine, bupivacaine, butamben, chloroprocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, pharmaceutically acceptable salts and esters thereof, and combinations thereof.

In a preferred embodiment, the local anesthetic is lidocaine or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising fenticonazole or a salt thereof as antifungal agent, one from tinidazole, metronidazole, ketoconazole, clindamycin or salts thereof as antibacterial agent, lidocaine or a salt thereof as analgesic or local anesthetic agent, and a pharmaceutically acceptable excipient and/or auxiliary agent.

Illustratively, the analgesic or a local anesthetic can be included in a composition of the invention in an amount of about 0.1% to about 20%, for example about 0.5% to about 5%, or about 1% to about 3%, by weight. The compositions of the invention can for example contain from about 0.1% to 3.5%, preferably about 2% by weight of lidocaine, and from about 0.1% to 3.0%, preferably about 1.5% by weight of lidocaine.

Typically, the amount of lidocaine or a salt thereof in the pharmaceutical compositions is from about 1 mg to 500 mg, more preferably from 10 mg to 400 mg. In a more preferred embodiment, the amount of lidocaine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is from about 50 mg to about 200 mg, preferably about 100 mg lidocaine. In a preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising from about 200 mg to about 1000 mg fenticonazole or a salt thereof as antifungal agent in combination with from about 500 mg to about 3000 mg tinidazole or a salt thereof as antibacterial agent and 50 mg to 200 mg lidocaine or a salt thereof as local anesthetic agent a pharmaceutically acceptable excipient and/or auxiliary agent. In a more preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising 600 mg fenticonazole or a salt thereof as antifungal agent in combination with 1000 mg to about 2000 mg tinidazole or a salt thereof as antibacterial agent and 75 mg to 150 mg lidocaine or a salt thereof and a pharmaceutically acceptable excipient and/or auxiliary agent.

In another preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising 600 mg fenticonazole or a salt thereof as antifungal agent in combination with

10 mg to about 800 mg metronidazole or a salt thereof as antibacterial agent and optionally, 75 mg to 150 mg lidocaine or a salt thereof and a pharmaceutically acceptable excipient and/or auxiliary agent.

In another preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising 600 mg fenticonazole or a salt thereof as antifungal agent in combination with 200 mg to about 2000 mg ketoconazole or a salt thereof as antibacterial agent and optionally, 75 mg to 150 mg lidocaine or a salt thereof and a pharmaceutically acceptable excipient and/or auxiliary agent.

In a more preferred embodiment, the present invention provides a pharmaceutical composition suitable for vaginal delivery comprising 600 mg fenticonazole or a salt thereof as antifungal agent in combination with 50 mg to about 150 mg clindamycin or a salt thereof as antibacterial agent and optionally, 75 mg to 150 mg lidocaine or a salt thereof and a pharmaceutically acceptable excipient and/or auxiliary agent. The pharmaceutical composition suitable for vaginal delivery according to the present invention can be present in a dosage form which includes but it is not limited to tablets, hard or soft gelatin capsules, creams, suppositories, pessaries, foams, ointments, gels, films, tampons, vaginal rings and douches. Preferably, the compositions take the form of pessaries. In a preferred embodiment the pharmaceutical composition may be in the form of a pessary containing the pharmaceutical composition suitable for vaginal delivery of the invention and a pessary base. The pessary base may be of any conventional material for vaginal administration such as glycerinated glycerin, macrogols (polyethylene glycols), natural, synthetic or semisynthetic hard fats, and fractionated palm kernel oil and mixtures thereof. A particularly preferred material is a hard fat such as triglyceride esters. Typically, the pessary base amounts from about 1% to about 90% by weight of the composition, for example from about 10% to about 70%, or from about 20% to about 60% by weight of the composition.

The pessary base can also comprise a surfactant to promote dispersal of the active substances and give continuous penetration of the active substances into the mucosa. Suitable surfactant agents may be selected from the group consisting of but not limited to benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, glycine, hypromellose, phospholipids, polysorbates, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sodium lauryl sulfate, sorbitan esters, tricaprylin or mixtures thereof. Preferably, the surfactant is polysorbate.

