FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Topical combination"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Technical field:
The present invention relates to a topical formulation with novel combination, in particular, for prophylaxis and/or treatment of an associated infection and/or disease and a method of manufacturing thereof.
Background and Prior art:
Sexually transmitted infections (STIs), referring to infections that are most often transmitted by direct sexual contact, remain an increasingly serious worldwide public health problem. These STIs, particularly viral infections, present a public health crisis.
Women are especially at risk as they are more susceptible to infection, many STIs are asymptomatic and there is a high morbidity rate associated with untreated infections.
Since its recognition in 1981, the acquired immunodeficiency syndrome (AIDS) has become a catastrophic pandemic. The AIDS pandemic is a premiere public health concern. Individuals who are at high risk of HIV/AIDS infection are also at risk of infection by other sexually transmitted pathogens. Similarly, individuals at risk for non-HIV/AIDS sexually transmitted pathogens are also at high risk for HIV/AIDS infection. Additionally, it is significant to note that women comprise the most rapidly increasing population of the AIDS epidemic. Sexual transmission of HIV/AIDS in women occurs by infected semen being placed into the vagina, rectum, or other orifice. Currently, the only prevention strategy available for HIV/AIDS prevention is the condom or abstinence.
Clinical pathologies attributable to STIs are profound. STIs cause acute and chronic infections, infertility, and in some cases cancer. Vaccines, which are costly and time-consuming to develop, are unavailable for STI/AIDS prevention. HIV/AIDS treatment employs therapeutic strategies, such as retrovirus triple therapy (e.g., AZT, DDI, etc.) to lower virus burden. However, the high expense of treatment renders this therapeutic option practically unavailable to populations in developing countries where HIV/AIDS is most prevalent. Indeed, the sum of all available STI/AIDS therapeutics is effective against only a limited number of susceptible pathogens. Furthermore, this limited


therapeutic arsenal is largely confined to proprietary formulations, which are costly for the afflicted to procure.
Common vaginal infections also pose an increasingly serious worldwide public health problem and can increase the risk of acquiring HIV/AIDS and other STIs. Vaginal candidiasis is the most common form of vaginitis, occurring more frequently than trichophyton, chlamydia, gonorrhea, or other bacterial infections. It is estimated that 75% of women will experience at least one episode of vulvovaginal candidiasis in their lifetime. Forty to 50% will experience a second episode in their life time. A much smaller (probably less than 5%), but still significant, number of women will suffer from repeated, often intractable attacks. Candidiasis is known to increase the risk of HIV/AIDS acquisition. Bacterial vaginosis (BV), previously known as nonspecific vaginitis or Gardnerella vaginitis, is the most common cause of vaginal discharge. It may be the cause of up to 50% of cases of vaginitis in all women and from 10-30%) in pregnant women. BV is not a sexually transmitted disease although it is sometimes listed as one. However, the risk of contracting the disease increases with multiple sex partners. Although treatment is available for these diseases, methods to prevent them and improved methods of treatment are still needed.
Presently marketed vaginal contraceptive compositions, often containing nonoxynol-9 as an active ingredient, are generally known in the art. While presently marketed vaginal contraceptive formulations aid in preventing pregnancy, their ability to effectively prevent STIs, particularly HIV/AIDS as well as oral, rectal and vaginal infections, is very limited. Nonoxynol-9 and other detergents as well as their compositions can destroy the natural and safe ecology of the vagina, such as by inactivating lactobacillus bacteria. Further, spermicides may cause vaginal irritation, particularly with frequent exposure or higher doses. Recent analyses show that nonoxynol-9, when used frequently by women at high risk, may increase the risk of HIV infection (WHO 2002, WHO/CONRAD technical consultation on nonoxynol-9, Geneva).
US20050037033 discloses a microbicidal compositions containing ciclopirox olamine for preventing the transmission of or treating sexually transmitted infections and/or common vaginal infections.


WO9602226 discloses a pharmaceutical composition comprising a combination of 1-hydroxy-2-pyridones such as ciclopirox or octopirox and crotamiton as an antifungal agent activity enchancer.
W09717075 discloses a topical foamable pharmaceutical composition of ciclopirox or ciclopiroxolamine and surfactant for treating skin diseases induced by oval Pityrosporum.
WO2007101848 discloses a combination of imazalil and silver compounds which provide synergistic biocidal effect.
US20070142533 discloses methods of manufacturing a nano-silver infused polymeric compound.
There still remains a need to develop a medicament and/or formulation which stands against a multitude of resistant strains while minimizing disruptions to vaginal ecology and epithelium.
Object of the invention:
The object of the present invention is to provide a novel pharmaceutical combination in particular, for prophylaxis and/or treatment of sexually transmitted infections including HIV/AIDS and/or common vaginal infections.
Another object of the present invention is to provide a novel pharmaceutical combination in particular, for prophylaxis and/or treatment of sexually transmitted infections including HIV/AIDS and/or common vaginal infections while minimizing disruptions to vaginal ecology and epithelium without compromising the stability and efficacy of the formulation.
Yet another object of the present invention is to provide a novel pharmaceutical composition and/or medicament in particular, for prophylaxis and/or treatment of sexually transmitted infections including HIV/AIDS and/or common vaginal infections which stands against resistant strains.