The surfactant agent may be present in an amount from about 0% to 30% by weight, preferably from about 0% to about 20%, more preferably from 0% to 15% based on the total weight of the composition.

The pessary may include at least one or more further auxiliary agents, to afford the appropriate mechanical and release properties. All such auxiliary agents must be compatible with the other ingredients of the dosage form and not injurious to the human being .The auxiliary agent may be selected from the group consisting of diluents, solubilizing agents, emulsifying agents and antioxidants, and/or mixtures thereof. Suitable solubilizing agents include corn oil (maize), polyethylene glycol, glycerin, cottonseed oil, dibutyl phthalate, diethyl phthalate, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl alcohol, ethyl lactate, ethyl oleate, glycofurol, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium-chain triglycerides, methyl lactate, mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyoxyl 35 castor oil, propylene carbonate, propylene glycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacetin, tricaprylin, triethanolamine, triethyl citrate, triolein, water, water-miscible or mixtures thereof. Preferably, the solubilizing agent is polyethylene glycol or glycerin or mixtures thereof.

The solubilizing agent may be present in an amount from about 0% to 80% by weight, preferably from about 0% to about 50%, more preferably from 0% to 30% based on the total weight of the composition. Emulsifying agents include lecithin, yucca extract, quillaja bark extract, lanolin, candelilla, carnauba, jojoba, rice bran, beeswax, xanthan gum, quince seed, glyceryl oleate, glyceryl stearate, citrate and mixtures thereof.

The emulsifying agent may be present in an amount from about 0.05% to 20% by weight, preferably from about 0.1% to about 15%, more preferably from 0.2% to 10% based on the total weight of the composition. The emulsifying agent may also be used as solubilizing agent. Suitable antioxidant agents include Pythrox LT 10-IP (lecithin, ascorbyl palmitate + tocopherol rch extract, sunflower oil), vitamin E (tocopheryl asetate/tocopheroll), ascorbic acid (vitamin C) or ascorbyl palmitat propolis extract, allium cepae (onion) bulb extract, glycyrrhiza glabra (organic licorice) root extract, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, propyl gallateand cysteine and mixtures thereof. Particularly preferred antioxidants according to the present invention are butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or mixtures thereof.

The antioxidant agent may be present in an amount from about 0.005% to 5% by weight, preferably from about 0.01% to about 4%, more preferably from 0.1% to 3% based on the total weight of the composition.

Besides the vaginal pessary the pharmaceutical composition suitable for vaginal delivery of the present invention can be used for other pharmaceutical preparations or dosage forms, for example for tablets, hard or soft gelatin capsules, creams, foams, ointments, gels, films, tampons, vaginal rings and douches.

For example, the pharmaceutical composition suitable for vaginal delivery of the present invention may be in the form of a cream. A conventional cream base may be used, e.g. containing oily or waxy materials such as liquid paraffin, white petroleum or cetyl alcohol, water and one or more surfactants to produce a water- in-oil emulsion.

Alternately, the pharmaceutical composition suitable for vaginal delivery of the invention may be in the form of vaginal tablets. The tablet comprises a combination of fenticonazole or a pharmaceutically acceptable salt thereof with an antibacterial agent, optionally together with one or more an analgesics or local anesthetics, and at least one pharmaceutically acceptable excipient or carrier, characterized in that the tablet comprises granules comprising the fenticonazole or a pharmaceutically acceptable salt thereof and/or the antibacterial agent and a pharmaceutically acceptable excipient and optionally, extragranular excipients. The intragranular and extragranular excipients can comprise one or more of binder, diluent, lubricant and disintegrant agents.

Suitable diluents include corn starch, microcrystalline cellulose, powdered cellulose, silicified cellulose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, sucrose, fructose, dextrose, and/or mixtures thereof. Preferably, lactose monohydrate and microcrystalline cellulose are used.

Diluents may be presents in an amount from about 20% to about 95% by weight, preferably from 35% to 90% by weight, and more preferably from 30 to 85% by weight of the total weight of the composition.

Suitably, the dosage form according to the invention comprises a binder. The binding agent can be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and/or mixtures thereof.

Binders may be presents in an amount from about 0.5% to about 20% by weight, preferably from 1 % to 18% by weight, and more preferably from 5 to 15% by weight of the total weight of the composition. The dosage form according to the invention can also comprise a disintegration agent. Disintegrating agents may be selected from the group consisting of low- substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, sodium croscarmellose, and/or mixtures thereof. Preferably sodium croscarmellose is used. Disintegrating agents may be present in an amount from about 2% to about 50% by weight, preferably from about 5% to about 45% by weight, and more preferably from 10% to 40% by weight of the total weight of the composition.

Lubricants and antiadherent agents are excipients that reduce interparticular friction and prevent adhesion of drug particles and improve fluidity of granular or pulverulent compositions.

Lubricants may be selected from the group consisting of talc, alkaline earth salts of stearic acid, specially magnesium and calcium stearate, stearic acid, glycerin palmitostearate, stearyl fumarate, and/or mixtures thereof.

The lubricant may be present in an amount from about 0% to 5% by weight, preferably from about 0% to about 3% based on the total weight of the composition.

The antiadherent agent may be present in an amount from about 0% to 5% by weight, preferably from about 0% to about 3% based on the total weight of the composition.

In another embodiment, the pharmaceutical composition suitable for vaginal delivery of the invention may be in the form of vaginal capsules. The vaginal capsule comprises a combination of fenticonazole or a pharmaceutically acceptable salt thereof with an antibacterial agent, optionally together with one or more an analgesics or local anesthetics, and at least one pharmaceutically acceptable excipient or carrier as defined above. The excipients can comprise one or more of disintegrant, filler/diluent, binder/adhesive, glidant and lubricant agents using the amounts or percentages stated above.

Suitable disintegrants may comprise but not limited to sodium starch glycolate, crosscarmellose sodium, crospovidone, aligns, gums, surfactants and the like and mixtures thereof.

Suitable fillers/diluents may comprise but not limited to dibasic calcium phosphate dihydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.

Suitable binders/adhesives may comprise but not limited to polyvinylpyrrolidone (povidone), gelatin, sugars, glucose, natural gums, synthetic celluloses, polymethycrylate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose and the like and mixtures thereof.

Suitable glidants may comprise but not limited to colloidal silicon dioxide, talc, aluminium silicate and the like and mixtures thereof. Suitable lubricants may comprise but not limited to magnesium stearate, sodium stearyl fumarate, polyethylene glycol, stearic acid, metal stearates, talc, boric acid, sodium chloride benzoate and acetate, sodium or magnesium lauryl sulfate and the like and mixtures thereof.

Another aspect of the present invention is, therefore, a process for preparing a dosage form suitable for vaginal administration comprising fenticonazole or a pharmaceutically salt thereof in combination an antibacterial agent, a pharmaceutically acceptable excipient and/or auxiliary agent and optionally, an analgesic or a local anesthetic.

In this aspect, the process comprises the steps of mixing fenticonazole or a pharmaceutically salt thereof, an antibacterial agent and optionally, an analgesic or a local anesthetic agent with at least one pharmaceutically acceptable excipient and/or auxiliary agent and, then, processing the mixture to produce the dosage form.

In an embodiment, the mixture is processed by filling it into capsules or compressing it to obtain tablets.

Typically, the composition is suitable for administration in a single dose on a single day. A preferred embodiment of the invention provides a process for the production of a pessary comprising fenticonazole or a pharmaceutically salt thereof in combination an antibacterial agent, a pharmaceutically acceptable excipient and/or auxiliary agent, and optionally an analgesic or a local anesthetic, comprising the following steps: a) Hard fat is melted b) If present, the surfactant and/or the solubilizing agent is added to the melted fat c) Fenticonazole, the antibacterial agent and optionally the analgesic or a local anesthetic are added to the melted hard fat of step a) or to the mixture obtained in step b) until homogeneous product is obtained d) the final product is filled in an appropriate package Another aspect of the invention is the pharmaceutical composition suitable for vaginal delivery comprising: a) fenticonazole or a pharmaceutically acceptable salt thereof and b) an antibacterial agent c) optionally, one or more analgesics or local anesthetics agents, and d) a pharmaceutically acceptable excipient and/or auxiliary agent for use as a medicament. Particularly, the invention is directed to the pharmaceutical composition suitable for vaginal delivery for use in the treatment of infectious diseases or conditions in female reproductive system, such as vulvovaginal infections Vulvovaginal infections include bacterial vaginosis, vulvovaginal candidiasis (both albicans and non-albicans caused infections), trichomonal vaginitis and mixed infections.