Still another object of the present invention is to provide a novel pharmaceutical composition and/or medicament with ease of manufacture.
Summary of the invention:
According to one aspect of the present invention there is provided a novel pharmaceutical combination comprising one or more anti-infectives or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
According to a second aspect, there is provided a novel pharmaceutical composition comprising one or more anti-infectives or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles and one or more pharmaceutically acceptable excipients.
According to a third aspect there is provided a novel pharmaceutical composition comprising clindamycin or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles and one or more pharmaceutically acceptable excipients.
According to a fourth aspect, there is provided a novel pharmaceutical composition comprising one or more antimycotics or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles and one or more pharmaceutically acceptable excipients.


According to a fifth aspect, there is provided a novel pharmaceutical composition comprising ciciopirox or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano-silver particles and one or more pharmaceutically acceptable excipients.
According to a sixth aspect, there is provided a process of manufacturing the said novel pharmaceutical composition comprising ciciopirox or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof; nano-silver particles and one or more pharmaceutically acceptable excipients.
According to a further aspect, there is provided a novel topical combination for prophylaxis and/or treatment of sexually transmitted infections including HIV/AIDS and/or related vaginal infections.
According to yet another aspect, there is provided a novel pharmaceutical composition for prophylaxis and/or treatment of sexually transmitted infections including HIV/AIDS and/or related vaginal infections.
Detailed Description:
The inventors have surprisingly found that by use of anti-infectives like ciciopirox and/or clindamycin and nano silver (e.g. colloidal or dried powder), specifically nano silver-silica adsorbed helps better penetration in the fungal and certain ST1 related infections like vaginal infections, by destroying plasma membrane thereby preventing or limiting contact of the fungus and/or virus or its carrier cells with the epithelium or prevent or hinder its entry into the orifice and wherein the nano silver-silica forms a physical barrier against pathogenic fungi and thereby preventing recurrence of diseases for a considerable period of time after pathogens are disinfected.


Opportunistic infections encountered in STIs and/or AIDS, such as vaginal infections are very common and wherein the ciclopirox and/or clindamycin in combination with nano silver exhibited excellent anti-infective activity without compromising on the stability and/or therapeutic efficacy of the formulation.
It was observed that the novel combination in a suitable topical composition such as cream via vaginal route bypasses the liver, thereby providing convenience, discretion and speed of administration and exhibited its activity against various resistant strains including, but not limited to, Candida, Cryptococcus, Aspergillus, Trichophyton, Trichomonas, Malassezia and Mucor.
According to the present invention, the protection from sexually transmitted infections, such as HIV/AIDS, and common vaginal infections, such as bacterial vaginosis and vaginal candidiasis, may be obtained by application of the novel pharmaceutical composition to vagina, rectum or other orifice.
According to the present invention, pharmaceutical compositions may be used alone or in conjunction with delivery and/or contraceptive devices or methods, such as mechanical barrier-type devices. Pharmaceutical compositions, according to the present invention, may be formulated in various dosage forms including a base or carrier, such as a foam, cream, wash, gel, suppository, ovule, lotion, ointment, film, foaming tablet, tampon, vaginal spray, or aerosol.
According to the present invention, the novel pharmaceutical combination comprise one or more anti-infectives selected from the class of, but not limited to, antimycotics, antimycobacterials, antibacterials, antivirals or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles.
According to one embodiment, the novel pharmaceutical combination comprises one or more antimycotics selected from the class of, but not limited to ketoconazole, Itaconazole, fluconazole, ravuconazole, posaconazole, voricnazole, caspofungin,


hydroxypyridones derivatives such as ciclopirox, mimosine, deferipone or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles.
According to another embodiment, the novel pharmaceutical combination comprises one or more antimycobacterial selected from the class of, but not limited to, p-aminosaliscyclic acid, isoniazid, pyrazinamide, ethambutol, ethionamide, rifampicin, vitamin B6, dapsone, clofazimine, ofloxacine, minocycline, clindamycin, levofloxacin, sparfloxacin, clarithromycin or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles.
According to a third embodiment, the novel pharmaceutical combination comprises one or more antibacterials selected from the class of but not limited to Penicillins, Tetracyclins, Macrolides, Aminoglycosides, Glycopeptides, Fluoroquinolones, Other beta lactams, Quinolones, Sulphonamides, silver or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles.
According to a fourth embodiment, the novel pharmaceutical combination comprises one or more antivirals selected from the class of but not limited to amantadine, rimantidine, pleconaril, acyclovir, valacyclovir, ganciclovir, panciclovir, famciclovir, zanamivir, oseltamivir, zidovudine, lamivudine, fomivirsen, foscarnet, ribavarin, interferon alfa or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver particles.


According to the present invention, the pharmaceutical composition comprises ciclopirox or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and nano silver-silica particles and one or more of pharmaceutically acceptable excipients.
According to the present invention, the pharmaceutical formulations may be applied to the body cavities such as the vagina and rectum. It will be readily acknowledged to a person skilled in the art; that the formulation may also be applied to the skin and other mucous membranes. Preferably, the said novel pharmaceutical formulations inactivate bacteria, fungi and/or viruses, and are stable at ambient temperature, compatible and active after mixture with cosmetically acceptable formulations, non-toxic and non-damaging to vulvar, vaginal, cervical, penile or other epithelium.
The pharmaceutical composition of the present invention prevents the transmission of or treats sexually transmitted infections and/or common vaginal infections. Sexually transmitted infections include, but are not limited to, HIV/AIDS, herpes (caused by herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2)), gonorrhea, Chlamydia, syphilis, and trichomoniasis. Common vaginal infections include, but are not limited to, bacterial vaginosis (BV) and vaginal candidiasis. Similar compositions and methods of application of such compositions, as described herein, can be used for treating sexually transmitted infections and/or common vaginal infections and for preventing the transmission of sexually transmitted infections and/or common vaginal infections.
Silver nanoparticles may be synthesized by methods known to a person skilled in the art including mechanical grinding, co-precipitation, spraying, sol-gel processing, electrolysis and reverse-phase microemulsion processing.
Preferably, the present invention involves the topical application of the formulation. In the context of the present invention, it is to be understood that the term topical application includes application to the body cavities as well as to the skin. Thus, in a preferred embodiment, the formulation is applied to a body cavity such as the vagina, anus, rectum


or mouth. In a particularly preferred embodiment, the composition is applied to the vagina.
In a preferred embodiment, the topical application is carried out prior to the beginning of vaginal intercourse, preferably from 0 to 8 hours, more preferably from 0 to 60 minutes. The composition including the combination may be used independent from intercourse.
According to the intended therapeutic purpose, the present composition may be formulated into pharmaceutical preparations common in the pharmaceutical field, which include granules, suspensions, emulsions, syrups, plasters, ointments, sprays, oils, gels, spirits, tinctures, baths, liniments, lotions, patches, pads and creams. Topical formulations may be also contained in a support base or matrix directly applicable to a desired area of the skin. Examples of the support base include gauze or bandages.
According to the present invention, the composition further comprises pharmaceutically acceptable excipients. As used herein, "excipients" refers to a substance, or mixture of substances, that is used in the formulation of vaginal cream compositions to give desirable physical characteristics to the formulation. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized international pharmacopeia for use in animals, and more particularly in humans. Various pharmaceutically acceptable excipients can be used. In preferred embodiments, the pharmaceutically acceptable excipients may be, but are not limited to, one or more surfactant, emollient or humectant, pH adjusting agent, fatty alcohol, preservative, chelating agents, or combinations thereof. The surfactants efficiently emulsifies the cream and imparts a high and stable viscosity even at a temperature of 37°C.The surfactants may be selected from, but not limited to,


Polyoxyethylene alcohol, alkylphenol ethoxylate, polysorbate 80, polysorbate 60, polymethylsiloxane, alkylphenol ethoxylate, poloxomer 407, sorbitan monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, preferably polysorbate 60, poloxamer 704, sorbitan monostearate.
Suitable humectants and/or emollients provides the cream with smoothness and lubricity which, in turn, facilitate the loading of the cream into and dispensing of the cream from a vaginal applicator. The emollients and/or humectants may be selected from, but not limited to, polyhydric alcohols such as glycols, and polysaccharides, such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, glycerin, diglycerin, sorbitol, malvitol, trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea, lanolin, lactic acid, esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the like, preferably myristyl alcohol, octyldodecanol, propylene glycol .
The pH adjusting agents may be selected from, but not limited to, lactic acid, sodium hydroxide, acetic acid, citric acid, tartaric acid, propionic acid, sodium phosphate, ammonia solution, triethanoiamine, sodium borate, sodium carbonate, potassium hydroxide and like, preferably lactic acid and sodium hydroxide.
The fatty alcohols may be selected from, but not limited to, stearyl alcohol, cetyl alcohol, capryl alcohol, myristyl alcohol, 1-dodecanol, palitoleyl alcohol, oleyl alcohol, linoleyl alcohol, isostearyl alcohol and like, preferably stearyl alcohol and cetyl alcohol.
The preservatives may be selected from, but not limited to, benzyl alcohol, hydroxybenzoates (parabens), Benzoic Acid, Chlorphenesin, Sorbic Acid, Phenoxyethanol and like, preferably disodium edetate.
Alternatively, gelling agents such as, alginic acid, sodium alginate, potassium alginate, agar, carrageenan, pectin, gelatin,calcium alginate, carbomers, methyl cellulose, sodium carboxy methyl cellulose, carbopol, bentonite (preferably carbomers) may be used in combination with bioadhesives which includes, but not limited to, gelatin, carbopol 934,