In a preferred embodiment, the antibacterial agent is selected from acriflavine, ampicillin, ceftriaxone, chloramphenicol, chlorquinaldol, ketoconazole, clindamycin, iodoquinol, metronidazole, nimorazole, ornidazole, pivampicillin, secnidazole, spiramycin, tetracycline, tinidazole, dequalinium chloride and pharmaceutically acceptable salts and esters thereof and combinations thereof. In a most preferred embodiment clindamycin, metronidazole, ketoconazole and tinidazole. In the most preferred embodiment, the antibacterial agent is tinidazole. The composition of the invention is also considered to be effective in treating any secondary candidial, bacterial and/or trichomonal infections which might result from treatment of such causative agents. Vaginal infections due to group B and D streptococcus and the like, infections due to microorganisms causing vulvitis and vulvovaginitis, and other vaginal infections (e. g. atrophic vaginitis, allergic or irritant vulvo vaginitis, genital psoriasis (with or without clinically relevant infection), vulvitis due to Lichen sclerosis, etc. ) may also be usefully treated using the compositions herein described.

Although primarily described for use in treating vaginal infections, the compositions in accordance with the invention may also find more general use in treating primary and/or secondary genital infections in both men and women, including sexually transmitted infections, e. g. infections due to chlamydia; balanitis; penile dermatitis; herpes genitalis; gonorrhea; etc.

Another aspect of the invention is directed to the pharmaceutical composition suitable for vaginal delivery for use in the treatment of any secondary Candida, bacterial and/or trichomonas infections which might result from treatment of such causative agents, and in general, in the treatment primary and/or secondary genital infections in both men and women, such us infections due to chlamydia; balanitis; penile dermatitis; herpes genitalis; gonorrhea; etc.

In a preferred embodiment, the antibacterial agent is selected from clindamycin, metronidazole, ketoconazole and tinidazole. In a most preferred embodiment, the antibacterial agent is tinidazole. As alternative to fenticonazole, the following antifungal agents could be used in the formulation of the invention: econazole, sertaconazol, or their pharmaceutically acceptable salts or mixtures thereof.

The amount of econazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is preferably from about 10 mg to about 500 mg, more preferably from about 20 mg to about 400 mg, and even more preferably from about 50 mg to about 300 mg. In a more preferred embodiment, the amount of econazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is 150 mg. The amount of sertaconazole or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the invention is preferably from about 80 mg to 600 mg more preferably from 150 mg to 400 mg and more preferably from 200 mg to 350 mg.

The pharmaceutical composition according to the present invention may be presented in a pack to providea complete course of treatment. Packs comprising at least one formulation containing the pharmaceutical composition according to the present invention are considered to form part of the invention.

The following examples are meant to illustrate this invention, the same not being limitative.

Examples

Example 1 A pharmaceutical composition including a fenticonazole or a salt thereof combination according to the invention in the form of pessary is prepared according to the following composition:

Unit Formula may contain one of Tinidazole, Metronidazole, Ketoconazole or Clindamycin.

Lidocaine ( w/wo ) means “Unit Formula with or without the presence of Lidocaine”. When lidocaine is not present, the amount of lidocaine is substituted by hard fat in the above formula General manufacturing process:

1. Hard fat is melted at 55 C

2. If present, surfactant and/or solubilizing agent(s) and/or is added and mixed (depends on the unit formula)

3. The APIs are added to this mixture and mixed until a homogeneous product is obtained. 4. The resulting mixture is filled into molds/casings. The molds/casings are passed through a cooling tunnel and completed sealing process

5. Packaging process is completed

Example 2

A pharmaceutical composition including a fenticonazole or a salt thereof combination according to the invention in the form of pessary is prepared according to the general process disclosed in example 1 , with the following composition:

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 3 A pharmaceutical composition including a fenticonazole or a salt thereof combination according to the invention in the form of pessary is prepared according to the general process disclosed in example 1 , with the following composition:

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 4

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 5

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 6

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 7

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 8

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 9

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin Example 10

Example 11

A pharmaceutical composition including a fenticonazole or a salt thereof combination according to the invention in the form of vaginal tablet is prepared according to the following composition:

General manufacturing process for Vaginal Tablet

1. PVP, polysorbate and ascorbic acid is solved in a proper solvent or solvent mixture as granulation solution.

2. APIs, MCC and crospovidone are mixed to obtain homogeneous powder and granulate with granulation solution. 3. These granules are sieved and dried.

4. Dry granules are sieved again.

5. Colloidal silicone dioxide are added by sieving and mixed. 6. Afterwards, glycerol behenate is added by sieving and mixed for a short time.

7. Finally, the mixture is pressed as tablets with obtained powder.

Example 12

A pharmaceutical composition including a fenticonazole or a salt thereof combination according to the invention in the form of vaginal capsule is prepared according to the following composition:

Unit Formula contains only one of Tinidazoie, Metronidazole, Ketoconazole or Clindamycin

General manufacturing process for Vaginal Capsule

1. APIs, lactose and croscarmellose sodium, sodium starch glycolate, HPC, and, tartaric acid are sived and mixed to obtain homogenious powder. 2. Colloidal silicone dioxide are added by sieving and mixed.

3. Afterwards, magnesium stearate is added by sieving and mixed for a short time.

4. Finally, the mixture is filled into the capsules.

STABILITY ASSAYS

Stability studies were performed in the pharmaceutical composition according to the present invention. Particularly, stability studies were performed by using the pharmaceutical composition of the present invention with and without Lidocaine.

PIPLC analytical test methods for fenticonazole nitrate, tinidazoie and lidocaine (w/wo) ovule product are detailed below.

1. CHROMATOGRAPHIC CONDITIONS FOR ASSAY ANALYSES

2. CHROMATOGRAPHIC CONDITIONS FOR TINIDAZOLE RELATED SUBSTANCES ANALYSES

3. CHROMATOGRAPHIC CONDITIONS FOR LIDOCAINE RELATED SUBSTANCES ANALYSES

4. CHROMATOGRAPHIC CONDITIONS FOR FENTICONAZOLE NITRATE RELATED SUBSTANCES

STABILITY ASSAYS for Example 2

Stability of formulation according to example 2 comprising fenticonazole nitrate, tinidazole, and lidocaine as active ingredients was tested at different conditions.

TEST RESULTS OF LONG-TERM STABILITY STUDIES STABILITY TEST CONDITION : 25°C ± 2° C / 60% ±5 RH

A detailed information for Impurities A to D of Fenticonazole Nitrate can be found at the European Pharmacopeia 10.0, 07/2014:1211 , corrected 10.0, p. 2622-2624, which is incorporated herein by reference. A detailed information for Impurities A and B of Tinidazole can be found at the European Pharmacopeia 10.0, 01/2017:1051 , p. 4048-4049, which is incorporated herein by reference.

TEST RESULTS OF INTERMEDIATE STABILITY STUDIES:30°C ± 2° C / 65% ±5 RH

TEST RESULTS OF ACCELERATED STABILITY STUDIES: STABILITY TEST CONDITION : 40°C ± 2° C / 75% ±5 RH

STABILITY ASSAYS for Example 2 without lidocaine Stability of formulation according to example 2 without lidocaine (the amount of lidocaine is substituted by the same amount of hard fat) comprising fenticonazole nitrate and tinidazole as active ingredients was tested at different conditions.