polycarbophil, cross-linked polymethacrylic acid, hydroxypropyl methyl cellulose, ethyl cellulose, preferably polycarbophil enhances the quality of the formulation.
The chelating agents may be selected from, but not limited to disodium edetate, sodium citrate, condensed sodium phosphate, diethylenetriamine pentaacetic acid and like.
Alternatively, for ointment formulation, taking into consideration various factors including temperature of the skin surface, pH of the skin, transdermal water loss levels and total lipid levels of the epidermis, the present composition may be mixed with oleaginous bases, which are exemplified by Vaseline, liquid paraffin, paraffin, plastibase, silicon, lard, vegetable oils, waxes and purified lanolin, water-soluble bases, emulsion bases, suspension bases, and the like. The ointments may be supplemented with an antioxidant (e.g, tocoperol, BHA, BHT, NDGA, etc.), an antiseptic (e.g., phenolic compounds, chlorobutanol, benzylalcohol, parabens, benzoic acid, etc.), a humectant (e.g., glycerin, propylene glycol, sorbitol, etc.), a solution adjuvant (e.g., ethanol, propylene glycol, etc.), a softening adjuvant (e.g., liquid paraffin, glycerin, propylene glycol, surfactants, etc.), and other additives.
Alternatively, for lotion formulation, the present composition may be formulated into various lotion forms including solutions, suspensions and emulsions. For lotions to be applied to the skin, the present composition may be formulated into lotions, for example, with a viscosity of 200 cps to 500 cps, and may be preferably supplemented with a humectant such as glycerin or propylene glycol to give a soft feeling upon application to the skin.
Alternatively, for spray formulation, the additives may be mixed with a propellant to disperse a water-dispersed concentrate or humidified powder. For patch formulation, a permeation stimulator may be used to increase the permeation of compounds through the skin.
The pH of the composition of the invention can be physiologically compatible and/or sufficient to maintain stability of the composition. According to preferred embodiments, the composition of the present invention has a pH range of 4.0 to 6.0.


According to the preferred embodiment, the pharmaceutical composition may be
processed by conventional methods as known to a person skilled in the art: Poloxamer
407, propylene glycol, octyldodecanol, polysorbate 60, ciclopirox and nano silver-silica
particles are added in part quantity of water and mixed.
Stearyl alcohol, cetyl alcohol, myristyl alcohol, Sorbian monostearate, liquid paraffin are
melted together & added this to above water solution under constant stirring.
The mixture of disodium edetate, benzyl alcohol, carbopol and polycarbophil were added
to the above mixture. Finally lactic acid and sodium hydroxide were added to adjust the
desired pH of the composition.
The present invention further provides for a method of prophylaxis and/or treatment of sexually transmitted infections including HIV/AIDS and/or common vaginal infections by application and/or use of a therapeutically effective amount of the combination in a suitable pharmaceutical composition of the present invention to a mammal in need thereof.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.

Sr. No. Ingredients Qty (% w/w)
1. Ciclopirox olamine 1.00
2. Nano Silver 100 ppb
3. Polysorbate 60 5.00
4. Propylene glycol 20.00
5. Poloxamer 407 2.00
6. Carbomer 974 P 0.10
7. Octyldodecanol 3.00
8. Stearyl alcohol 5.00
9. Cetyl alcohol 5.00


10. Disodium edetate 0.10
11. Sorbitan monostearate 2.00
12. Myristyl alcohol 1.50
13. Liquid paraffin 4.00
14. Benzyl alcohol 1.00
15. Lactic acid q.s. to adjust pH 4.0 - 6.0
16. Sodium hydroxide q.s. to adjust pH 4.0-6.0
17. Purified water q.s. to 100%
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of ''including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a preservative" includes a single preservative as well as two or more different preservatives, reference to a "surfactant" refers to a single surfactant or combination of two or more surfactants, and the like.
Dated this 13th day of December, 2007