TEST RESULTS OF LONG-TERM STABILITY STUDIES: STABILITY TEST CONDITION : 25°C ± 2° C / 60% ±5 RH

TEST RESULTS OF INTERMEDIATE STABILITY STUDIES: STABILITY TEST CONDITION : 30°C ± 2° C / 65% ±5 RH

TEST RESULTS OF ACCELERATED STABILITY STUDIES: STABILITY TEST CONDITION : 40°C ± 2° C /75% ±5 RH

STABILITY ASSAYS for Example 6

Stability of formulation according to example 6 comprising fenticonazole nitrate, tinidazole and lidocaine as active ingredients was tested at different conditions.

STABILITY ASSAYS for Example 6 without lidocaine

Stability of formulation according to example 6 without lidocaine (the amount of lidocaine is substituted by the same amount of hard fat) comprising fenticonazole nitrate and tinidazole as active ingredients was tested at different conditions.

Claims

1. Pharmaceutical composition suitable for vaginal delivery comprising: a) fenticonazole or a pharmaceutically acceptable salt thereof, b) an antibacterial agent or a pharmaceutically acceptable salt thereof and, c) optionally, one or more analgesics or local anesthetics agents d) a pharmaceutically acceptable excipient and/or auxiliary agent.

2. A pharmaceutical composition according to claim 1 , wherein, fenticonazole is present as fenticonazole nitrate.

3. Pharmaceutical composition according to any one of claims 1 or 2, wherein the amount of fenticonazole or a pharmaceutically acceptable salt thereof is from 50 mg to 2000 mg.

4. Pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of fenticonazole or a pharmaceutically acceptable salt thereof is about 600 mg.

5. Pharmaceutical composition according to any one of claims 1 to 4, wherein the antibacterial agent is selected from acriflavine, ampicillin, ceftriaxone, chloramphenicol, chlorquinaldol, ketoconazole, clindamycin, iodoquinol, metronidazole, nimorazole, ornidazole, pivampicillin, secnidazole, spiramycin, tetracycline, tinidazole, dequalinium chloride and pharmaceutically acceptable salts thereof and esters thereof and combinations thereof.

6. Pharmaceutical composition according to any one of claims 1 to 5, wherein the antibacterial agent is tinidazole or a pharmaceutically acceptable salt thereof.

7. Pharmaceutical composition according to claim 6, wherein the amount of tinidazole or a pharmaceutically acceptable salt thereof is from 200 mg to 5000 mg.

8. Pharmaceutical composition according to any one of claims 6 to 7, wherein the amount of tinidazole or a pharmaceutically acceptable salt thereof is from 1000 mg to 2000 mg.

9. Pharmaceutical composition according to any one of claims 1 to 8 comprising from 200 mg to 1000 mg fenticonazole or a pharmaceutically acceptable salt thereof, and 500 mg to 3000 mg tinidazole or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or auxiliary agent.

10. Pharmaceutical composition according to any one of claims 1 to 9 comprising from 600 mg fenticonazole or a pharmaceutically acceptable salt thereof, and 1000 mg to 2000 mg tinidazole or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or auxiliary agent.

11. Pharmaceutical composition according to any one of claims 1 to 10, further comprising an analgesic or a local anesthetic agent selected from butorphanol, codeine, dihydrocodeine, fentanyl, hydrocodone, levorphanol, meperidine, methadone, morphine, naloxone, oxycodone, oxymorphone, pentazocines propoxyphene, pharmaceutically acceptable salts thereof and esters thereof, and combinations thereof.

12. Pharmaceutical composition according to any one of claims 1 to 11, wherein the local anesthetic agent is lidocaine or a pharmaceutically acceptable salt thereof.

13. Pharmaceutical composition according to claim 12, wherein the amount of lidocaine or a pharmaceutically acceptable salt thereof is from about 50 mg to about 200 mg.

14. Pharmaceutical composition according to any one of claims 1-13 for use in the treatment of infectious diseases or conditions in female reproductive system.

15. Pharmaceutical composition according to claim 14 for use in the treatment of vulvovaginal infections.

16. Pharmaceutical composition according to any one of claims 1 to 11 comprising fenticonazole or a pharmaceutically acceptable salt thereof, one antibacterial agent selected from the group consisting of tinidazole, metronidazole, ketoconazole, clindamycin or pharmaceutically acceptable salts thereof or esters thereof or combinations thereof, lidocaine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or auxiliary agent.